Goodmanufacturing Practice: Guidelines F O R

R e v is e d
GUIDELINES F O R
GOOD M A N U F A C T U R I N G
P R A C T IC E
IN EGY P T
Central A d m i ni s trati o n o f P h arm ac eu ti c al A f f ai rs ,
M i ni s try o f H ealth and P o p u lati o n
F ac u lty o f P h arm ac y , Cai ro U ni v ers i ty
W o rld H ealth O rg ani z ati o n
Cai ro - E g y p t
2 0 0 4
GMP - E g y p t
2
GMP - E g y p t
Contributers - R ev ised E dition
F ro m C e n t r a l A d m in is t r a t io n o f P h a r m a c e u t ic a l A f f a ir s
• Dr. Zeinab E bied , General M anager, Technical Research and
Training
• Dr. M o u s t af a I br ah im , General M anager of Pharmaceutical
Inspection
P h a r m a c e u t ic a l In d u s t r y E x p e r t s
• Dr. R ed a S h o u k r y
• Dr. O s am a E l -G h af f ar y
• Dr. A bd el A z iz A bd el R eh iem
U n d e r S e c r e t a r y o f S t a t e f o r P h a r m a c e u t ic a l A f f a ir s
• Dr. O s am a E l -K h o l y
C o n t r ib u t e r s -F ir s t E d it io n , 1 9 9 7
From Fa c u l t y of P h a rma c y . C a i ro U n i v e rs i t y
• P r o f . D r . Ah m e d Ab d E l -B a r y , D e a n , p r o f e s s o r o f p h a r m a c e u t i c s a n d i n d u s t r i a l
p h a rm a c y .
• P r o f . D r . Al i a A. B a d a w y , p r o f e s s o r o f p h a r m a c e u t i c s a n d i n d u s t r i a l p h a r m a c y .
• D r . Mo n a M. E l -K a t t i b , l e c t u r e r o f p h a r m a c e u t i c s a n d i n d u s t r i a l p h a r m a c y .
From M i n i s t ry of H e a l t h a n d P op u l a t i on
• D r . Ab d E l -H a m i d Ab d E l -A z i z , f o r m e r u n d e r s e c re ta ry o f s ta te fo r
p h a r m a c e u t ic a l a f f a ir s .
3
GMP - E g y p t
4
GMP - E g y p t
Table of C on t en t s
I N TR O D U C TI O N .................................................................................... 1 2
C H A P TE R I : C O N C E P TS A N D D E F I N I TI O N S ................................. 1 4
C H A P TE R I I : Q U A L I TY M A N A G E M E N T I N D R U G I N D U S TR Y . 2 7
CO NC EP T AND O B J EC T I V E ....................................................................... 27
QU AL I T Y ASSU R ANC E ............................................................................. 3 0
Concept and objective ....................................................................... 3 0
T h e or g aniz ation of a q u al ity assu r ance sy stem ................................ 3 0
R esponsibil ity of th e q u al ity assu r ance of f icer .................................. 3 2
QU AL I T Y C O NT R O L ................................................................................. 3 3
Concept and objective ....................................................................... 3 3
I n-P r ocess q u al ity contr ol ................................................................. 3 6
SAM P L I NG ............................................................................................... 3 7
T ests f or sam pl es ............................................................................... 3 8
QU AL I T Y C O NT R O L R EL EASE SY ST EM ..................................................... 4 0
CH EC K L I ST F O R P R EM I SES ...................................................................... 4 4
CH EC K L I ST F O R P ER SO NNEL ................................................................... 4 5
CH EC K L I ST F O R EQ U I P M ENT ................................................................... 4 6
C H A P TE R I I I : P E R S O N N E L ................................................................ 4 8
CO NC EP T AND O B J EC T I V E ....................................................................... 4 8
K ey per sonnel .................................................................................... 4 9
PER SO NNEL R ESP O NSI B I L I T I ES ................................................................ 5 0
F actor y M anag er ( F M ) ..................................................................... 5 0
P r odu ction S ector Ch ief ( P S C) ......................................................... 5 0
Q u al ity Contr ol S ector Ch ief ( O CS C) ............................................... 5 1
S ector s S u per visor s ( S S ) .................................................................... 5 2
Consu l tant ......................................................................................... 5 2
TR AI NI NG ............................................................................................... 5 3
C H A P TE R I V : P R E M I S E S ..................................................................... 5 6
CO NST R U C T I O N AND F I NI SH ES ................................................................ 5 8
i. F l oor s and w al l s............................................................................. 5 8
ii. Ceil ing s ......................................................................................... 5 9
iii. D oor s and w indow s ..................................................................... 6 0
ENV I R O NM ENT ........................................................................................ 6 3
a. R eq u ir em ents f or specif ic m anu f actu r ing ar eas............................ 6 3
5
GMP - E g y p t
i. Sterile areas .......................................................................................... 6 3
ii. L iq u id s, c ream s, an d o in tm en ts m an u f ac tu rin g ................................... 6 5
iii. So lid d o se area.................................................................................... 6 5
iv . D isp en sary .......................................................................................... 6 6
b. D u st and du st ex tr action ............................................................... 6 7
c. L ig h ting ......................................................................................... 6 7
d. N oise.............................................................................................. 6 8
e. Col or and decor ation .................................................................... 6 8
REQ U I R EM ENT S O F D I F F ER ENT AR EAS .................................................... 6 8
i. A ncil l ar y ar eas............................................................................... 6 8
ii. S tor ag e ar ea.................................................................................. 6 9
iii. W eig h ing ar eas ............................................................................ 7 0
iv. P r odu ction ar eas .......................................................................... 7 0
v. Q u al ity contr ol ar ea ...................................................................... 7 2
CL EANI NG O F T H E B U I L D I NG ................................................................... 7 3
C H A P TE R V : M A TE R I A L S .................................................................. 7 6
RAW M AT ER I AL S .................................................................................... 7 6
PAC K I NG M AT ER I AL S .............................................................................. 7 8
INT ER M ED I AT E AND B U L K P R O D U C T S ..................................................... 7 9
FI NI SH ED P R O D U C T S ............................................................................... 7 9
REJ EC T ED AND R EC O V ER ED M AT ER I AL S ................................................. 7 9
REC AL L ED P R O D U C T S ............................................................................. 8 0
RET U R NED G O O D S .................................................................................. 8 0
REAG ENT S AND C U L T U R E M ED I A ............................................................ 8 1
REF ER ENC E ST AND AR D S ......................................................................... 8 1
WAST E M AT ER I AL S ................................................................................. 8 1
GASES ..................................................................................................... 8 2
SO L V ENT S ............................................................................................... 8 3
MI SC EL L ANEO U S .................................................................................... 8 3
CH EC K L I ST F O R P R EM I SES O F R AW M AT ER I AL S ...................................... 8 4
CH EC K L I ST F O R P ER SO NNEL W O R K I NG I N R AW M AT ER I AL S .................... 8 5
CH EC K L I ST F O R EQ U I P M ENT O F R AW M AT ER I AL S ................................... 8 6
C H A P TE R V I : E Q U I P M E N T ................................................................ 8 8
LO C AT I O N AND SEP AR AT I O N O F EQ U I P M ENT .......................................... 8 9
CL EANI NG AND M AI NT ENANC E ............................................................... 9 0
AU T O M AT I C AND EL EC T R O NI C EQ U I P M ENT ............................................ 9 0
VAL I D I T Y O F T H E D EV I C E ....................................................................... 9 1
UT I L I T I ES AND SER V I C ES ........................................................................ 9 1
6
GMP - E g y p t
1 . W ater ............................................................................................. 9 1
a. P o tab le w ater........................................................................................ 9 2
b .P u rif ied w ater ...................................................................................... 9 2
c .W ater f o r in j ec tio n s.............................................................................. 9 4
d .C o o lin g w ater ...................................................................................... 9 4
2 . S team ............................................................................................. 9 5
3 . E l ectr icity ...................................................................................... 9 6
C H A P TE R V I I : P R O D U C TI O N ............................................................ 9 8
VAL I D I T Y O F T H E P R O D U C T I O N M ET H O D .............................................. 1 0 0
BAT C H NU M B ER SY ST EM ...................................................................... 1 0 0
MEASU R I NG O U T (D I SP ENSI NG ) ............................................................ 1 0 1
CR O SS-C O NT AM I NAT I O N AND B AC T ER I AL C O NT AM I NAT I O N I N
P R O D U C T I O N ......................................................................................... 1 0 3
MANU F AC T U R I NG ................................................................................. 1 0 5
A . I nter m ediate and bu l k pr odu cts .................................................. 1 0 5
R e-m an u f ac tu rin g .................................................................................. 1 0 6
T im e o f m an u f ac tu rin g .......................................................................... 1 0 6
B . S ol id pr odu cts ............................................................................. 1 0 7
M ix in g , g ran u latio n , d ry in g ................................................................... 1 0 7
C o m p ressio n .......................................................................................... 1 0 8
C o atin g .................................................................................................. 1 0 8
H ard an d so f t g elatin c ap su les ............................................................... 1 0 8
C. S ol u tions, cr eam s, ointm ents and oth er l ocal pr epar ations........ 1 0 9
MANU F AC T U R E O F ST ER I L E M ED I C I NAL P R O D U C T S .............................. 1 1 0
P r incipl e.......................................................................................... 1 1 0
G ener al ............................................................................................ 1 1 0
I sol ator tech nol og y .......................................................................... 1 1 5
B l ow , f il l , and seal tech nol og y ........................................................ 1 1 6
T er m inal l y ster il iz ed pr odu cts......................................................... 1 1 6
A septic pr epar ation......................................................................... 1 1 7
P er sonnel ........................................................................................ 1 1 8
P r em ises .......................................................................................... 1 2 0
E q u ipm ent ....................................................................................... 1 2 2
S anitation ........................................................................................ 1 2 3
P r ocessing ....................................................................................... 1 2 4
S ter il iz ation ..................................................................................... 1 2 7
S ter il iz ation by h eat......................................................................... 1 2 8
M oist h eat........................................................................................ 1 2 9
D r y h eat........................................................................................... 1 3 0
S ter il iz ation by r adiation................................................................. 1 3 0
S ter il iz ation w ith eth y l ene ox ide ..................................................... 1 3 1
7
GMP - E g y p t
F il tr ation of m edicinal pr odu cts w h ich cannot be ster il iz ed in th eir
f inal container ................................................................................. 1 3 2
F inish ing of ster il e pr odu cts ........................................................... 1 3 4
Q u al ity contr ol ................................................................................ 1 3 4
CH EC K L I ST F O R P R EM I SES O F M I X I NG AND F O R M U L AT I O N ................... 1 3 6
CH EC K L I ST F O R P ER SO NNEL W O R K I NG I N M I X I NG AND F O R M U L AT I O N . 1 3 7
CH EC K L I ST F O R EQ U I P M ENT O F M I X I NG AND F O R M U L AT I O N ................ 1 3 8
CH EC K L I ST F O R P ER SO NNEL W O R K I NG I N F I NI SH ED D O SAG E F O R M
P R EP AR AT I O NS ...................................................................................... 1 3 9
CH EC K L I ST F O R EQ U I P M ENT O F F I NI SH ED D O SAG E F O R M P R EP AR AT I O NS
............................................................................................................. 1 4 0
CH EC K L I ST F O R P R EM I SES O F F I NI SH ED G O O D S, ST O R AG E AND
W AR EH O U SI NG ...................................................................................... 1 4 1
CH EC K L I ST F O R P ER SO NNEL W O R K I NG I N F I NI SH ED G O O D S, ST O R AG E AND
W AR EH O U SI NG ...................................................................................... 1 4 2
CH EC K L I ST F O R EQ U I P M ENT O F F I NI SH ED G O O D S, ST O R AG E AND
W AR EH O U SI NG ...................................................................................... 1 4 3
C H A P TE R V I I I : P A C K A G I N G ........................................................... 1 4 5
CO NC EP T S AND D EF I NI T I O NS ................................................................ 1 4 5
PAC K AG I NG P R AC T I C E .......................................................................... 1 4 6
PAC K AG I NG O P ER AT I O N ....................................................................... 1 4 7
FI NAL I Z AT I O N O F P AC K AG I NG .............................................................. 1 5 2
ISSU E O F P AC K AG I NG M AT ER I AL S ......................................................... 1 5 3
CH EC K S O N R EC EI P T I NT O P R O D U C T I O N................................................ 1 5 4
OV ER P R I NT I NG ..................................................................................... 1 5 4
PR EP AR AT I O N O F O T H ER P R I M AR Y P AC K AG I NG M AT ER I AL S ................. 1 5 6
CH EC K L I ST F O R P R EM I SES O F P AC K AG I NG AND L AB EL I NG .................... 1 5 7
CH EC K L I ST F O R P ER SO NNEL W O R K I NG I N P AC K AG I NG AND L AB EL I NG . 1 5 8
CH EC K L I ST F O R EQ U I P M ENT O F P AC K AG I NG AND L AB EL I NG ................. 1 5 9
C H A P TE R I X : D O C U M E N TA TI O N .................................................. 1 6 1
CO NC EP T S AND D EF I NI T I O NS ................................................................ 1 6 1
TY P ES O F D O C U M ENT S .......................................................................... 1 6 2
1 . S pecif ications .............................................................................. 1 6 3
i. Sp ec if ic atio n s f o r startin g ( raw ) m aterials .......................................... 1 6 3
ii. Sp ec if ic atio n s f o r in term ed iate an d b u lk p ro d u c ts............................. 1 6 5
iii. Sp ec if ic atio n s f o r p ac k ag in g m aterials ............................................. 1 6 5
iv . Sp ec if ic atio n s f o r f in ish ed p ro d u c ts.................................................. 1 6 6
2 . R ecor ds........................................................................................ 1 6 6
i. B atc h p ro c essin g rec o rd s .................................................................... 1 6 7
ii. B atc h p ac k ag in g rec o rd s.................................................................... 1 6 8
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GMP - E g y p t
iii. B atc h an aly sis rec o rd s ...................................................................... 1 6 9
iv . R ec eip t rec o rd s ................................................................................. 1 7 0
v . D istrib u tio n rec o rd s ........................................................................... 1 7 0
v i. Stab ility stu d ies rec o rd ..................................................................... 1 7 0
v ii. R ec o rd f o r m ac h in e c lean in g an d m ain ten an c e ............................... 1 7 1
v iii. T rain in g rec o rd o n G M P ................................................................. 1 7 1
ix . Self in sp ec tio n rec o rd ....................................................................... 1 7 1
x . R ec o rd f o r th e d estru c tio n o f m aterials.............................................. 1 7 2
x i. Q u ality c o n tro l rec o rd s ..................................................................... 1 7 2
x ii. R ec o rd f o r eq u ip m en t stan d ard iz atio n ............................................. 1 7 4
x iii. T h e m eth o d an d rec o rd f o r c lean in g th e in d u strial area.................. 1 7 4
x iv . M eth o d an d rec o rd f o r c o n tro llin g th e su sp en d ed p artic les in air an d
m ic ro b es in c ertain areas........................................................................ 1 7 5
x v . M eth o d an d rec o rd f o r d estru c tio n o f in sec ts an d rep tiles an d o th ers
............................................................................................................... 1 7 5
x v i. C o m p lain ts rec o rd s ......................................................................... 1 7 6
3 . S tandar d oper ating pr ocedu r es ( S O P ' s) ..................................... 1 7 6
MANU F AC T U R I NG F O R M U L A AND P R O C ESSI NG I NST R U C T I O NS ............. 1 8 1
PAC K AG I NG I NST R U C T I O N .................................................................... 1 8 2
CO M P L AI NT S F R O M P H AR M AC EU T I C AL P R O D U C T S ............................... 1 8 4
PR O D U C T R EF U ND ................................................................................. 1 8 5
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F R AW M AT ER I AL S
H AND L I NG ............................................................................................. 1 8 8
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F M I X I NG AND
F O R M U L AT I O N ...................................................................................... 1 8 9
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F F I NI SH ED D O SAG E F O R M
P R EP AR AT I O NS ...................................................................................... 1 9 1
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F P AC K AG I NG AND
L AB EL I NG ............................................................................................. 1 9 3
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F Q U AL I T Y ASSU R ANC E,
P R O D U C T I O N, P R O C ESS, AND L AB O R AT O R Y C O NT R O L S ......................... 1 9 5
CH EC K L I ST F O R W O R K P R O C ED U R ES AND SO P S O F F I NI SH ED G O O D S
ST O R AG E AND W AR EH O U SI NG ............................................................... 1 9 7
EX AM P L ES O F ST AND AR D O P ER AT I NG P R O C ED U R ES ............................. 1 9 9
1 . S tandar d oper ating pr ocedu r e f or cal ibr ation of anal y tical bal ance
M ettl er ty pe A E 2 0 0 ......................................................................... 1 9 9
2 . S tandar d oper ating pr ocedu r e f or sam pl ing of r aw and pack ag ing
m ater ial s.......................................................................................... 2 0 4
3 . S tandar d oper ating pr ocedu r e f or cl ear ance and disinf ecting of
sam pl ing booth ar ea........................................................................ 2 1 4
4 . S tandar d oper ating pr ocedu r e f or oper ation of H I 8 5 6 4 por tabl e
th er m oh y g r om eter ........................................................................... 2 1 6
9
GMP - E g y p t
5 . S tandar d oper ating pr ocedu r e f or f u m ig ation of th e ster il e ar ea
w ith f or m al deh y de g as .................................................................... 2 2 1
C H A P TE R X : S E L F I N S P E C TI O N A N D Q U A L I TY A U D I TS ........ 2 2 5
CO NC EP T S AND O B J EC T I V ES ................................................................. 225
IT EM S F O R SEL F -I NSP EC T I O N ................................................................ 225
SEL F -I NSP EC T I O N T EAM ........................................................................ 226
FR EQ U ENC Y O F SEL F -I NSP EC T I O N ......................................................... 227
SEL F -I NSP EC T I O N R EP O R T ..................................................................... 227
FO L L O W -U P AC T I O N ............................................................................. 227
QU AL I T Y AU D I T .................................................................................... 227
SU P P L I ER 'S AU D I T ................................................................................. 227
C H A P TE R X I : V A L I D A TI O N ............................................................. 2 3 0
CO NC EP T S AND O B J EC T I V ES ................................................................. 23 0
PR O C ESS V AL I D AT I O N SY ST EM ............................................................. 23 2
PR O C ESS V AL I D AT I O N M ET H O D ............................................................ 23 3
PR O SP EC T I V E V AL I D AT I O N ................................................................... 23 4
CER T I F I C AT I O N ..................................................................................... 23 8
REV AL I D AT I O N ..................................................................................... 23 9
RET R O SP EC T I V E VAL I D AT I O N .............................................................. 24 0
DO C U M ENT AT I O N ................................................................................. 24 0
PR O D U C T R EL EASE-AD D I T I O NAL R EQ U I R EM ENT F O R V AL I D AT I O N
B AT C H ES ............................................................................................... 24 3
CH ANG E C O NT R O L ................................................................................ 24 3
C H A P TE R X I I : H A Z A R D O U S M A TE R I A L S ................................... 2 4 6
MANU F AC T U R I NG AR EAS ..................................................................... 24 7
SAM P L I NG ............................................................................................. 24 7
TR AI NI NG ............................................................................................. 24 7
VENT I L AT I O N O F AR EAS W H ER E H AZ AR D O U S M AT ER I AL S AR E H AND L ED
............................................................................................................. 24 8
PR O T EC T I V E C L O T H I NG ........................................................................ 24 8
WAST E D I SP O SAL .................................................................................. 24 9
EM P L O Y EE EX P O SU R E ........................................................................... 24 9
ENV I R O NM ENT AL AND P ER SO NNEL M O NI T O R I NG ................................. 25 0
MAI NT ENANC E ..................................................................................... 25 0
C H A P TE R X I I I : S TA B I L I TY .............................................................. 2 5 3
PU R P O SE O F ST AB I L I T Y T EST I NG ........................................................... 25 4
1 0
GMP - E g y p t
DESI G N O F ST AB I L I T Y ST U D I ES ............................................................. 25 5
T est S am pl es.................................................................................... 2 5 6
TY P ES O F ST AB I L I T Y ST U D I ES AND T EST C O ND I T I O NS ........................... 25 6
A ccel er ated stu dies.......................................................................... 2 5 6
So lid d o sag e f o rm .................................................................................. 2 5 7
Sem i-so lid d o sag e f o rm s........................................................................ 2 5 7
L iq u id d o sag e f o rm s .............................................................................. 2 5 8
ii. Cl im atic Z ones S tabil ity T esting ................................................. 2 5 8
iii. L ong ter m stu dy ( r eal -tim e stu dies) ........................................... 2 5 8
F req u en c y o f testin g an d ev alu atio n o f test resu lts ................................ 2 5 9
A n aly tic al m eth o d .................................................................................. 2 5 9
REC O M M END ED ST O R AG E C O ND I T I O NS ................................................ 26 0
ST AB I L I T Y O V ER AG E J U ST I F I C AT I O N ..................................................... 26 0
NEW EX P I R Y D AT E ................................................................................ 26 0
LI ST O F L ESS ST AB L E D R U G SU B ST ANC E ............................................... 26 1
LI ST O F SU B ST ANC ES R ESI ST ANT T O D EG R AD AT I O N ............................. 26 4
CO NT ENT O F ST AB I L I T Y R EP O R T S ......................................................... 26 7
G ener al pr odu ct inf or m ation .......................................................... 2 6 7
S pecif ications and test m eth odol og y inf or m ation............................ 2 6 7
S tu dy desig n and stu dy Conditions.................................................. 2 6 7
S tabil ity data/ inf or m ation ............................................................... 2 6 8
DAT A ANAL Y SI S AND C O NC L U SI O NS ..................................................... 26 9
B I B L I O G R A P H Y ................................................................................... 2 7 1
1 1
GMP - E g y p t
Introduction
Drug products, manufactured locally in Egypt, cover more
than 90% of the local consumption. The standards and principles
contained in this guide are intended to serve as a reference for the
preparation of information on manufacturing practice as requested
under the pharmaceutical inspection convention.
This guideline contains the updates of international GM Ps for

pharmaceuticals with the recommendations of ISO system.
Administrative measures of the Egyptian National Health Authority
should be directed towards the application of these standards in
practice, and any new or amended national regulations for good
manufacturing practice should at least meet their level. These
standards are also intended to serve manufacturers as a basis for
the elaboration of specific rules adapted to their individual needs.
The guide is applicable to all large-scale operations for the

production of drugs in their finished dosage forms, including large-
scale processes in hospitals and the preparation of clinical trials.
This guide to GM P can be used as a standard to justify GM P

status on the Quality of Pharmaceutical Products in Egypt, through
the assessment of applications for manufacturing authorizations and
as a basis for the inspection of manufacturing facilities.
It may also be used as training material for Egyptian drug

inspectors as well as for production and quality control personnel in
the industry.
1 2
R e v is e d G U I D E L I N E S F O R G O O D M A N U F A C T U R I N G P R A C T I C E I N E G Y P T , 20 0 4
GMP - E g y p t
Chapter I
C O N C E P T S A N D D E F IN IT IO N S
C e n tr a l A d m in is tr a tio n o f P h a r m a c e u tic a l A ffa ir s , M in is tr y o f H e a lth a n d P o p u la tio n
1 3
GMP - E g y p t
Chapter I: CO N CE P T S A N D D E F IN IT IO N S
C once p ts a nd D e f initions
Active Ing r ed ient A pharmacologically active substance in a
pharmaceutical product.
Air L o ck An enclosed space with two or more doors only one of

which should be opened at any one time and which is
interposed between two or more rooms for the purpose of
controlling the air flow between them.
Au th o r iz ed Per s o n A person responsible for the release of batches

of finished product for sale.
B a tch o r L o t A defined quantity of a drug product and/or other

material that is intended to have uniform character and
quality, within specified limits, and is produced according
to a single manufacturing order during the same cycle of
manufacture.
B a tch N u m b er (L o t N u m b er ) A distinctive combination of numbers

and/or letters, which identifies a batch from which the
complete history of the manufacture, processing, packing,
holding and distribution of a batch or lot of drug product or
other material can be determined.
B a tch N u m b er ing S y s tem Standard operating procedure describing

the details of the batch numbering.
B a tch Reco r d s All documents associated with the manufacture of a

batch of bulk product or finished product which provide a
1 4
GMP - E g y p t
history of each batch of product and of all circumstances
pertinent to the quality of the final product.
B u l k Pr o d u ct Any product that has completed all processing stages

up to, but not including, final packaging.
C a l ib r a tio n The set of operations that establish, under specified

conditions, the relationship between values indicated by
an instrument or system for measuring, recording, and
controlling or the values represented by a material
measure, and the corresponding known values of a
reference standard.
C l ea n Ar ea An area with defined environmental control of particulate

and microbial contamination, constructed and used in
such a way as to reduce the introduction, generation and
retention of contaminations within the area.
C o ns ig nm ent (O r D el iver y ) The quantity of starting material, or of a

drug product, made by one manufacturer and supplied at
one time in response to a particular request or order.
C o m p o nent Any ingredient intended for use in manufacture of a

drug product.
C r itica l Pr o ces s A process that may cause variation in the quality of

the pharmaceutical product.
C r o s s -C o nta m ina tio n Contamination of starting material,

intermediate product, or finished product with another
starting material or product during production.
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GMP - E g y p t
C l im a tic Z o nes The concept of dividing the world into four zones
based on defining the prevalent annual climatic
conditions.
D o s a g eF o rm Refers to the gross physical form in which a drug is

administered to or used by a patient.
D o cu m enta tio n All written procedures, instructions, descriptions,

specifications and records involved in the manufacture of
a drug product. It is a prime necessity in quality
assurance. Its purposes are to define the system of
control, to reduce the risk of error inherent in purely oral
communication, to insure that personnel are instructed in
the details of, and follow, the procedures concerned, and
to permit investigation and tracing of defective products.
D ru g p r o d u ct A dosage form containing one or more active

therapeutic ingredients along with other substances
included during the manufacturing process.
E x p ir a tio n D a te The date placed on the immediate container label

of a drug product that designates the date through which
the product is expected to remain within specifications. If
the expiration date includes only a month and year, it is
expected that the product will meet specifications through
the last day of the month. K inetically it is the time required
for 10% of the material to disappear.
E x p ir a tio n D a ting Per io d (S h el f -L if e) The interval of time that a

drug product is expected to remain within specifications
as determined from stability studies on a limited number
1 6
GMP - E g y p t
of batches of the product. The expiration dating period is
used to establish the expiration date of individual batches.
F inis h ed Pr o d u ct A product that has undergone all stages of

production, including packaging in its final container and
labeling.
G o o d M a nu f a ctu r ing Pr a ctice (G M P( That part of quality assurance

aimed at ensuring that products are manufactured to a
quality appropriate to their intended use.
G o o d Ph a r m a cy Pr a ctice Is a means of providing service of

appropriate quality to every patient. The mission of
pharmacy practice is to provide medications and other
health care products and services and to help people and
society to make the best use of them.
in-Pr o ces s C o ntr o l Checks performed during production to monitor

and if necessary to adjust the process to ensure that the
product confirms to its specifications.
IS O (Inter na tio na l S ta nd a r d iz a tio n O r g a niz a tio n) Is a worldwide

federation of national standards bodies (ISO M ember
Bodies). The work of preparing international standards is
normally carried out through ISO technical committees.
T y p es o f Inter na tio na l S ta nd a r d s o n Q u a l ity S y s tem s
IS O 9 0 0 0 For use as a guide to all organizations for quality

management purposes.
IS O 9 0 0 1 For use when conformance to specified requirements is to

be assured by the supplier during several stages which
1 7
GMP - E g y p t
may include design/development, production, installation
and servicing.

be assured by the supplier during production and
installation.

be assured by the supplier solely at final inspection and
test.
IS O 9 0 0 4 U sed together with ISO 9000 as a guide to all

organizations for quality management purposes.
Inter m ed ia te Pr o d u ct Partly processed material that must undergo

further manufacturing steps before it becomes a bulk
product.
Ina ctive Ing r ed ient Any component other than an active ingredient.
L a r g e-V o l u m e Pa r enter a Is Sterile solutions for parenteral

application with a volume of 100 ml or more in one
container of the finished dosage form.
M a nu f a ctu r e All operations of purchase of materials and products,

production, quality control, release, storage, shipment of
finished products, and the related controls.
M a r k eting Au th o r iz a tio n (Pr o d u ct L icens e, Reg is tr a tio n

C er tif ica te) A legal document issued by the competent
chug regulatory authority that establishes the detailed
composition and formulation of the product and the
pharmacopoeia or other recognized specification of its
1 8
GMP - E g y p t
ingredients and of the final product itself, and includes
details of packaging, labeling, and shelf life.
M a s ter F o r m u l a A document or set of documents specifying the

starting materials with their quantities and the packaging
materials, together with a description of the procedures
and precautions required to produce a specified quantity
of a finished product as well as the processing
instructions, including the in-process controls.
M a s ter Reco r d A document or set of documents that serve as a

basis for the batch documentation (Blank Bach Record).
M ea n K inetic T em p er a tu r e The mean value of the temperature

established according to the formula developed by J.D.
Haynes. It is a higher value than that of the arithmetic
mean temperature. It should be pointed out that the
effective or mean kinetic temperature reflects the actual
situation better than measured mean temperature, i.e.
there is a difference between a product being kept for one
month at 20° C and one month at 40° C and two months
at 30° C.
O ver a g e The excess quantity of drug that must be added to the

preparation to maintain at least 90% of the labeled
amount during the expected shelf-life of the drug.
Pa ck a g ing All operations including filling and labeling, that a bulk

product has to undergo to become a finished product.
Pa ck a g ing M a ter ia l Any material, including printed material,

employed in the packaging of a pharmaceutical product,
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GMP - E g y p t
excluding any outer packaging used for transportation or
shipment.
Ph a r m a ceu tica l Pr o d u ct Any medicine intended for human use or

veterinary product administered to food producing animals
presented in its finished dosage form or as a starting
material for use in such a dosage form, that is subject to
control by pharmaceutical legislation in both the exporting
state and the importing state.
Pr o ces s V a l id a tio n A validated manufacturing process is one which

has been proved to do what it purports or is represented
to do.
Pr o d u ctio n All operations involved in the preparation of a

pharmaceutical product, from receipt of materials, through
processing and packaging, to completion of the finished
product.
Q u a r a ntine The status of starting or packaging material,

intermediate, or bulk or finished products isolated
physically or by other effective means while a decision is
awaited on their release, rejection, or reprocessing.
Q u a l ity It is the intrinsic characters of the product which satisfy the

user’ s need.
Q u a l ity As s u r a nce Is a wide-ranging concept covering all matters

that individually or collectively influence the quality of a
product. It is the totality of the arrangements made with
the object of ensuring that pharmaceutical products are of
the quality required for their intended use.
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GMP - E g y p t
Q u a l ity C o ntr o l That part of GM P concerned with sampling,
specifications, and testing and with the organization,
documentation, and release procedures which ensure that
the necessary and relevant tests are actually carried out
and that the materials are not released for use, nor
products released for sale or supply, until their quality has
been judged to be satisfactory.
Q u a l ity M a na g em ent Is the aspect of management function that

determines and implements the quality policy, i.e., the
overall intentions and direction of an organization
regarding quality as formally expressed and authorized by
top management.
U til iz a tio n Per io d A period of time during which a reconstituted

preparation or the finished dosage form in an opened
multi-dose container can be used.
Reco ncil ia tio n A comparison, making allowance for normal

variation, between the amount of product or materials
theoretically produced or used and the amount actually
produced or used.
Reco ver y (o r B l end ing ) The introduction of all or part of previous

batches of the required quality into another batch at a
defined stage of manufacture.
Rep r o ces s ing The reworking of all or part of a batch of product of

an unacceptable quality from a defined stage of
production so that its quality may be rendered acceptable
by one or more additional operations.
21
GMP - E g y p t
Retu r ned Pr o d u ct Finished product sent back to the manufacturer.
Rea l T im e (L o ng T er m S ta b il ity S tu d y ) Evaluation of experiments

for physical, chemical, biological and microbiological
characteristics of a drug, during and beyond the expected
time of shelf-life and storage of samples at expected
storage conditions in the intended market.
S p ecif ica tio n A document describing in detail the requirements with

which the products or materials used or obtained during
manufacture have to conform. Specifications serve as a
basis for quality evaluation.
S ta nd a r d O p er a ting Pr o ced u r e (S O P) An authorized written

procedure giving instructions for performing operations
not necessarily specific to a given product or material but
of a more general nature e.g. equipment operation,
maintenance and cleaning, validation, cleaning of
premises and environmental control, sampling and
inspection. Certain SOPs may be used to supplement
product-specific master and batch production
documentation i.e. it is written instructions describing how
to do jobs which could affect product quality.
S ta r ting M a ter ia l Any substance of a defined quality used in the

production of a pharmaceutical product, but excluding
external packaging materials.
S ta b il ity The ability of a pharmaceutical product, in a specific

container closure system, to remain within the defined
physical, chemical, microbiological, therapeutic, and
22
GMP - E g y p t
toxicological specifications till the end of the stated
dazing, under defined storage conditions.
S ta b il ity Ind ica ting As s a y The assay which is sensitive and

selective to determine quantitatively the active ingredient
in the presence of its decomposition products.
S h el f -S ta b il ity The stability of the drug or drug product at ambient

room temperature (15-30° C).
S to r a g e The term used to describe the safe keeping of starting

materials, packaging materials, components received,
semi finished, in-process and finished products awaiting
dispatch. The term also applies for safe keeping of
materials and drug products in drug stores, pharmacies,
hospitals, etc. under the specified conditions.
S to r a g e C o nd itio ns The conditions specified for storing the product

e.g. temperature, humidity, container, etc.
S to r a g e T em p er a tu r es The actual storage temperature (numerical)

used during stability studies.
S tr es s T es ting (Accel er a ted T es ting ) Studies designed to increase

the rate of chemical or physical degradation of a drug
substance or drug product by using exaggerated storage
conditions. The purpose is to determine kinetic
parameters, if possible, and/or to predict the tentative
expiration dating period.
S tr eng th
23
GMP - E g y p t
i. The concentration of the drug substance (for example
weight/weight, weight/volume, or unit dose/volume).
ii. The potency, that is, the therapeutic activity of the drug product
as indicated by appropriate laboratory tests or by adequately
developed and controlled clinical data (expressed, for
example, in terms of units by reference to a standard(.
S y s tem A regulated pattern of interacting activities and techniques

that are united to form an organized whole.
T em p er a tu r e C o ntr o l All temperatures are in degree Celsius.
a. Cold Place The temperature does not exceed 8.
i. Refrigerator The temperature is thermostatically controlled

between 2 and 8.
ii. Freezer The temperature is thermostatically controlled to not

higher than -10.
b. Cool Place The temperature is between ٨ and 15.
c. Warm Place Any temperature between 30 and 40.
d. Room Temperature The temperature is between 15 and 30.
e. Excessive Heat Any temperature above 40.
f. Extreme Temperature Fluctuation Cycling through temperature

conditions that simulate the changes that may be encountered once
the drug product is in distribution.
V a l id a tio n The documented act of proving that any procedure,

process, equipment, material, activity, or system actually
leads to the expected results.
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GMP - E g y p t
25
R e v -i E s e g d y p G t U I D E L I N E S F O R G O O D M A N U F A C T U R I N G
GMP P R A C T I C E I N E G Y P T , 20 0 4
Chapter II
Q U A L IT Y M A N A G E M E N T
IN D R U G IN D U S T R Y

26
GMP - E g y p t
Chapter II: Q U A L IT Y M A N A G E M E N T IN D R U G IN D U S T R Y
Concept a nd ob j ecti v e
Quality management is defined as the aspect of
management function that determines and implements the quality
policy. The quality policy as mentioned in ISO 9000 is the overall
intentions and direction of an organization regarding quality, as
formally expressed and authorized by top management.
Quality management includes strategic planning, allocation

of resources and other systemic activities for quality, such as quality
planning, operations and evaluations.
The attainment of desired quality requires the commitment

and participation of all members of the organization whereas the
responsibility for quality management belongs to top management.
The quality system of an organization is influenced by the

objectives of the organization, by the product or service and by the
practices specific to the organization, and therefore the quality
system varies from one organization to another.
Within an organization, quality assurance serves as a

management tool. In contractual situation, quality assurance also
serves to generate confidence in the supplier.
In drug manufacture and supply the terminology may differ.

In particular, the term quality system is rarely used, and it is the
quality assurance that usually embraces such elements as
organizational structure, procedures and processes.
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GMP - E g y p t
Quality must be built into a drug product during product and
process design, and it is influenced by the physical plant design,
space, ventilation, cleanliness, and sanitation during routine
production.
The concepts of quality assurance, GM P, and quality control

are interrelated aspects of quality management.
- The relationship of the different concepts are shown in Figure (1)
1. A c t i v i t i e s ai m e d at p r o v i d i n g c o n f i d e n c e t o t h e m an ag e m e n t o f an
o r g an i z at i o n t h at t h e i n t e n d e d q u al i t y i s b e i n g ac h i e v e d ar e o f t e n
c al l e d i n t e r n al q u al i t y as s u r an c e .
2. A c t i v i t i e s ai m e d a p r o v id in g c o n fid e n c e to t h e p u r c h as e r t h at t h e
s u p p l i e r ’ s q u al i t y s y s t e m w i l l p r o v i d e a p r o d u c t o r s e r v i c e t h at w i l l
s at i s f y t h e p u r c h as e r ’ s s t at e d q u al i t y r e q u i r e m e n t s ar e o f t e n c al l e d
e x t e r n al q u al i t y as s u r an c e .
Fig. (1) R e l a t io n s h ip o f C o n c e p t s
28
GMP - E g y p t
29
GMP - E g y p t
Q u a l i ty a s s u r a nce
Concept and obj ective
Quality assurance is a wide-ranging concept covering all
matters that individually or collectively influence the quality of a
product. It is the totality of the arrangements made with the quality
required for their intended use.
Quality is not an accident, it has to be planned, quality can

not be tested in the final product, it must be designed and built in.
Quality must not be confined to compliance with

specification, it requires adoption of wide view of quality. Highest
quality is customer full satisfaction. M anufacturing and marketing of
safe effective products of the highest quality is the main objective of
quality assurance.
Quality assurance therefore, incorporate both GM P, quality

control and other factors such as product design a development.
T he org aniz ation of a qu al ity assu rance sy stem

The organization of a quality assurance system may vary according
to the structure of an individual company, but it should incorporate
certain basic features e.g.
a. A quality policy which defines the purpose and objectives of the

organization and outlines the ways in which these will be
achieved.
b. Resources, including personnel, equipment, facilities, finance,

materials and technical skills.
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GMP - E g y p t
c. Documentation, including procedures, standards and methods.
d. An audit process to assure proper adherence to the defined

procedures and to provide a mechanism for improving the
quality system itself.
T he s y s tem o f q u al i ty as s u ran c e appro pri ate to the m an u f ac tu re

o f pharm ac eu ti c al pro d u c ts s ho u l d en s u re that
a. Pharmaceutical products are designed and developed in a way

that takes account of the requirements of GM P and other
associated codes such as those of good laboratory practice
(GLP) and good clinical practice (GCP).
b. Production and control operations are clearly specified in a

written form.
c. M anagerial responsibilities are clearly specified in job

descriptions.
d. Arrangements are made for the manufacture, supply, and use of

the correct starting and packaging materials.
e. All necessary controls on starting materials, intermediate

products, and bulk products and other in-process controls,
calibrations, and validations are carried out.
f. The finished product is correctly processed and checked,

according to the defined procedures.
g. Pharmaceutical products are not sold or supplied before the

authorized persons have certified that each production batch
has been produced and controlled in accordance with the
requirements of the marketing authorization and any other
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GMP - E g y p t
regulations relevant to the production, control and release of
pharmaceutical products.
h. Satisfactory arrangements exist to ensure, as far as possible,

that the pharmaceutical products are stored by the
manufacturer, distributed, and subsequently handled so that
quality is maintained throughout their shelf-life.
i. There is a procedure for self-inspection and/or quality audit that

regularly appraises the effectiveness and applicability of the
quality assurance system.
R esponsibil ity of the qu al ity assu rance officer

The responsibilities of the quality assurance officer can be
summarized as follows
1. S am pl er To obtain representative samples of intermediates and

finished product
a. For each batch.
b. According to the specification.
c. As required to meet special needs e.g. process problems.
2. Chec k er To perform independently in-process quality control

(checks and tests)
a. At random throughout process.
b. For critical start-up tests.
c. To check for correctness of printed materials and overprinted

items.
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GMP - E g y p t
3. O b s erv er To observe conditions on line and in process area
a. For compliance with the process method.
b. For correct operation of procedures.
c. For cleanliness, and clearance of other components.
4. R epo rter To prepare a batch report on
a. The key components used and their status.
b. Clearance and cleanliness.
c. In-process checks.
d. General comments on conditions in the area and flow of

process e.g. machine stoppage and actions taken.
5. R ev i ew er To review the manufacturing/packaging record for
a. Completeness.
b. Correctness.
c. Compliance of in-process control results with specification.
d. Reporting of "unusual incidents".
Q u a l i ty contr ol
Concept and obj ective
Quality control is the part of GM P concerned with sampling,
specifications. and testing and with the organization, documentation,
and release procedures which ensure that the necessary and
relevant tests are actually carried out and that materials are not
released for use, nor products released for sale or supply, until their
33
GMP - E g y p t
quality has been judged to be satisfactory. Quality control as
mentioned in ISO 9000 is the operational techniques and activities
that are used to fulfill requirements for quality.
Provision for a cross referencing system to allow any batch

of a product to be traced from its raw materials to its final destination
in the event of unexpected difficulties is required.
In order to avoid confusion, care should be taken to include a

modifying term when referring to a sub-set of quality control, such as
manufacturing quality control, or when referring to a broader
concept, such as company-wide quality control.
Quality control involves operational techniques and activities

aimed both at monitoring a process and at eliminating causes of
unsatisfactory performance at relevant stages of the quality loop
(quality spiral) in order to result in economic effectiveness.
T o ac hi ev e ef f ec ti v e c o n tro l o f q u al i ty the f o l l o w in s ho u l d b e
tak en i n c o n s i d erati o n
a. Adequate facilities, trained personnel and approved

procedures must be available for sampling, inspecting, and
testing starting materials, packaging materials, and
intermediate, bulk, and finished products, and where
appropriate for monitoring environmental conditions for GM P
purposes.
b. Samples of starting materials, packaging materials,

intermediate products, bulk products and finished products
must be taken by methods and personnel approved by the
quality control department.
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GMP - E g y p t
c. Test methods must be validated.
d. Records must be made (manually and/or by recording

instruments) demonstrating that all the required sampling,
inspecting, and resting procedures have actually been
carried out and that any deviations have been fully recorded
and investigated.
e. The finished products must contain ingredients complying

with the qualitative and quantitative composition of the
product described in the marketing authorization; the
ingredients must be of the required purity, in their proper
container, and correctly labeled.
f. Records must be made of the results of inspecting and

testing materials and intermediate, bulk, and finished
products against specifications; product assessment must
include a review and evaluation of the relevant production
documentation and an assessment of deviations from
specified procedures.
g. No batch of product is to be released for sale or supply prior

to certification by the authorized person(s) that it is in
accordance with the requirements of the marketing
authorization.
h. Sufficient samples of starting materials and products must be

retained to permit future examination of the product if
necessary; the retained product must be kept in its final pack
unless the pack is exceptionally large.
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GMP - E g y p t
The quality control department as a whole will also have
other duties, such as to establish, validate, and implement all quality
control procedures, to evaluate, maintain and store the reference
standards for substances, to ensure the correct labeling of
containers of materials and products, to ensure that the stability of
the active pharmaceutical ingredients and products is monitored, to
participate in the investigation of complaints related to the quality of
the product, and to participate in environmental monitoring. All these
operations should be carried out in accordance with written
procedures and, where necessary, recorded.
Assessment of finished products should embrace all relevant

factors, including the production conditions, the results of in-process
testing, the manufacturing (including packaging) documentation,
compliance with the specification for the finished product, and an
examination of the finished pack.
Quality control personnel must have access to production

areas of sampling and investigation as appropriate.
I n-Process qu al ity control

To guarantee the manufacturing symmetry, controlling tests
should be carried out on certain samples at each production step.
Approved production steps should be controlled and assured for
example
• Variation in weight for any pharmaceutical product.
• Disintegration of tablets.
• Assurance of mixing to verify homogeneity for powders.
36
GMP - E g y p t
• Dissolution rate for certain solid dosage form.
• Volume, pH, clarity tests for solutions.
• Appropriate tests for semisolids, or sterile products.
These tests must comply with the final requirements of

products. If the raw material is kept in the store for long period,
controlling tests during manufacturing must be carried out for
assurance of its purity and validity. Raw materials do not pass these
controlling tests must be quarantined, identified by special labels, not
be used and be returned to the quarantine store for damage under
concerning committee supervision.
S a mpl i ng
All raw materials, packaging materials, containers should be
kept in the quarantine area until sampled by quality control and
approval result is issued. No batch is used until all tests are
approved by quality control.
Any batch that does not conform to standards should be

rejected. All tests should be changed according to the latest
pharmacopoeia and its addendum and other advanced text books
and the most recent modification devised by factory.
The samples should cover a certain part of the batch, with a

written procedure and fixed plan. Sampling should be taken without
causing any contamination to the containers.
S am pl i n g P ro c ed u re S ho u l d In c l u d e
• How to take the sample.
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GMP - E g y p t
• The equipment used for sampling.
• Quantity to be sampled.
• Instructions for how to divide the sample.
• Care should be taken for the cleanliness of the sampling

container especially for sterilized materials, and highly effective
materials.
T he s am pl i n g c o n tai n er s ho u l d b e l ab el ed w i th the f o l l o w i n g
req u i rem en ts
• M aterial name.
• Batch no.
• The container no. which is sampled.
• Name and signature of the sampler.
• Date of sampling.
T ests for sam pl es

Raw materials Each material should be tested according to
the specification specially physical properties (including particle size,
crystal shape, hydrated form) purity, content identification and others
including content of degradation products. Quality control results are
the only accepted ones.
Intermediate containers and large volumes All specifications

of tests specially identification, purity, homogeneity in mixing and
other tests.
38
GMP - E g y p t
Large volume containers Tests may include weighing
variance, disintegration rate, dissolution rate for tablets and
capsules, clarity, volume, pH for solutions, homogeneity in content
and sterility rests (if needed).
All batches that are not accepted from quality control results
are rejected and take a different label color indicating that it is
rejected except if it require reworking.
Each product should have its up-to-date specifications, and

tests to be done on each batch before release.
No release is issued for batches that does not confirm with

any specification. It is rejected or remanufactured and requested for
quality control to be released or rejected.
Sterile products should be tested for sterility. This test does

not assure the sterility of the whole batch, because it is a random
sample and the contaminated products are not sampled or the
sensitivity of the test method does not permit the growth of
microorganism so precautions have to be done.
Samples should be taken randomly from the coldest

sterilization place and samples from start and end of sterilization.
Samples are taken as a percentage of batch quantity, and tests are
made for aerobic and anaerobic bacteria.
M edia for test should be chosen to permit the growth of

microorganism at any number. M edia should be sterile. If a batch
failed, the test should be validated. The results should be recorded,
for future knowledge of the reason for the test failure, or method of
preparation.
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GMP - E g y p t
Pyrogen test (coming from raw materials, personnel,
equipment or environment on long preparation time) needs a big
attention for large volume products for
• Water should be pyrogen free specially for volumes more than

15 ml
• On the preparation of large volume parenteral all precautions

should be made to avoid the formation of pyrogen.
• All parentral solutions that are more than 10 ml. should be free
from pyrogen.
Q u a l i ty contr ol r el ea s e s y s tem
In defining the overall system for quality control release of
finished products, it is for the manufacturing organization to decide
on
• The timing of the review of batch documents and analytical

results
• The extent to which batch data are used to authorize further

processing of intermediates and pan finished products.
The two most convenient ways of doing this are
• To review batch documents/analytical data on completion of

each manufacturing stage and release finished product on the
basis of finished pack "inspection" and confirmation that earlier
stages have been previously approved.
40
GMP - E g y p t
• To sample finished packs for full analytical testing and carry out
the batch document evaluation and finished pack inspection on
completion of packaging.
Whatever system is chosen, quality control release of

finished products will depend on the availability of satisfactory
• Bulk manufacturing records (e.g. Granulation).
• Intermediate processing records (e.g. tablet compression).
• Packaging records.
• Records of in-process checks (the majority of these normally

appear in the production records).
• Reconciliations of product and material usage at each stage of

the process and evaluation of the yield for the manufacturing
process overall.
• Reports giving analytical and/or microbiological results.
• Requests for release/transfer/shipping of the batch.
In practice it may be convenient to use checklists for each

product category or activity which ensure and record that all the
necessary documents and results have been gathered together,
reviewed, checked, assessed as satisfactory and filed. The checklist
should be filed with the batch records and the document or copy
document authorizing the disposition of the batch.
The batch documentation or a suitable summary should be

submitted to a person authorized to carry out quality control release
who should then satisfy him/herself that all the documents detailed
41
GMP - E g y p t
above have been duly completed and checked, and any exceptions
investigated and reported.
Where checks reveal deviations from accepted practices,

unforeseen events or analytical results outside "release" limits, the
person legally responsible for quality control and the appropriate
"qualified person" must agree the fate of the batch concerned. In
these circumstances, the following factors should be taken into
account
• The requirements of the product license and manufacturer’ s

license.
• The stability of the product and the end of life (check)

specification for the product.
• The results of investigations carried out into the history of the

batch
On completion of all the necessary checks, the person

authorized to carry out quality control release should sign for the
disposition of the batch in the formal records. If this person is also
carrying out the duties of the “ qualified person” he or she will need to
ensure that additional checks are carried out as appropriate and that
the batch is entered on the register which is then signed. Where a
second person is carrying out the duties of the “ qualified person”
quality control must ensure that he or she is provided with sufficient
information to carry out his/her duties and that each batch has been
signed off in the register.
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GMP - E g y p t
Once all these checks and the batch certification are
completed, the person responsible for quality control release can
sign the documents that authorize transfer to stock or shipping.
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GMP - E g y p t
Ch eck l i s t for pr emi s es

for quality assurance, production, process and laboratory controls
Facilities S tatu s
General cleanliness of area
No leaks, holes, cracks in building/windows
No insects/rodents/vermin
No unrelated traffic/pedestrian flow
Area secured behind closed doors
Floors/walls covered with material to facilitate
cleaning
Size of facility adequate
Separate area for
- QC/QA for
- Raw materials
- M ixing/blending intermediates
- Finished dosage forms
- QC/QA , tests that are performed
- Animal receipt/holding/testing
- Special storage for special requirements
Necessary utilities in sufficient quality and quantity
Adequate lighting and Ventilation
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GMP - E g y p t
Ch eck l i s t for per s onnel

working in quality assurance, production, process and laboratory
controls
P er so n n el S tatu s
Determine minimum number of personnel needed
Position Description (PD) for each employee
Chart key functions/personnel
Identify basic qualification for each PD
Identify special skills for each PD
Identify key staff and delegate / assign responsibilities
needed for proper functioning e.g. supervising /
training / maintenance
Develop training program
Schedule periodic retraining
Schedule periodic performance evaluations
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GMP - E g y p t
Ch eck l i s t for eq u i pment

of quality assurance, production, process and laboratory controls
E q u ip m en t S tatu s
D ed i c ated eq u i pm en t an d i n s tru m en ts av ai l ab l e f o r
Special storage constant room temperature and humidity
M easuring/weighing/sampling
Laboratory for all assays and tests conducted
Cleaning equipment
Sealable containers for storage of materials to be tested
Equipment in good working order
Cleanliness
M aintenance/lubrication according to schedule
Calibration
Validation
Correct equipment available
Equipment/supplies/ available to lubricate, calibrate,

maintain, and repair
46
R e v is e d G U I D E L I N E S F O R G O O D M A N U F A C T U R I N G P R A C T I C E I N GMP
E G Y - PE T g y , p 20t 0 4
Chapter III
P E R S O N N E L

47
GMP - E g y p t
Chapter III: P E R S O N N E L
There should be sufficient personnel at all levels with the
ability, training, experience and, where necessary, the
professional/technical qualifications and managerial skills
appropriate to the tasks assigned to them. Their duties and
responsibilities should be clearly explained to them and recorded as
written job descriptions or by other suitable means. Training should
cover not only specific tasks but Good M anufacturing Practice
generally and the importance of personal hygiene.
The manufacturer should have an organization chart. All

responsible staff should have their specific duties recorded in written
descriptions and adequate authority to carry out their responsibilities.
Their duties may be delegated to a designated person of a
satisfactory qualification level. There should be no gaps or
unexplained overlaps in the responsibilities of personnel concerned
with the application of GM P.
All personnel should be aware of the principles of GM P that

affect them and receive initial and continuing training, including
hygiene instructions, relevant to their needs. All personnel should be
motivated to support the establishment and maintenance of high-
quality and standards.
Steps should be taken to prevent unauthorized people from

entering production, storage, and quality control areas. Personnel
who do not work in these areas should not use them as a
passageway.
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GMP - E g y p t
K ey personnel
K ey personnel include, factory manager (FM ), production
sector chief (PSC), quality control sector chief (QCSC), the head of
sales/distribution, and the authorized person(s). Normally, key posts
should be occupied by full-time personnel. The heads of each
production and quality control should be independent of each other.
In large organizations, it may be necessary to delegate some of the
functions; however, the responsibility can not be delegated.
K ey personnel responsible for supervising the manufacture

and quality control of pharmaceutical products should possess the
qualifications of a scientific education and practical experience
required by national legislation. Their education should include the
study of an appropriate combination of (a) chemistry (analytical or
organic) or biochemistry, (b) chemical engineering, (c) microbiology,
(d) pharmaceutical sciences and technology, (e) pharmacology and
toxicology, (f) physiology, or (g) other related sciences. They should
also have adequate practical experience in the manufacture and
quality assurance of pharmaceutical products. In order to gain such
experience, a preparatory period may be required, during which they
should exercise their duties under professional guidance. The
scientific education and practical experience of experts should be
such that enable them to exercise independent professional
guidance, based on the application of scientific principles and
understanding of the practical problems encountered in the
manufacture and quality control of pharmaceutical products.
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GMP - E g y p t
P er s onnel r es pons i b i l i ti es
Factory Manag er (FM)
FM must be a pharmacist, registered in M inistry of Health,
has experience in pharmaceutical manufacturing not less than 15
years. He (she) receives the reports from the different sectors' chiefs,
put the general present and future plans for manufacturing. He (she)
helps in selecting the supervisors.
Produ ction S ector Chief (PS C)

PSC must be a pharmacist registered in ministry of health,
has experience in pharmaceutical manufacturing not less than 10
years. He (she) generally has the following responsibilities
a. To ensure that products are produced and stored according to

the appropriate documentation in order to obtain the required
quality.
b. To approve the instructions relating to production operations,

including the in-process controls, and to ensure their strict
implementation.
c. To ensure that the product records are evaluated and signed by

a designated person before they are made available to the
quality control department.
d. To check the maintenance of the quality production

departments, premises, and equipment.
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GMP - E g y p t
e. To ensure that the appropriate process validation and
calibrations of control equipment are performed and recorded
and the reports made available.
f. To ensure that required initial and continuing training of

production personnel is carried out and adapted according to
need.
Q u al ity Control S ector Chief (O CS C)

QCSC must be a pharmacist, registered in M inistry of
Health, has experience in quality control not less than 10 years. He
(she) generally has the following responsibilities
a. To approve or reject starting materials, packaging materials,

and intermediate, bulk, and finished products.
b. To evaluate batch records.
c. To ensure that all necessary testing is carried out.
d. To approve sampling instructions, specifications, test methods,

and other quality control procedures.
e. To approve and monitor analyses carried out under contract.
f. To check the maintenance of the quality production

departments, premises and equipment.
g. To ensure that the appropriate validations, including those of

analytical procedures, and calibrations of control equipment are
done.
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GMP - E g y p t
h. To ensure that the required initial and continuing training of
quality control personnel is carried out and adapted according to
need.
S ectors S u pervisors (S S )
In the manufacturing, quality control, and others, sectors
supervisors should be with high professional levels according to their
responsibilities. They give reports to the sector chiefs.
Consu l tant
Consultant should be with special high level of scientific and
experience background. The work of any consultant should be
continuously reported.
The heads of the production and quality control departments

generally have some shared, or jointly exercised, responsibilities
relating to quality. These may include, depending on national
regulations
a. The authorization of written procedures and other documents

including amendments.
b. The monitoring and control of the manufacturing environment.
c. Plant hygiene.
d. Process validation and calibration of analytical apparatus.
e. Training, including the application and principles of quality

assurance.
f. The approval and monitoring of suppliers of materials.
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GMP - E g y p t
g. The approval and monitoring of contract manufacturer.
h. The designation and monitoring of storage conditions for

materials and product.
i. The retention of records.
j. The monitoring of compliance with GM P requirements.
k. The inspection, investigation, and taking of samples, in order to

monitor factors that may affect product quality
l. Follow up of the product recall and dealing with complaints.
P ers o n al H y g i en e The importance of personal cleanliness, washing

of hands, and general personal hygiene should be emphasized.
P ers o n al H eal th Pre-employment and periodic medical checks

should be required and staff should be encouraged to report any
infections, disease, skin lesions or any condition that may endanger
product quality. M anagement should develop procedures as to
actions to be taken in the event of an infection being observed
among workers.
T r a i ni ng
The first need in developing national competence in drug
control is the training of key staff in every aspect of regulation and
enforcement. It is recognized that international coordination of
training programs and of the production of educational material is
essential to success.
Besides basic training on the practice of GM P, newly

recruited personnel should receive training appropriate to the duties
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GMP - E g y p t
assigned to them. Continuing training should also be given, and its
practical effectiveness should be periodically assessed. Training
programs should be available, approved by the head of either
production or quality control, as appropriate, training records should
be kept.
Personnel working in areas where contamination is a hazard,

e.g., clean areas or areas where highly active, toxic, infectious, or
sensitizing materials are handled should be given specific training.
Priority, if suggested, should be according to the following elements
• Budgeting for and management of quality control laboratories.
• Training of laboratory technicians.
• M aintenance of equipment.
• Training on new technology in drug production.
• Promotion of the WHO certification scheme on the quality of

pharmaceutical products moving in international commerce.
• The concept of quality assurance and all the measures capable

of improving its understanding and implementation should be
fully discussed during the training sessions.
54
E G Y - PE T g y , p 20t 0 4
Chapter IV
P R E M IS E S

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GMP - E g y p t
Chapter IV : P R E M IS E S
Premises must be located, designed, constructed, adapted,
and maintained to suit the operations to be carried out. Their layout
and design must aim to minimize the risk of errors and permit
effective cleaning and maintenance in order to avoid cross-
contamination, build-up of dust or dirt, and in general, any adverse
effect on the quality of products. Premises should be situated in an
environment that, when considered together with measures to
protect the manufacturing process, presents minimum risk of causing
any contamination of materials or products.
Premises used for the manufacture of drug products should

be suitably designed and constructed to facilitate good sanitation.
Premises should be carefully maintained, and it should be ensured
that repair and maintenance operations do not present any hazard to
the quality of products. Premises should be cleaned and, where
applicable, disinfected according to detailed written procedures.
Electrical supply, lighting, temperature, humidity, and

ventilation should be appropriate and such that they do not adversely
affect, directly or indirectly, either the pharmaceutical products during
their manufacture and storage, or the accurate functioning of
equipment.
There should be air filtration devices which have the ability to

change the air at suitable rate for each area. For each area number
of particulate matter must be identified according to special
specifications related to each area.
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GMP - E g y p t
There should be water source under continuously high
pressure in the water which must be of suitable capacity to prevent
any defect. Tanks must not allow the loss or contamination of water.
There should be unit for removal of large particles, microbes and
hardness from the water. System used for preparing sterile water
requires continuous validation.
T he f ac to ry s ho u l d c o n tai n areas f o r
• Receiving the raw materials, packages and others. These

receiving areas should be separated according to the size of
each item.
• Raw materials store.
• Rejected raw materials, final products and labels.
• Central dispensing for general weighing and preparation. This

area must be separated according to the type of ingredients.
Laminar flow is a must for weighing materials used for sterile
product.
• M anufacturing area.
• Packaging area.
• Quarantine area for product under testing for their release.
• In process quality control room inside production.
• Quality control department.
• Sterile area needs
Washing area.
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GMP - E g y p t
M ixing area.
Filling and sealing area.
Closed area adjacent to the filling.
Dressing room for sterile area.
Sterile area.
Cons tr u cti on a nd fi ni s h es
Construction must be adequate to minimize the entry or
harboring of insects, birds or rodents and have smooth, robust, non-
porous, easy to clean and easily maintained surfaces, free from
cracks, crevices and ledges.
Finishes in processing areas should not shed or harbor

particulates or absorb micro-organisms. Parameters such as
porosity, density, texture and electrostatic properties must be
considered. The use of wood should be avoided in production and
packaging areas. Where present, it should be adequately sealed with
emphasis on flexible coating to minimize chipping.
The type of material and finish used for floors, walls and
ceilings cannot be considered in isolation as in many instances the
same or similar materials are used. The compatibility of the different
materials used must be considered together with the junctions
between them.
i. Fl oors and wal l s

Floors should be hard, smooth, sealed, impervious, laid to an
even surface and not affected by cleaning materials. For clean and
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GMP - E g y p t
aseptic areas higher standards are appropriate. Expansion joints and
cracks, if present, should be sealed with a suitable resilient
compound flush with the surrounding surfaces.
Floors and walls must be sealed to render them impervious

to penetration by materials processed in the area. Defects in the floor
and wall surfaces which could admit and harbor materials processed
in the area, dirt, insects, birds, rodents and debris should be
repaired. Where necessary, floors should be adequately sloped
towards floor drains to prevent accumulation of washings and
spillages.
Joints between walls and floors should be easy to clean,

adequately sealed and preferably coved. Any piping, ducting or other
structural materials passing through walls must be sealed at point of
entry to prevent contamination by dust and debris of products
processed below.
ii. Ceil ing s

Ceilings should be constructed and finished so that they are
easy to clean. The ceiling surface must be well maintained and free
from peeling or other visible deterioration. If ceiling tiles are used
they must fit securely into position, have a smooth surface and be
adequately sealed to prevent contamination from the space above
them.
The joint of the ceiling with the wall should be complete and
preferably coved. Any piping, ducting or other structural materials
passing through the ceiling must be sealed at point of entry to
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GMP - E g y p t
prevent contamination by dust and debris of products processed
below.
Overhead ducts, roof joists, pipes and lighting fixtures should

be avoided in the manufacturing and packaging areas since they are
not readily cleanable surfaces. They should be contained within a
suspended ceiling to reduce surfaces where dust can accumulate
and access for maintenance must be clearly identified. Where the
ceiling consists of the floor of an area above, it should incorporate a
damp proof membrane to prevent seepage.
iii. D oors and windows

Doors and windows should have a smooth, hard, impervious
finish and should close tightly. Window and door frames should be
flush with the surrounding walls. Windows, if present in the
production area, should be tightly sealed and not be permitted to
open.
Outside doors should be well sealed and be closed except

when used for entry or exit. Inside doors used to segregate
operations to prevent cross contamination must be closed except
when used for entry or exit. Doors which lead to the outside directly
from production areas should be absolutely sealed and closures
designed such that they can only be used as emergency exits.
Sliding doors are a potential problem if they cannot be cleaned
easily. A major advantage however is the extra space that such
doors provide.
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GMP - E g y p t
Consideration must be given to the potential conflict of Good
Pharmaceutical M anufacturing Practice (GPM P) and fire, health and
safety requirements.
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GMP - E g y p t
(1 ) ( 2) ( 3) ( 4) ( 5) ( 6) ( 7)
F lo o r s
H i g h -d e n s i t y c o n c r e t e x x x x x x x
T r o w e l e d e p o xy f i n i s h x x x x
T e r r a z z o e p o xy f i n i s h x x x x
C o n c re te w ith m e ta l c h ip s x x x x x x x
d ra in s
V in y l a s b e s to s tile x x x x x
W a lls
S m o o th x x x x x x x
E p o xy p a i n t x x x x x x x
W a s h a b le x x x x x x x
G la z e d tile x x x x x x
W a ll p a p e r (w a s h a b le ) x x
C e ilin g s
H u n g x x x x x x
A c o u s tic a l x x x x x
S m o o th w a te rp ro o f x
O p e n x
L ig h tin g
F o o t c a n d le s 7 5 1 0 0 1 0 0 7 5 7 5 7 5 5 0
F lu s h m o u n te d x x x x x x
A ir c o n d itio n in g
O p tio n a l x x
C o m fo rt c o n tro l x x x
4 5 % R H /2 2 .2 °C x x x
< 2 0 % R H /2 2 .2 °C x
(1) = C h e m ic a l W e ig h in g
(2) = G r a n u la tin g
(3) = T a b le ttin g
(4) = C o a tin g
(5) = L iq u id m a n u fa c tu r e
(6) = P a c k a g in g
(7) = W a r e -h o u s i n g
Table (1) Facilities G u id elin es
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GMP - E g y p t
E nv i r onment
M icrobial and particulate quality is especially important in the
manufacture of sterile and many oral and topical products. It is
necessary to monitor production areas regularly for the absence of
micro organisms and for particulate levels as appropriate to ensure
that the environment is satisfactory for manufacturing.
a. R equ irem ents for specific m anu factu ring areas
i. St e r il e ar e as
The requirements for a clean and correct environment in
sterile areas are most stringent because most products
manufactured therein are for direct injection into the body thus
avoiding some of the normal body defense mechanisms. Other
products manufactured in sterile area such as eye, nose and ear
medicines are applied to sensitive areas. The prevention of
contamination by particles and micro-organisms is, therefore,
important, and the way of preventing this contamination is to control
carefully the environment in which they are manufactured. There are
other environmental factors which can affect sterile products
including humidity and temperature. These are normally product
specific and need to be considered as special cases.
Contamination of a sterile area environment by particles and

micro-organisms can normally be considered together when
discussing the methods of producing a satisfactory aseptic
environment but have to be considered separately in terms of
monitoring methods. Sterile areas should normally be flushed with at
least 20 air changes per hour, the air having passed through "High
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GMP - E g y p t
Efficiency Sub-micron Particulate Air" (HESPA) filters. The air flow is
arranged to pass over the most critical areas before exhaustion or
recirculation. HESPA filter integrity checks should be conducted on a
regular basis. Clean room conditions are maintained by providing
positive pressure to reduce ingress of particles and micro-organisms
from surrounding areas. The temperature of the filtered air controls
the temperature of the sterile area. Very often the humidity of the air
is also controlled simultaneously in order to provide a comfortable
environment for the operators, who should be clad in non-particle
shedding clothing to minimize their contribution of particles to the
atmosphere. Localized laminar flow protection may be necessary if
the entire area cannot be ventilated to an acceptable standard.
Particulate contamination is normally measured using light

scattering instruments such as the Royco counter. This instrument
draws air into a chamber where the number and size of particles is
determined. The results of these counts need careful interpretation in
the context of the operations being carried out and the accuracy of
the determinations. Output from these instruments is normally by
means of a digital display or printed chart, but may be connected to a
loudspeaker to give an audible count. This latter output is useful for
giving an immediate indication of leaks when inspecting filter
surfaces. Care is necessary to ensure that standard procedures are
available for particle counters including locations and times of tests.
Detection of viable micro-organisms in the air can be carried

out by two methods. The first includes the use of centrifugal or slit
type samplers which collect a measured volume of air and direct it
over solid nutrient medium in the form of a plate or strip so that the
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GMP - E g y p t
microorganisms impinge on it and can grow colonies on subsequent
incubation. These colonies can be counted and related to the volume
of air sampled. The second method relies on the exposure of settle
plates in various areas of the production suite. One advantage of this
technique is that it is easier to cover more of the area for more of the
time, but it has the drawback of needing much background data
before limits can be applied as the response (collection of viable
micro-organisms) relies on air currents, settling rate of particles, time
of exposure, etc. Contact plates may also be used in conjunction
with settle plates. A formal and agreed testing regimen with defined
action should be drawn up and agreed.
ii. L iq u ids , c r e ams , an d o in t me n t s man u f ac t u r in g

The environment for the manufacture of these products does
not need to be the same as for sterile products but, because they
need to be manufactured in an environment from which significant
microbial contamination is excluded. Particular care is required with
the environment for creams and ointments as such products may be
used on abraded skin surfaces.
It is preferable that this environment is at positive pressure

relative to the surrounding area and that it is kept clean and the
facility adequately disinfected. The air supply should ideally be
filtered to remove particles which could contaminate the product or
harbor micro-organisms.
iii. So l id do s e ar e a
The major contamination of the environment in solid dose
areas arises from the product itself, although care must also be
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GMP - E g y p t
taken to minimize the microbial exposure. Environmental conditions
must also be maintained to protect the operator in these areas
because dust of any nature is potentially harmful to the lungs, and
active dust could have physiological effects on the operator.
Control of the environment in these areas is normally

achieved by directing the filtered ventilation air across the product
towards the extract and away from the operator position. There
should also be localized dust extraction for certain operations such
as milling. No amount of ventilation and dust extraction can
substitute the prevention of dust generation. This must be the prime
aim in achieving a clean environment. Tabletting areas also need to
have humidity control for many types of products such as
effervescent tablets and this is achieved by controlling the input air.
M easurement of dust is normally achieved by drawing air

through a suitable cellulose or glass fiber filter and collecting and
weighing the dust. Static monitors are useful for measuring the dust
created by a machine or an operation, whereas personal monitors
indicate the exposure of the operator to a potential hazard. Tests
could be performed on operators to determine the concentration of
active ingredients in their blood or urine samples.
iv . D is p e n s ar y
Dispensing areas are similar to solid dose areas and care
needs to be taken to control dust generation whilst transferring
material. The design of the ventilation and dust extraction equipment
needs to keep dust away from the operator and at the same time not
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GMP - E g y p t
cause contamination of other products. M easurement of dust in
dispensing areas is by the same methods as for solid dose areas.
b. D u st and du st ex traction
Dust, if it contaminates other products, may be a risk to a
patient’ s health. It may also harm the personnel working in a
manufacturing area by blocking nasal passages, causing accidents
due to the effect of the drug on the person or even inducing diseases
in the lungs.
There is a conflict between the GPM P and the health and

safety approach to dust control and prevention. The former requires
the product to be protected and could, therefore, mean that clean air
is directed at the product (and then over the operator), whereas the
latter requires the clean air to pass over the operator first. In fact,
these two views can largely be reconciled by using correct protective
clothing ‘ for the operator and minimizing dust generation using
closed vessels where possible and adequate dust extraction. Certain
hazard cabinets can protect both the operator and the final product.
The presence of dust in the atmosphere is restricted where

limits of less than 10 mg/cubic meter of air are applied.
c. L ig hting
Without adequate lighting, personnel cannot carry out their
work satisfactorily. Too little light causes eye strain and fatigue,
especially where detailed work is performed, whereas too much light
can cause glare and dazzle. Where possible, daylight is preferable to
any artificial lighting because the human eye is more accustomed to
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GMP - E g y p t
the color balance of normal daylight. Some substances are,
however, sensitive to U V radiation present in daylight.
Not all rooms can be lit completely by daylight and artificial

lighting is widely used. Due consideration must then be given to
positioning, color balance and intensity. Domestic fluorescent tubes
give an emission spectrum which is deficient in certain colors and
daylight tubes should be selected where possible (see table1)
d. N oise
Noise is part of the environment and can affect personnel
severely once a threshold level of 90 dB has been reached - a
maximum of 80 dB should be the objective. It is difficult to define
because the frequency of noise volume and the annoyance it causes
are not related. Certain frequencies and combinations of frequencies
at a low level can be more irritating than other combinations.
e. Col or and decoration

Companies often use a common color scheme for decoration
throughout a factory which means that the environment may have a
monotonous appearance. Careful choice of decoration color can
enhance the working environment.
R eq u i r ements of d i ffer ent a r ea s

i. Ancil l ary areas
Rest and refreshment rooms should be separate from other
areas. Facilities for changing and storing clothes and for washing
and toilet purposes should be accessible and appropriate for the
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GMP - E g y p t
number of users. M aintenance workshops should if possible be
separated from production areas.
Animal houses should be well isolated from other areas, with

separate entrance and air handling facilities.
ii. S torag e area

Storage areas should be of sufficient capacity to allow
orderly storage of the various categories of materials and products;
starting and packaging materials, intermediates bulk and finished
products, products in quarantine, and released, rejected, returned, or
recalled products.
Storage areas should be designed or adapted to ensure

good storage conditions. In particular, they should be clean and dry
and maintained within acceptable temperature limits. Where special
storage conditions are required (e.g., temperature, humidity) these
should be provided, checked, and monitored.
Receiving and dispatch areas should protect materials and

products from the weather. Reception areas should be designed and
equipped to allow containers of incoming materials to be cleaned if
necessary before storage.
Where quarantine status is ensured by storage in separate

areas, these areas must be clearly marked and their access
restricted to authorized personnel. Any system replacing the physical
quarantine should give equivalent security.
There should normally be a separate sampling area for

starting materials. If sampling is performed in the storage area, it
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GMP - E g y p t
should be conducted in such a way as to prevent contamination or
cross-contamination.
Segregation should be provided for the storage of rejected,

recalled, or returned materials or products. Highly active materials,
narcotics, other dangerous drugs, and substances presenting special
risks of abuse, fire, or explosion should be stored in safe and secure
areas.
Printed packaging materials are considered critical to the

conformity of the pharmaceutical product to its labeling, and special
attention should be paid to the safe and secure storage of these
materials.
iii. W eig hing areas

The weighing of starting materials and the estimation of yield
by weighing should usually be carried out in separate weighing areas
designed for that use, for example with provisions for dust control.
iv. Produ ction areas

In order to minimize the risk of a serious medical hazard due
to cross-contamination, dedicated and self-contained facilities must
be available for the production of particular pharmaceutical products,
such as highly sensitizing materials (e.g. penicillin) or biological
preparations (e.g. life microorganisms). The production of certain
other products, such as some antibiotics, hormones, cytotoxic
substances, highly active pharmaceutical products, and non-
pharmaceutical products, should not be conducted in the same
facilities. The manufacture of technical poisons, such as pesticides,
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GMP - E g y p t
and herbicides should not normally be allowed in premises used for
the manufacture of pharmaceutical products. In exceptional cases,
the principle of campaign working in the same facilities can be
accepted provided that specific precautions are taken and the
necessary validations are made.
Premises should preferably be laid out in such a way as to

allow the production to take place in areas connected in a logical
order corresponding to the sequence of the operations and to the
requisite cleanliness levels.
The adequacy of the working and in-process storage space

should permit the orderly and logical positioning of equipment and
materials so as to minimize the risk of confusion between different
pharmaceutical products or their components, to avoid cross-
contamination, and to minimize the risk of omission or wrong
application of any of the manufacturing or control steps.
Where starting and primary packaging materials and

intermediate or bulk products are exposed to the environment,
interior surfaces (walls, floors, and ceilings) should be smooth and
free from cracks and open joints, should not shed particulate matter,
and should permit easy and effective cleaning and, if necessary,
disinfection.
Pipe work, light fittings, ventilation points, and other services

should be designed and sited to avoid the creation of recesses that
are difficult to clean. As far as possible, for maintenance purposes,
they should be accessible from outside the manufacturing areas.
Drains should be of adequate size and equipped to prevent back-
flow. Open channels should be avoided where possible, but if they
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GMP - E g y p t
are necessary they should be shallow to facilitate cleaning and
disinfection.
Production areas should be effectively ventilated, with air-

control facilities (including control of temperature and, where
necessary, humidity and filtration) appropriate to the products
handled, to the operations undertaken, and to the external
environment. These areas should be regularly monitored during
production and non-production periods to ensure compliance with
their design specifications.
Premises for the packaging of pharmaceutical products

should be specifically designed and laid out so as to avoid mix-ups
or cross-contamination. Production areas should be well lit,
particularly where visual on-line controls are carried out.
v. Q u al ity control area

Quality control area laboratories should be separated from
production areas. Areas where biological, microbiological, or
radioisotope test methods are employed should be separated from
each other. Control laboratories should be designed to suit the
operations to be carried out in them. Sufficient space should be
given to avoid mix-ups and cross-contamination. There should be
adequate suitable storage space for samples, reference standards (if
necessary, with cooling), and records.
The design of the laboratories should take into account the

suitability of construction material, prevention of fumes, and
ventilation. Separate air handling units and other provisions are
needed for biological, microbiological, and radioisotope laboratories.
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A separate room may be needed for instruments to protect them
against electrical interference, vibration, contact with excessive
moisture, and other external factors, or where it is necessary to
isolate the instruments.
Cl ea ni ng of th e b u i l d i ng
All production units, packaging and others should be always
clean and in the adequate maintenance. There should be written
procedure for cleaning of all sectors with clear insurance of cleaning
responsibility with identified and fixed steps for cleaning. The rubbish
and the manufacturing remainders should be removed as soon as
they are collected. Equipment, raw materials and pharmaceutical
products should not be contaminated by pesticides and rodenticides.
Workers uniform should be kept in special lockers. There should be
special places for eating, drinking and smoking. It should be left
clean and controlled. There should be places for water closets and
dressing units in separated areas from the manufacturing and control
areas. Separation is achieved by doors and positive pressure.
Personnel in the manufacturing and the other areas and all

workers should practice the different hygienic methods by the written
methods with attention if they didn't obey. All workers should keep
their dressings and their bodies clean. U nclean clothes are kept in
special places. All workers must be subjected to periodical medical
check up to protect the pharmaceutical products from contamination
with germs. In case where possibility of workers contamination,
check up for liver and kidney functions are required. Persons who
work in the sterile sections should be subjected to periodical medical
check up. All efforts must be carried to prevent contact between the
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workers and the raw materials or packaging materials. Teaching the
workers how to wash their hands before entering the manufacturing
areas is essential with unknown marks if possible to test if they didn't
obey.
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Chapter V
M A T E R IA L S

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Chapter V: M ateri al s
The main objective of a pharmaceutical plant is to produce
finished products for patients’ use from a combination of materials
(active, auxiliary, packaging). Special attention should be given to
the materials as such.
R a w ma ter i a l s
The main requirements for raw materials used in pharmaceutical
processing are that
• Adequate systems exist to ensure that all raw materials are

purchased from approved sources and also that, prior to use,
each batch is approved by quality control as conforming to the
specifications.
• They are properly labeled with the name, code number and
expiry and retest dales.
• Their quality control status is evident either from a label or an

equivalent system.
• They are stored under conditions which prevent unacceptable

changes.
The elements of purchasing and inventory control policy that

affect the quality of raw materials and products should be approved
by the person responsible for quality control and should be stated
formally. M aterials should be ordered, taken from stock (normally on
a first-in first-out basis) and supplied to processing units in
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accordance with formally approved procedures which should include
checks to ensure that
• The correct material, grade, amount and batches are ordered,

drawn from stock and delivered.
• Each container is correctly labeled with the amount contained,

identity, batch and code numbers and, if necessary, the quality
status of its contents (where labeling does not include quality
status this should be confirmed by alternative means).
Checks should also be carried out to ensure that containers

are externally clean and in a satisfactory condition. If not, they should
be cleaned on entry into production or measuring-out areas.
All transfers of material and associated checks should be

recorded in formal documents which permit the details of the
transaction to be traced and checked retrospectively. All transfers
should be recorded in terms of
• Quantities
• Dates
• Personnel involved
• Batch numbers
• M aterials code numbers
• Quality control status
Records should also permit reconciliation procedures to be

carried out in order to verify that the correct amounts have been
used.
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Where materials are transferred from suppliers’ containers to
special in-house ones, all the relevant information must be
transferred from the original to the new container, with a recorded
check being carried out to ensure that this has been done correctly.
When raw materials are being allocated to individual batch of

product, care must be taken to avoid the inclusion of too many
batches of any one item as later this can pose problems with batch
traceability and the investigation of problems.
Raw materials are liable to deterioration during storage and,

as a consequence, should normally be given a “ retest” date when
they are approved for use by quality control. This information should
be carried forward into production to ensure that any materials stored
there, are not used after the specified date without having first being
retested.
Where production planning policies and practices influence

the quality of finished products, they should be approved by the
person responsible for quality control and should be staled formally.
Where raw materials are handled for products which have a

microbiological specification, special procedures and monitoring may
be necessary. These may include disinfection of equipment and
areas, use of special protective clothing and procedures together
with microbiological monitoring.
P a ck i ng ma ter i a l s
Special characteristics should be put for all packaging materials.
• Every package batch should be inspected
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• Every printed package should be kept in the quarantine till pass
through special tests carried out by quality control responsible
persons.
• Packages which are affected by humidity should be kept in

suitable conditions to protect them.
• Package kept in papery boxes should not be kept on the floor.
• Outdated or obsolete primary packaging materials or printed

packaging material should be destroyed under strict security
controls and its disposal recorded.
I nter med i a te a nd b u l k pr od u cts

Intermediate and bulk products purchased as such should be
handled on receipt as though they were starting materials and should
be kept under appropriate storage conditions.
F i ni s h ed pr od u cts
Finished products should be held in quarantine until their
final release, after which they should be stored as usable stock
under conditions established by the manufacturer.
R ej ected a nd r ecov er ed ma ter i a l s

Rejected materials and products should be clearly marked
as such and stored separately in restricted areas. They should either
be returned to the suppliers or, where appropriate, reprocessed or
destroyed.
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The reprocessing of rejected products should be exceptional.
It is permitted only if the quality of the final product is not affected, if
the specifications are met, and if it is done in accordance with a
defined and authorized procedure after evaluation of the risks
involved. A record should be kept of the reprocessing. A reprocessed
batch should be given a new batch number. The need for additional
testing of any finished product that has been reprocessed, or into
which a recovered product has been incorporated, should be
considered by the quality control department.
R eca l l ed pr od u cts
Recalled products should be identified and stored separately
in a secure area until a decision is taken on their fate. The decision
should be made as soon as possible.
R etu r ned g ood s

Products returned from the market should be destroyed
unless it is certain that their quality is satisfactory; they may be
considered for resale, re-labeling, or balking with a subsequent batch
only after they have been critically assessed by the quality control
department in accordance with a written procedure. The nature of
the product, any special storage conditions it requires, its condition
and history, and the time elapsed since it was issued should all be
taken into account in this assessment. Where any doubt arises over
the quality of the product, it should not be considered suitable for
reissue or reuse, although basic chemical reprocessing to recover
the active ingredient may be possible. Any action taken should be
appropriately recorded.
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R ea g ents a nd cu l tu r e med i a
All reagents and culture media should be recorded upon
receipt or preparation. Reagents made up in the laboratory should be
prepared according to written procedures and appropriately labeled.
The label should indicate the concentration, standardization factor,
shelf-life, the date when re-standardization is due, and the storage
conditions. The label should be dated and signed by the person
preparing the reagent.
R efer ence s ta nd a r d s
Reference standards may be available in the form of official
reference standards. Reference standards prepared by the producer
should be tested, released, and then stored in the same way as
official standards. They should be kept under the responsibility of a
designated person in a secure area.
W a s te ma ter i a l s
Provision should be made for the proper and safe storage of
waste materials awaiting disposal. Toxic substances and flammable
materials should be stored in suitably designed, separate, enclosed
cupboards, as required by national legislation.
Waste material should not be allowed to accumulate. It

should be collected in suitable receptacles for removal to collection
points outside the buildings and disposed in safely and in a sanitary
manner at regular and frequent intervals.
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G a s es
Gases include a wide range of active and inert gases used in
various stages of pharmaceutical manufacture and laboratory testing
and may be categorized as those gases which come into contact
with the pharmaceutical product or container. These should be
treated as normal raw materials, and be subjected to standard
testing and release procedures. Filtration should occur, preferably at
the point of use. Control is also necessary with gases of which the
quality may influence the results of laboratory testing of products.
Where possible, an identity test (as a minimum) should be

conducted on each cylinder to prevent the use of incorrectly filled
cylinders. Since this is not always feasible, a high level of supplier
assurance should be obtained by detailed auditing of the supplier’ s
facilities and procedures. For cylinder gases, particular attention
must be paid to the batching, filling, segregation from other gases,
procedures to avoid cross-connecting of pipe-work, and care of
cylinders. The frequency of checking, and cleaning of both cylinder
and valve system, is of particular significance.
All cylinders should be correctly color-coded according to the

required standards, and be marked with a unique identifying mark,
ideally at the shoulder to allow traceability of individual cylinders in
use.
Cylinders should be stored under cover, and not subjected to

extremes of temperature. Areas where they are stored should be
clean, dry, well ventilated and free from combustible materials.
Pressure gauges should be checked frequently and re-calibrated
regularly against a primary standard.
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S ol v ents
Solvents which are used in any pharmaceutical
manufacturing process should be considered as raw materials,
regardless of whether they remain in the finished product or are
removed during processing. The solvent is properly identified and
assayed, before permission is given to unload the material. To avoid
potential safety risks, the identity test chosen must be as specific as
possible for the solvent.
Whenever possible, a certificate of analysis from the supplier

should accompany each consignment. Strict written procedures
should be followed to ensure the receipt, testing and quality control
release.
M i s cel l a neou s
Rodenticides, insecticides, fumigating agents, and sanitizing
materials should not be permitted to contaminate equipment, starting
materials, packaging materials, in-process materials, or finished
products.
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Ch eck l i s t for pr emi s es of r a w ma ter i a l s
Fa c i l i t i e s S ta tu s
S eparate areas f o r
Quarantine.
Testing and evaluation.
Weighing.
Storage of approved materials.
Special storage for special requirements.
Necessary utilities in sufficient quality and quantity.
Adequate lighting and ventilation.
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Ch eck l i s t for per s onnel w or k i ng i n r a w

ma ter i a l s
Pe r s o n n e l S ta tu s
Position Description (P.D) for each employee
Identify basic qualification for each P.D.
Identify special skills for each P.D.
Identify key staff and delegate/assign responsibilities

needed for proper functioning e.g. supervising
/training / maintenance.
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Ch eck l i s t for eq u i pment of r a w ma ter i a l s
E q u ip m e n t S ta tu s
Ded i c ated eq u i pm en t av ai l ab l e f o r
Lifting and transporting
Special storage-constant room temperature
Laboratory testing
Cleaning equipment
Sealed containers available for transfer to mixing area
Cleanliness
M aintenance/lubrication according to schedule.
Calibration
Validation
Equipment/supplies/manuals available to lubricate,

calibrate, maintain, and repair
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Chapter V I
E Q U IP M E N T

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Chapter VI: E q u i pm en t
Equipment must be located, designed, constructed, adapted,
and maintained to suit the operations to be carried out. The layout
and design of equipment must aim to minimize the risk of errors and
permit effective cleaning and maintenance in order to avoid cross-
contamination, build-up of dust or dirt, and, in general, any adverse
effect on the quality of products.
Equipment should be installed in such a way as to minimize

any risk of error or of contamination. Fixed pipe-work should be
clearly labeled to indicate the contents and, where applicable, the
direction of flow. All service piping and devices should be adequately
marked and special attention paid to the provision of non-
interchangeable connections or adaptors for dangerous gases and
liquids.
Balances and other measuring equipment of an appropriate

range and precision should be available for production and control
operations and should be calibrated on a scheduled basis.
Production equipment should be designed, located, and

maintained to serve its intended purpose. They should be designed
so that they can be easily and thoroughly cleaned on a scheduled
basis.
Control-laboratory equipment and instruments should be

suited to the testing procedures undertaken.
Washing and cleaning equipment should be chosen and

used so as not to be a source of contamination.
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Production equipment should not present any hazard to the
products. The parts of the production equipment that come into
contact with the product must not be reactive, additive, or absorptive
to an extent that would affect the quality of the product.
Defective equipment should, if possible, be removed from

production and quality control areas, or at least be clearly labeled as
defective.
M aterials used for cooling or for lubrication (grease) should

not be cross mixed with the starting materials, pharmaceutical
products, packaging materials or packaged products.
Liquid filtration should not release any filter media fiber to the
liquid or solution to be filtered. The asbestos filter should not
absolutely be used for liquid filtration or for any purpose in the
factory. It is preferable also to use the automatic multipurpose
device, with routine testing of its efficiency and validity according to a
fixed recorded program.
There should be a device to avoid any problem reflected by

inflammable materials.
L oca ti on a nd s epa r a ti on of eq u i pment

The equipment should be separated from each other by
certain partition to prevent mixing and/or cross contamination. Water,
steam, pressure and vacuum pipes should be covered, isolated and
colored to be easily recognized. Steam pipes should be supplied with
steam traps and drainage for water. Conveyor and belt conveyor
should be provided with special security measures.
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Cl ea ni ng a nd ma i ntena nce
Equipment and containers should be kept clean and
maintained according to a fixed written schedule to prevent its
inefficiency. The cleaning and maintenance methods should offer the
following
• Cleaning and maintenance responsibilities.
• Cleaning maintenance programs should be easy and clear.
• Dis-and reassembling of equipment should be described in

details (if necessary).
• M ethod for the removal of the relevant materials from the

previous batches before the next batch.
• How to keep the equipment cleaned dining and after operations.
• Inspection of the equipment just before and after operations.
A u toma ti c a nd el ectr oni c eq u i pment

Equipment should not be put in use except after
standardization and confirmation of its performance. There should be
fixed program to assure the validity and calibration with the
establishment of a record program. In case of using computer for
recording the batch record, all the batch changes should be
registered with the assurance of continuous validity of what have
been recorded on the device.
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V a l i d i ty of th e d ev i ce
Validity system should be applied to all the equipment that
are characterized by variation in its performance specially balances,
different filtration devices, sterilization, mixing, homogenization,
quality control equipment and others, complying to fixed program
each according to its variation probabilities with special record for
each device to be established.
U ti l i ti es a nd s er v i ces
1. W ater
Four types of water supply are normally used in a
pharmaceutical plant
a. Potable (M ains) Water.
b. Purified Water (De-mineralized or Distilled)
c. Water for Injection.
d. Cooling Water.
All types of water should be monitored for chemical and

microbiological purity at frequent intervals. Formal procedures should
be established for the sampling and testing of water. Written warning
and action limits should be agreed between quality control,
production and engineering management, including procedures to be
taken when the quality falls below these limits.
Records should be maintained of the results of all testing,

and made available to relevant personnel. All “ points of use” should
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be opened and allowed to flow for a minimum of one minute at least
once per day.
a. P o t abl e wat e r
It is the normal source of water for drinking, and hand-
washing purposes. It should be supplied under continuous positive
pressure. Particular care is necessary whenever a storage tank is
provided in the system (e.g. in the case of a hot water supply tank).
This can act as a focus for microbial growth, and particular vigilance
should be maintained with routine quality monitoring.
b. P u r if ie d wat e r
Purified Water is normally produced by exchange treatment,
distillation and/or reverse osmosis. The use of ion-exchange or
reverse osmosis may increase the risk of microbial contamination
unless suitable precautions are taken. Ion-exchange columns are
particularly vulnerable to bacterial contamination, and acid/base
regeneration should be frequent to reduce the risks. Frequent
chemical and microbial monitoring of such systems is essential.
Wherever possible the water in the distribution system would

be kept in circulation to avoid the build-up foci of bacterial growth
and maintained above 80 °C. In these cases, localized cooling at the
off-take points is usually necessary. Particular care must be taken to
ensure that cooling water does not contaminate the purified water.
Where storage tanks are used rapid turn around of contents must
occur.
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The use of in-line ultra-violet radiation within the circulating
system to reduce the proliferation of microorganisms may also be
considered but its efficacy has been queried, particularly if the water
does not flow in the normal manner in a well designed system.
Stainless steel piping (normally passivated 316 grade) is the

material of choice for the distribution system although it is very
expensive for large systems. A disadvantage of stainless steel is lack
of resistance to hypochlorite. Its advantages, however, for both
purified water and water for injections systems are
• M inimum joints - since the system can be smooth-welded.
• Steam sterilizable.
• Chemically resistant to many sanitizing agents.
• Tough and resistant to mechanical damage.
If plastic pipe-work is utilized it should be solvent welded and

be capable of effective sanitation. Particular care should be given to
the design of the distribution system to ensure that
• The system can be sterilized (by steam or other means).
• Dead legs are minimized (maximum dead leg length of 6 pipe

diameters is recommended).
• Lines are sloped to permit free drainage.
• Low points of the system are drainable.
• Flow rate in relation to pipe diameter should be designed to

avoid microbial build up.
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c . W at e r f o r in j e c t io n s
Water for injections is normally produced by distillation of
potable water or purified water, usually by means of multiple-effect
still. This ensures that entrainment of water droplets is avoided, and
that water is produced free from pyrogens. The water should be kept
circulated at a temperature over 80 °C under ultraviolet. It should be
used within 24 hours.
Systems should be monitored frequently for absence of

pyrogens, usually on a daily basis when the water is being used in
production processes. Testing in rabbits or using the Limulus
Amoebocyte Lysate (LAL) test may be utilized; the latter is usually to
be preferred because of more rapid result generation, reduced costs
and enhanced sensitivity.
Water for injections should have facilities to monitor storage

temperature. Storage tanks for the storage of purified water or water
for injections require venting to prevent their collapse when water is
withdrawn. This is normally accomplished using a 0.45 micron or
0.22 micron hydrophobic bacterial retentive filter.
Water for injections should be kept in sterile container, which

does not interact, nor interfere but protect water from any
contamination. K eeping inside system is preferable.
d. C o o l in g wat e r
Water used in the chamber of autoclaves as a coolant after
the sterilization cycle should conform to the standards of water for
injections, specified in the pharmacopoeias and be treated to
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eliminate microorganisms and should not alter the safety of drug
product.
2. S team
Steam is used for a variety of purposes within a
pharmaceutical plant including
• Environmental heating.
• Process temperature control, e.g. steam-jacketed vessels,

heating coils, etc.
• Cleaning, e.g. steam cleaning, or as admixture with water.
• Sterilization, e.g. "live-steaming" of vessels pipelines,

autovalving, ethylene oxide sterilization.
Pipelines and valves carrying steam should be tagged and

clearly identified. The differentiation between high-pressure and low-
pressure steam should be obvious by clear labeling. Attention must
be given to valve joint maintenance and valve design.
Steam mains should have expansion joints or loop’ s bends

and must be laid to a defined gradient. Condensation traps should be
present on all equipment and at suitable points in the supply lines.
The quality of steam which comes into contact with the

product or pack should be monitored regularly and at frequent
intervals. Where necessary, the steam should be filtered.
When used as a sterilant in autoclaves, the condensed

steam should comply with the monograph for water for injections,
specified in the pharmacopoeias and be free from condensable
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gases. Care should be taken to avoid superheating when using
steam for surface sterilization.
3. E l ectricity
Electricity is one of the most universal utility needs in a
modern pharmaceutical plant. Critical areas should have adequate
back-up systems in the event of a mains failure. The changeover
time should be minimal. A list of critical areas and items should be
agreed between production, engineering and quality assurance
management.
Action to be taken in emergency situations should be agreed

and published, and names and telephone numbers of key personnel
should be made available to relevant staff (security staff, production
and engineering supervisors, etc.)
Certain equipment (microprocessors, analytical instruments,

etc.) may require voltage stabilization to ensure reproducibility of
operation.
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Chapter V I I
P R O D U C T IO N

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Chapter VII: P ro d u c ti o n
Production operations must follow clearly defined
procedures. Standard operation procedures should be written for all
production stages. The following should be agreed, specified and
documented in accordance with relevant company and/or legislative
requirements before processing is initiated.
• Specifications and sources for the starting materials.
• The system for ordering, handling, storing and approving starting

materials prior to use.
• Standards for facilities and process equipment (normally in terms

of construction, installation, operation and performance).
• The master formula and method of manufacture written in a clear

and unambiguous manner.
• Commissioning and qualification results obtained for the facilities

and manufacturing equipment.
• Process validation data for the plant to be used for the full-scale
process.
• Acceptable ranges for key facility and process variables which

have been established during the course of commissioning,
qualification and validation.
• In-process control and monitoring systems.
• Cleaning procedures for process plant and facilities.
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• Product inspection systems and associated standards.
• Supplementary standard operating procedures for all important

activities not covered by the method of manufacture.
• Specifications for the partially finished product (where

appropriate).
• "Release and check" specifications for the finished product.
• Storage systems and conditions to protect the integrity and

quality of products at all processing stages.
• Systems for ensuring that adequate batch records are

completed, checked, and stored.
• Systems for ensuring that the personnel controlling and carrying

out the process are suitably qualified and properly trained.
• Systems and procedures to ensure safe working practices.
• Operations on different products should not be carried out

simultaneously or consecutively in the same room unless there is
no risk of mix-up or cross-contamination.
• At all times during processing, all materials, bulk containers,

major items of equipment, and where appropriate the rooms
used should be labeled or otherwise identified with an indication
of the product or material being processed, its strength (where
applicable), and the batch number. Where applicable, this
indication should also mention the stage of production.
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• Normally, non-medicinal products should not be produced in
areas or with equipment destined for the production of
pharmaceutical products.
• Where systems have a direct influence on product quality, they

should be approved by persons responsible for production and
quality control. Other items may need the approval of those
responsible for research, development, engineering and safety,
as appropriate.
• Documents such as master formulae and methods,

specifications, validation protocols and reports and master batch
records should be formally approved before use by the persons
responsible for production and quality control.
V a l i d i ty of th e pr od u cti on meth od
The validity of the production method, introduced by the research
and development department should be assured in case of
• U sing new production procedures, new raw material or new

equipment
• Essential change in the main lines.
There should be periodical evaluation to assure the validity of the

method.
B a tch nu mb er s y s tem
• There should be a special number for each batch.
• The number given to a batch should not be repeated.
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• Batch numbers and volume should be recorded in special
records.
M ea s u r i ng ou t ( d i s pens i ng )
The measuring out of raw materials for use in
pharmaceutical processes is a fundamentally important activity
which, if correctly performed should provide a high degree assurance
as to the composition of finished products.
M easuring out of raw materials must be done
• According to formally defined procedures.
• U sing relevant batch documents and records.
• By trained and authorized personnel.
• In an environment that avoids contamination and preserves the

integrity of the materials being handled.
• U sing calibrated and properly maintained equipment.
• U nder the general standard of environmental control and

hygiene appropriate to the finished product in which they are to
be used.
Centralization of measuring out activities within the

manufacturing unit may be an efficient and convenient means of
handling materials. Care must be taken to ensure that the measuring
system used is of sufficient capacity, accuracy and sensitivity for the
amounts being measured. This applies to scales, load cells, flow-
meters, volumetric measures, and level sensors/indicators.
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The calibration of weighing and measuring systems must be
carried out at regular intervals in accordance with a written schedule,
and must be recorded. In addition to checks on the actual weighing
or measuring operation, further checks should be carried out and
recorded for
• The labeling of the containers from which measuring out is

performed (name, batch number, grade, code number and,
where applicable, quality status).
• The labeling of the materials when measured out (name, batch

number, grade, code number and batch in which it is to be used).
• The quantities measured out compared with those required.
• The net amount of the measured out material and the tare and
gross of the container.
• The reconciliation of the amounts used and those remaining

against the initial stock holding.
All of the checks should involve two operators, one

performing the operation, the second double-checking, with both
recording the results in the batch records. However, for certain
operations, electronic checking and recording systems provide an
opportunity for omitting the second check.
Checks on labeling, condition and quantity should be carried

out when containers of measured out materials are received by the
manufacturing unit. To prevent mixing between materials in
preparation area the following precautions must be taken
• Not more than one material to be handled at the same time.

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• When any package is transferred from the raw material store to
the preparation area, this requires confirmation from the label.
• Weighing should be done by two persons separately.
• Preparation area and its balances should be kept clean.
• Weighing must be carried out by clean balances and equipment.
• After weighing, the packages returned back to the store must be

confirmed from the labels which bear contents. In case of
materials left for long time reconfirmation for its content must be
carried out by the quality control department.
Cr os s -conta mi na ti on a nd b a cter i a l
conta mi na ti on i n pr od u cti on
Cross contamination is the unwanted presence of a material,
component or product in another raw material, component or
product. It may arise from activities associated with the item under
consideration or from extraneous sources. When dry materials and
products are used in production, special precautions should be taken
to prevent the generation and dissemination of dust. Cross
contamination may be caused by the release of dust, gases, vapors,
sprays or organisms from materials and processes, from residues in
equipment, from operators’ clothing, from operators, from the
environment, from utilities and from other external sources.
Cross contamination should be absent from medicinal

products but in practice it cannot be eliminated. M oreover
monitoring, and hence control, is only possible within the limits of
detection for known and potential contaminants. The significance of
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cross contamination should be assessed in relation to the chemical,
physiological and microbiological effects of the known contaminant in
relation to the characteristics and use of the product in which it is
present.
In preventing cross contamination, particular emphasis

should be placed on good practices in the handling of highly potent
and toxic materials or sensitizing agents used in manufacture (such
as hormones, cytotoxic products, certain antibiotics and biological
materials). Cross-contamination should be avoided by appropriate
technical or organizational measures, for example
a. Production in segregated areas (which may be required for

products such as penicillin, live bacterial preparations and
certain other biologicals) or by campaign (separation in time)
followed by appropriate cleaning.
b. Providing appropriate airlocks, pressure differentials, and air

extraction.
c. M inimizing the risk of contamination caused by recirculation or

re-entry of untreated or insufficiently treated air.
d. Wearing protective clothing in areas where products with special

risk of cross-contamination are processed.
e. U sing cleaning and decontamination procedures of known

effectiveness, as ineffective cleaning of equipment is a common
source of cross-contamination.
f. U sing a "closed-system" of production.
g. Testing for residues.
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GMP - E g y p t
h. U sing cleanliness status labels on equipment.
M easures to prevent cross-contamination and their

effectiveness should be checked periodically according to standard
operating procedures. Production areas where susceptible products
are processed should undergo periodic microbiological monitoring.
M a nu fa ctu r i ng
A. I nterm ediate and bu l k produ cts
Before any processing operation is started, steps should be
taken to ensure that the work area and equipment are clean and free
from any starting materials, products, product residues, labels, or
documents not required for the current operation. Any necessary in-
process controls and environmental controls should be carried out
and recorded. Constituents "raw materials or labels" of each batch
must be put in a closed cage or cages to be transferred to the
concerning production site, accompanied with all data related to the
batch.
All packaging materials must be checked before use in each

production batch. Raw materials must be checked twice from
packaging and weighing point of view and be sure that both
packaging data and weight comply with the documented data of the
concerned batch. The conditions of production unit must comply with
all the specified conditions (e.g. temperature, relative humidity, air
flow ability, class-requirements, etc).
All machines and devices used for production and support

sections must comply with the specified validated standards. The
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GMP - E g y p t
written procedure should be followed in all steps of production,
analysis, controlling and in case of any changes, these changes
must be approved and recorded in a written way by reasons from the
concerned persons or committee. It should be confirmed that all
preparation containers are clean, carry code numbers or cards and
confirm the clearance of the previous numbers or cards.
After termination of the preparation, packages are put in the

quarantine area till allowed to transfer to the final product
warehouse. The actual volume of production should be mentioned
and compared with the calculated volume and in case of
fundamental difference between the actual and the theoretical
volumes, reasons must be mentioned and parameters should be
issued to prevent such big difference in future. U nder all conditions
all precautions should be taken to prevent cross mixing of any batch.
R e -man u f ac t u r in g
In case of re-manufacturing for the products which are not
passed by quality control, the new method for re-manufacturing
process should be recorded at any production step. Re-
manufacturing should not be carried out without approval of
concerning authority of quality control department.
T ime o f man u f ac t u r in g
The timing of some manufacturing steps must be fixed,
especially those which are strongly affected by the time factor such
as mixing operations. In case of varying any specified procedure,
time must be recorded in operation sheet with reasons.
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GMP - E g y p t
B. S ol id produ cts
Circulating air of solid product and powder preparation area
must be isolated to prevent cross mixing of air. All air handling units
and filters used must be periodically validated. Powders must not be
contaminated by metal particles and the glassy tools must not be
used with the continued inspection of sieves and any utensils in
direct contact with powders to be sure that they are not injured
before and after manufacturing process.
Tablets and capsules which are invisible inside the

manufacturing machine must not be ejected without notice. Dust-
vacuum devices must be available. Relative humidity and
temperature must be fixed at the specified level for each batch.
M ix in g , g r an u l at io n , dr y in g
If the processes of mixing and sieving are not isolated, dust-
vacuum devices must be available. M ixing time, temperature and
relative humidity must be fixed as mentioned in the preparation
steps. Filters for driers, if any, must be controlled and assured for
their clean condition. Sensitive materials need specified filters. All
precautions must be taken to prevent microbial contamination for the
solutions used in granulation process. Specified humidity percentage
must be kept in the dried granules. The granules should not be
exposed to any external factors that may change humidity. U nder all
conditions all precautions must be taken to prevent cross mixing
between different batches.
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GMP - E g y p t
C o mp r e s s io n
Compression machines must be isolated with the dust
vacuum device which must be available. If compression machine is
not isolated, circulating air of its area must be separated. Control test
devices must be available during manufacturing processes. Any
rejected tablet samples must not be returned and its number should
be mentioned in the batch documents. Compression machine should
be checked before use. All precautions must be taken to prevent
cross-mixing.
C o at in g
The air used for drying of tablets should be filtered. Vapor
limits initiated from solvents of coating materials must not exceed the
healthy specified limits.
The conditions must be adjusted to prevent microbial

contamination of coating solutions, to prevent evaporation of
solvents and to prevent any reaction with the container.
H ar d an d s o f t g e l at in c ap s u l e s
Capsule machine should be isolated. In case of soft gelatin
capsules care should be taken regarding the oil supply and the
waste products. Extreme of humidity and temperature should be
avoided. High humidity (> 60% RH at 21-24 °C) produces more
lasting effects on the capsule shell, since as moisture is absorbed,
the capsules become softer, tackier and bloated. Capsules should be
stored in an-air conditioned area in which the humidity does not
exceed 45% RH at 21- 24 °C.
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GMP - E g y p t
Empty hard gelatin capsules, generally range in moisture
content between 12-15%. Exposure to either heat or moisture
extremes can distort empty capsules to the extent that they can not
be handled by automatic filling machine. All precautions must be
taken to prevent cross mixing during packing. Inspection during
polishing of capsules and coated tablets is essential.
C. S ol u tions, cream s, ointm ents and other l ocal

preparations
Liquids, creams and ointments should be manufactured so
as to protect the product from microbial and other contamination.
The use of closed systems of manufacture and transfer is
recommended where possible. Water used for the manufacturing
should comply with the specifications of the pharmacopoeias for
salts and microorganisms limitations. All pipes used for the transfer
of solid sugar, water or other solutions must be easily cleaned and
maintained and should have the facilities to assure the arrival of the
material to the desired place.
Where pipe lines are used to transfer bulk materials to

remote holding vessels or filling machines it must be ensured that
the material is, in fact, delivered to the intended vessel or machine.
Care should be taken, when bulk tanker deliveries are received, to
ensure the quality and quantity of the delivery before use. The
instruments that can be cleaned in its place are always preferable.
All measurement instruments should be calibrated and validated,
also it is possible to use a dipping measure in case the container
permits that, but it must not react or adsorb the active constituents.
1 0 9
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M a nu fa ctu r e of s ter i l e med i ci na l pr od u cts
Principl e
The manufacture of sterile products is subject to special
requirements in order to minimize risks of microbiological
contamination, and of particulate and pyrogen contamination. M uch
depends on the skill, training and attitudes of the personnel involved.
Quality Assurance bears a particularly great importance and this type
of manufacture must strictly follow carefully established and
validated methods of preparation and procedure. Sole reliance for
sterility or other quality aspects must not be placed on any terminal
process or finished product test. This section does not lay down
detailed methods for determining the microbiological and particulate
cleanliness of air, surfaces, etc. Reference is made to other
compendia such as the CEN/ISO standards.
G eneral
1. The manufacture of sterile products should be carried out in clean
areas, entry to which should be through airlocks for personnel and/or
for equipment and materials. Clean areas should be maintained to
an appropriate cleanliness standard and supplied with air which has
passed through filters of an appropriate efficiency.
2. The various operations of component preparation, product

preparation and filling should be carried out in separate areas within
the clean area. M anufacturing operations are divided into two
categories; firstly those where the product is terminally sterilized, and
secondly those which are conducted aseptically at some or all
stages.
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3. Clean areas for the manufacture of sterile products are classified
according to the required characteristics of the environment. Each
manufacturing operation requires an appropriate environmental
cleanliness level in the operational state in order to minimize the
risks of particulate or microbial contamination of the product or
materials being handled.
In order to meet "in operation" conditions these areas should

be designed to reach certain specified air-cleanliness levels in the "at
rest" occupancy state. The "at-rest' state is the condition where the
installation is complete with production equipment installed and
operating but with no operating personnel present. The "in operation"
state is the condition where the installation is functioning in the
defined operating mode with the specified number of personnel
working.
For the manufacture of sterile medicinal products normally 4

grades can be distinguished.
G ra d e A The local zone for high risk operations, e.g. filling zone,
stopper bowls, open ampoules and vials, making aseptic
connections. Normally such conditions are provided by a laminar air
flow work station. Laminar air flow systems should provide a
homogeneous air speed of 0.45 m/s ± 20% (guidance value) at the
working position.
G ra d e B In case of aseptic preparation and filling the background

environment of Grade A zone.
G ra d e C a n d D Clean areas for carrying out less critical stages in

the manufacture of sterile products.
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The airborne particulate classification for these grades is given in the
following table.
At rest In o perati o n
(b)
G rad e Maximum permitted number of particles/m3 eq ual to or abov e
0.5 µ m 5µ m 0.5 µ m 5µ
A 3 500 0 3 500 0
B 3 500 0 350 000 2 000

(a )
C 350 000 2 000 3 500 000 20 000

(a )
D 3 500 000 20 000

(a )
not defined not defined
(c) (c)
In order to reach the B, C and D air grades, the number of air

(a )
changes should be related to the size of the room and the

equipment and personnel present in the room. The air system
should be provided with appropriate filters such as HEPA for
grades A, B and C.
The guidance given for the maximum permitted number of

(b)
particles in the "at rest" condition corresponds approximately to

the U S Federal Standard 209 E and the ISO classifications as
follows grades A and B correspond with class 100, M 3.5, ISO 5;
grade C with class 10000, M 5.5, ISO 7 and grade D with class
100000, M 6.5, ISO 8.
The requirement and limit for this area will depend on the nature of
(c )
the operations carried out.
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GMP - E g y p t
Examples of operations to be carried out in the various grades are
given in the table below
G rad e Examples of operations for terminally sterilized products
A F il l ing of p r odu c ts , w h en u nu s u a l l y a t r is k
C P r ep a r a tion of s ol u tions , w h en u nu s u a l l y a t r is k . F il l ing of

p r odu c ts
D P r ep a r a tion of s ol u tions a nd c om p onents for s u b s eq u ent fil l ing
G rad e Examples of operations for aseptic preparations
A As ep tic p r ep a r a tion a nd fil l ing
C P r ep a r a tion of s ol u tions to b e fil ter ed
D H a ndl ing of c om p onents a fter w a s h ing
The particulate conditions given in the table for the "at-rest"

state should be achieved in the unmanned state after a short "clean
up" period of 15-20 minutes (guidance value), after completion of
operations. The particulate conditions for grade A in operation given
in the table should be maintained in the zone immediately
surrounding the product whenever the product or open container is
exposed to the environment. It is accepted that it may not always be
possible to demonstrate conformity with particulate standards at the
point of fill when filling is in progress, due to the generation of
particles or droplets from the product itself.
4. In order to control the particulate cleanliness of the various grades

in operation, the areas should be monitored.
5. In order to control the microbiological cleanliness of the various

grades in operation, the areas should be monitored.
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GMP - E g y p t
Where aseptic operations are performed monitoring should be
frequent using methods such as settle plates, volumetric air and
surface sampling (e.g. swabs and contact plates). Sampling
methods used in operation should not interfere with zone protection.
Results from monitoring should be considered when reviewing batch
documentation for finished product release. Surfaces and personnel
should be monitored after critical operations.
Additional microbiological monitoring is also required outside

operations, e.g. after validation of systems, cleaning and sanitation.
Recommended limits for microbiological monitoring of clean areas in

operation
Recommended limits for microbial contamination

(a )
G rade A ir sample S ettle plates C ontact plates G lov e print 5

cfu/m3 ( diam. 9 0 mm) ( diam. 5 5 mm) fing ers
cfu/4 h ours ( b ) cfu/plate cfu/g lov e
A < 1 < 1 < 1 < 1

B 1 0 5 5 5
C 1 0 0 50 2 5 -
D 2 0 0 1 0 0 50 -
These are average values

(a )
Individual settle plates may be exposed for less than 4 hours

(b )
6. Appropriate alert and action limits should be set for the results of
particulate and microbiological monitoring. If these limits are
exceeded operating procedures should prescribe corrective action.
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GMP - E g y p t
I sol ator technol og y
7. The utilization of isolator technology to minimize human
interventions in processing areas may result in a significant decrease
in the risk of microbiological contamination of aseptically
manufactured products from the environment. There are many
possible designs of isolators and transfer devices. The isolator and
the background environment should be designed so that the required
air quality for the respective zones can be realized. Isolators are
constructed of various materials more or less prone to puncture and
leakage. Transfer devices may vary from a single door to double
door designs to fully sealed systems incorporating sterilization
mechanisms.
The transfer of materials into and out of the unit is one of the
greatest sources of contamination. In general the area inside the
isolator is the local zone for high risk manipulations although it is
recognized that laminar air flow may not exist in the working zone of
all such devices. The air classification required for the background
environment depends on the design of the isolator and its
application. It should be controlled and for aseptic processing be at
least grade D.
8. Isolators should be introduced only after appropriate validation.

Validation should take into account all critical factors of isolator
technology, for example the quality of the air inside and outside
(background) the isolator, sanitation of the isolator, the transfer
process and isolator integrity.
9. M onitoring should be carried out routinely and include frequent

leak testing of the isolator and glove/sleeve system.
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GMP - E g y p t
Bl ow, fil l , and seal technol og y
10. Blow/fill/seal units are purpose built machines in which, in one
continuous operation, containers are formed from a thermoplastic
granulate, filled and then sealed, all by the one automatic machine.
Blow/fill/seal equipment used for aseptic production which is fitted
with an effective grade A air shower may be installed in at least a
grade C environment, provided that grade A/B clothing is used. The
environment should comply with the viable and non-viable limits at-
rest and the viable limit only when in operation. Blow/fill/seal
equipment used for the production of products for terminal
sterilization should be installed in at least a grade D environment.
Because of this special technology particular attention should be

paid to at least the following equipment design and qualification,
validation and reproducibility of cleaning-in-place and sterilization-in-
place, background clean room environment in which the equipment
is located, operator training and clothing, and interventions in the
critical zone of the equipment including any aseptic assembly prior to
the commencement of filling.
T erm inal l y steril iz ed produ cts

11. Preparation of components and most products should be done in
at least a grade D environment in order to give low risk of microbial
and particulate contamination, suitable for filtration and sterilization.
Where there is unusual risk to the product because of microbial
contamination, for example, because the product actively supports
microbial growth or must be held for a long period before sterilization
or is necessarily processed not mainly in closed vessels, preparation
should be done in a grade C environment. Filling of products for
1 1 6
GMP - E g y p t
terminal sterilization should be done in at least a grade C
environment. Where the product is at unusual risk of contamination
from the environment, for example because the filling operation is
slow or the containers are wide-necked or are necessarily exposed
for more than a few seconds before sealing, the filling should be
done in a grade A zone with at least a grade C background.
Preparation and filling of ointments, creams, suspensions and
emulsions should generally be done in a grade C environment before
terminal sterilization.
Aseptic preparation
12. Components after washing should be handled in at least a grade
D environment. Handling of sterile starting materials and
components, unless subjected to sterilization or filtration through a
micro-organism-retaining filter later in the process, should be done in
a grade A environment with grade B background. Preparation of
solutions which are to be sterile filtered during the process should be
done in a grade C environment; if not filtered, the preparation of
materials and products should be done in a grade A environment
with a grade B background. Handling and filling of aseptically
prepared products should be done in a grade A environment with a
grade B background. Transfer of partially closed containers, as used
in freeze drying, should, prior to the completion of stoppering, be
done either in a grade A environment with grade B background or in
sealed transfer trays in a grade B environment. Preparation and
filling of sterile ointments, creams, suspensions and emulsions
should be done in a grade A environment, with a grade B
1 1 7
GMP - E g y p t
background, when the product is exposed and is not subsequently
filtered.
Personnel
13. Only the minimum number of personnel required should be
present in clean areas; this is particularly important during aseptic
processing. Inspections and controls should be conducted outside
the clean areas as far as possible.
14. All personnel (including those concerned with cleaning and

maintenance) employed in such areas should receive regular training
in disciplines relevant to the correct manufacture of sterile products,
including reference to hygiene and to the basic elements of
microbiology. When outside staff who have not received such
training (e.g. building or maintenance contractors) need to be -
brought in, particular care should be taken over their instruction and
supervision.
15. Staff who have been engaged in the processing of animal tissue
materials or of cultures of micro-organisms other than those used in
the current manufacturing process should not enter sterile-product
areas unless rigorous and clearly defined entry procedures have
been followed.
16. High-standards of personnel hygiene and cleanliness are

essential. Personnel involved in the manufacture of sterile
preparations should be instructed to report any condition which may
cause the shedding of abnormal numbers or types of contaminants;
periodic health checks for such conditions are desirable. Actions to
be taken about personnel who could be introducing undue
1 1 8
GMP - E g y p t
microbiological hazard should be decided by a designated
competent person.
17. Changing and washing should follow a written procedure

designed to minimize contamination of clean area clothing or carry-
through of contaminants to the clean areas.
18. Wristwatches, make-up and jeweler should not be worn in clean

areas.
19. The clothing and its quality should be appropriate for the process
and the grade of the working area. It should be worn in such a way
as to protect the product from contamination. The description of
clothing required for each grade is given below
G rad e D Hair and, where relevant, beard should be covered. A

general protective suit and appropriate shoes or overshoes should
be worn. Appropriate measures should be taken to avoid any
contamination coming from outside the clean area.
G rad e C Hair and, where relevant, beard and moustache should be

covered. A single or two-piece trouser suit, gathered at the wrists
and with high neck and appropriate shoes or overshoes should be
worn. They should shed virtually no fibers or particulate matter.
G rad e A/ B Headgear should totally enclose hair and, where

relevant, beard and moustache; it should be tucked into the neck of
the suit; a face mask should be worn to prevent the shedding of
droplets. Appropriate sterilized, non-powdered rubber or plastic
gloves and sterilized or disinfected footwear should be worn.
Trouser-buttons should be tucked inside the footwear and garment
1 1 9
GMP - E g y p t
sleeves into the gloves. The protective clothing should shed virtually
no fibers or particulate matter and retain particles shed by the body.
20. Outdoor clothing should not be brought into changing rooms

leading to grade B and C rooms. For every worker in a grade A/B
area, clean sterile (sterilized or adequately sanitized) protective
garments should be provided at each work session, or at least once
a day if monitoring results justify this. Gloves should be regularly
disinfected-during operations. M asks and gloves should changed at
least at every working session.
21. Clean area clothing should be cleaned and handled in such a

way that it does not gather additional contaminants which can later
be shed. These operations should follow written procedures.
Separate laundry facilities for such clothing are desirable.
Inappropriate treatment of clothing will damage fibers and may
increase the risk of shedding of particles.
Prem ises
22. In clean areas, all exposed surfaces should be smooth,
impervious and unbroken in order to minimize the shedding or
accumulation of particles or micro-organisms and to permit the
repeated application of cleaning agents, and disinfectants where
used.
23. To reduce accumulation of dust and to facilitate cleaning there

should be no un-cleanable recesses and a minimum of projecting
ledges, shelves, cupboards and equipment. Doors should be
designed to avoid those un-cleanable recesses; sliding doors may be
undesirable for this reason.
1 20
GMP - E g y p t
24. False ceilings should be sealed to prevent contamination from
the space above them.
25. Pipes and ducts and other utilities should be installed so that
they do not create recesses, unsealed openings and surfaces which
are difficult to clean.
26. Sinks and drains should be prohibited in grade A/B areas used
for aseptic manufacture. In other areas air breaks should be fitted
between the machine or sink and the drains. Floor drains in lower
grade clean rooms should be fitted with traps or water seals to
prevent back-flow.
27. Changing rooms should be designed as airlocks and used to

provide physical separation of the different stages of changing and
so minimize microbial and particulate contamination of protective
clothing. They should be flushed effectively with filtered air. The final
stage of the changing room should, in the at-rest state, be the same
grade as the area in into which it leads. The use of separate
changing rooms or entering and leaving clean areas is sometimes
desirable. In general hand washing facilities should be provided only
in the first stage of the changing rooms.
26. Both airlock doors should not be opened simultaneously. An

interlocking system or a visual and/or audible warning system should
be operated to prevent the opening of more than one door at a time.
29. A filtered air supply should maintain a positive pressure and an

air flow relative to surrounding areas of a lower grade under all
operational conditions and should flush the area effectively. Adjacent
rooms of different grades should have a pressure differential of 10-
1 21
GMP - E g y p t
15 Pascal's (guidance values). Particular attention should be paid to
the protection of the zone of greatest risk, that is, the immediate
environment to which a product and cleaned components which
contact the product are exposed. The various recommendations
regarding air supplies and pressure differentials may need to be
modified where it becomes necessary to contain some materials,
e.g. pathogenic, highly toxic, radioactive or live viral or bacterial
materials or products. Decontamination of facilities and treatment of
air leaving a clean area may be necessary for some operations.
30. It should be demonstrated that air-flow patterns do not present a

contamination risk, e.g. care should be taken to ensure that air flows
do not distribute particles from a particle-generating person,
operation or machine to a zone of higher product risk.
31. A warning system should be provided to indicate failure in the air

supply. Indicators of pressure differences should be fitted between
areas where these differences are important. These pressure
differences should be recorded regularly or otherwise documented.
E qu ipm ent
32. A conveyor belt should not pass through a partition between a
grade A or B area and a processing area of lower air cleanliness,
unless the belt itself is continually sterilized (e.g. in a sterilizing
tunnel).
33. As far as practicable, equipment, fittings and services should be

designed and installed so that operations, maintenance and repairs
can be carried out outside the clean area. If sterilization is required, it
should be carried out after complete reassembly wherever possible.
1 22
GMP - E g y p t
34. When equipment maintenance has been carried out within the
clean area, the area should be cleaned, disinfected and/or sterilized
where appropriate, before processing recommences if the required
standards of cleanliness and/or asepsis have not been maintained
during the work.
35. Water treatment plants and distribution systems should be

designed, constructed and maintained so as to ensure a reliable
source of water of an appropriate quality. They should not be
operated beyond their designed capacity. Water for injection should
be produced, stored, and distributed in a manner which prevents
microbial growth, for example by constant circulation at a
temperature above 70 °C.
36. All equipment such as sterilizers, air handling and filtration

systems, air vent and gas filters, water treatment, generation,
storage and distribution systems should be subject to validation and
planned maintenance; their returning to use should be approved.
S anitation
37. The sanitation of clean areas is particularly important. They
should be cleaned thoroughly in accordance with a written program.
Where disinfectants are used, more than one type should be
employed. M onitoring should be undertaken regularly in order to
detect the development resistant strains.
38. Disinfectants and detergents should be monitored for microbial

contamination; dilutions should be kept in previously cleaned
containers and should only be stored for defined periods unless
1 23
GMP - E g y p t
sterilized. Disinfectants and detergents used in Grades A and B
areas should be sterile prior to use.
39. Fumigation of clean areas may be useful for reducing

microbiological contamination in inaccessible places.
Processing
40. Precautions to minimize contamination should be taken during all
processing stages including the stages before sterilization.
41. Preparations of microbiological origin should not be made or

filled in areas used for the processing of other medicinal products;
however, vaccines of dead organisms or of bacterial extracts may be
filled, after inactivation, in the same premises as other sterile
medicinal products.
42. Validation of aseptic processing should include a process

simulation test using a nutrient medium (media fill). Selection of the
nutrient medium should be made based on dosage form of the
product and selectivity, clarity, concentration and suitability for
sterilization of the nutrient medium. The process simulation test
should imitate as closely as possible the routine aseptic
manufacturing process and include all the critical subsequent
manufacturing steps. It should also take into account various
interventions known to occur during normal production as well as
worst case situations. Process simulation tests should be performed
as initial validation with three consecutive satisfactory simulation
tests per shift and repeated at defined intervals and after any
significant modification to the HVAC-system, equipment, process
and number of shifts. Normally process simulation tests should be
1 24
GMP - E g y p t
repeated twice a year per shift and process. The number of
containers used for media fills should be sufficient to enable a valid
evaluation. For small batches, the number of containers for media
fills should at least equal the size of the product batch. The target
should be zero growth but a contamination rate of less than 0.1%
with 95% confidence limit is acceptable. The manufacturer should
establish alert and action limits. Any contamination should be
investigated.
43. Care should be taken that any validation does not compromise
the processes.
44. Water sources, water treatment equipment and treated water

should be monitored regularly for chemical and biological
contamination and, as appropriate, for endotoxins. Records should
be maintained of the results of the monitoring and of any action
taken.
45. Activities in clean areas and especially when aseptic operations

are in progress should be kept to a minimum and movement of
personnel should be controlled and methodical, to avoid excessive
shedding of particles and organisms due to over-vigorous activity.
The ambient temperature and humidity should not be uncomfortably
high because of the nature of the garments worn.
46. M icrobiological contamination of starting materials should be

minimal. Specifications should include requirements for
microbiological quality when the need for this has been indicated by
monitoring.
1 25
GMP - E g y p t
47. Containers and materials liable to generate fibers should be
minimized in clean areas.
48. Where appropriate, measures should be taken to minimize the

particulate contamination of the end product.
49. Components, containers and equipment should be handled after

the final cleaning process in such a way that they are not re-
contaminated.
50. The interval between the washing and drying and the sterilization
of components, containers and equipment as well as between their
sterilization and use should be minimized and subject to a time-limit
appropriate to the storage conditions.
51. The time between the start of the preparation of a solution and its
sterilization or filtration through a micro-organism-retaining filter
should be minimized. There should be a set maximum permissible
time for each product that takes into account its composition and the
prescribed method of storage.
52. The bio-burden should be monitored before sterilization. There

should be working limits on contamination immediately before
sterilization which are related to the efficiency of the method to be
used. Where appropriate the absence of pyrogens should be
monitored. All solutions, in particular large volume infusion fluids,
should be passed through a micro-organism-retaining filter, if
possible sited immediately before filling.
53. Components, containers, equipment and any other article

required in a clean area where aseptic work takes place should be
sterilized and passed into the area through double-ended sterilizers
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GMP - E g y p t
sealed into the wall, or by a procedure which achieves the same
objective of not introducing contamination. Non-combustible gases
should be passed through micro-organism retentive filters.
54. The efficacy of any new procedure should be validated, and the
validation verified at scheduled intervals based on performance
history or when any significant change is made in the process or
equipment.
S teril iz ation
55. All sterilization processes should be validated. Particular
attention should be given when the adopted sterilization method is
not described in the current edition of the European Pharmacopoeia,
or when it is used for a product which is not a simple aqueous or oily
solution. Where possible, heat sterilization is the method of choice.
In any case, the sterilization process must be in accordance with the
marketing and manufacturing authorizations.
56. Before any sterilization process is adopted its suitability for the
product and its efficacy in achieving the desired sterilizing conditions
in all parts of each type of load to be processed should be
demonstrated by physical measurements and by biological indicators
where appropriate. The validity of the process should be verified at
scheduled intervals, at least annually, and whenever significant
modifications have been made to the equipment. Records should be
kept of the results.
57. For effective sterilization the whole of the material must be

subjected to the required treatment and the process should be
designed to ensure that this is achieved.
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58. Validated loading patterns should be established for all
sterilization processes.
59. Biological indicators should be considered as an additional

method for monitoring the sterilization. They should be stored and
used according to the manufacturers' instructions, and their quality
checked by positive controls. If biological indicators are used, strict
precautions should be taken to avoid transferring microbial
contamination from them.
60. There should be a clear means of differentiating products which

have not been sterilized from those which have. Each basket, tray or
other carrier of products or components should be clearly labeled
with the material name, its batch number and an indication of
whether or not it has been sterilized. Indicators such as autoclave
tape may be used, where appropriate, to indicate whether or not a
batch (or sub-batch) has passed through a sterilization process, but
they do not give a reliable indication that the lot is, in fact, sterile.
61. Sterilization records should be available for each sterilization run.

They should be approved as part of the batch release procedure.
S teril iz ation by heat

62. Each heat sterilization cycle should be recorded on a
time/temperature chart with a suitably large scale or by other
appropriate equipment with suitable accuracy and precision. The
position of the temperature probes used for controlling and/or
recording should have been determined during the validation and,
where applicable, also checked against a second independent
temperature probe located at the same position.
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GMP - E g y p t
63. Chemical or biological indicators may also be used, but should
not take the place of physical measurements.
64. Sufficient time must be allowed for the whole of the load to reach
the required temperature before measurement of the sterilizing time-
period is commenced. This time must be determined for each type of
load to be processed.
65. After the high temperature phase of a heat sterilization cycle,

precautions should be taken against contamination of a sterilized
load during cooling. Any cooling fluid or gas in contact with the
product should be sterilized, unless it can be shown that any leaking
container would not be approved for use.
Moist heat
66. Both temperature end pressure should be used to monitor the
process. Control instrumentation should normally be independent of
monitoring instrumentation and recording charts. Where automated
control and monitoring systems are used for these applications they
should be validated to ensure that critical process requirements are
met. System and cycle faults should be registered by the system and
observed by the operator. The reading of the independent
temperature indicator should be routinely checked against the chart
recorder during the sterilization period. For sterilizers fitted with a
drain at the bottom of the chamber, it may also be necessary to
record the temperature at this position, throughout the sterilization
period. There should be frequent leak tests on the chamber when a
vacuum phase is part of the cycle.
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67. The items to be sterilized, other than products in sealed
containers, should be wrapped in a material which allows removal of
air and penetration of steam but which prevents recontamination
after sterilization. All parts of the load should be in contact with the
sterilizing agent at the required temperature for the required time.
68. Care should be taken to ensure that steam used for sterilization
is of suitable quality and does not contain additives at a level which
could cause contamination of product or equipment.
D ry heat
69. The process used should include air circulation within the
chamber and the maintenance of a positive pressure to prevent the
entry of non-sterile air. Any air admitted should be passed through a
HEPA filter. Where this process is also intended to remove
pyrogens, challenge tests using endotoxins should be used as part
of the validation.
S teril iz ation by radiation

70. Radiation sterilization is used mainly for the sterilization of heat
sensitive materials and products. M any medicinal products and some
packaging materials are radiation-sensitive, so this method is
permissible only when the absence of deleterious effects on the
product has been confirmed experimentally. U ltraviolet irradiation is
not normally an acceptable method of sterilization.
71. During the sterilization procedure the radiation dose should be

measured. For this purpose, dosimetry indicators which are
independent of dose rate should be used, giving a quantitative
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measurement of the dose received by the product itself. Dosimeters
should be inserted in the load in sufficient number and close enough
together to ensure that there is always a dosimeter in the irradiator.
Where plastic dosimeters are used they should be used within the
time-limit of their calibration. Dosimeter absorbance should be read
within a short period after exposure to radiation.
72. Biological indicators may be used as an additional control.
73. Validation procedures should ensure that the effects of variations

in density of the packages are considered.
74. M aterials handling procedures should prevent mix-up between

irradiated and non-irradiated materials. Radiation-sensitive color
disks should also be used on each package to differentiate between
packages which have been subjected to irradiation and those which
have not.
75. The total radiation dose should be administered within a

predetermined time span.
S teril iz ation with ethy l ene ox ide

76. This method should only be used when no other method is
practicable. During process validation it should be shown that there
is no damaging effect on the product and that the conditions and
time allowed for degassing are such as to reduce any residual gas
and reaction products to defined acceptable limits for the type of
product or material.
77. Direct contact between gas and microbial cells is essential;

precautions should be taken to avoid the presence of organisms
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likely to be enclosed in material such as crystals or dried protein. The
nature and quantity of packaging materials can significantly affect the
process.
78. Before exposure to the gas, materials should be brought into

equilibrium with the humidity and temperature required by the
process. The time required for this should be balanced against the
opposing need to minimize the time before sterilization.
79. Each sterilization cycle should be monitored with suitable

biological indicators, using the appropriate number of test pieces
distributed throughout the load. The information so obtained should
form part of the batch record.
80. For each sterilization cycle, records should be made of the time
taken to complete the cycle, of the pressure, temperature and
humidity within the chamber during the process and of the gas
concentration and of the total amount of gas used. The pressure and
temperature should be recorded throughout the cycle on a chart. The
record(s) should form part of the batch record.
81. After sterilization, the load should be stored in a controlled

manner under ventilated conditions to allow residual gas and
reaction products to reduce to the defined level. This process should
be validated.
Fil tration of m edicinal produ cts which cannot be

steril iz ed in their final container
82. Filtration alone is not considered sufficient when sterilization in
the final container is possible. With regard to methods currently
available, steam sterilization is to be preferred. If the product cannot
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be sterilized in the final container, solutions or liquids can be filtered
through a sterile filter of nominal pore size of 0.22 micron (or less), or
with at least equivalent micro-organism retaining properties, into a
previously sterilized container. Such filters can remove most bacteria
and moulds, but not all viruses or mycoplasma. Consideration should
be given to complementing the filtration process with some degree of
heat treatment.
83. Due to the potential additional risks of the filtration method as

compared with other sterilization processes, a second filtration via a
further sterilized micro-organism retaining filter, immediately prior to
filling, may be advisable. The final sterile filtration should be carried
out as close as possible to the filling point.
84. Fiber shedding characteristics of filters should be minimal.
85. The integrity of the sterilized filter should be verified before use
and should be confirmed immediately after use by an appropriate
method such as a bubble point, diffusive flow or pressure hold test.
The time taken to filter a known volume of bulk solution and the
pressure difference to be used across the filter should be determined
during validation and any significant differences during routine
manufacturing from this should be noted and investigated. Results of
these checks should be included in the batch record. The integrity of
critical gas and air vent filters should be confirmed after use. The
integrity of other filters should be confirmed at appropriate intervals.
86. The same filter should not be used for more than one working
day unless such use has been validated.
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87. The filter should not affect the product by removal of ingredients
from it or by release of substances into it.
Finishing of steril e produ cts

88. Containers should be closed by appropriately validated methods.
Containers closed by fusion, e.g. glass or plastic ampoules should
be subject to 100% integrity testing. Samples of other containers
should be checked for integrity according to appropriate procedures.
89. Containers sealed under vacuum should be tested for

maintenance of that vacuum after an appropriate, pre-determined
period.
90. Filled containers of parenteral products should be inspected

individually for extraneous contamination or other defects. When
inspection is done visually, it should be done under suitable and
controlled conditions of illumination and background. Operators
doing the inspection should pass regular eye-sight checks, with
spectacles if worn, and be allowed frequent breaks from inspection.
Where other methods of inspection are used, the process should be
validated and the performance of the equipment checked at
intervals. Results should be recorded.
Q u al ity control
91. The sterility test applied to the finished product should only be
regarded as the last in a series of control measures by which sterility
is assured. The test should be validated for the product(s)
concerned.
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92. In those cases where parametric release has been authorized,
special attention should be paid to the validation and the monitoring
of the entire manufacturing process.
93. Samples taken for sterility testing should be representative of the

whole of the batch, but should in particular include samples taken
from parts of the batch considered to be most at risk of
contamination, e.g.
a) for products which have been filled aseptically, samples should

include containers filled at the beginning and end of the batch and
after any significant intervention;
b) for products which have been heat sterilized in their final

containers, consideration should be given to taking samples from the
potentially coolest part of the load.
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GMP - E g y p t
Checklist for premises of mixing and formulation
F ac i l i ti es S tatu s
No insects/rodents
Floors/walls covered with material to facilitate cleaning
S eparate area f o r
Storage of approved raw materials
Weighing/re-checking/QC.
Storage of mixed/bulk formulated batches awaiting transfer
Special storage for special requirements
QA/QC testing of intermediates
Adequate lighting and ventilation
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Checklist for personnel working in mixing and

formulation
P erso n n el S tatu s

needed for proper functioning e.g. supervising/training/
maintenance
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Checklist for eq uipment of mixing and formulation
E q u i pm en t S tatu s
Laboratory testing
Cleaning equipment
Sterilizers/autoclaves
M ixing machinery
Drying equipment
Granulation/re-granulation
Sealable containers for storage/transfer to mixed batches
to final dosage form preparation area
Cleanliness
M aintenance according to schedule
Calibration
Validation
Equipment/ supplies/ manuals available to lubricate,
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Checklist for personnel working in finished dosage

form preparations
Identify key staff and delegate/ assign responsibilities

maintenance.
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Checklist for eq uipment of finished dosage form

preparations
Laboratory testing
Cleaning equipment
Tableting, encapsulating and powder packaging
machinery
Sterilization
Sealable containers for storage transfer to mixed batches
Granulation/re-granulation
Sealable containers for storage/transfer to mixed batches
Cleanliness
Calibration
Validation
Critical equipment (punches, dies, etc.) special handling
procedures
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Checklist for premises of finished goods, storage
and warehousing
No insects/rodents
QA/QC sampling/testing
Storage of packed and labeled goods awaiting shipment
Special storage for special temperature/humidity

requirements
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Checklist for personnel working in finished goods,

storage and warehousing

maintenance.
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Checklist for eq uipment of finished goods, storage

and warehousing
Special storage-constant room temperature and humidity
Cleaning equipment
Cleanliness
Calibration
Validation
SOP's

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Chapter V III
P A CK A GI NG
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Chapter VIII: P ac k ag i n g
Concepts and definitions

Packaging involves the sub-division of bulk finished product
into packs that contain a sufficient quantity either for a course of
treatment, for dispensing purposes or for retail sale.
The purpose of packaging is to
• Protect the product from damage, deterioration and

contamination during storage and distribution.
• Identify the product, its origins and batch number.
• Give directions for use.
• Give mandatory and advisory warnings of hazards in use.
• Help with patient compliance.
• Where appropriate, present the product in a form that can be

easily used by the patient.
It is essential that the process used for packaging is
• Properly designed.
• Shown to be capable of producing packages which comply in all

respects with the finished product specifications.
• Comprehensively and formally defined.
• Carried out by properly trained personnel with adequate

supervision.
And that
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GMP - E g y p t
• Relevant stages in the packaging operation are checked and
monitored.
• Samples of finished packs are inspected to ensure that they

comply with the finished pack specifications.
Packag ing pr actice

The following should be agreed, specified and documented
in accordance with relevant company and legislative requirements
prior to any packaging process being started:
• Sources and specifications of all packaging materials.
• The system for ordering, handling and approving all categories of

packaging materials.
• Standards for the facilities and equipment to be used (in terms of

construction and performance).
• Commissioning and qualification results as necessary for the

facilities and packaging equipment.
• M aster packaging instruction and method (detailing all materials

to be used) written in clear and unambiguous language.
• Process validation, if required.
• The definition of a packaging batch.
• Acceptable ranges for process control parameters and operating

conditions.
• In-process control and monitoring systems.
• Cleaning and inspection procedures for all packaging equipment

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GMP - E g y p t
• Product inspection systems and standards.
• Systems for the control of printed material and overprinting of

variable information (e.g. batch numbers and expiry dales).
• Standard operating procedures.
• Finished pack specifications.
• Storage systems and conditions to protect the integrity of the

products at all stages of packaging.
• Systems for ensuring that adequate packaging records are

completed, checked, and stored.
• System for ensuring that all personnel involved in the packaging

operation are suitably qualified and adequately trained.
• Systems for ensuring safe working practices.
Packag ing oper ation

The packaging operation for each product or product type
will have its own requirements as specified in the master packaging
instruction and method. Packaging should only be carried out in
accordance with these formally approved procedures and methods.
Details of the packaging operation must be recorded on the batch
packaging record. Packaging lines are normally used for a variety of
different products. Packaging of similar packages should not be in
near areas. It is essential therefore that thorough checks are carried
out on completion of each run and prior to the commencement of the
next operation. These should ensure that:
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GMP - E g y p t
• The packaging equipment and environment comply with that
specified in the master packaging instruction and method and
with appropriate GM P standards.
• The line clearance should be performed according to an

appropriate checklist and recorded.
• The packaging line has been cleaned in accordance with

specified procedures.
• There are no residual bulk products, containers, labels, cartons,

leaflets or finished packs present.
• On-line printing and coding equipment has been set up correctly.
• The line is correctly identified with the name and batch number
of the next batch to be packed.
Checks should be carried out to demonstrate adherence to

the performance requirements of the packaging process. These
include checks on:
• The weight, number or volume contained in the finished pack.
• The cleanliness of the primary containers.
• Freedom from defective items in the bulk product or in

components that have been accepted on the basis of statistical
sampling.
• Product, labels, canons, leaflets, line identification etc.
• Appearance and function of the pack.
• Adequacy of closures and seals.
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GMP - E g y p t
• Function of checking systems (e.g. check-weighing units,
barcode readers).
The checks described above should be carried out at the

commencement of the packaging run and thereafter at set intervals.
They are normally carried out by production personnel backed up by
less frequent audit checks performed by quality control personal. On-
line control of the product during packaging should include at least
checks on:
• The general appearance of the packages.
• The completion of the packages.
• The use of the correct products and packaging materials.
• The correct overprinting.
• The correct functioning of line monitors.
Where automatic machines are used to check dimensions,

weights, missing product labels, barcodes etc. test pieces should be
used to check their correct operation. This should be done in
accordance with written procedures and should be recorded. Where
appropriate, statistical quality control methods should be used to
control variables and attributes. Those most commonly used are
concerned with fill weights and volumes and with batch assessment
using standard sampling plans and tables.
Where the amount of packaging materials originally issued is

found to be insufficient to complete the packaging run, additional
quantities may be required. The issue of extra material should be
1 49
GMP - E g y p t
authorized by a formal procedure which specifies the same level of
checking and documentation as required for the initial issue.
Excess overprinted packaging materials should be counted

as far as is practical and be destroyed. The results of this count
should be used to check that the correct quantity has been used.
U nprinted items may be used either for further packaging operations
(provided they satisfy the start-up checks) or returned to stock. In the
latter case they should be counted as far as is practical, and checked
by quality control before being returned to stock. Surplus product
may be returned for re-use following similar procedures. Rejected
product should either be destroyed or set aside for recovery of the
active ingredient.
Occasionally, packaging materials and bulk products may be

found to be unsatisfactory or isolated defective items picked out
during packaging. It is important that these occurrences are
recorded, reported and investigated to find their cause. The materials
or products should be impounded or quarantined until their fate has
been decided.
Where products are packaged in two separate stages, each

stage should be regarded as a separate packaging operation with
appropriate start-up checks, accountability of materials,
supplementary documentation and records. It may be necessary to
handle and store unlabelled packs. Where this happens, the part
finished packs should be marked and the containers in which they
are held labeled and stored in such away as to preserve batch
integrity and allow them to be identified as regards product name,
batch number, quantity and production stage.
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GMP - E g y p t
Effective reconciliation of materials used in packaging
operations provides assurance of product integrity. The most critical
items in this respect are the product itself and printed packaging
materials. Some methods of handling packaging components such
as roll-feed labels are a benefit to product security but may
themselves make exact reconciliation more difficult as a result of the
problem of obtaining exact counts. In practice it is better to improve
the security of materials storage and usage than expend effort on
trying to achieve better but still incomplete reconciliation figures.
Repackaging of any kind should only be carried out in

accordance with formally approved procedures and with the
agreement of quality control. Non-standard and unforeseen
circumstances should be notified to production management and to
quality control immediately. This should be confirmed in writing
promptly and the results of any follow-up action should be included in
the batch packaging record.
On completion of packaging, the operators and supervisors

involved should ensure that the batch packaging record is complete
and check them for irregularities, mistakes and omissions. When
packaging personnel have assured themselves that the records are
satisfactory, the documents should be submitted to quality control for
further review. On completion of the packaging operation, each batch
should be either physically or procedurally quarantined, until quality
control release and "qualified person" certification are complete.
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GMP - E g y p t
F inal iz ation of packag ing
When the packaging is final it should be assured that
packaging volume is in accordance with processing order. All
packages should be put on pallets and be sure from the safety of the
outer pack. It should be assured that batch no. and product name is
written on all containers by a supervisor. Batch size should be
recorded in a special record. If there is a difference between
theoretical yield and actual yield it should be recorded in the special
file, with reasons. All packaged goods are transferred to its special
store. U pon completion of a packaging operation, any unused batch-
coded packaging materials should be destroyed and the destruction
recorded. A documented procedure should be followed if returned
printed materials are returned to stock.
All bad packed products should be returned to a responsible

person to correct its pack or to damage it and all data must be
recorded. Where any of the above systems and documents have a
direct influence on finished product quality (e.g. control limits on fill
weights), the limits, procedures and documents involved should be
approved by the persons responsible for production and quality
control. In addition, some aspects may need to be approved by the
persons or units responsible for packaging development, engineering
and safety. The master packaging instruction and standard operating
procedures should be formally approved by the persons responsible
for production and quality control prior to use.
Before packaging operations are begun, steps should be

taken to ensure that the work area, packaging lines printing machine
and other equipment are clean and free from any products,
1 52
GMP - E g y p t
materials, or documents previously used and not required for the
current operation. Any utensils like combs or others must not be
used to avoid hair fall or others in the package. No person should be
ill. Inks, pastes, cleaning equipments should be kept in its package,
with a label to identify the kind. Printed and embossed information on
packaging materials should be distinct and resist to fading or
erasing. Special care should be taken when cut labels are used and
when overprinting is carried out off-line, and in hand packaging
operations. On-line verification of all labels by automated electronic
means can be helpful in preventing mix-up, but checks should be
made to ensure that all used devices are operating correctly.
I ssu e of packag ing m ater ial s

Packaging materials should be issued from stock in
accordance with formal systems which ensure that they have been
approved for use by quality control as complying with the relevant
specifications. They are issued in rotation, the oldest being used first.
M aterials are used within their shelf-life. The correct quantity is
issued. The containers used to transport packaging materials are
adequately labeled to indicate the identity, quantity, batch number,
code number and where appropriate, quality status of the contents.
Primary packaging material and products are issued separately for
each packaging run.
Records should be kept of each issue which include
• The name of the material.
• The code number.
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GMP - E g y p t
• The batch or other reference number, if available.
• The amount issued.
• The personnel making the issue.
• The date of issue.
Ch ecks on r eceipt into pr odu ction

Each delivery of packaging materials received by the
packaging unit should be checked to ensure that they are
• The materials as required by the packaging instructions.
• Correctly code numbered as specified in the packaging

instructions.
• In a satisfactory condition in terms of cleanliness and freedom

from damage.
• The quantity specified in the batch packaging documents.
• Approved by quality control.
These checks should be included in the batch packaging

records along with the dates when the materials were received and
the initials of the persons involved.
O v er pr inting
In many cases, printed components may be required to be
overprinted with batch specific information i.e. Batch number, expiry
date, date of manufacture etc. This may be carried out on the
packaging line as part of the packaging operation or alternatively as
a separate off-line activity. What ever the arrangements, overprinting
1 54
GMP - E g y p t
should only be carried out in accordance with the instructions
contained in the batch packaging instruction, with the details being
recorded in the batch packaging record. Checks must be carried out
on the overprinting facilities used to ensure that
• The overprinting equipment and surrounding area are clear of all

traces of the materials handled previously.
• The equipment has been set up correctly for the printing run to
be carried out
These checks must be recorded in the batch records along

with details of
• The numbers of items taken for overprinting.
• The number overprinted.
• The number of surplus unprinted items.
• The number of spoiled items.
An explanation of any discrepancy between the number of

items issued and the number accounted for (outside agreed limits)
should be given. Overprinted items should be stored in suitable
containers which protect them from contamination and prevent mix-
ups with other items. They should be clearly labeled with:
• The name and strength of the product on which they are to be

used.
• Code number.
• Batch number (as overprinted).
1 55
GMP - E g y p t
• The packaging order number if different from the batch number.
Transfer into the packaging unit should be checked and

recorded in the same way as packaging materials received from
stores.
Pr epar ation of oth er pr im ar y packag ing

m ater ial s
In some circumstances primary packaging materials (e.g.
closures and containers) need to be cleaned prior to use. This may
take place either as part of the packaging operation or separately as
an off-line activity. In the latter case, it must be done according to a
separate written procedure and the following included in the batch
record:
• The date the operation was carried out.
• The name of the operator(s) carrying out the procedure.
• In-process control results.
• The quantities of components received from and delivered back

to the packaging line.
• Losses and rejects.
Where these items are pre-printed with product or batch

related information, care should be taken to avoid mix-ups. This will
require similar checks to those described above for overprinted
materials.
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GMP - E g y p t
Ch eckl ist for pr em ises of packag ing and

l ab el ing
Floors/walls covered with material to facilitate cleaning
Storage of approved incoming materials to be processed
Storage of packed and labeled batches awaiting transfer to

Warehouse area
Special storage for special requirements
Protected storage for labels before, during and after a

labeling run
1 57
GMP - E g y p t
Ch eckl ist for per sonnel w or king in packag ing
and l ab el ing

maintenance.
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GMP - E g y p t
Ch eckl ist for eq u ipm ent of packag ing and
l ab el ing
Special storage-constant room temperature and humidity
Cleaning equipment
Packaging and labeling
Sealable containers for storage/transfer of final dosage

form batches to packaging and labeling area
Cleanliness
Calibration
Validation

1 59
GMP - E g y p t
Chapter IX
D O CU M E NT A T I O N
1 60
GMP - E g y p t
Chapter IX : Do c u m en tati o n
Concepts and definitions

A document is the written procedures, instructions,
requirements, registration files and others that to be needed in
storage, procedures, manufacturing and quality control.
Documentation is a prime necessity in quality assurance. Its
purposes are to:
• Define the system of control
• Reduce the risk of error inherent in purely oral communication
• Insure that personnel are instructed in the details of, and follow
the procedures concerned
• Permit investigation and tracing of defective products.
Good documentation constitutes an essential part of the quality

assurance system, hence it helps in:
• Reducing the number of mistakes
• Finding the causes of poor quality
• Giving clear message on how work should be done
• K eeping records of how work was done
• Tracing which batches of materials were used in which batches

of product and where the batches were delivered when
dispatched from the factory
Documents should be designed, prepared, reviewed and

distributed with care. They should comply with the relevant parts of
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GMP - E g y p t
the manufacturing and marketing authorization dossiers. Documents
should be approved, signed and dated by appropriate and authorized
persons. Documents should have unambiguous contents; title,
nature and purpose should be clearly stated. They should be laid out
in an orderly fashion and be easy to check. Reproduced documents
should be clear and legible. The reproduction of working documents
from master documents must not allow any error to be introduced
through the reproduction process.
Documents should be regularly reviewed and kept up-to

date. When a document has been revised, systems should be
operated to prevent inadvertent use of superseded documents.
Documents should not be handwritten; although, where documents
require the entry of data, these entries may be made in clear, legible,
indelible handwriting. Sufficient space should be provided for such
entries. Data may be recorded by electronic data processing
systems, photographic or other reliable means. Any alteration made
to the entry on a document should be signed and dated; the
alteration should permit the reading of the original information.
Where appropriate, the reason for the alteration should be recorded.
T y pes of docu m ents

Three most important types of documents for quality assurance are
• S pec i f i c ati o n s: they give the standards of quality that can be

measured and is used by quality department in deciding if a
batch is passed or rejected.
• R ec o rd s: Batch manufacturing records (processing and

packaging) which reviewed by quality department. Batch
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analysis records, completed and reviewed by quality department.
Logs, used in production, engineering and quality department for
records not directly related to a batch for e.g. cleaning, use of
equipment, machine maintenance, etc.
• P ro c ed u res: Describe and give instruction on how work must be

carried out. It can be special types of procedure, such as
analytical methods or more general standard operating
procedures (SOPs). SOPs must be used by anybody whose
work can affect product quality, e.g. production, quality control
department, warehouse and engineers.
1. S pecifications
There should be appropriately authorized and dated
specifications, including rests on identity, content, purity, and quality,
for starting and packaging materials and finished products, where
appropriate, they should also be available for intermediate or bulk
products. Specifications for water, solvents and reagents used in
production should be included.
i. Sp ecif ica t io n s f o r s t a r t in g ( r a w ) m a t er ia l s
Specifications for raw materials should include, if applicable
• The designated name and the internal code reference
• The reference, if any, to a pharmacopoeia monograph
• Name of final company
• The approved suppliers and, if possible, the original procedure of

the products
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• General specifications (color, taste, odor, form and dimension)
• Pharmacopoeia shape and strength
• M ethod of analysis
• Expiry date
• Storage conditions and precautions
• The maximum period of storage before re-examination
• Directions for sampling and testing or reference to procedures
• Qualitative and quantitative requirements with acceptance limits
Raw mat e ri als spe ci f i cat i o ns ce rt i f i cat e mu st e mbrace
• Trade name
• Scientific or chemical name
• Company trademark
• General specifications
• Origin certificates
• Storage requirements
• M ethod of analysis of raw materials including identification, purity

tests, assays with their limits, physical and chemical characters,
microbiological specifications with their limits. All these should be
referred to the latest pharmacopoeia data, their addendum and
references.
• Validity period and date of reanalysis.
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Raw mat e ri als e x pi ry dat e ce rt i f i cat e
• Expiry date should be given to all raw materials with special

attention to biological materials such as antibiotics, some
vitamins, enzymes, hormones, vaccines and sera. After the
termination of the expiry date these raw materials are destroyed.
• The other materials should be given validation date not more

than 5 years. After that it can be re-analyzed and validation
period may be prolonged according to the condition of the raw
materials.
ii. Sp ecif ica t io n s f o r in t er m ed ia t e a n d b u l k

p r o d u ct s
Specifications for intermediate and bulk products should be
available if these are purchased or dispatched, or if data obtained
from intermediate products are used for the evaluation of the finished
product. The specifications should be similar to specifications for
starting materials or for finished products, as appropriate.
iii. Sp ecif ica t io n s f o r p a ck a gin g m a t er ia l s

Spe ci f i cat i o ns f o r pack ag i ng mat e ri als sh o u ld i nclu de
• Company trade name
• Supplier trade name.
• General description (material, thickness, dimensions, color,

touch)
• The required drawing
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• Origin certificate
• Storage specifications and how to handle
• Inspection date of specifications
iv. Sp ecif ica t io n s f o r f in is h ed p r o d u ct s

Spe ci f i cat i o ns f o r f i ni sh e d pro du ct s sh o u ld i nclu de
• The designated name of the product and the code reference

where applicable
• The formula
• A description of the pharmaceutical form and package details
• Directions for sampling and testing or a reference to procedure
• Qualitative and quantitative requirements, with acceptable limits
• The storage conditions and precautions, where applicable
• The shelf-life
2. R ecords
Records should be made or completed when any action is
taken and in such a way that all significant activities concerning the
manufacture of pharmaceutical products are traceable. Records and
associated standard operating procedures should be retained for at
least one year after the expiry date of the finished product. Records
include batch manufacturing records (processing and packaging),
batch analysis records and logs used in production, engineering and
quality department.
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i. Ba t ch p r o ces s in g r eco r d s
A batch processing record should be kept for each batch
processed. It should be based on the relevant parts of the currently
approved manufacturing formula and processing instructions. The
method of preparation of such records should be designed to avoid
transcription errors. The record should carry the number of the batch
being manufactured. Before any processing begins, there should be
recorded checks that the equipment and work station are clear of
previous products, documents or materials not required for the
planned process, and that equipment is clean and suitable for use.
During processing, the following information should be recorded at
the time each action is taken and, after completion
• The name of the product
• Dates and times of commencement, of significant intermediate

stages and of completion of production
• Name of the person responsible for each stage of production
• Initial of the operator of different significant steps of production

and, where appropriate, of the person who checked each of
these operations (e.g. weighing)
• The batch number and/or analytical control number as well as

the quantities of each starting material actually weighed
(including the batch number and amount of any recovered or
reprocessed material added)
• Any relevant processing operation or event and major equipment

used
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• A record of the in-process controls and the initials of the
person(s) carrying them out, and the results obtained
• The amount of product obtained at different and pertinent stages

of manufacture (yield)
• Notes on special problems including details, with signed

authorization, for any deviation from the manufacturing formula
and processing instructions
ii. Ba t ch p a ck a gin g r eco r d s

A batch packaging should carry the batch number and the
quantity of bulk product to be packed, as well as the batch number
and the planned quantity of finished product that will be obtained.
There is a master filling method for batch packaging records
including
• The name of the product dosage form and strength
• The date(s) and times of the packaging operations
• The name of the responsible person carrying out the packaging

operation
• The initials of the operators of the different significant steps
• Records of checks for identity and conformity with the packaging

instructions including the results of in-process controls
• Details of the packaging operations carried out, including

references to equipment and the packaging lines used
Whenever possible, samples of printed packaging materials

used, including specimens of the batch coding, expiry dating and any
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additional overprinting. Notes on any special problems including
details for any deviation from the packaging instructions with written
authorization by an appropriate person. The quantities and reference
number or identification of all printed packaging materials and bulk
product issued, used, destroyed or returned to stock and the
quantities of obtained product, in order to provide for an adequate
reconciliation.
iii. Ba t ch a n a l y s is r eco r d s
There must be record for test, analysis, approval, rejection of
raw materials, in-process and final product. These records should be
carefully kept and if they are booked, paper serial number must be
given without tear off any paper. The record must include
• Date of test
• M aterial identification and its code number
• Supplier’ s name
• Batch number from quality control
• Batch size
• Date of batch size
• M ethod of analysis references
• Test results
• Comparison with standard product
• Name and signature of the analyst
• Analysis serial number

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iv. Receip t r eco r d s
The records of the receipts should include
• The name of the material on the delivery note and the containers
• Date of receipt and code of the material
• Supplier’ s name and, if possible, manufacturer’ s name
• M anufacturer’ s batch or reference number
• Total quantity and number of containers received
• Any relevant comment (e.g. state of the containers)
v. D is t r ib u t io n r eco r d s
To facilitate effective recall, records of distribution should be
kept showing the name and addresses of all persons to whom the
manufacturer supplies a product.
vi. St a b il it y s t u d ies r eco r d

I t sh o u ld i nclu de
• Product name
• Complete description of package
• Stability studies period
• Storage specification as temperature, relative humidity and light
• Stability studies results for each period
• The final results in comparison with the product original

concentration
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vii. Reco r d f o r m a ch in e cl ea n in g a n d m a in t en a n ce
M ai nt e nance : each machine card (m/c) must has its maintenance
record to assure best operation, record for machine operation
condition, maintenance procedure and record of all steps that have
been done for its maintenance specially change of spare parts.
C le ani ng : each m/c must has its cleaning method before and after
operation mentioning the way of cleaning, tools used for this
purpose, make a record to clarify application of cleaning method and
the person concerned for cleaning and also concerned for cleaning
inspection with correlation between m/c and record.
viii. T r a in in g r eco r d o n G M P
Pe rso nne l t rai ni ng re co rd o n G M P sh o u ld be av ai lable and i nclu de
• Training date
• The under training personnel during this period
• The training personnel
• M eans and papers of training
• Schedule for training
ix. Sel f in s p ect io n r eco r d

E ach se lf i nspe ct i o n re co rd sh o u ld me nt i o n t h e f o llo w i ng
• Self inspection date
• Inspection documents
• M embers of inspection
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• Inspection results
• Copy of inspection list.
x. Reco r d f o r t h e d es t r u ct io n o f m a t er ia l s
The following requirements should be recorded
• M aterial name, batch number, and quantity
• Original supplier
• M ethod of destruction of materials
• Name and persons responsible for destruction
• M ethod of the refund materials record
xi. Q u a l it y co n t r o l r eco r d s
a. G e ne ral re q u i re me nt s
There must be record for test, analysis, approval, rejection of

raw materials, in-process and final product. These records should be
carefully kept and if they are booked, paper serial number must be
given without tear off any paper. The record must include
• Date of test
• M aterial identification and its code number
• Supplier’ s name
• Batch number from quality control
• Batch size
• Date of batch size

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• M ethod of analysis references
• Test results
• Comparison with standard product
• Name and signature of the analyst
• Analysis serial number
b. Appro v e d sampli ng me t h o d
Appro v e d sampli ng me t h o d sh o u ld i nclu de
• Sampling procedure
• Sampling devices
• Protective measures for sampling (including sampling uniform)
• Sector involved in sampling
• Time of sampling
• Specifications of sampling
• The containers from which the samples were taken
c. C e rt i f i cat e o f analy si s o f ph armace u t i cal pro du ct
I t sh o u ld i nclu de
• M anufacturing site
• M anufacturing name and address
• Certificate number
• Product name (batch no., pharmaceutical shape, product

strength, lot no of the raw materials, test limits, date of sampling)
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• Result and their dales
• Notes
• Approval of product acceptance
• Signature of quality control manager
xii. Reco r d f o r eq u ip m en t s t a n d a r d iz a t io n
To confirm good performance of the device (thermometers,
spectrophotometers, pressure gauges, etc) periodical
standardization of the device should be done and recorded in
specific records for this purpose. This method must include:
• Time schedule for standardization
• Standard device
• U sed measuring devices and detectors if any
• Standard procedure
• Any deviation record
• Name and signature of standardization operator
xiii. T h e m et h o d a n d r eco r d f o r cl ea n in g t h e
in d u s t r ia l a r ea
A valid method should be available for cleaning of each
industrial area and its record must include
• Area name
• Cleaning procedures in details
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• Required materials and equipment for cleaning
• Time and schedule of cleaning
Cleaning schedule should be recorded clarifying the time

needed for cleaning, zero balance time of cleaning agent stock and
operator in charge.
xiv. M et h o d a n d r eco r d f o r co n t r o l l in g t h e
s u s p en d ed p a r t icl es in a ir a n d m icr o b es in cer t a in
a r ea s
Th i s me t h o d i s a mu st i n ce rt ai n are as and mu st i nclu de
• Working date
• Working area
• Results
• Required specifications
• Name and signature of operator in charge
xv. M et h o d a n d r eco r d f o r d es t r u ct io n o f in s ect s

a n d r ep t il es a n d o t h er s
Independent method for destruction of insects, reptiles and others
should be available and include
• Work field
• The required work area
• Procedures in details with mentioning the required materials and

measures
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• Time schedule
Sectors, persons in charge for this work with the concerned

records clarifying work date, the cleaning responsible company
operation supervisors and used materials in each time.
xvi. C o m p l a in t s r eco r d s
A record should maintain of all complaints relating to product
or packaging quality. This record should show the nature of the
complaint, results of investigations and action taken. The record
should be maintained in such a manner that significant recurrent
complaints can be recognized and appropriate action taken.
3. S tandard operating procedu res (S O P' s)

It is useful and probably necessary that there be a written
standard operating procedure (SOP) describing how written
procedures for production and process controls is initiated, reviewed
and finalized. There shall be written procedures for procedures and
process control designed to assure that the drug products have the
identity, strength, quality, and purity they purport or are represented
to possess. These written procedures, including any changes, shall
be drafted, reviewed, and approved by the appropriate organizational
units and reviewed and approved by the quality control unit.
There should be standard operating procedures and records

for the receipt of each delivery of starting materials and primary and
printed packaging materials. There should be standard operating
procedures for internal labeling, quarantine and storage of starting
materials, packaging materials and other materials as appropriate.
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Standard operating procedures should be available for each
instrument and piece of equipment and placed in close proximity to
the equipment. There should be standard operating procedures for
sampling, which specify the person(s) authorized to take samples.
The sampling instruction should include
• The method of sampling and the sampling plan
• The equipment to be used
• Any precautions to be observed to avoid contamination of the

material or any deterioration in its quality
• The amount(s) of sample(s) to be taken
• Instructions for any required subdivision of the sample
• The type of sample containers to be used and whether they are

for aseptic sampling or for normal sampling
• Any specific precautions to be observed, especially in regard to

the sampling of sterile or noxious material
Written procedures should be established and followed

prescribing a system for reprocessing batches that do not conform to
standards or specifications and the steps to be taken to insure that
the reprocessed batches will conform to all established standards,
specifications, and characteristics. There should be a standard
operating procedure describing the details of the batch (lot)
numbering system, with the objective of ensuring that each batch of
intermediate, bulk, or finished product is identified with a specific
batch number.
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The standard operating procedures for batch numbering that
are applied to the processing stage and to the respective packaging
stage should be related to each other. The standard operating
procedure for batch numbering should assure that the same batch
numbers will not be repeatedly used; this applies also to
reprocessing. There should be written procedures for testing
materials and products at different stages of manufacture, describing
the methods and equipment to be used. The tests performed should
be recorded.
Written release and rejection procedures should be available

for materials and products, and in particular for the release for sale of
the finished product by an authorized person. Records should be
maintained of the distribution of each batch of a product in order to
facilitate the recall of the batch if necessary. Standard operating
procedures and associated records of actions taken or, where
appropriate, conclusions reached should be available for:
• Equipment assembly and validation
• Analytical apparatus and calibration
• M aintenance, cleaning, and sanitization
• Personnel matters including qualification, training, clothing, and

hygiene
• Environmental monitoring
• Pest control
• Complaints
• Recalls
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• Returns
Log books should be kept with major and critical equipment

and should record, as appropriate, any validations, calibrations,
maintenance, cleaning, or repair operations, including dates and the
identity of the people who carried these operations out. Written
procedures should be established and followed for cleaning and
maintenance of equipment, including utensils, used in the
manufacture, processing, packing, or holding of a drug product,
these procedures shall include, but are not necessarily limited to, the
following:
• Assignment of responsibility for cleaning and maintaining

equipment
• M aintenance and cleaning schedules, including, where

appropriate, sanitizing schedules
• A description in sufficient detail of the methods, equipment,

materials used in cleaning and maintenance, operations, and the
methods of disassembling and reassembling equipment as
necessary to assure proper cleaning and maintenance
• Removal or obliteration of previous batch identification
• Protection of clean equipment from contamination prior to use
• Inspection of equipment for cleanliness immediately before use
The procedures for sterile equipment are more involved and

critical. In addition to the normal washing procedures, sterility must
be ensured for certain containers and equipment used in
manufacturing and filling operations. Terminal sterilization of the
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product is not an acceptable substitute for proper cleanliness of
manufacturing components, equipment, and utensils. F o r st e ri le
o pe rat i o ns:
• Containers used for holding sterile products must be sterilized

and show the date of sterilization
• Components coming in contact with sterile products must be

sterilized and show the date of sterilization
• Sterilized equipment or components should be used within 3

days of sterilization
• Sterilized equipment should be replaced between consecutive lot

numbers of the same product to maintain the integrity of the
control number
• Sterilization indicators should be used with equipment to show

completion of the sterilization cycle
Written procedures describing the warehousing of drug

products shall be established and followed, t h e y sh all i nclu de :
• Quarantine of drug products before release by quality control unit
• Storage of drug products under appropriate conditions of

temperature, humidity, and light so that the identity, strength,
quality, and purity of the drug products are not affected
Written procedures shall be established, and followed,

describing the distribution of drug products, t h e y sh all i nclu de :
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• A procedure whereby the oldest approved stock of a drug
product is distributed first. Deviation from this requirement is
permitted if such deviation is temporary and appropriate.
• A system by which the distribution of each lot of drug product

can be readily determined to facilitate its recall if necessary
M anu factu r ing for m u l a and pr ocessing

instr u ctions
Formally authorized manufacturing formula and processing
instructions should exist for each product and batch size to be
manufactured. They are often combined in one document.
Th e manu f act u ri ng f o rmu la sh o u ld i nclu de :
• The name of the product, with a product reference code relating

to its specification.
• A description of the pharmaceutical form, strength of the product

and batch size.
• A list of all starting materials to be used, with the amount of

each, described using the designated name and a reference
which is unique to that material, mention should be made of any
substance that may disappear in the course of processing.
• A statement of the expected final yield with the acceptable limits,

and of relevant intermediate yields, where applicable.
Th e pro ce ssi ng i nst ru ct i o ns sh o u ld i nclu de :
• A statement of the processing location and the principal

equipment to be used.
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• The methods, or reference to the methods, to be used for
preparing the critical equipment (e.g. cleaning, assembling,
calibrating, sterilizing).
• Detailed stepwise processing instructions (e.g. checks on

materials, pretreatments, sequence for adding materials, mixing
times, temperatures).
• The instructions for any in-process controls with their limits.
• Where necessary, the requirements for bulk storage of the

products; including the container, labeling and special storage
conditions where applicable.
• Any special precautions to be observed.
Packag ing instr u ction

There should be formally authorized packaging instructions
for each product for pack size and type. These should normally
include, or have a reference to, the following
• Name of the product.
• Description of its pharmaceutical form, and strength where

applicable.
• The pack size expressed in terms of the number, weight or

volume of the product in the final container.
• A complete list of all the packaging materials required for a

standard batch size, including quantities, size and types, with the
code or reference number relating to the specifications of each
packaging material.
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• Where appropriate, an example or reproduction of the relevant
printed packaging materials, and specimens indicating where to
apply batch number references, and shelf-life of the product.
• Special precautions to be observed, including a careful

examination of the area and equipment in order to ascertain the
line clearance before operations begin.
Th e re sh o u ld be f i x e d pro ce du re s t o re f u nd a bat ch , i t mu st i nclu de
• Refund field
• Refund threshold
• Refund regulation
• General protective measurements and what have done before
• Product name and batch no. and size
• Date of start and end of refund
• Refund reasons
• Refund quantity
• The source of refund goods
• Rectification of the subject
• The measurements have done for refund
• Final report including the report state
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Com pl aints fr om ph ar m aceu tical pr odu cts
It is essential to find a way how to deal with pharmaceutical
product complaint specially the serious side effects and should
include
• Complaint definition or serious effect of the drug product
• K ind of complaints
• Dealing with complaints
• Rectification of complaints
I n addi t i o n a re co rd mu st be e st abli sh e d and i nclu de t h e f o llo w i ng
• Product name and batch no.
• Type of complaint
• Complaint sources
• Sample from the product
• Summary of complaint
• Test results
• Summary for complaint to follow its solution
Th e pro du ct re f u nd sh o u ld be t h ro u g h v ali d me t h o d i nclu de
• Product name
• Refund reasons
• How to refund
Re f u nd re co rd sh o u ld be e st abli sh e d and me nt i o n t h e f o llo w i ng
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• Information about product origin and method of storage
• Refund reasons
• Any tests can be done for the product
• The quantities to be destroyed
Pr odu ct r efu nd
The product recall from the market means the refund of its all packs
from everywhere it is found, in case of valid record declare serious
side effects which may affect patient's health. This refund can be
done by manufacturer. The main aim of the refund is the rapid return
back to prevent any damage of health care. The decision comes
after the assurance of
• Production mistake
• Direction from authorities
• Direction from factory or supplier
Re f u nd di v i si o ns
• Class (1) this indicates a very serious product that must be

recalled within 24 hours.
• Class (2) this indicate not so serious product and must be

recalled within 3 days.
• Class (3) product that must be returned back for different

reasons.
Re f u nd le v e ls
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Level (A) Concerned with patient
Level (B) Sale area
Level (C) Auxiliary distributors
Level (D) M ain distributors
Pro du ct s re f u nd re g u lat i o n
The induction of product refund is the responsibility of factory

manager and also it is the responsibility of public pharmacists,
factory, and government distribution areas. The Following
precautions should be taken for product refund:
• Certain person should completely carry the responsibilities of

products refund.
• Refund method should be determined. Communication ways, all

the persons proposed to be contacted to prevent product
distribution and its collection from government authority,
pharmacists, physician distributors and even the public.
Pre ce di ng i nf o rmat i o n f o r re f u nd
• Batch no., name and pharmaceutical dosage form
• The risk if not refund
• Reasons for risk that lead to refund. (This only for government
authority)
• Regulation of refund process
• The method used for contacting the person responsible for

refund receipt
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• Phone no., address, telex of pharmacy, clinics distributors,
hospitals and others that have the product under refund
Re f u nd pro ce du re s
• Refund class should be known (1, 2 or 3) to determine the time

allowed for recall
• The use of rapid communication ways to contact areas of

product under refund
• Determine the product quantity in the factory in order to not put it

in use
• Refund receiving and holding in specified area
• A record for results should be established
• Determination of quantity and confirmation that the product is

completely drawn from the market
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Ch eckl ist for w or k pr ocedu r es and sops of

r aw m ater ial s h andl ing
P rocedure
S O P
Work procedures and S O P ’ s b ei ng
av ai l ab l e
perf orm ed
Description of w ork/ tasks done in Departm ent
Q uarantine of incom ing m aterials during testing
H andling ing redients arriv ing in dam ag ed
containers
V erif y ing ing redients w ith lab els/ purch ase order,
etc.
T esting b eing done f or identity streng th , purity
S pecial env ironm ent/ tem perature storing w h en
req uired
S torag e of b ag g ed m aterials
Clean-up of spills/ b reakag e
S am pling w ith out contam ination
W eig h ing / m easuring m aterials to b e transf erred
Ensuring critical steps ch ecked b y 2nd person
M onitoring tem perature/ h um idity control
Cleaning storag e areas according to sch edule
M onitoring sh elf -lif e of raw m aterials
A ssuring only auth oriz ed personnel in w ork area
A ssuring personnel w earing protectiv e cloth ing
w h en appropriate
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m ix ing and for m u l ation
P rocedure
S O P
av ai l ab l e
perf orm ed
R eceiv ing and storing approv ed raw m aterials in
secure areas
V erif y ing ing redients w ith lab el
S pecial env ironm ent/ tem perature storag e w h en
req uired
Docum enting th at Q C/ Q A approv ed raw m aterials
W eig h ing out raw m aterials to b e m ix ed
A ssuring production/ process/ m ix ing steps
perf orm ed according to m aster b atch procedures
and docum ented
A ssuring approv ed b atch f orm ulation, production,
and control inf orm ation is in th e m ix ing area
M aster b atch record av ailab le
R ecords av ailab le
B atch es properly lab eled
S am pling procedures conducted properly
A ssuring m ix ed q uantities eq ual to correct b atch
w eig h t
A ssuring all interm ediates, m ix ed b atch es,
containers are properly lab eled at all tim es
A ssuring and docum enting correct m ix ing tim es
A ssuring correct interm ediate sam ples, tests, and
docum entation f or b atch to h av e desired ph y sical
properties
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P rocedure
S O P
av ai l ab l e
perf orm ed
A ssuring Q A / Q C testing of interm ediates
A ssuring proper h andling and storag e of
interm ediates
A ssuring f inal dosag e f orm sam pling and testing
Ensuring only one b atch in process per
contam inant control z one
Cleaning / lub ricating / m aintaining of eq uipm ent and
install needed supplies according to sch edule
Clean-up area af ter each b atch
A ssuring personnel w ear appropriate cloth ing
(Continued: Checklist for work procedures a nd S O P s of m ix ing a nd form ula tion)
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finish ed dosag e for m pr epar ations
P rocedure
S O P
av ai l ab l e
perf orm ed
R eceiv ing and storing approv ed m aterials in
secure areas
V erif y ing contents w ith lab els
req uired
Docum enting th at Q C/ Q A h as approv ed m aterials
W eig h ing out and docum enting m aterials to b e
prepared as dosag e f orm s
and control inf orm ation is in th e dosag e f orm
preparation area
B atch es property lab eled
S am pling procedures properly conducted
A ssuring all dosag e f orm critical steps
docum ented and ch ecked b y 2nd person
F inal dosag e f orm production/ processing
conducted according to m aster b atch and
docum ented
F illing processes
Coating processes
1 91
GMP - E g y p t
P rocedure
S O P
av ai l ab l e
perf orm ed
S ealing processes
A ssuring produced q uantities eq ual to correct
b atch w eig h t accounting f or spillag e, etc.
A ssuring all appropriate in-process tests are
carried out
A ssuring all m ix ed b atch es and containers are
properly lab eled at all tim es
A ssuring correct storag e and h andling in sealed
containers
Correct Q A / Q C f inal dosag e f orm testing including
sam ples, tests, docum entation f or each b atch to
h av e desired ch em ical / ph y sical properties an
m eet f inal approv al standards
(Continued: Checklist for work procedures a nd S O P s of finished dosa g e form

prepa ra tions)
1 92
GMP - E g y p t

packag ing and l ab el ing
P rocedure
S O P
av ai l ab l e
perf orm ed
Description of w ork/ tasks done in departm ent
R eceiv ing and storing approv ed m aterials in
secure areas
req uired
Docum enting th at Q C/ Q A h as approv ed m aterials
Docum enting / accounting f or packag ed and
lab eled m aterials
Ensuring accountab ility and Q C f or lab els
and control inf orm ation is in th e packag ing and
lab eling area
B atch es properly lab eled
S am pling procedures properly conducted
A ssuring all packag ing and lab eling steps are
perf orm ed according to m aster b atch record,
A ssuring produced q uantities eq ual to correct
b atch w eig h t accounting f or spillag e, etc
1 93
GMP - E g y p t
P rocedure
S O P
av ai l ab l e
perf orm ed
A ssuring all appropriate in-process tests are
carried out
A ssuring all packag ed containers are properly
stored and properly lab eled in sealed containers at
all tim es
Q A / Q C conducted according to sch edule to
assure correct sam ples, tests, docum entation f or
b atch to m eet f inal approv al standards
A ssuring th at all lab els are accounted f or
(Continued: Checklist for work procedures a nd S O P s of pa cka g ing a nd la b eling )
1 94
GMP - E g y p t

q u al ity assu r ance, pr odu ction, pr ocess, and
l ab or ator y contr ol s
P rocedure
S O P
av ai l ab l e
perf orm ed
S toring raw m aterials, sem i f inish ed, and f inish ed
m aterials req uiring special env ironm ents
Docum enting th at Q C/ Q A h as approv ed testing
m aterials f or use
A ssuring m ost current approv ed b atch f orm ulation,
production, and control inf orm ation is av ailab le to
th e Q C/ Q A staf f
Documenting QC/QA approval of
R aw m aterials and interm ediates
F inal dosag e f orm
A ssuring all steps in Q C/ Q A process are
Docum enting appropriate in process and f inal
tests
Docum enting release of b atch only af ter it
com plies w ith f inal approv al standards
Docum enting th at f inal b atch h as all th e
estab lish ed ph y sical, ch em ical, and
m icrob iolog ical properties
A ssuring correct b atch w eig h ts at all points in th e
process
A ssuring all interm ediates, m ix ed b atch es, dosag e
f orm , containers are properly lab eled at all tim es
1 95
GMP - E g y p t
P rocedure
S O P
av ai l ab l e
perf orm ed
Docum enting all raw data in a seq uentially
pag inated b ound noteb ook w ith attach m ent of
pertinent ch rom atog ram s, etc.
A ssuring all departm ents h av e docum ented
procedures to f ollow w h en Q A / Q C tests sh ow
m aterials do not m eet th e req uired standards and
h av e docum ented procedures f or conducting
inv estig ations to determ ine th e causes and m ake
corrections
Cleaning -up areas af ter each Q C/ Q A operation
A ssuring only auth oriz ed Q C/ Q A personnel in
Q C/ Q A w ork area
(Continued: Checklist for work procedures a nd S O P s of q ua lity a ssura nce,

production, process, a nd la b ora tory controls)
1 96
GMP - E g y p t

finish ed g oods stor ag e and w ar eh ou sing
P rocedure
S O P
av ai l ab l e
perf orm ed
R eceiv ing , storing , accounting f or approv ed
f inish ed g oods in secure areas
S pecial env ironm ent storag e w h en req uired
Docum enting th at Q C/ Q A h as approv ed th e
f inish ed g oods
Ensuring correct product and b atch production
record lab els attach ed to f inish ed g oods
A ccounting f or and docum enting f inish ed g oods
g oing into or leav ing storag e
A ssuring th at f inish ed g oods sh ipped m atch
incom ing order
A ssuring periodic cleaning of w areh ouse
1 97
GMP - E g y p t
EXAMPLES OF
S T A N D A R D O P E R A T IN G
P R O C E D U R E S
(S O P s )
1 98
GMP - E g y p t
E x am pl es of standar d oper ating pr ocedu r es

1. St a n d a r d o p e r a t i n g p r o c e d u r e f o r c a l i b r a t i o n
o f a n a l y t i c a l b a l a n c e M e t t l e r t y p e A E 20 0
1. Pri nci ple
The accurate weighing of a material is the basic fundamental

procedure in proceeding analytical methods. To have an accurate
weight, the following steps should be followed:
• A standard operation procedure should be applied for weighing

materials
• The balance should be checked at certain frequency and

calibrated in order to be sure that it is proceeding well all over
the work hours.
• The balance should be labeled "un-repaired, under repair or out

of order", if it has any defect and should not be used until this
label is changed by the person responsible for calibration.
2 . E q u i pme nt de scri pt i o n
• Type AE 200
• M anufacturer: M ettler
• Range 205.00 g.
• Precision 0.0001 g.
3 . O pe rat i o n and cali brat i o n pro ce du re
A. I nt e rnal cali brat i o n (dai ly ch e ck )

1 99
GMP - E g y p t
• M ake absolutely sure that the balance is left connected to the
power supply for at least 60 minutes before calibration.
• Press and hold the single control bar until "CAL" appears in the
display, then release control bar. The display changes to "CAL --
-" followed by "100.0000" then "CAL 0" blinks.
• M ove calibration lever all the way back towards the front of the
balance, the display changes to "---" followed by zero.
B . O pe rat i o n pro ce du re
• Level the balance by the leveling feet if necessary.
• Press lightly the "ON/OFF" button for a second to switch the

display ON.
• Clear and clean the pan.
• Press "Tare" button.
• Load the sample to be weighed in the middle of the pan, close

the balance door.
• After stability (the green dot in the display goes out), record the
display reading.
• Not less than 50 mg should be weighed on the balance.
• There is a brief operating instruction which can be found on a

card that swings out from underneath the balance housing.
• See manual for further information and details.
C . C ali brat i o n
i. Frequency: M onthly and after maintenance.

20 0
GMP - E g y p t
ii. A series of weights are weighed on the balance. If one weight
or more is greater than the maximum tolerance allowed, the
balance is calibrated by an internal calibration, and then all
weights are checked again. If all weights are within
specification limits, the balance is approved. In event that one
or more weights are still out of specification limits, the balance
is calibrated by an external calibration weight, then all weights
are rechecked. If all weights are within specification limits, then
the balance is approved. In event that one or more weights are
still out of specification limit, the balances is labeled "out of
order" and notify the person responsible for maintenance or
the agent (for service).
iii. Put your result, comment and sign.
D . E x t e rnal cali brat i o n
• M ake absolutely sure that the balance is left connected to the

power supply for at least 60 minutes before calibration.
• Press and hold the single control bar until "CAL" appears in the
display then release control bar. The display changes to "CAL ---
" followed by "100.0000" then "CAL 0" blinks.
• Load an external weight of 100.0000 g. on the middle of the pan,

the display changes to "----" followed by zero.
20 1
GMP - E g y p t
4. M ax i mu m To le rance (Spe ci f i cat i o n li mi t )
W e ig h t T o le r a n c e
10 mg 9.8000 - 10.2000 mg
50 mg 49.7000 - 50.3000 mg
500 mg 499.5000 - 500.5000 mg
5 g 4.9995 - 5.0005 g
50 g 49.9995 - 50.0005 g
100 g 99.999 - 100.0010 g
5 . E q u i pme nt pi ct u re
6 . C ali brat i o n mat e ri al u se d
• A series of weights according to accuracy class F1 comprising 10

mg, 50 mg, 500 mg, 5 g, 50 g and 100 g are used to check the
balance before calibration adjustment.
• A 100.0000 g standard weight used for external calibration,

supplied from the agent, when requested.
20 2
GMP - E g y p t
7 .N o te s
• Vibration, air currents, heat radiation and aggressive substances

in the environment will affect not only the weighing result but also
the balance integrity.
• After power connection, give the balance a warm-up time of 30

minutes.
8 . Re f e re nce s
Pre pare d by Appro v e d by
D at e D at e
20 3
GMP - E g y p t
2. St a n d a r d o p e r a t i n g p r o c e d u r e f o r s a m p l i n g o f
r a w a n d p a c k a g in g m a te r ia ls
1. Pri nci ple
• Each delivery of materials should be visually checked on receipt

for general condition, integrity of container(s), spoilage and
possible deterioration. This physical inspection should be
performed by the responsible warehouse personnel and
recorded in the material Receiving Record.
• Sampling procedure must be carried out by QA responsible

personnel and in the special sampling area in the warehouse
(sampling booth).
• Care should be taken during sampling to guard against

contamination of, or by, or causing deterioration to the material
being sampled. Some particularly hazardous or potent materials
may require special precautions.
• All sampling equipments that come in contact with the material

must be dry and clean, and should be cleaned after each use
and stored separately in the sampling area.
• Samples should be taken in such a manner that they are

representative of the batches of material from which they are
drawn and in a quantity at least twice that necessary to carry out
all required tests, excluding samples for sterility and pyrogen
testing.
20 4
GMP - E g y p t
• A sample of the raw material should be retained according to a
suitable program and in a size sufficient to permit analytical re-
examination.
• Stocks of materials should be inspected at intervals to ensure

that the containers are properly closed, labeled and in a good
storage condition. They should be re-sampled and submitted for
retest at the intervals given in the material specification. Such re-
sampling should be initiated by an effective documentary
system.
2 . Pro ce du re
• Check each container label for correctness and clarity of the

following information: item description, item number, vendor
name, vendor lot number, weight of contents, total lot quantity
received, manufacture date and expiry date whenever available
and date of receipt to warehouse.
• Ensure that the container lids and surroundings are free from all
potential sources of superficial contamination, (dust, wet, stain,
etc), before opening, otherwise they should be wiped with
dispensable cloth if necessary.
• After wearing the necessary protective clothing, remove the lid of

the container and open the bag inside if any. Open one container
at a time.
• Inspect the opened container visually for homogeneity of

physical characteristics such as color, odor, particle size and
absence of foreign particles.
20 5
GMP - E g y p t
• According to the sampling protocol take the required sample
quantity using a suitable tool. Do not sample from the surface but
scrape aside or whip and sample from the depth, then transfer to
a suitable container.
• Reseal the inner bag, if any, then replace the lid and seal the
container using the scotch sticker. Apply a label indicating the
sample size, date of sampling and initials of the sampler.
• Each sample should bear a label with the same information as

original container label in addition to the sample size and date.
• The quantity of sample drawn must be recorded in the receiving

record.
• The details of inspection and sampling for each lot should be

recorded in the inspection and sampling report.
3 . Sampli ng t o o ls and co nt ai ne rs
• Sampling tools which are available for sampling include stainless

steel scoops and thief scraper for powders, pipettes for liquids,
stainless steel pipes for viscous liquids and stainless steel
scrapers for waxy materials.
• These tools should be kept clean and dry, inspected periodically

by the QA sampler and should not be used for dispensing or
used by production personnel.
• Containers for keeping samples should be empty, clean and dry,

preferably of glass with a tight closure, while those for sterility
testing must be previously sterilized in an adequate manner by
microbiology personnel.
20 6
GMP - E g y p t
4. Pre cau t i o ns
• Every container of materials intended for manufacturing of

injectable product should normally be sampled aseptically and
identified, either on receipt or before use in production.
• Samples for microbiological testing should be taken under

aseptic conditions, e.g. under laminar flow, and as quickly as
possible.
• Powders are sampled under the extraction hood (sampling

booth), wearing the safety cloths, masks and gloves.
• Wear eye protection, respirator, gloves as well as overhead and

laboratory coat while sampling potent drugs; irritant powders or
toxic substances.
• Acids, caustic and inflammable liquids are sampled using a

propipette and wearing gloves and masks.
• M aterials that contain water of crystallization or photosensitive,

should be sampled quickly and put in well tight dark containers
e.g. Na2HPO412H2O.
• Hygroscopic materials should be sampled in a dry area or under

controlled humidity. The sample is taken quickly in a well tight
container.
20 7
GMP - E g y p t
5 . Sampli ng Pro t o co l: Re f . M I L -STD -10 5 D
A. N u mbe r o f co nt ai ne rs o r u ni t s t o be sample d pe r lo t o r bat ch
i. Active Raw M aterials
N o. of units O pen
2 - 1 5 2
1 6 - 25 3
26 - 90 5
91 - 1 50 8
1 51 & ov er 1 3
ii. Inactive raw materials and primary packaging components
N o. of containers units O pen & sam ple

2 - 8 2
9 - 1 5 3
1 6 - 25 5
26 - 50 8
51 - 90 1 3
91 - 1 50 20
1 51 - 280 32
281 - 50 0 50
50 1 - 1 20 0 80
1 20 1 - 320 0 1 25
320 1 - 1 0 0 0 0 20 0
1 0 0 0 1 - 350 0 0 31 5
350 0 1 - 1 50 0 0 0 50 0
1 50 0 0 1 - 50 0 0 0 0 80 0
50 0 0 0 1 & ov er 1 250
iii. Other packaging components
N o. of units O pen & sam ple

2 - 1 5 2
1 6 - 50 3
51 - 1 50 5
1 51 - 50 0 8
50 1 - 320 0 1 3
320 1 - 350 0 0 20
350 0 1 - 50 0 0 0 0 32
50 0 0 0 1 & ov er 50
20 8
GMP - E g y p t
B . Th e q u ant i t y o f co mpo si t e sample sh o u ld be at le ast t w i ce t h at
ne e de d t o pe rf o rm all t e st s, e x ce pt f o r st e ri li t y and py ro g e n t e st i ng ,
o t h e rw i se apply t h e f o llo w i ng
Quantity Received Sample Taken
Less than 250 g. 5-15 % of weight
250 – 5000 g. 2.5-10 % of weight
M ore than 5000 g. 125-260 g
20 9
GMP - E g y p t
Appendix I
M ATERIAL RECEIVING RECORD
Item d es c r i p ti o n Item n u mb er
Lot nu m b er V endor V endor lot nu m b er
Recei p t da te Mf g da te E x p da te PO : i m p or ted( ) loca l (
)
W a r eh o u s e
C om m ents S ta tu s Q u a nti ty U /M # of cont
Recei v ed
Rej ected
Ph y si ca lly
Accep ted
S a m p le S i z e Ta k en b y /da te:
Posted to RC D a te Posted By D a te
P r o d u c ti o n c o mmen ts – f o r p a c k i n g i tems
S IG NATU RE D ATE
Qu a l i ty
Q. Ser . #
Acti on Ta k en S i gn & da te r etest da te
A Accep ted E x p i r y da te
Z Rej ected Potency %
Qu a l i ty c o mmen ts
S IG NATU RE D ATE
Posted b y
21 0
GMP - E g y p t
Appendix II
RAW M ATERIAL RETEST RECORD
Item d es c r i p ti o n Item n u mb er
Lot nu m b er V endor V endor lot nu m b er
Recei p t da te Retest da te Q u a li ty ser i a l nu m b er
S ta tu s Q u a nti ty U /M Loca ti on S i gna tu r e/da te
O n H a nd
Ta k en b y D a te
S a m p led
C om m ents
S i gna tu r e D a te
Test i tem s S p eci f i ca ti ons Resu lts
Ana ly st R.M. S eni or

Ba tch A Accep ted Z Rej ected
sta tem ent
N.B. Ti ck " /" i n th e S ta tem ent Box
C om m ents
La b Ma na ger S i gna tu r e D a te
Posted b y D a te
21 1
GMP - E g y p t
Appendix III
INSPECTION AND SAM PLING REPORT
Item descr i p ti on Item nu m b er

Lot nu m b er
I. L a b el In f o r ma ti o n
C la r i ty O k /Not ok --------- Lot no O k /Not ok ---------
Item descr i p t O k /Not ok --------- W t of cont O k /Not ok ---------
Item no O k /Not ok --------- Mf g da te Pr es/Ab s ---------
V endor na m e O k /Not ok --------- E x p da te Pr es/Ab s ---------
V endor lot no. O k /Not ok --------- Rece da te Pr es/Ab s ---------
II. G en er a l C o n d i ti o n
A. Integr i ty of conta i ner s B. S u p er f i ci a l conta m i na ti on
Tea r i ng Ab s/Pr es --------- D u st & di r t Ab s/Pr es ---------
Im p a i r m ent Ab s/Pr es --------- W et Ab s/Pr es ---------
S ea li ng Per f /Im p er f --------- S ta i n Ab s/Pr es ---------
Rodent sca r s Ab s/Pr es --------- O th er s --------- ---------
III. P h y s i c a l C h a r a c ter i s ti c s C o n ten ts
S ta tu s soli d/li q u i d/ sem i soli d C om m ent (i f a ny )
U ni f or m i ty : h om ogeneou s /non-h om ogeneou s
F or ei gn p a r ti cles: a b sent/p r esent
IV . Sa mp l i n g P r o c ed u r e
S a m p le si z e soli d/li q u i d/ sem i soli d
Resea li ng & la b eli ng of sa m p led conta i ner s: … … … … .. D one
D i sp a tch i ng of sa m p les to q u a li ty dep t: … … … … D one
Per f or m ed b y D a te / /
21 2
GMP - E g y p t
Appendix IV
Sampli ng f o r i de nt i f i cat i o n pu rpo se s
The sampler must be aware of the possibility that containers of raw

materials may be incorrectly labeled, and take steps to ensure that
only the correct materials are used. Sampling and identity testing the
contents of each container can provide the necessary assurance, but
large deliveries in many containers can present practical and
economic problems. In such circumstances it may be possible to
relax the policy of identity testing the contents of every container and
to apply our sampling protocol, if account is taken of the following
• The use to which the material is to be put. Every container of
material intended for use as an ingredient of injectable
products should normally be sampled and identified. In the
light of further consideration, which follows, it may not be
necessary to sample and identify each container of material
for use in other product categories.
• The range of materials produced and handled by the original
producer and any subsequent agents. The hazards of
mislabeling are markedly reduced if the supplier deals only in
one product or type of product. It is likely to be small if the
supplier deals only in food products, greater if the supplier
deals in a wide range of pharmaceutical materials, and
probably greater still if the supplier deals in materials for both
pharmaceutical and other industries. The broker who breaks
and re-packages bulk martial may well represent a high level
of risk.
• The status of the supplying company. If not well reputed or
with problems from history, the sampled containers should
be increased by two and each container is identified.
P r ep a r ed b y A p p r o v ed b y
D a te D a te
21 3
GMP - E g y p t
3. St a n d a r d o p e r a t i n g p r o c e d u r e f o r c l e a r a n c e
a n d d is in fe c tin g o f s a m p lin g b o o th a r e a
1. Pri nci ple
• Sampling booth area should present a good appearance, be well

maintained and must be kept in an orderly, clean and hygienic
condition free from accumulated waste. It is a critical area.
• Sampling area as any area in the warehouse must be kept free

of vermin, insects, birds and other pests.
• Control treatment should be carried out for cleaning according to

this written procedure which does not contaminate the materials
being held.
• Precautions must be taken to minimize the contamination of the

area by dirty, damaged or unsuitable containers of raw materials
which should not be accepted in this area for sampling. Also,
considerations should be given to the provision of clean pallets
for holding materials.
• In weighing process of sampling, and where raw materials

containers are opened, all staff must wear protective clothing
including, overheads, factory shoes, gloves, masks, etc. and
must use appropriate safety equipment and use only new clean
P.E. bags, clean glass or stainless steel containers for sampling.
2 . Pro ce du re
• Ensure that the sampling booth electricity is switched off before

carrying out the cleaning procedure for sampling area.
21 4
GMP - E g y p t
• All materials and portable equipment must be removed outside
the area.
• Clean up the settlement and spillages at the end of every

working period using the vacuum cleaner to ensure that
contamination is not carried outside the area.
• Clean the internal surfaces of booth to remove accumulated

contamination using vacuum cleaner or clean towel.
• Clean the epoxy coated mild steel with warm water and mild
detergent (liquid soap) or citric acid solution or sodium lauryl
sulphate, then dry with clean towel.
• Tools of machines cleaned by using warm water and soap, then

disinfected by using cotton wetted with alcohol 70% and dried.
3 . C le ani ng F re q u e ncy
• Cleaning procedure concerning sampling area must be carried

out at the end of every working day.
D a te D a te
21 5
GMP - E g y p t
4. St a n d a r d o p e r a t i n g p r o c e d u r e f o r o p e r a t i o n o f
H I 8 56 4 p o r t a b l e t h e r m o h y g r o m e t e r
1. Pri nci ple
a. Spe ci f i cat i o ns
R H °C °F
- Range 10 to 95% RH 0 to 60 °C 32 to 140 °F
- Resolution 0.1 % RH 0.1 °C 0.1 °F
- Accuracy ± 2 % RH ± 0.4 °C ± 0.8 °F
• Response time: 6 seconds for 95% accuracy
• By means of three trimmers housed in the probe calibration of

the Relative Humidity and temperature is done.
• Display: A 4-digit LCD display plus symbols. Battery wear

indicator.
• Power supply: One 9 V battery for 100 hours of continuous use.
• Operation conditions: Room temperature from 0 °C to + 50 °C,

humidity 95% maximum.
• Optional accessories: HI7101 calibration kit.
b. G e ne ral D e scri pt i o n
The HI8564 portable thermohygrometer measures both

temperature and relative humidity and is composed of a display
panel and a probe connected by means of a spiral cable. A shock-
resistant plastic box houses the display panel where the various
measures are shown. It is also equipped with a keyboard for the
selection of the various functions and an electronic circuit which
converts the signals sent by the probe into digits. The probe contains
21 6
GMP - E g y p t
both the sensors and the electronic circuits necessary to transit the
temperature and humidity readings in current which are then
translated by the display panel. The probe must never come into
contact with water or other liquids.
Battery housing: When the battery has almost run down and
only a few hours of functioning remain, The "V" symbol will appear
on the display to indicate that the battery must be replaced.
c. Te mpe rat u re / Re lat i v e H u mi di t y Ro le
It is very important to measure the temperature and humidity

of the stores and this requires an absolute determination of the
required conditions for warehousing of the different critical materials
e.g. raw materials, cartons, etc. Portable thermohygrometer must be
daily used and checked as early as possible and during the course of
the day in different locations for each store. Every check also, must
be recorded and initiated by the checker on the temperature/relative
humidity record sheets and translate it on graphic drawing charts
weekly concerning the main store. All registered records must be
reported immediately to the warehouse supervisor/manager and then
to the QA M anager.
2 . U si ng t h e I nst ru me nt
• In order to obtain a rapid response, the end of the humidity probe

should be exposed to a current of air moving at more than 0.5
m/second. In the absence of air movement, the response can be
speeded up by shaking the probe.
• If condensation causes drops of water to form upon the surface

of the humidity sensors, the instrument must be turned OFF and
21 7
GMP - E g y p t
you must wait until this water has evaporated completely. In
order to speed up the evaporation process, the humidity sensors
may be exposed to a current of air.
• Whenever the humidity probe is to be used in dusty

surroundings, the filter must be kept on at all times.
• Recording of temperature is in degrees centigrade and that of

Relative Humidity in "RH-Percentage".
• There are many different stores with different levels or zones that
must be checked daily for temperature and humidity as follows:
1. M ain store, three levels and two zones
2. Receiving area, two zones (main entrance + waiting

area)
3. Reject store, one zone
4. Officer's area, one zone
5. Refrigerator, one zone
6. Flammable store (outside the warehouse building), one

zone
7. Narcotic store, one zone
8. Explosives store, one zone
9. Central dispensing area, three zones (Weighing area +

Batch assembly area + Printing House area)
21 8
GMP - E g y p t
H I 8 5 6 4 : P o r t a b l e T h e r m o -h y g r o m e t e r
21 9
GMP - E g y p t
Temperature / Relative humidity recording chart
8 a.m. 2 p.m.
L e v e l /Z o n e L e v e l /Z o n e S u pe r v i s o r
Day C h e c k e r
1 2 3 1 2 3 C o mme n t
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5. St a n d a r d o p e r a t i n g p r o c e d u r e f o r f u m i g a t i o n
o f th e s te r ile a r e a w ith fo r m a ld e h y d e g a s
1. Pri nci ple
Fumigation of clean room environment using formaldehyde gas is

done for the purpose of killing micro-organisms even in their spore
forms, which may be found on walls, floor, and equipments or in the
air condition (AC) system.
2 . Sco pe o f appli cat i o n and f re q u e ncy
• When the routine biological monitoring indicate high microbial

count in certain or whole of the area which resist the usual
sanitizers in use.
• Fumigation is also indicated after major maintenance work in the

area especially in the AC system.
• Normally fumigation should be affected monthly.
3 . Pre cau t i o ns
Formaldehyde gas is a very irritant gas to lungs and eyes, avoid

exposure to concentrations higher then 2 p.p.m.
Fumigation of the area must be affected while the area is empty from
operators, product solutions, holding tanks or primary packaging
materials
This procedure is applicable only when the other production

departments are not working i.e. at the week-end.
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4. Pro ce du re
• Remove any packaging materials, solutions or holding tanks

from the area
• Clean the area from dust or debris
• Rinse the floors and walls using water for injection and leave it
wet
• Wear protection masks and eye protection glasses while

dispensing the required amount of formalin solution
• U se a measuring cylinder to deliver 8 liters of formalin solution

into 2 stainless steel bins each with 4 liters
• Place the filled stainless steel bin on electric heater with

magnetic stirrer, in the corner near the sterilizing oven and the
other in front of the changing room
• Adjust the timer clock of the power supply to the 2 electric

heaters, so that to start the heater "ON" for the required time and
lasts for 6 hours from the start
• Stop the AC to the area at the beginning of fumigation
• Re-start the AC system after 2 hours of fumigation while the

fresh air supply is closed and leave for 5 minutes and then stop it
again. This step is done to allow the formaldehyde gas to
penetrate the A. C. ducts and filters.
• Close the doors of the area and seal the gaps around them using
adhesive tape
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• Run the AC system again when the timer clock indicates the end
of fumigation time
• Re-start running the area at least after 10 hours of the fumigation

process
• M ake sure that the timer clock is in position "OFF" i.e. the power
supply to the heaters is "OFF"
• Enter into the area and make sure that all the formalin liquid in
the bin has been evaporated
• Close the containers and transfer to the air lock
• Test for the residual formaldehyde vapors in the environment this

must not exceed 2 p.p.m.
D a te D a te
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Chapter X
S E L F IN S P E C T IO N
A N D Q U A L IT Y A U D IT S
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Ch a p t e r X : S e l f I n s p e c t i o n a n d Q u a l i t y A u d i t s
Concepts and ob jectives

The aim of self-inspection is to confirm that the GM P for
pharmaceutical industries is applied properly inside the factory and
that there is no defect in application with the suggestion of solutions
enough to solve the problems. Inspection includes all manufacturing
areas of the factory. Self inspection should follow a self inspection
list approved by the GM P committee and must be classified into:
• Conform.
• Not conform.
• Report about (not conform).
• Report about if it is necessary to re-control any batch.
I tems f or self -inspection

Written instructions for self-inspection should be established
to provide a minimum and uniform standard of requirements. These
may include questionnaires on GM P requirements covering at least
the following items
a. Personnel
b. Premises including personnel facilities
c. M aintenance of buildings and equipment
d. Storage of starting materials and finished products
e. Equipment
f. Production and in-process controls

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g. Quality control
h. Documentation
i. Sanitation and hygiene
j. Validation and revalidation programmes
k. Calibration of instruments or measurement systems
l. Recall procedures
m. Complaints management
n. Labels control
o. Results of previous sell-inspections and any corrective steps

taken
S elf -inspection team

M anagement should appoint a self-inspection team from
local staff who are expert in their own fields and familiar with GM P.
The members of the team may be appointed from inside or outside
the company. It consists of at least three persons (the number must
be odd) they are chosen by factory manager (FM ). The team must
be chosen to cover different categories as follows:
• Quality control/quality assurance
• Production and engineer side
• Planning
• Public relations
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F req uency of self -inspection
The frequency at which self-inspections are conducted may
depend on company requirements.
S elf -inspection report

A report should be made at the completion of a self-
inspection. The report should include:
a. Self-inspection results
b. Evaluation and conclusions
c. Recommended corrective actions
F ollow -up action

The company management should evaluate both the self-
inspection report and the corrective actions as necessary.
Q uality audit
It may be useful to supplement self-inspections with a quality
audit. A quality audit consists of an examination and assessment of
all or part of a quality system with the specific purpose of improving
it. A quality audit is usually conducted by outside or independent
specialists or a team designated by the management for this
purpose. Such audits may also be extended to suppliers and
contractors.
S upplier' s audit
The quality control department should have responsibility
together with other relevant departments for approving suppliers who
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can reliably supply starting and packaging materials that meet
established specifications. Before suppliers are approved and
included in the specifications they should be evaluated. The
evaluation should take into account a suppliers history and the
nature of the materials to be supplier's. If an audit is required, it
should determine the supplier’ s ability to conform to GM P standards
for active pharmaceutical ingredients.
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Chapter X I
V A L ID A T IO N

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Ch a p t e r X I : V a l i d a t i o n

Validated manufacturing process is one which has been
proved to do what it purports or is represented to do. The proof of
validation is obtained through the collection and evaluation of data,
preferably, beginning from the process development phase and
continuing through into the production phase. Basis of process
validation include:
a. Calibration, verification and maintenance of equipment
b. Qualification and/or validation of both process and equipment
c. Challenge, audit, monitor, or sample the recognized critical or

key steps in the process
d. Requalification or revalidation
Validation studies are an essential part in any quality

assurance system and should be conducted in accordance with
predefined protocols. A written report summarizing recorded results
and conclusions should be prepared and stored. Processes and
procedures should be established on the basis of a validation study
and undergo periodic revalidation to ensure that they remain capable
of achieving the intended results. Process validation enables
production and quality control to have confidence that:
• M anufacturing processes will perform in a predictable manner
• There will be a high probability of test results on samples being

representative of the entire production batch or run
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• Process variables affecting quality have been identified and
control limits set for them that will be effective and economic
Critical processes should be validated, prospectively or

retrospectively. When any new master formula or method or
preparation is adopted, steps should be taken to demonstrate its
suitability for routine processing. The defined process, using the
materials and equipment specified, should be suitable to yield a
product consistently of the required quality.
Any manufacturing process will involve a number of

variables that affect product quality. It is the purpose of validation to
explore this relationship, to establish the degree of variation that can
be tolerated and the extent to which the process needs to be
controlled in order to achieve acceptable quality product. It has been
recommended that validation should be carried out at the extremes
of these variables or under "worst case" conditions. Discretion must
be exercised; otherwise it can lead to a large number of
permutations of process conditions requiring validation. It is therefore
logical to restrict variations and permutations of variations to:
• Those likely to yield product complying with the target and

extreme values of specification limits
• Those that can reasonably be expected to be encountered
• Those that can be changed by human intervention or error
• Those that are known to affect important product characteristics

and product quality
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In theory, validation should only need to be carried out once
for a given process in relation to a particular item of equipment. In
practice when any aspect of the materials, process or plant known to
affect quality is changed, revalidation should be carried out. The
scope of the revalidation may well differ from the initial validation
exercise as it is possible to use historical data accumulated both
during the original validation and subsequently during routine
production. The overall process of validation can be broken down
into four distinct stages as follows:
• Commissioning - proving that the process plant/facility/utility

installation is correct and functions in the absence of products.
• Qualification-demonstrates that each particular piece of

equipment is capable of operating to pre-determined
performance standards in the presence of placebo or product.
• Process validation-where the performance of the production

process is evaluated in terms of compliance of the finished
product with its specification and other relevant quality
requirements and standards.
• Certification-formal documented acceptance of qualification,

commissioning and validation results.
Process validation sy stem

The process validation system should include the following key
stages:
• Assessment of the need for validation work
• Preparation of a validation protocol

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• Review and acceptance of the protocol by the person
responsible for quality control
• Reporting of all the work carried out and the results obtained
• Review and acceptance (or otherwise) of the results and findings

of the study
• Agreement on any changes needed to the process, and the in-

process controls and monitoring to be performed routinely as
part of the process
• Setting of the criteria for revalidation, maintenance, calibration,

etc.
Process validation meth od

Assessment of the need for validation should be undertaken
either by a team set up to monitor validation activities or by the
person or organizational unit responsible for quality control. In any
event, the person responsible for quality control should be
represented in the decision making processes involved in validation.
The validation protocol should be prepared by the technical
personnel responsible for carrying out the validation exercise. It
should state the way in which the process is to be operated, identify
the controls to be exerted, specify the variables to be monitored,
state the samples to be taken for subsequent testing, specify the
product performance characteristics/attributes to be monitored along
with acceptable limits and refer to the test methods to be used.
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Prospective validation
Prospective validation is establishing documented evidence
that a system does what is purports to do based on a preplanned
protocol. Prospective validation makes validation an integral part of a
carefully planned, logical product/process developmental program.
There are four key elements that form the basis of a prospective
process validation program.
1. Definition of the desirable attributes of the drug product or

components thereof as well as those characteristics that are not
desired
2. Establishment of limitations or constraints for these attributes
3. Determination of the controls or testing parameters that will be

measured or tested
4. Initiation of studies to establish control or boundary limits for

those key attributes that influence the product, process, quality
and performance
As an example of prospective validation, for a granulated product the

following steps should be considered:
• Typical process flow chart (fig. 1)
• Typical Variables and responses (table 1)
• Cause and effect diagram (fig. 2)
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F i g u re 1. Ty pi cal pro ce ss f lo w - g ranu lat e d pro du ct
A d d itio n o f r a w m a te r ia ls
Active
Excipients
P r e -b l e n d i n g
High-speed mixer granulator
G r a n u la tin g
High-speed mixer granulator
D r y in g
Fluid-bed dryer
S iz in g
M ill/Sieve
A d d itio n o f r a w m a te r ia ls
Lubricants
Disintegrants
B le n d in g
V-Blender
T a b le tin g
High speed rotary with pre-compression
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Table 1. Ty pi cal v ari able s and re spo nse s - g ranu lat e d pro du ct
Process S t ep C on t rol V a ri a b l es M ea su red R esp on ses

Pre-b l en di n g B l en di n g T i m e B l en d un i fo rm i ty
RPM
L o ad si z e
O rder o f addi ti o n
G ran ul ati n g L o ad si z e D en si ty
A m o un t o f g ran ul ati n g ag en t Yi el d
S o l ven t addi ti o n rate
RPM
G ran ul ati o n T i m e
D ry i n g I n i ti al tem perature D en si ty
L o ad si z e M o i sture co n ten t
D ray i n g tem perature pro g ram Yi el d
A i r fl o w pro g ram
D ry i n g ti m e
C o o l i n g ti m e
S iz in g S creen ty pe G ran ul e si z e di stri b uti o n
S creen si z e L o o se den si ty
F eed rate Pack ed den si ty
B l en di n g L o ad si z e B l en d un i fo rm i ty
RPM F l o w ch aracteri sti cs
B l en di n g ti m e
T ab l eti n g C o m pressi o n rate W ei g h t vari ati o n
G ran ul e feed rate F ri ab i l i ty
Pre-co m pressi o n fo rce H ardn ess
C o m pressi o n fo rce T h i ck n ess
D i si n teg rati o n ti m e
D i sso l uti o n
D o sag e fo rm un i fo rm i ty
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F i g u re 2 . C au se and e f f e ct di ag ram - g ranu lat e d pro du ct
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In theory, the number of process runs cairned out and
observations made should be sufficient to allow the normal extent of
variation and trends to be established and to provide sufficient data
for evaluation. In practice, it may take some considerable time to
accumulate full data. The validation protocol should also indicate the
way in which the work is to be cairned out and how the data
generated are to be analyzed and reported. Statistical methods may
be of value in assessing the data generated. Review and acceptance
of the validation protocol is an essential stage in ensuring that on
completion the validation results will be acceptable. It should be
cairned out by the person or organizational unit that is responsible
for quality control.
Certif ication
Validation reports should give a comprehensive
explanation of the work carried out and should include the values for
the process variables measured together with any in-process control
results obtained. They should also incorporate results obtained on
examination of the product for compliance with its specification and
performance standards. Where raw data are not included, reference
should be made to the sources used and where they can be found.
Any work done in addition to that specified in the protocol or any
deviations from the protocol should be formally noted along with a
justification.
The review of results may either be carried out by the

team appointed for the purpose or by the technical personnel
responsible for the validation work. In both cases, the review of the
validation data must be carried out in conjunction with the person
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responsible for quality control. On completion of the review and
completion of any corrective actions/repeated work, the result of the
validation exercise must be formally recorded as being either
accepted or rejected. The team carrying out the review should also
make written recommendations on the extent of monitoring and in-
process controls necessary for routine production. These should
include details of the methods, limits and frequencies and of the
actions to be taken when limits are exceeded. Consideration should
be given at this stage to the need for any alterations to the finished
product or raw materials specifications.
Setting of criteria for re-validation, maintenance and

calibration should be the final step in the validation process where
the reviewing team should specify the interval or conditions that will
necessitate re-validation. This should also include recommendations
for maintenance and calibration to be carried out on the process
plant and related utilities.
R evalidation
Whenever there is a change in a validated process or in
any of the main factors affecting product quality, consideration
should be given as to whether revalidation is necessary. This should
happen through a formal system and the necessary revalidation work
should be organized, carried out and reported in the same way as
initial validation. Certain processes may require a level of routine
monitoring which may equate to revalidation. In this case the same
protocol can be used on each occasion that the process is checked.
An example of this would be the routine monitoring of aseptic
processes by simulated processing and filling trials.
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R etrospective V alidation
Retrospective process validation involves the use of
historical data to provide the necessary documentary evidence that a
process does what it purports to do. The sequence of events in the
validation system may differ but will still involve the preparation and
review of a protocol, the reporting of results abstracted from
accumulated data, the review of the report, and conclusions and
recommendations. The sources of information for this activity will
include batch records and process control charts along with
analytical and storage stability results. Figure 3 shows the method of
selection of candidates for retrospective validation and table 2
illustrates the selected critical manufacturing steps quality-control
release tests to be considered in a typical compressed tablet
product.
D ocumentation
The validation process is incomplete without adequate
documentation. It is essential therefore that the documents written in
preparation for validation, the records of the work done, the results
and the records of decisions made are retained on file for at least the
same period of time as batch records. These should include:
• A record of the decision to carry out validation
• The validation protocol and a record of its approval
• Comprehensive records for each batch of product/placebo

processed
• Environmental monitoring results, if appropriate
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F i g u re 3 . Se le ct i o n o f candi dat e s f o r re t ro spe ct i v e v ali dat i o n
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GMP - E g y p t
Table 2 . C o mpre sse d t able t s - se le ct e d cri t i cal manu f act u ri ng st e ps
and q u ali t y co nt ro l re le ase t e st s
P r o c e s s in g S te p s
Premix blending time
Oscillator screen size
Q u a l i t y -Co n t r o l R e l e a s e T e s t s
Disintegration time
Hardness
Average tablet weight (ATW)
Assay
Dissolution
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• Details of how the validation work was carried out, and results or
at least summaries of results and observations
• Records of the evaluation of results and decisions to

accept/reject the validation work by the person or unit
responsible for quality control
• Records of proposals for suitable in-process controls,

revalidation intervals, calibration, monitoring and maintenance
Product release-additional req uirement f or

validation b atch es
There should be a system which ensures that products made
by new or altered processes are not released for sale until quality
control procedures are complete and the results of successful
validation reported. In practice this may be incorporated in the formal
batch release procedure particularly where periodic revalidation or
monitoring is necessary. Regulatory requirements must be taken into
account when assessing the acceptability of batches made for the
purpose of process validation.
Ch ang e control
Change control is another important element in any quality
assurance system. Whilst there might not be procedures that are
specifically titled "change control", systems should exist which
ensure that proposed changes are identified, their significance
evaluated and any consequent actions identified, evaluated and,
where necessary implemented prior to the change being authorized.
Change control is therefore closely linked to process validation. The
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change control system should require formal notification of proposed
changes in:
M aterials Components
Systems Sources
Equipment M ethods
Conditions Location
Specifications Documentation
Relating to established processes and products, it can therefore be

used to "trigger" validation work. Requests for and notifications of
changes need to be considered either by a team which includes
quality control or by the latter alone. The team should ensure that the
validation system is followed as appropriate and also ensure that
products made by processes subjected to changes are not
automatically released for sale. Further to this, the change control
system should ensure, by means of regular checks, that all notified
or requested changes are satisfactorily completed, reported and
validated.
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Chapter X II
H A Z A R D O U S M A T E R IA L S

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Ch a p t e r X I I : H a z a r d o u s M a t e r i a l s

There are a number of potent chemical agents which cause
special hazards to the health of employees who handle them.
Examples of these agents are cytotoxic substances, certain steroids,
cardiac glycosides, anti-coagulants, sensitizing agents, enzymes,
prostaglandins and radioactive materials. When dealing with these
substances, operating procedures need to ensure that the people
involved are adequately protected from exposure. In many cases,
these "employee protection" considerations make it more difficult to
comply with good manufacturing practice.
An example of conflicting requirements is where health and

safety considerations would dictate that the least number of people
possible are exposed to a hazardous raw material whereas GM P
requirements for check-weighing requires the presence of two
Persons. M anagement must be aware of the potential for such
conflict, anticipate or recognize it when it occurs, and implement
solutions which satisfy both requirements. Possible ways in which
these problems can be resolved include the use of:
• Closed circuit television for remote supervision and monitoring
• Enclosed manufacturing systems
• Remote handling techniques e.g. robotics
• Purpose built isolators
• Pressurized air suits
• Safety cabinets
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• Segregated areas
M anuf acturing A reas

Hazardous materials are normally handled in purpose-built
units which, by virtue of their design, ensure that manufacturing
activities are isolated from other operations and also provide
adequate protection for the employees involved. Such units are
normally only used for one product or for one category of product.
The operation of these areas raises a number of problems, which
demand special controls and procedures. Additional problems arise
where hazardous products have to be handled under clean or
aseptic conditions as there is likely to be a direct conflict in air
handling systems needed to meet employee protection and good
manufacturing practice requirements.
S ampling
Because of the need to minimize exposure to the smallest
number of persons possible, it may be necessary for production
personnel to sample active ingredients and finished products. Quality
control must however ensure that the operators involved have
sufficient training and knowledge so that a representative,
homogeneous sample is taken.
Training
Special training is required both for personnel likely to be
exposed to hazardous materials and those authorized to enter the
areas where they are handled. This should cover both safe working
practices and good manufacturing practice, together with training in
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the use and handling of protective clothing and in other special
procedures. A log which lists the trained personnel authorized to
work with various categories of materials should be maintained.
V entilation of areas w h ere h az ardous

materials are h andled
These areas are normally kept under negative pressure with
respect both to the external environment and to adjacent areas in
order to prevent emission of the materials being handled. A system
should be established to verify and record that the differential
pressure of the processing area is correct throughout the process
cycle. Any air exhausted from the manufacturing areas to the
external environment should be treated in order to remove all traces
of active material. The environment in special manufacturing areas
should be controlled in order to preserve the integrity of the product
and provide acceptable working condition in terms of temperature
and relative humidity.
Protective cloth ing

The handling of some classes of hazardous materials
requires the use of totally enclosed protective suits which are
provided with their own air supply. Where these are used,
procedures are needed to cover:
• Entry and exit from the suit
• Decontamination and storage of suits when not in use
• Precautions for working in a protective suit i.e. indicator light or

alarm bell when the air supply fails.
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Enclosed suits restrict mobility and dexterity and, as a result,
certain in-process controls may not be possible. Where this happens
increased end-product testing may be required provided that the
risks of exposure for laboratory staff are acceptable.
W aste disposal
Waste usually consists of disposable filters; dust from
collector units or from suction cleaning systems and material used in
manufacture. It should be handled using the same precautions
required during production and the containers used for disposal
should be cleaned externally before they leave the controlled area.
All waste from areas where hazardous materials are handled should
be packaged in well closed, sturdy containers marked with the
appropriate warning labels. The most effective means of disposal is
by incineration, if it is permitted.
Special systems may be necessary to deal with certain

waste materials, washings from cleaning activities and other forms of
effluent. This may involve inactivation or absorption of the active
material and disposal by approved methods.
E mploy ee ex posure
The exposure of employees to hazardous materials should
be limited by containment of the sources of emission, where this is
not possible personal protection should be employed. In addition,
exposure can be limited by restricting the time that each operator is
allowed to work on a particular process and by using different
operators according to a rotation. A log should be kept of time spent
in controlled areas for each employee. Consideration should be
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given to excluding certain categories of employee, who may be
particularly at risk from exposure.
E nvironmental and personnel monitoring

Procedures should be carried out for environmental
monitoring which involve both sampling at the point of "personal"
exposure and static sampling within the area at specified points.
"Personal" sampling involves an individual carrying a pump and
sampling head within or attached to the protective clothing worn in
the processing area. This should sample air within his/her breathing
zone.
Results of personal and static area monitoring should be

compared with available standards or in-house target levels and
standards. It should be clearly specified what action is to be taken if
the target or action limits are exceeded. In addition, appropriate
physiological and medical checks of the personnel working in the
area should be carried out. These may involve monitoring either
blood or urine for levels of contaminants as well as general medical
examination.
M aintenance
Difficulties may be experienced in carrying out maintenance
in areas where hazardous materials are manufactured. In particular,
care is needed when maintaining systems (such as ventilation) which
may be located outside the manufacturing area but may still be
contaminated with hazardous materials. Some of these problems
may be overcome by the careful design of units requiring
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maintenance e.g. sealed systems for the disposal of filter/dust
extractor residues.
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Chapter X III
S T A B IL IT Y

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Ch a p t e r X I I I : S t a b i l i t y

Stability studies demonstrate that the necessary critical
characteristics present at the time of production and release can be
expected to be present when the dosage form is administered. If
safety and efficacy values decline, stability studies provide
information to determine when and under what conditions the
product should be withdrawn from the market. The quality control
department should evaluate the quality and stability of finished
pharmaceutical products, and when necessary, of starting materials
and intermediate products. The quality control department should
establish expiry dates and shelf-life specifications on the basis of
stability tests related to storage conditions. A written programme for
ongoing stability determination should be developed and
implemented to include elements such as:
• A complete description of the drug involved in the study
• The complete testing parameters and methods describing all

tests for potency, purity, and physical characteristics and
documented evidence that these tests indicate stability
• Provision for the inclusion of a sufficient number of batches
• The testing schedule for each drug
• Provision of special storage conditions
• Provision for adequate sample retention and a summary of all

data generated, including the evaluation and the conclusions of
the study.
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• A summary of all the data generated, including the evaluation
and the conclusions of the study.
Stability should be determined prior to marketing and

following any significant changes in processes, equipment,
packaging and materials, etc.
Purpose of stab ility testing

The main objectives of stability testing are:
• To select adequate (from the viewpoint of stability) formulations

and container closure systems
• To determine shelf-life and storage conditions
• To substantiate the claimed shelf-life
• To verify that no changes have been introduced in the

formulation or manufacturing process that can adversely affect
the stability of the product
The type of stability studies depends on the different phases of drug

and use:
I n t h e de v e lo pme nt ph ase : Accelerated stability studies are used to

predict the stability, shelf-life and storage condition of the final
formulation. Real time studies have to be started for confirmation.
F o r t h e re g i st rat i o n do ssi e r: The results of stability studies from both

accelerated and real time studies for the final dosage form in its final
container and packaging should be submitted to the drug regulatory
authority. Studies at the worldwide climate zone will be fruitful.
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I n t h e po st -re g i st rat i o n pe ri o d: Real time stability studies as well as
studies at the climatic zones II and III and worldwide are used to
substantiate the expiry date and the storage conditions previously
projected.
Stability data should be submitted when required. In the

course of GM P inspection, their availability and validity are normally
verified. The stability and quality of the dosage form on the market
should be checked through a follow-up inspection and testing
program
D esig n of stab ility studies

The design of the stability testing program needs to take into
consideration the intended market and the climatic conditions of the
area in which the drug product will be used. Four climatic zones can
be distinguished for the purpose of worldwide stability testing as
follows:
Standard Stro ng C o ndi ti o ns

Z o ne R e l ati v e
T e m p e ratu re
H u m i di ty
I. T e m p e r a t e 21 °C ± 2°C 4 5%±5%
II. S u b -T r o p i c a l & M e d i t e r r a n e a n 25°C ± 2°C 6 0 %±5%
III. H o t , D r y 3 0 °C ± 2°C 3 5%±5%
IV . H o t , H u m i d 3 0 °C ± 2°C 7 0 %±5%
Temperature l i s ted ab o v e i s th e mean k i n eti c temperature
In Egypt the climate, varies with seasons and place, roughly

corresponding to climates of zones II and III round the year.
255
GMP - E g y p t
Test S a mpl es
For registration purposes test samples are taken from three
different batches prepared under conditions simulating production of
the finished products in the market packages. Two batches are
tested if the drug is known to be stable. For on-going studies batches
from current production should be sampled in accordance with a
predetermined schedule. The following approach may be suggested:
• One batch every other year may be tested for formulations

considered to be stable, (otherwise one batch per year).
• One batch every 3-5 years may be tested for formulations when
the stability profile has been established, unless a major product
change has been made.
Ty pes of stab ility studies and test conditions

A c c el era ted stu dies
Stress and acceleration tests are used to:
• Identify the weakness of an active ingredient or a formulation
• M ake stability prediction
• Obtain information on extreme loading during transport
The storage temperatures used to test for chemical changes

are within the range between 40 and 80 °C. It thus becomes possible
to accelerate the rate of decomposition to such an extent that
relevant results are available within three months on the basis of
which stability predictions can be made applying the laws of
reactions kinetics.
256
GMP - E g y p t
The temperatures are a continuation of those used for long-
term testing. The temperature is increased in 10°C steps (21°C,
25°C, 30°C), 40°C, 50°C, 60°C, 70°C and 80°C. Which and how
many of these are used depends on the problem under consideration
and the dosage form. For a reliable stability prediction, however, at
least three temperatures will be necessary. Low temperature (-15°C)
freezer, (2-8°C) refrigerator, and freeze-thaw cycling should be used
when necessary.
Humidity condition and effect of light should be taken in

consideration. The storage conditions for stress testing for
organoleptic and physico-chemical changes differ depending on the
dosage form. Accelerated stability studies can be designed to
simultaneously test the influence of several variables and with
appropriate statistical methodology determine actions and
interactions between variables. High correlation between the results
obtained from accelerated stability testing and from long term shelf
studies are necessary.
Solid dosa g e form

The samples are stored in open container. U ntil equilibrium is
reached under the storages of long-term testing and two further
frequently used stress conditions 21°C/45%, 25°C/60%, 30°C/70%
or 40°C/75%.
Semi-solid dosa g e forms

Studies should be conducted at a temperature between 4°C and
40°C. Also between freeze and 25°C if cold storage is required.
257
GMP - E g y p t
L iq u id dosa g e forms
≥ 10°C, lying down and upside down to test compatibility with closure
Stability of reconstituted product during utilization period shall be
determined.
The influence of humidity and temperature on chemical

stability is tested by storing in parallel two samples of different initial
moisture content in packaging materials impermeable to water vapor
(e.g. glass container with twist-off closure) at temperatures between
40°C and 80°C.
ii. C l ima tic Z o n es S ta b il ity Testin g

From the storage conditions, testing intervals and storage
period, the following schemes have been derived for worldwide use.
W o r ld w id e
Temp RH% storage period and testing intervals (months)

°C 0 6 12 14 36 48 60
25 60 x x x x x x x
30 70 x x x x x x
N u m b e r o f B a t c h e s : 3 batches.
Co n t a i n e r : It should be the same or simulate the actual packaging

used for shipping and/or storage.
iii. L o n g term stu dy (rea l -time stu dies)

Experimental storage conditions should be close to the
projected actual storage conditions in the distribution system, as
258
GMP - E g y p t
practicable. As for the length of studies for registration purposes,
results of at least 6 months studies should be available at the time of
registration. It should be possible to submit the registration dossier
before the end of this 6 months period.
F req u en c y of testin g a n d ev a lu a tion of test resu lts

In the development phase and for studies in support of an
application for registration, a reasonable frequency of testing is
considered to be a time period of:
F o r acce le rat e d st u di e s: 0, 1, 2, 3, and when appropriate 6 months.
F o r cli mat i c z o ne s: as indicated above
F o r re al-t i me st u di e s: 0, 3,6,12 months and beyond once a year.
F o r o n-g o i ng st u di e s: samples may be tested less frequently, e.g. at

6 months intervals for the confirmation of provisional shelf-life, or
every 12 months for well established products.
A n a ly tic a l meth od
Assay methods should be chosen to be stability indicating.
Tests for related compounds or products of decomposition used
should be validated to demonstrate that they are specific to the
product being examined and are of adequate sensitivity, especially if
proved to have potential toxicity. Test methods to prove the efficacy
of additives, such as antimicrobial agents, should be foreseen to see
if they remain effective and unchanged throughout the projected
shelf-life. Stability regarding dissolution and sterility should be
considered.
259
GMP - E g y p t
R ecommended storag e conditions
After evaluation of the stability, the product may be labeled
with the following storage conditions:
N o rmal st o rag e co ndi t i o ns: storage in dry, well ventilated premises at

temperatures of 15-25°C or, depending on climatic conditions, up to
30°C. Extraneous odors, contamination, and intense light have to be
excluded.
D e f i ne d St o rag e C o ndi t i o ns:
• Store up to 30°C
• Store up to 25°C
• Store between 2-8°C under refrigeration, no freezing
• Store below 8°C under refrigeration
• Store in a freeze at -5 to -20°C
• Store below -18 °C a deep freezing
General precautionary statement, such as "protect from light"

and/or "store in a dry place", may be included.
S tab ility overag e justif ication

The stability overage is acceptable only in limited cases and
on grounds of scientific and practical justification.
N ew ex piry date
Time-expired drugs should only be used in exceptional
cases. The decision to utilize such products may be taken on a case-
260
GMP - E g y p t
by-case basis by a responsible national health authority only. In such
cases, samples of these products have to be retested by stability-
indicating method. When a decision is taken to use time-expired
material, a new expiry date, well defined, and as limited as
practicable has to be established.
L ist of less stab le drug sub stance

The experimental conditions used to compile this list of less stable
substances were the following: initial exposure for 30 days to air at
5°C and 100% humidity; if no degradation was demonstrable after
this time. The temperature was raised to 70°C for a further period of
3-7 days. All other factors being equal, finished products containing
the following substances require particular attention from the stability
viewpoint.
Acetylsalicylic acid C r eso l

Am in o p h yllin e
Am itr ip tylin e h ydr o ch lo r ide D ap so n e
Am m o n iu m ch lo r ide D esam eth ax o n e so diu m p h o sp h ate
Am p h o ter icin B D iclo x acillin so diu m ( m o n o h ydr ate)
Am p icillin so diu m D ieth ylcar b am az in e dih ydr o g en citr ate
An tim o n y so diu m tar tr ate D o x ycyclin e h yclate
Am p icillin tr ih ydr ate
Asco r b ic acid E m etin e h ydr o ch lo r ide
E p h edr in e
B acitr acin E p h edr in e su lp h ate
B acitr acin z in c E p in ep h r in e
B en z ath in e b en z ylp en icillin E p in ep h r in e h ydr o g en tar tr ate
B en z ylp en icillin p o tassiu m E r g o calcif er o l
B en z ylp en icillin so diu m E r g o m etr in e h ydr o g en m aleate
B ep h en u im h ydr o x yn ap h o th o ate E r g o tam in e m aleate
E r g o tam in e tar tr ate
C alciu m g lu co n ate E th o su x im ide
C alciu m p ar a-am in o salicylate E th ylm r p h in e h ydr o ch lo r ide
C ar b en icillin so diu m
261
GMP - E g y p t
C ef alex in Fer r o u s su lp h ate
C h lo r al h ydr ate Flu p h en az in e decan o ate
C h lo r am p h en ico l so diu m su ccin ate Flu p h en az in e h ydr o ch lo r ide
C h lo r am p h en ico l h ydr o g en m aleate Fo r m aldeh yde so lu tio n
C h lo r p r o m az in e h ydr o ch lo r ide
C h lo r tetr acylcin e h ydr o ch lo r ide G en tam icin su lf ate
C lo x acillin so diu m ( m o n o h ydr ate) G u an th idin e su lf ate
C o dein e p h o sp h ate
C o licalcif er o l H ex ylr eso r cin o l
C o al tar H ydr alaz in e h ydr o ch lo r ide
H ydr o co r tiso n e so diu m su ccin ate P r o m az in e h ydr o ch lo r ide

H ydr o x o co b alam in P r o m eth az in e h ydr o ch lo r ide
H yo scym ain e su lf ate P yr ido x in e h ydr o ch lo r ide
I m ip r am in e h ydr o ch lo r ide Q u in in e b isu lf ate

I p ecacu an h a p o w der Q u in in e dih ydr o ch lo r ide
I so p r en alin e h ydr o ch lo r ide
I so p r en alin e su lf ate R etin o l ( V itam in A)
L ido cain e h ydr o ch lo r ide S alb u tam o l su lf ate

S en n a leaf
M elar so p r o l S liv er n itr ate
M er cu r ic o x ide yello w S o diu m calciu m edetate
M ter if o n ate S o diu m lactate
S o diu m n itr ite
N alo x o n e h ydr o ch lo r ide S o diu m p ar a-am in o salicylate
N eo m ycin su lf ate S o diu m stib o g lu co n ate
N ystatin S u lf acetm ide so diu m
S u lf adiaz in e so diu m
O m ep r az o le S u lf am idin e so diu m
O r cip r en alin e su lf ate S u x am eth o n iu m ch lo r ide
O x ytetr acyclin e h ydr o ch lo r ide
T etr acain e h ydr o ch lo r ide
P ar o m o m ycin su lf ate T etr acyclin e h ydr o ch lo r ide
P en icillam in e T h iam in e h ydr o ch lo r ide
P eth idin e h ydr o ch lo r ide T h iam in e m o n o n itr ate
P h en o b ar b ital so diu m T h io p en tal so diu m
P h en o x ym eth ylp en icillin T o lb u tam ide
P h en o x ym eth ylp en icillin calciu m
P h en o x ym eth ylp en icillin p o tassiu m U n decylen ic acid
P h en to lam in e m esilate
262
GMP - E g y p t
P h en ylb u taz o n e W ar f ar in so diu m
P ilo car p in e h ydr o ch lo r ide
P ilo car p in e n itr ate
P r o cain am ide h ydr o ch lo r ide
P r o cain e b en z ylp en icillin
P r o cain e h ydr o ch lo r ide
P r o car b az in e h ydr o ch lo r ide
263
GMP - E g y p t
L ist of sub stances resistant to deg radation

The following substances proved to be resistant to degradation
under the conditions of the test. It is important to emphasize that light
was excluded, since some of these substances may be readily
degradable under the influence of light.
Acetaz o lam ide C h lo r o th aiz ide

Acr if lav in iu m ch lo r ide C h lo r talido n e
Aj m alin e C lo f az im in e
Allo p u r in o l C lo f ib r ate
Alu m in iu m diacetate C lo m if en e citr ate
Alu m in iu m h ydr o x ide C o dein e m o n o h ydr ate
Am ik acin C o lch icin e
Am ilo r ide h ydr o ch lo r ide C yan o co b alam in e ( V it. B 1 2 )
Am in o cap r o ic acid
Am o b ar b ital D ex am th aso n e
Atr o p in e su lf ate D ex am th aso n e acetate
Az ath io p r in e D iaz ep am
D iaz o x ide
B ar b ital D icu m ar o l
B ar iu m su lf ate D ieth ylstilb estr o l
B eclo m etaso n e dip r o p io n ate D ig ito x in
B en z o cain e D ig o x in
B en z o ic acid D im er cap r o l
B en z yl b en z o ate D ip h en ydr am in e h ydr o ch lo r ide
B etam eth aso n e D iso diu m edetate
B etam eth aso n e v aler ate D o p am in e h ydr o ch lo r ide
B u su lf an
E p h edr in e h ydr o ch lo r ide
C af f ein e E r yth r o m ycin
C ar b am az ep in e E r yth r o m ycin eth ylsu ccin ate
C etr im ide E r yth r o m ycin stear ate
C h ar co al, activ ated E th am b u to l h ydr o ch lo r ide
C h lo r am p h en ico l E th in ylestr adio l
C h lo r am p h en ico l p alm itate
C h lo r o q u in e p h so sp h ate Flu dr o co r tiso n e
264
GMP - E g y p t
Flu dr o co r tiso n e acetate M ico n az o le n itr ate

Flu r o scein so diu m M o r p h in e h ydr o ch lo r ide
Flo r o u r acil
Fo lic acid N eo stig m in e b r o m ide
Fu r o sem ide N eo stig m in e m etilsu lf ate
N ico tin am ide
G lib en clam ide N ico tin ic acid
G lu co se N itr o f u r an to in
G r iseo f u lv in N o r eth ister o n e
N o r eth ister o n e acetate
H alo p er ido l
H alo th an e P ap av er in e h ydr o ch lo r ide
H ex o b ar b ital P ar acetam o l
H ydr o ch lo r th iaz ide P h en acetin
H ydr o co r tiso n e P h en o b ar b ital
H ydr o co r tiso n e acetate P h en o lp h th alein
P h en yto in
I b u p r o f en P h en yto in so diu m
I n do m eth acin P h yso stig m in e salicylate
I o din e P ip er az in e adip ate
I so n iaz id P ip er az in e citr ate
P o tassiu m b r o m ide
L actic acid P o tassiu m ch lo r ide
L acto se P o tassiu m io dide
L ev o do p a P r edn iso lo n e
L ido cain e P r edn iso lo n e acetate
L in dan e P r o b en ecid
L ith iu m car b o n ate P r o g ester o n e
P o r p r an o lo l h ydr o ch lo r ide
M ag n esiu m ch lo r ide P r o p ylth io u r acil
M ag n esiu m o x ide, h eav y P yr az in am ide
M ag n esiu m o x ide, lig h t P yr ido stig m in e b r o m ide
M an n ito l
M eb en daz o le Q u in idin e su lf ate
M ep acr in e h ydr o ch lo r ide Q u in in e su lf ate
M eth yldo p a
M etclo p r am ide h ydr o ch lo r ide R eser p in e
M etr o n idaz o le R ib o f lav in
265
GMP - E g y p t
R if am p icin T esto ster o n e en an tate
T esto ster o n e p r o p io n ate
S alicylic acid T h eo b r o m ide
S o diu m b r o m ide T h eo p h yllin e
S o diu m ch lo r ide T h io acetaz o n e
S o diu m f lu o r ide T h iab en daz o le
S o diu m h ydr o g en car b o n ate T r im eth adio n e
S o diu m n itr o p r u sside T r im eth o p r im
S o diu m salicylate
S o diu m th io su lf ate Z in c o x ide
S p ir o n o lacto n e Z in c u n decylen ate
S tr ep to m ycin su lf ate
S u cr o se
S lu f adiaz in e
S u lf ado x in e
S u lf am eth o x az o le
266
GMP - E g y p t
Content of stab ility reports

It is suggested that stability reports include the following information
and data to facilitate decisions concerning the stability proposals.
G en era l pro du c t in f o rma tio n

• Name of drug substance and drug product or biological product
• Dosage form and strength, including formulation. The application

should provide a table of specific formulations under study when
more than one formulation has been studied.
• Labeling
• Composition, type, and size of container-closure
S pec if ic a tio n s a n d test meth o do l o g y in f o rma tio n

• Physical, chemical, and microbiological characteristics and prior
submission specifications
• Test methodology used for each sample tested
• Information on accuracy, precision, and suitability of the

methodology
• For biological products, a description of the potency test(s) for

measuring biological activity, including specifications for potency
determination
S tu dy desig n a n d stu dy C o n ditio n s

- Description of the sampling plan, including:
• Batches and number selected

267
GMP - E g y p t
• Container-closures and number selected
• Number of dosage units selected and whether tests were

conducted on individual units or on composites of individual units
• Sampling times
• Testing of drug or biological products for reconstitution at the

time of dispensing (as directed on the labeling) as well as after
they are reconstituted
- Expected duration of the study
- Conditions of storage of the product under study (temperature,

humidity, light)
S ta b il ity da ta / in f o rma tio n

• Lot number (research, pilot, production) and associated
manufacturing date
• For antibiotic drug products, the age of the bulk active drug
substance(s) used in manufacturing the lot
• Analytical data and source of each data point (e.g., lot, container,
composite, etc). Pooled estimates may be submitted if individual
data points are provided
• Summary of information on previous formulations obtained

during product development. Summary should include other
container-closures investigated.
268
GMP - E g y p t
D ata analy sis and conclusions
• Documentation of appropriate statistical methods and formulae
used in the analysis.
• Evaluation of data, including calculations, statistical analysis,

plots, or graphics.
• Results of statistical tests used in arriving at microbiological

potency estimates.
• Proposed expiration dating period and its justification.
• Release specifications (establishment of acceptable minimum

potency at the time of initial release for full expiration dating
period to be warranted).
269
Revised GUIDELINES FOR GOOD MANUFACTURING PRACTICE IN EGYPT, 2004
GMP - E g y p t
B IB L IO G R A P H Y
Cen t r a l Adm in ist r a t io n o f Ph a r m a c eu t ic a l Af f a ir s, Min ist r y o f H ea l t h a n d Po p u l a t io n

270
GMP - E g y p t
Bibliograp h y
1. W i l l i g SH , T u c k e r m a n M M , & H i t c h i n g s W S IV . G o o d
m a n u f a c tu r in g pr a c t i c e s f o r ph a r m a c e u t i c a l s. 2 E d . 1982,
nd
M a r c e l D e k k e r In c ., N e w Y o r k , Ba se l .
2. Sh a r p J R. G u i d e to ph a r m a c e u t i c a l m a n u f a c t u r i n g pr a c t i c e .
1983, Lo n d o n . H e r M a j e st y ’ s st a t i o n a r y o f f i c e , (T h e O ra n g e
G u i d e ).
3. C o n n e r K A, Am i d e n G L, & St e l l a V J. C h e m i c a l st a b i l i t y o f
ph a r m a c e u t i c a l s. 2 E d . 1986. A W i l e y . In t e r sc i e n c e P u b l i c a t i o n ,
nd
N e w Y o r k , C h i c h e st e r , Br i sb a n e , T o r o n t o , Si n g a po r e .
4. Lo f t u s B. & N a sh RA. P h a r m a c e u t i c a l pr o c e ss va l i d a t i o n . vo l . 23,
1984, M a r c e l D e k k e r , In c . N e w Y o r k .
5. La c h m a n L. & Le i b e r m a n H A. T h e th e o ry a n d pr a c t i c e o f
i n d u st r i a l ph a r m a c y . 31 E d . 1986, P h i l a d e l ph i a , LE A a n d
s t
F e b ig e r .
6. W H O T e c h n ic a l Se r i e s. W H O E x pe r t C o m m itte e o n
spe c i f i c a t i o n s f o r P h a r m a c e u t i c a l P r e pa r a t i o n s, 32 r e po r t 1992.
nd
G e n e va .
7. T h e In st i t u t e o f Q u a lit y Assu r a n c e a n d th e P h a r m a c e u tic a l
Q u a lit y G r o u p. P h a r m a c e u t i c a l m a n u f a c t u r i n g (pr o c e ssi n g a n d
pa c k a g i n g ). 1988.
8. In t e r n a t i o n a l O r g a n i z a t i o n f o r St a n d a r d i z a t i o n . ISO 90 0 0 , 90 0 1,
90 0 2, 90 0 3, 90 0 4. 1987. Sw i t z e r l a n d .
9. G e n n a r o AR. Re m i n g t o n ’ s ph a r m a c e u t i c a l sc i e n c e s, 18 E d .
th
1990 . M a c k P u b l i sh i n g C o m pa n y .
27 1
GMP - E g y p t
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R e v is e d

F ac u lty o f P h arm ac y , Cai ro U ni v ers i ty

W o rld H ealth O rg ani z ati o n

This guideline contains the updates of international GM Ps for

The guide is applicable to all large-scale operations for the

This guide to GM P can be used as a standard to justify GM P

It may also be used as training material for Egyptian drug

C e n tr a l A d m in is tr a tio n o f P h a r m a c e u tic a l A ffa ir s , M in is tr y o f H e a lth a n d P o p u la tio n

Air L o ck An enclosed space with two or more doors only one of

Au th o r iz ed Per s o n A person responsible for the release of batches

B a tch o r L o t A defined quantity of a drug product and/or other

B a tch N u m b er (L o t N u m b er ) A distinctive combination of numbers

B a tch N u m b er ing S y s tem Standard operating procedure describing

B a tch Reco r d s All documents associated with the manufacture of a

B u l k Pr o d u ct Any product that has completed all processing stages

C a l ib r a tio n The set of operations that establish, under specified

C l ea n Ar ea An area with defined environmental control of particulate

C o ns ig nm ent (O r D el iver y ) The quantity of starting material, or of a

C o m p o nent Any ingredient intended for use in manufacture of a

C r itica l Pr o ces s A process that may cause variation in the quality of

C r o s s -C o nta m ina tio n Contamination of starting material,

D o s a g eF o rm Refers to the gross physical form in which a drug is

D o cu m enta tio n All written procedures, instructions, descriptions,

D ru g p r o d u ct A dosage form containing one or more active

E x p ir a tio n D a te The date placed on the immediate container label

E x p ir a tio n D a ting Per io d (S h el f -L if e) The interval of time that a

F inis h ed Pr o d u ct A product that has undergone all stages of

G o o d M a nu f a ctu r ing Pr a ctice (G M P( That part of quality assurance

G o o d Ph a r m a cy Pr a ctice Is a means of providing service of

in-Pr o ces s C o ntr o l Checks performed during production to monitor

IS O (Inter na tio na l S ta nd a r d iz a tio n O r g a niz a tio n) Is a worldwide

T y p es o f Inter na tio na l S ta nd a r d s o n Q u a l ity S y s tem s

IS O 9 0 0 0 For use as a guide to all organizations for quality

IS O 9 0 0 1 For use when conformance to specified requirements is to

IS O 9 0 0 2 For use when conformance to specified requirements is to

IS O 9 0 0 3 For use when conformance to specified requirements is to

IS O 9 0 0 4 U sed together with ISO 9000 as a guide to all

Inter m ed ia te Pr o d u ct Partly processed material that must undergo

L a r g e-V o l u m e Pa r enter a Is Sterile solutions for parenteral

M a nu f a ctu r e All operations of purchase of materials and products,

M a r k eting Au th o r iz a tio n (Pr o d u ct L icens e, Reg is tr a tio n

M a s ter F o r m u l a A document or set of documents specifying the

M a s ter Reco r d A document or set of documents that serve as a

M ea n K inetic T em p er a tu r e The mean value of the temperature

O ver a g e The excess quantity of drug that must be added to the

Pa ck a g ing All operations including filling and labeling, that a bulk

Pa ck a g ing M a ter ia l Any material, including printed material,

Ph a r m a ceu tica l Pr o d u ct Any medicine intended for human use or

Pr o ces s V a l id a tio n A validated manufacturing process is one which

Pr o d u ctio n All operations involved in the preparation of a

Q u a r a ntine The status of starting or packaging material,

Q u a l ity It is the intrinsic characters of the product which satisfy the

Q u a l ity As s u r a nce Is a wide-ranging concept covering all matters

Q u a l ity M a na g em ent Is the aspect of management function that

U til iz a tio n Per io d A period of time during which a reconstituted

Reco ncil ia tio n A comparison, making allowance for normal

Reco ver y (o r B l end ing ) The introduction of all or part of previous

Rep r o ces s ing The reworking of all or part of a batch of product of

Rea l T im e (L o ng T er m S ta b il ity S tu d y ) Evaluation of experiments