ICH, WHO, USFDA GUIDELINES ON STABILITY TESTING AND SHELF LIFE FOR INTERNATIONAL REGISTRATION OF PHARMACEUTICALS

Mr. Ajay Kumar Tiwari, M.Pharm Lecturer Department of Pharmaceutics, School Of Pharmaceutical Sciences Jaipur National University Jaipur

GLOBALISATION GLOBAL TRADE CUSTOMER QUALITY SERVICE.

WORLD WIDE MARKETING APPLICATIONS MINIMUM ACCEPTABLE STANDARDS EVOLVED BY

INTERNATIONAL CONFERENCE ON HORMONISATION

BY SELECTIVE COUNTRIES.

TO ELIMINATE REDUNDANT AND DUPLICATE REQUIREMENTS FOR REGISTRATION IN INDIVIDUAL COUNTRIES (LEGAL).

SIGNIFICANCE: BENEFITS ARE DIRECT IN TERMS OF SAVING - TIME, COST AND RESOURCES

PRE FORMULATION STUDY WITH API FOR

* STORAGE CONDITION * DOSAGE FORM DESIGN * SUITABLE CONTAINERS AND CLOSURES

ICHICH 1

EU, USA, JAPAN

YRS.

NOV. 1991 (BRUSSELS)

ICH 2

OCT. 1993 (FLORIDA)

ICH3

NOV. 1995 (YOKOHOMA)

ICH 4

JUL. 1997 (BRUSSELS)

ICH 5 2000 (JAPAN) DOES NOT SEEK NECESSARILY REGISTRATION FOR EXPORT TO OTHER AREAS OF THE WORLD

HARMONIZATION ON
EFFICACY QUALITY

SAFETY
MULTI

DISCIPLINARY

TABLE 1
TABLE 1: UPDATED LIST OF CODES, TOPICS AND CORRESPONDING GUIDELINES DEVELOPED BY ICH
CODE NAME OF THE TOPIC CODE NAME OF THE GUIDELINES DEVELOPED UNDER SPECIFIC TOPICS

A. EFFICACY
E1 EXPOSURE E1 THE EXTEND OF POPULATION EXPOSURE TO ASSESS CLINICAL SAFETY DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING

E2

CLINICAL SAFETY DATA MANAGEMENT

E2A

E2B

E2C

DATA ELEMENTS FOR TRANSMISSION OF INDIVIDUAL CASE SAFETY REPORTS PERIODIC SAFETY UPDATE REPORTS FOR MARKETED DRUGS
STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS DOSE-RESPONSE INFORMATION TO SUPPORT DRUG REGISTRATION

E3 E4

CLINICAL REPORTS

STUDY E3

DATA RESPONSE E4 STUDIES

E5

ETHNIC FACTORS

E5

ETHNIC FACTORS IN THE ACCEPTABILITY OF FOREIGN CLINICAL DATA

E6 E7

GOOD CLINICAL E6 PRACTICES CLINICAL TRAILS IN E7 SPECIAL POPULATIONS CLINICAL TRIAL E8 DESIGN

GOOD CLINICAL PRACTICE: CONSOLIDATED GUIDELINE CLINICAL TRAILS IN SPECIAL POPULATIONS : GERIATRICS GENERAL CONSIDERATIONS FOR CLINICAL TRAILS

E8

E9
E10

STATISTICAL PRINCIPLES FOR CLINICAL TRIALS

CHOICE OF CONTROL GROUP

B. QUALITY
Q1 STABILITY Q1A Q1B STABILITY TESTING OF NEW DRUGS AND PRODUCTS PHOTO STABILITY TESTING OF NEW DRUGS AND PRODUCTS

Q1C
Q2 ANALYTICAL VALIDATION Q2A Q2B

STABILITY TESTING FOR NEW DOSAGE FORMS

TEXT ON VALIDATION OF ANALYTICAL PROCEDURES VALIDATION OF ANALYTICAL PROCEDURE: METHODOLOGY

Q3

IMPURITIES

Q3A

IMPURITIES IN SUBSTANCES

NEW

DRUG

Q3B IMPURITIES IN NEW DRUG PRODUCTS Q3C IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS Q4 PHARMACOPOEIAS

Q5

QUALITY OF Q5A VIRAL SAFETY EVALUATION BIOTECHNOLOGICAL OF BIOTECHNOLOGY PRODUCTS PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN Q5B ANALYSIS OF THE EXPRESSION CONSTRUCT IN CELLS SUBSTRATES USED FOR PRODUCTION OF R-DNA DERIVED PROTEIN PRODUCTS

Q5C

STABILITY TESTING OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS

Q5D

Q6

SPECIFICATIONS FOR Q6A NEW DRUG SUBSTANCES AND PRODUCTS Q6B

DERIVATION AND CHARACTERIZATION OF CELL SUBSTRATES USED FOR PRODUCTION OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS CHEMICAL SUBSTANCES

BIOTECHNOLOGICAL SUBSTANCES

C.SAFETY
S1 CARCINOGENICITY STUDIES S1A GUIDELINE ON THE NEED FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS TESTING FOR CARCINOGENICITY OF PHARMACEUTICALS

S1B

S1C / ADDENDUM TO THE GUIDELINE Rev. ON DOSE SELECTION FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS : ADDITION OF A LIMIT DOSE AND RELATED NOTES S2 S2B A STANDARD BATTERY GENOTOXICITY TESTING PHARMACEUTICALS FOR OF

S3

KINETICS

S3A

NOTE FOR GUIDANCE ON TOXICOKINETICS: THE ASSESSMENT OF SYSTEMIC EXPOSURE IN TOXICITY STUDIES PHARMACOKINETICS: GUIDANCE FOR REPEATED DOSE TISSUE DISTRIBUTION STUDIES DURATION OF CHRONIC TOXICITY TESTING IN ANIMALS (RODENT AND NON RODENT TOXICITY TESTING) DETECTION OF TOXICITY TO REPRODUCTION FOR MEDICINAL PRODUCTS

S3B

S4

TOXICITY

S4A

S5

REPRODUCTIVE TOXICITY

S5A

S6

M1 M2

AN ADDENDUM TO TOXICITY TO MALE FERTILITY SAFETY STUDIES FOR S6A PRECLINICAL SAFETY BIOTECHNOLOGICAL EVALUATION OF PRODUCTS BIOTECHNOLOGY-DERIVED PHARMACEUTICALS D. MULTIDISCIPLINARY MEDICINAL TERMINOLOGY ELECTRONIC STANDARDS FOR TRANSMISSION REGULATORY INFORMATION (ESTRI) OF

S5B

M3

M4

GUIDELINE FOR THE TIMING OF NON-CLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRAILS FOR PHARMACEUTICALS THE COMMON TECHNICAL DOCUMENT

THE PHARMACOPOEIAL AUTHORITIES HAVE BEEN CLOSELY INVOLVED WITH THE WORK OF ICH
SINCE THE OUTSET AND HARMONIZATION BETWEEN THE MAJOR PHARMACOPOEIAS STARTED BEFORE ICH.

THE ICH STEERING COMMITTEE RECEIVES REGULAR REPORTS ON PHARMACOPOEIAL HARMONIZATION AT ITS MEETINGS.

WHO ADVOCATED ICH (17 MEMBERS) GUIDELINES TO ALL MEMBERS (191)

GLOBAL GUIDELINES GLOBAL DOSSIER (DOCUMENT)
REPORTS OF TOXICITY DUE TO DEGRADED PRODUCT

[EPIANHYDROTETRACYCLINE FANCONI (RENAL) SYMPTOMS] [DIMER/POLYMER OF PENICILLIN ALLERGY]

EFFECT OF ENVIRONMENTAL FACTORS (TEMP., LIGHT, HUMIDITY) TO BE AVOIDED

QUALITY, SAFETY, EFFICACY DURING SHELF LIFE (EXPIRY DATE) IS MUST BEFORE APPROVAL, STABILITY DATA AND STORAGE CONDITIONS TO BE SUBMITTED (LEGAL) ICH DEVELOPED - FOUR STABILITY GUIDELINES SHELF LIFE BASED ON LONG TERM TESTING AND NOT ON ACCELERATED OR STRESS TESTING

IMPLEMENTATION IN THE THREE REGIONS

C O D E NAME OF THE GUIDELINE STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS DATE OF DATE OF DATE OF DATE OF PUBLICATION ADOPTION ADOPTION FINALIZATION IN FEDERAL BY CPMP* IN BY MHW**, BY ICH REGISTER, EU JAPAN USA

Q1 A

OCT. 1993

DEC. 1993

APR.1994

SEP. 1994

Q1 B

NOV. 1996

DEC. 1996

MAY 1997

MAY 1997

*COMMITTEE FOR PROPRIETORY MEDICINAL PRODUCTS **MINISTRY OF HEALTH & WELFARE

Q1C

STABILITY TESTING FOR NEW DOSAGE FORMS

NOV. 1996

DEC. 1996

MAY 1997

MAY 1997

Q5C

STABILITY TESTING OF BIOLOGICAL / BIOLOGICAL PRODUCTS

NOV. 1995

DEC. 1995

JAN. 1998

JUL. 1996

DISADVANTAGE :
ICH COVERED NEW DRUG SUBSTANCES AND PRODUCTS ONLY. WHO DEVELOPED SEPARATE GUIDELINE FOR STABILITY TESTING OF ESTABLISHED DRUGS IN CONVENTIONAL DOSAGE FORMS.

US FDA WENT AHEAD AND CAME OUT STABILITY TESTING OF SOLID ORAL DOSAGE FORMS, DRUGS CONTAINING IRON FOR INDIA NO SPECIFIC GUIDELINES HAS TO FOLLOW ICH FOR MORE EXPORT POTENTIAL

STABILITY DATA GENERATION: Protocol (8 steps)

1. TYPE, SIZE AND NO. OF BATCHES:
Drug Substances Drug Products (Clinical Formulation)

AT LEAST 3 BATCHES (MINIMUM OF PILOT SCALES: SYNTHETIC ROUTE, METHOD OF MANUFACTURE SIMULATING FINAL MANUFACTURE)
QUALITY IS SAME AS THAT TO BE USED IN CLINICAL STUDY (ANY STABILITY DATA OF LAB SCALE MAY BE USED AS SUPPORTING DATA)

AT LEAST 3 BATCHES (PREFERABLY 3 DIFFERENT BATCH) OF DRUG PRODUCTS (ONE MAY BE FROM SMALLER: 25,000 TO 50, 000 TABLET OR CAPSULE) (TWO SHOULD BE AT LEAST PILOT SCALE)
QUALITY SAME AS THAT FOR MARKETING (LAB DATA ARE NOT ACCEPTABLE, DATA ON ASSOCIATED FORMULATION OR PACKAGING MAY BE USED AS SUPPORTING DATA)

2. TYPE, SIZE & SOURCE OF CONTAINER AND CLOSURES:

DRUG SUBSTANCES: IN PROPOSED BULK CONTAINER AND CLOSURE DRUG PRODUCT: IN PROPOSED DOSAGE FROM CONTAINER AND CLOSURE PROPOSED FOR STORAGE AND DISTRIBUTION MEANT FOR MARKETING
3. STORAGE ORIENTATION FOR FULL INTERACTION:

eg.

VIAL IN INVERTED POSITION

4. TEST PARAMETERS (ICH Q6):

DRUG ASSAY ANALYSIS OF DEGRADATION PRODUCTS PHYSICAL, CHEMICAL, MICROBIOLOGICAL QUALITY ATTRIBUTES (E.g. TABLET: DISSOLUTION TEST ETC.) LOSS OF PRESERVATIVE RELEASE SPECIFICATION PRESERVATIVE EFFICACY TESTING etc.

US FDA GIVES ELABORATE GUIDELINES: ASSAY AND DEGRADATION PUT TOGETHER BE 100 % OF INITIAL VALUE (MEET ADEQUACY OF MASS BALANCE)

5. TEST METHODS: (ICH Q6)

STP BE DEVELOPED FOR ANALYSIS: VALIDATED FOR SPECIFICITY, ACCURACY, PRECISION & LINEARITY LIMITS FOR DETECTION AND QUANTIFICATION PRESCRIBED. (REPLICATION IF NECESSARY)
6. ACCEPTANCE CRITERIA:

DERIVED FROM MATERIAL USED IN PRE AND CLINICAL STUDIES AND BIOAVAILABILITY STUDIES. IS FIXED AS NUMERICAL LIMITS.

EG.: MOISTURE PICKUP, VISCOSITY, PARTICLE SIZE, ASSAY, DEGRADATION PRODUCTS, IMPURITIES (INDIVIDUAL AND TOTAL UPPER LIMITS)

7. SAMPLING TIME POINTS: (TESTING FREQUENCY)

a)

REAL TIME TESTING (ICH): ON SAMPLES (LONG TERM) FREQUENCY OF 3 MONTH IN FIRST YEAR (MINIMUM PERIOD FOR INITIAL SUBMISSION) FREQUENCY OF 6 MONTH IN SECOND YEAR & THEN ANNUALLY (RE TEST PERIOD SUBMITTED DURING ASSESSMENT UP TO PROPOSED SHELF LIFE)

b) ACCELERATED CONDITIONS: (3 POINTS) ICH : 0,3,6 MONTHS IF REQUIRED. ADDITIONAL SAMPLES AT FINAL TIME OR A FOURTH TIME POINT. USFDA : 0,2,4 & 6 MONTHS WHO : 0,1,2,3 APPROPRIATE, 6 MONTHS c) INTERMEDIATE CONDITIONS: (IF FAILURE OCCUR AT ACCELERATED): FOUR TEST POINTS: 0,6,9,12 MONTHS

8. TEST STORAGE CONDITIONS:

IN CURRENT PRACTICE:

a) ISOTHERMAL CONDITION AND b) CONTROLLED HUMIDITY BOTH a & b (FOR STABILITY MANDATORY

STUDIES)

INSTEAD OF MULTI TEMPERATURE TESTING, SINGLE ACCELERATED TESTING IS ACCEPTED (ICH, WHO AND USFDA) HAYNES: 4 CLIMATIC ZONES (TABLE 4) IN WORLD CLIMATIC ZONE FOR WORLD STABILITY TESTING (TABLE 5)

TABLE 4 CLIMATIC ZONES FOR WORLD WIDE STABILITY TESTING

CLIMATIC ZONE MEASURED DATA MEASURED IN OPEN AIR DATA IN OC STORAGE ROOM %RH OC %RH

ZONE I : TEMPERATE
ZONE II : SUB-TROPICAL ZONE III : HOT / DRY ZONE IV : HOT / HUMID

10.9
17.0 24.4 26.5

75
70 39 77

18.7
21.1 26.0 28.4

45
52 54 70

CLIMATIC ZONE

CALCULATED DATA
OC OC

(MKT)

DERIVED STORAGE CONDITIONS %RH (FOR REAL TIME STUDIES) OC %RH

ZONE I : TEMPERATE

20.0

20.0

42

21

45

ZONE II : SUB-TROPICAL 21.6

ZONE III : HOT / DRY ZONE IV : HOT / HUMID 26.4 26.7

22.0
27.9 27.4

52
35 76

25
30 30

60
35 70

MKT = MEAN KINETIC TEMP.

TABLE 5. DISTRIBUTION OF WORLD NATIONS INTO DIFFERENT ZONES

REGION EUROPE AMERICA ZONE I AND II COUNTRIES ALL COUNTRIES ARGENTINA, BOLIVIA, CHILE, CANADA, MEXICO, URUGUAY, USA ZONE III AND IV COUNTRIES -----BARBADOS, BELIZE, BRAZIL, COSTA RICA, DOMINICAN REPUBLIC, ECUADOR, EI SALVADOR, GUATEMALA, GUYANA, HAITI, HONDURAS, JAMAICA, COLUMBIA, CUBA, NICARAGUA, DUTCH ANTILLES, PANAMA, PARAGUAY, PUERTO RICO, VENEZUELA. ALL OF THESE COUNTRIES ARE ASSIGNED TO CZ IV

ASIA

AFGHANISTAN, ARMENIA, AZERBAIJAN, CHINA, GEORGIA, IRAN, ISRAEL, JAPAN, KAZAKSTAN, KIRGHIZIA, KOREA, LEBANON, NEPAL, SYRIA, TADZHIKISTAN, TURKEY, TURKMENIA, UZBEKISTAN

BAHRAIN, BANGALADESH, HONG KONG, INDIA, INDONESIA, IRAQ (III), JORDAN (III), KAMPUCHEA, QATAR, KUWAIT, LAOS, MALAYSIA, MALDIVES ISLANDS, MYANMAR, OMAN, PAKISTAN, PHILIPPINES, SAUDI ARABIA, SINGAPORE, SRI LANKA, TAIWAN, THAILAND, UNITED ARAB EMIRATES, VIETNAM, YEMEN

AFRICA

EGYPT, ALGERIA, TUNISIA, LIBYA, MOROCCO, NAMIBIA, RWANDA, SOUTH AFRICA, ZAMBIA, ZIMBABWE

ANGOLA, ETHIOPIA, BENIN, BOTSWANA (III), BURKINA FASO, BURUNDI, DJIBOUTI, IVORY COAST, GABON, GAMBIA, GHANA, GUINEA, CAMEROON, KENYA, LONGO, LIBERIA, MADAGASCAR, MALAWI, MALI, MAURITANIA, MOZAMBIQUE, NIGER, NIGERIA, SENEGAL, SIERRA LEONE, SOMALIA, SUDAN, TANZANIA, TOGO, CHAD (III), UGANDA, ZAIRE, CENTRAL AFRICAN REPUBLIC FIJI, SOCIETY ISLANDS, MARSHOULD ISLANDS, NEW CALEDONIA, PAPUA-NEW GUINEA, SAMOA, TONGA

AUSTRALIAN AUSTRALIA, / OCEANIC NEW ZEALAND

A. GENERAL CASE: (FOR DRUG SUBSTANCE AND DRUG PRODUCTS)

STORAGE CONDITIONS:

FOR LONG TERM TESTING

ZONE I & II ZONE III & IV (ICH) ZONE III & IV (WHO) 25O 2O C; 60% R.H 5% R.H

30O 2O C; 60% R.H 5% R.H

MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: 12 MONTH CONTINUED FOR SUFFICIENT RESTEST PERIOD FOR ASSESSMENT.

FOR ACCELERATED TESTING (ICH & WHO)

40oC 2oC; 75% R.H 5% R.H;

MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: 6 MONTHS (DATA SUBMITTED AS IMPACT STUDY ABOUT SHORT TERM EXCURSION SIMULATING SHIPPING)
IF THE PRODUCT IS UNSTABLE IN THE ABOVE DURING 6 MONTHS

INTERMEDIATE CONDITIONS PERFORMED

30oC 2oC; 60% R.H 5% R.H; MINIMUM TIME PERIOD FOR INITIAL SUBMISSION: AT LEAST 6 MONTHS OUT OF 12 MONTHS

ACCEPTANCE: RESULTS WITHIN SIGNIFICANT CHANGE OTHERWISE NOT MEETING SPECIFICATION.

DEFINITION OF SIGNIFICANT CHANGE: 1. FAILURE TO MEET ACCEPTANCE CRITERIA LIKE APPEARANCE COLOUR PHASE SEPARATION RESUSPENDABILITY CAKING HARDNESS DELIVERY PER ACTUATION AND AS APPROPRIATE TO PRODUCT TYPE. 2. pH EXCEEDING 3. DISSOLUTION EXCEEDING FOR 12 DOSAGE UNITS 4. SPECIFIC DEGRADATION EXCEEDING 5. A 5% POTENCY CHANGE FROM INITIAL ASSAY

B. TO BE STORED IN REFRIGERATOR (FOR DRUG SUBSTANCE AND DRUG PRODUCT) : 5O 3O C MINIMUM 12 MONTHS FOR INITIAL SUBMISSION ACCELERATED : 25O 2O C; MINIMUM 6 MONTHS LONG TERM
IF SIGNIFICANT CHANGE OCCUR IN ACCELERATED

a. WITHIN 3 MONTHS, TEST NOT TO BE CONTINUED BUT STRESS TEST DATA TO BE SUBMITTED (OUTSIDE LABEL CONDITION) TO COVER SHIPPING CONDITION. b. BETWEEN 3 AND 6 MONTHS, ANY RETEST PERIOD (FOURTH) BASED ON REAL TIME TESTING.

C. TO BE STORED IN A FREEZER: (FOR DRUG SUBSTANCE AND DRUG PRODUCTS) LONG TERM : - 20O 5O C, AMBIENT HUMIDITY; MINIMUM 12 MONTHS FOR INITIAL SUBMISSION. RETEST PERIOD DEPEND ON STABILITY IN LONG TERM. ACCELERATED : 60% 5% R.H 5O 3O C;

STRESS TESTING: 25O 2O C

ON A SINGLE BATCH TO COVER OUTSIDE LABEL CONDITION (SHIPPING)

D. TO BE STORED IN DEEP FREEZER BELOW - 20O C (FOR DS & DP) TREATED CASE BY CASE BASIS

E. DRUG PRODUCT PACKED IN IMPERMEABLE CONTAINER (ICH / USFDA) SEMI SOLIDS IN SEALED COLLAPSIBLE TUBES,INJECTIONS GLASS AMPOULES ALUMINIUM IN SEALED

NO MOISTURE OR SOLVENT ENTRY OR LOSS (PERMANENT BARRIERS) THEREFORE CONDITIONS AS ABOVE (GENERAL REFRIGERATOR, FREEZER AT ANY RELATIVE HUMIDITY).

F. DP PACKED IN SEMI PERMEABLE CONTAINERS: (PLASTIC BAG, LOW DENSITY POLYETHYLENE POUCH FOR LVP, AMPOULES AND VIALS) i)AQUEOUS BASED PRODUCTS: EVALUATED FOR WATER LOSS UNDER LOW RH

Study Long Intermediate Accelerated

Condition 25O 2O C; 40%; R.H 5% R.H 30O 2O C; 60%; R.H 5% R.H 40O 2O C; 60%; NMT 25% R.H

Minimum Time Period at submission 12 months 6 months 6 months (water loss after 3 months)

SIGNIFICANT CHANGE: WATER LOSS OF > 5%. AFTER 3 MONTHS STORAGE AT ACCELERATED REQUIRED: THROUGHOUT THE PROPOSED SHELF IT SHOULD BE WITHIN ACCEPTANCE CRITERIA. ii) NON AQUEOUS BASED PRODUCT: ANY COMPARABLE APPROACH MAY BE FOLLOWED

STABILITY COMMITMENT: FOR DS AND DP

LONG TERM STUDY DATA ON PRIMARY BATCHES: A. IF NOT COVERED PROPOSED SHELF LIFE AT TIME OF APPROVAL, STUDY TO BE CONTINUED TO ESTABLISH SHELF LIFE AS WELL AS FOR POST APPROVAL B. IF COVERED PROPOSED SHELF LIFE, POST APPROVAL COMMITMENT NOT NECESSARY.

EVALUATION FOR DS AND DP

A. SHOULD BE SYSTEMATIC APPROACH B. IF DATA SHOW LITTLE VARIATION, (APPARENT BY LOOKING) : NO FORMAL STATISTICAL ANALYSIS C. ACCELERATED STABILITY DATA SHOW MORE STABILITY, SHELF LIFE MAY BE EXTENDED AT APPROVAL TIME (FOR LIMITED CASES)

D. STABILITY OF DRUG PRODUCT AFTER RECONSTITUTION OR DILUTION TO BE PROVIDED AS SUPPORTIVE INFORMATION

FOR STABILITY TESTING

3 TYPES OF EQUIPMENTS

a. HUMIDITY CUM THERMOSTATIC CHAMBERS b. REFRIGERATORS (5O 3O C; 15O 5O C ) c. THERMOSTATIC CHAMBERS WITH AMBIENT HUMIDITY (25OC, 30OC, 40OC) FOR PRODUCTS IN IMPERMEABLE CONTAINERS, AMPOULE, VIAL, etc. AVAILABLE IN STANDARD COMPANIES: ( REF. TABLE 7 )

Table 7 Name & addresses of a few International Vendors for ICH Stability Test Chambers ADDRESS VENDORS NAME CONTACT PERSON / LOCAL
AGENTS
ENVIRONMENTAL SPECIALTIES LIMITED 4412 TYRON ROAD, RALEIGH, NORTH CAROLINA, USA . PHONE. 919/829-9300 toll free 1-800-6885859, fax:919/829-7357 10940 DUTTON ROAD, PHILADELPHIA, PA 19154, USA ph.212-824-1700 fax:215-673-0519 toll free 1800-523-3608 ASIA PACIFIC REGIONAL OFFICE 7L-1 JALAN GOTTLIEB, 10350 PENANG, MALAYSIA FAX: + 60-4-2274831 BERGSTR. 14 D 78532 , TUTTLINGEN, GERMANY, PH. 0049/7461/1792-0; FAX: 0049/7461/1792-0 MR. EDWARD P. FRANTZ JR., PRODUCT MANAGER, SALES FAX : 919-833-9476 MR. JOE GRIPPI, NATIONAL SALES MANAGER, LOCAL AGENTS: BIONICS EQUIPMENT PTE LTD., 91-44-840512 MR. THILO KOPPE, SALES MANAGER ASIA PACIFIC

HOTPACK CORPORATION

VOTSCH INDESTRITECHNIK (PREVIOUSLY SOLD AS HERAEUS) WTB BINDER LABORTECHNIK GMBH

LOCAL AGENTS: S.V. INSTRUMENTS ANALYTICA PVT. LTD., 3269 RANJIT NAGAR, NEAR PUSA GATE, NEW DELHI 110008, PH. 5731571; FAX: 5761571, 5751590

SANYO GALLENKAM (USA)

900 N, ARLINGTON HEIGHTS RD. SUITE 320, ITASCA IL 60143, USA PH.708-875-3542; FAX: 708775-0427 TOLL FREE:1-800-528-7083 1719 RT. 10, SUITE 301 PARSIPPANY, NJ 07054, USA 1-800-LUNAIRE (5862473) FAX 201-540-0367

LUNIARE ENVIRONMENTAL

APPROACH 1: SAMPLES IN REPLICATE ANALYSE 1, OTHER KEPT AT LOW TEMP ALL SAMPLES ANALYSED AFTER LAST SAMPLES WITHDRAWN. (IMPROVED ASSAY MAY COME LATER). APPROACH 2: TAKE ONE OR TWO INITIAL SAMPLES. FROZEN KEEP FOR ENTIRE SHELF PERIOD FOR ASSAYS DONE AT DIFFERENT TIMES, IT IS KEPT AS INTERNAL STANDARD AND MAKE CORRECTIONS IF NECESSARY.

STABILITY DATA IS RECORDED IN AN ORGANIZED WAY AND DOCUMENTED (REF TABLE 8 & 9) FOR DIFFERENT SCIENTIFIC SITUATIONS ALTERNATIVE APPROACHES MAY BE USED

TABLE 8. COMPARISON OF THE CURRENT AND HARMONIZED PROTOCOLS FOR WORLD WIDE MARKETING.
STORAGE CONDITION TEMP. OC HUMIDITY (%RH) TESTING INTERVAL (MONTHS) 1 2 3 6 9 12 18 24 30 36 48 60

A. CURRENT WORLD WIDE STABILITY TESTING PROTOCOL 2 X X X X X X X X X X 5 X X X X X X X X X X 8 X X X X X X X X X X 15 X X X X X X X X X X 20 X X X X X X X 25 60 X X X X X X X X X X 25 75 X XX X X X X X X X X 30 40 X X X X X X X X X X

X X

X X X X X X

30 70 X X X X X X X X X X 40 25 X XX X X X X X X X 40 75 X XX X X X 40 90 X XX X 50 X XX 60 X XX 70 X B. WORLD WIDE STABILITY PROTOCOL FOR MARKETING APPLICATIONS: HARMONIZED PROTOCOL 2 X X X X X X X X 25 60 X X X X X X X X 30 60 X X X X X X X X 40 75 X X X

X X

TABLE 9. SAMPLE FORMAT SHEET FOR RECORDING STABILITY INFORMATION STABILITY RAW DATA

PRODUCT NAME / STRENGTH : STUDY NUMBER : BATCH NUMBER : DATE OF MANUFACTURE : CONTAINER / SIZE / SUPPLIER :

DATE STUDY STARTED : BATCH SIZE :

MANUFACTURER / SITE :
SEAL SUPPLIER : PACKAGER / SITE :

CLOSURE COMPOSITION / SUPPLIER : DATE PACKAGED : STORAGE CONDITION : CHAMBER # :

STORAGE ORIENTATION : SHELF # : LOCATION :

ATTRIBUTES

METHOD SPECIFICA TIME (MONTHS) TION Sop # (LOW / 0 3 6 9 12 18 24 etc HIGH)

APPEARANCE ASSAY DEGRADATION PRODUCT A DEGRADATION PRODUCT B DEGRADATION PRODUCT C ETC.

CONDUCT OF STABILITY STUDY AND RECORDING OF STABILITY DATA:

SAMPLE IN SELECTED STORAGE CONDITIONS. SAMPLING AT PRESCRIBED INTERVALS.. ANALYZING IMMEDIATELY (IF FORCED, FROZEN IMMEDIATELY TILL ANALYSIS)

AVOIDANCE OF CALENDRIC ASSAY BIAS ( DAY TO DAY VARIABILITY)

ICH GUIDELINES OF PHOTOSTABILITY TESTING

DONE ON BOTH DRUG SUBSTANCE AND PRODUCT (ICH QIB). AT LEAST ONE PRIMARY BATCH

LIGHT SOURCE
1. ARTIFICIAL DAY LIGHT FLUORESCENT LAMP / XENON OR METAL HALIDE LAMP (SIMILAR TO D65/ID65 EMISSION STANDARD) 2. EXPOSURE OF SAMPLE TO COMBINATION OF COOL LIGHT FLUORESCENT LAMP AND A NEAR UV LAMP (FROM 320NM TO 400 NM)

EXPOSE SAMPLES TO OVERALL ILLUMINATION OF NOT LESS THAN 1.2 MILLION LUX HOURS AND AN INTEGRATED NEAR UV LIGHT OF NOT LESS THAN 200 WATT HOURS/SQUARE METER ( SIDE BY SIDE SAMPLES BE EXPOSED TO A VALIDATED ACTINOMETRIC SYSTEM)

DECISION FLOW CHART FOR PHOTO STABILITY TESTING OF DRUG PRODUCTS:

Formulation Change? Yes

Start

Directly Exposed

Acceptable Change?
No Immediate pack Change? Yes Immediate Pack

Yes

Test End

Acceptable Change? No Marketing pack Change? Redesign Package or Reformulation No Marketing Pack

Yes Test End

Acceptable Change?

Yes

Test End

ICH GUIDELINES (QIA) STATISTICAL TREATMENT

STABILITY DATA FROM THREE BATCHES SUBJECT TO STATISTICAL TEST TO CHECK WHETHER TO POOL OR NOT DIFFERENT POSSIBILITIES OF CONCENTRATION - TIME DATA

Time

SLOPES AND INTERCEPTS EQUAL (DATA POOLED)

Time

SLOPES EQUAL, INTERSECTS DIFF. (BATCH VARIATION)

Time

SLOPES VARY INTERCEPTS SAME (DIFFERENT LOSS STORAGE FACTOR)

Time

SLOPES AND INTERCEPTS DIFF. (BATCH & STORAGE FACTOR) II

STATISTICAL SIGNIFICANCE:
t Table At A p VALUE OF 0.25 (p VALUE FOR LEVEL OF SIGNIFICANCE OF REJECTION OF MORE THAN 0.25)
IF DATA IS NOT REJECTED, THREE DATA ARE POOLED IF P VALUE LESS THAN 0.25 , DECISION MADE BY JUDGEMENT, ESTIMATES ARE MADE FORM WORST BATCH WE HAVE POOL OF THREE BATCH OR A INDIVIDUAL WORST BATCH DATA HAS FIVE POINTS (INITIAL, 3,6,9 & 12 MONTHS)

NOW, SHELF LIFE IS ESTIMATED BASED ON 95%ONE SIDED CONFIDENCE LEVELS (NOW INCLUDED IN USFDA ALSO)Q

100 Linear Regression Line (50% Confidence Limit Line)

Time (Months)

100

Not statistically significant

Time (Months)

One sided 95% confidence

100 95 90

Along regression line

Time (Months)

Read time (Shelf life) taken for 90% Label claim

EXTRAPOLATION BEYOND EXPIRY DATA IS DISCOURAGED. ACTUAL STABILITY DATA UPTO GRANTED EXPIRATION TIME IS REQUIRED ADDITIONAL GUIDELINES BY USFDA
EXPIRY

DATE BEGIN FROM QUALITY CONTROL RELEASE OF THE BATCH ------- DATE OF RELEASE NOT TO EXCEED 30 DAYS FROM PRODUCTION DATE IRRESPECTIVE OF PACKAGING DATE DATE IS UPTO LAST DAY OF MONTH (ALTHOUGH THERE IS NO SUDDEN DEATH)

EXPIRY

ADDITIONAL POINTS: SOFTWARE PACKAGES TO HANDLE STATISTICAL DATA AS PER ICH OR FDA ARE AVAILABLE DRUG FORMULATION STABILITY PGM (STAB) DEVELOPED BY US FDA AVAILABLE FREE OF CHARGE ( INTERNET SITE www.fda.gov) SOFTWARE (SAS): COMMERCIAL PACKAGE AVAILABLE
a. b.

c.

J.T. CARSTENSEN, 1995, DRUG STABILITY PRINCIPLES AND PRACTICES, 2ND EDN. MARCEL DEKKER, NEW YORK. P.WESSELS ET AL., STATISTICAL EVALUATION OF STABILITY DATA FOR PHARMACEUTICAL PRODUCTS FOR SPECIFICATION SETTING DRUG. DEV. IND. PHARM 24, 313 (1998) EQUATION FOR CALCULATING CONFIDENCE LIMIT AND ANOTHER DETAILS AVAILABLE. COMMON STATISTICAL PACKAGE (SIGMASTAT): USEFUL FOR CALCULATING LIMITS OF REGRESSION LINE.

SUMMARY
ICH GUIDELINES : ONLY FOR NEW DRUG SUBSTANCES AND PRODUCTS. WHO GUIDELINES: FOR ESTABLISHED DRUG IN CONVENTIONAL DOSAGE FORM ALLOWS 24 MONTHS SHELF LIFE STUDY..NO SUGGESTION OF STATISTICAL TREATMENT.
VARIOUS CONDITIONS ARE1. MOIETY IS KNOWN TO BE STABLE 2. STABILITY STUDIES CARRIED OUT AS PER ACCELERATED STUDY FOR ZONE III AND IV WITH NO SIGNIFICANT CHANGE 3. SUPPORTING DATA INDICATE SIMILAR FORMULATION ASSAYED FOR SHELF LIFE OF 24 MONTHS OR MORE. 4. MANUFACTURER CONTINUE REAL TIME STUDY UNTIL PROPOSED SHELF LIFE IS CONVERED

 GUIDELINES

ARE GUIDELINES.. DIFFICULTIES AND COMPLEXITIES MAY ARISE. ALTERNATE APPROACHES ARE POSSIBLE.. IT SHOULD BE CONVINCING WITH GUARANTEE FOR PROTECTION (GOAL OF REGULATORY AUTHORITIES ALSO)

STABILITY DATA HANDLING AND SHELF LIFE ESTIMATION CONVENTIONAL (NOW IT IS STRESS TESTING)
MULTI TEMPERATURE ACCELERATED TESTING USING CLASSICAL ARRHENIUS APPROACH EFFECT OF TEMPERATURE ON REACTION VELOCITY: K = S.e-Ha/RT
K = Specific Rate Degradation R = Gas Constant (1.987 cal. Deg 1mole-1 Ha = Heat Of Activation T = Absolute Temperature (=oC + 273) S = Frequency Factor = 8.314 x 107erg. Mole 1 deg-1 it is: log K = -Ha/2.303 R.1/T + log S = Plot log K (vs) 1/T; Slope is calculated -Ha/2.303R; Ha Is

K VALUE AT LOW TEMPERATURE MAY BE OBTAINED (Ref. Fig 1)

Fig 1
80oC 70oC 60oC 50oC 40oC

30oC

25oC

20oC

Fig 3
25oC 40oC 50oC 60oC 70oC 80oC

1/T
100% 90%

Fig 2
% Drug conc. (log scale)

40oC 50oC 60oC 70oC 80oC

1/T

Time in days

PRIMARY DATA FOR MULTI TEMPERATURE INITIAL CONCENTRATION = a TEMP. CONCENTRATION AT DIFFERENT K TIME VALUES 2 6 12 HOURS HOURS HOURS 24 HOURS

(a-x)
40oC 50oC 60oC

K=2.303/t log a/a-x

FIRST ORDER KINETICS

ANOTHER METHOD: PLOT TIME (DAYS) VS LOG % CONC.REMAINING

READ DAYS TO 90% (LOG SCALE) (REF. FIG 2)

---------PLOT THIS WITH 1/T (REF. FIG 3) T 90% IS READ DIRECTLY. EXCESS QUANTITY OF DRUG (OVER AGE) TO BE ADDED TO MAINTAIN 100% OF LABELED AMOUNT DURING SHELF LIFE (NOT FOR POTENT DRUGS)

DISADVANTAGES
ONLY FOR DRUGS UNDERGO DEGRADATION WITH TIME NOT POSSIBLE TO FIND OUT ORDER OF REACTION CHANGE IN DEGRADATION MECHANISM ABOVE CRITICAL TEMPERATURE IS IGNORED

HENCE

ACCELERATED STABILITY TESTING IS : SUPPORTING ROLE NOW FOR NDA; O.K. ONLY FOR QUALITY CONTROL MEASURES.

STORAGE CONDITION IS NECESSARY DURING SHELF LIFE: TO BE MENTIONED IN LABEL.

ICH: STORAGE TEMPERATURE SPECIFIC RANGE BASED ON NATIONAL / REGIONAL REQUIREMENTS (AMBIENT / ROOM TEMPERATURE CONDITION NOT ALLOWED).

WHO:
STORE 2 8OC (UNDER REFRIGERATION, NO FREEZING) STORE BELOW 8OC (UNDER REFRIGERATION) STORED BELOW - 8OC TO - 20OC(IN FREEZER) STORE BELOW -18OC (DEEP FREEZER) STORE UNDER NORMAL CONDITION (IN DRY, WELL VENTILATED PREMISE OF 15 25OC UPTO 30OC ; EXTRANEOUS ODOUR, CONTAMINATION, INTENSE LIGHT TO BE EXCLUDED). STORAGE CONDITION AT THE COUNTRY OF USE ALSO FOLLOW F.I.F.O (FIRST IN FIRST OUT SYSTEM) ALSO F.I.F.E.O (FIRST IN FIRST EXPIRY OUT)

STRESS TESTING FOR DS AND DP: (DATA OUTSIDE LABELED CONDITION ) SINGLE BATCH OF MATERIAL EFFECT OF ACCELERATED TEMPERATURE (EG. 50O, 60O.) HUMIDITY (75% RH OR ABOVE), OXIDIZATION, PHOTOLYSIS, HYDROLYSIS OVER DIFFERENT pH WITH SOLUTION OR SUSPENSION TO ESTABLISH INTRINSIC STABILITY BY STUDYING DEGRADATION PATHWAYS AND MECHANISMS, DEGRADATION PRODUCTS AND TO ESTABLISH SUITABLE ANALYTICAL PROCEDURE AND ITS VALIDATION (THEREFORE STRESS TESTING WILL NOT PREDICT PHYSICAL CHANGES). SINCE IT MAY OCCUR DURING SHIPPING. ALTHOUGH PRODUCTS OF HIGHER STRESSES UNLIKELY IN STORAGE CONDITION, (RESULT FROM INTEGRAL PART OF SUBMISSIONS).

THE CONTENT OF AMPOULES ARE ANALYSED AT DIFFERENT TIME INTERVALS

AMPOULE CONTAINING O2 ABOVE THE SOLUTION 1. EXPOSED TO LIGHT EXPOSED TO HEAT STORED IN DARK

AMPOULE MARK

AMPOULE CONTAINING NITROGEN GAS ABOVE THE SOLUTION EXPOSED TO LIGHT EXPOSED TO HEAT STORED IN DARK

AMPOULE MARK

A1

B1

2.

A2

B2

3.

A3

B3

THE RESULTS ARE SUMMARIZED AS FOLLOWS:

DECOMPOSITION IN ALL THE AMPOULES IRRESPECTIVE OF THE AMPOULES HAVING OXYGEN OR NITROGEN ABOVE THE SOLUTION INDICATES HYDROLYTIC DECOMPOSITION. DEGRADATION BY OXIDATION IS INDICATED BY THE DECOMPOSITION IN ONLY THREE GROUPS OF AMPOULES (A1,A2 AND A3) CONTAINING OXYGEN IRRESPECTIVE OF EXPOSURE TO LIGHT, HEAT OR DARKNESS. A PHOTOCHEMICAL REACTION IS INDICATED BY THE DECOMPOSITION ONLY IN AMPOULES A1 AND B1 GROUPS EXPOSED TO LIGHT. THERMAL DECOMPOSITION IS INDICATED BY THE DECOMPOSITION ONLY IN A2 AND B2 AND NOT IN ALL THE OTHER AMPOULES. IN A SIMILAR WAY, THE EFFECT OF PH ON DECOMPOSITION OF DRUG SOLUTIONS CAN BE CARRIED OUT.

BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS BRACKETING is the design of a stability schedule such that only the extremes of certain design factors are tested at all time points. MATRIXING is the design of a stability schedule such: that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested.

(ICH Q1D)

BRACKETING
SAMPLES ON THE EXTREMES ARE TESTED AT ANY TIME FOR STABILITY Eg. (A) CONTAINER SIZE (B) DOSAGE STRENGTHS. STABILITY OF INTERMEDIATE REPRESENTED BY THE EXTREMES. SAMPLES ARE

CONDITION: (a) FOR MATERIAL OR CONTAINER COMPOSITION AND TYPE OF CLOSURE ARE SAME FOR ALL. (b) FOR STRENGTH TO BE CLOSELY RELATED IN COMPOSITION (TABLETS WITH DIFFERENT COMPRESSION WEIGHTS / CAPSULE WITH DIFFERENT FILL WEIGHTS BUT SAME COMPOSITION)

 MATRIXING:

(STATISTICAL DESIGN)
FRACTION OF TOTAL NUMBER OF SAMPLES TESTED AT ANY SPECIFIED SAMPLING POINT & AT SUBSEQUENT SAMPLING POINT, DIFFERENT SETS OF SAMPLES OF TOTAL NUMBERS

RESULT WILL REFLECT ON STABILITY OF ALL SAMPLES DIFFERENCES IN THE SAMPLES OF SAME PRODUCT MAY BE DIFFERENT

Batches Strengths Size of same container and closures

WHEN MORE THAN ONE VARIABLE, REDUCED TESTING DESIGN OF MATRIX DICTATED BY ALL FACTORS DESIGN TO BE DISCUSSED WITH LICENSING AUTHORITIES IT IS ESSENTIAL ALL BATCHES ARE TESTED INITIALLY AND END OF LONG TEST TERM TESTING

TABLE - 3
EXPORT OF BULK & FORMULATIONS (RS. IN CRORES)
YEAR 92-93 93-94 94-95 95-96 2005 2006 FORMULATIONS 553.70 771.80 1336.30 1028.00 9000 BULK DRUGS 856.06 1009.60 842.80 1518.00 16,000 TOTAL 1410.03 1781.40 2179.10 2536.00 25,000

HOWEVER 2% OF WORLD CONTRIBUTION REASON : STRINGENT REGULATORY & APPROVAL REQUIREMENTS

BENEFITS OF HARMONISATION
SAVING OF TIME RESOURCES COST (SAVINGS OF 2/3 COST OF IN DUPLICATION TEST FOR OTHER COUNTRIES) POTENTIAL EXPORT POSSIBILITY IN THE GLOBAL TRADE INDIA IS FAST PICKING UP.

KINETICS AND DRUG STABILITY

Rate velocity with which the chemical reaction occurs. drug A drug B If the amount of the drug A is decreasing with respect to time (i.e. the reaction is going in a forward direction:

GENERAL CONSIDERATIONS AND CONCEPTS

The negative sign concentration of drug A decreases with time. Since the amount of drug B is increasing with respect to time, the rate of the reaction : The positive sign the concentration of the product B increases with time. Usually, in pharmacokinetics, only the parent (or pharmacologically active) drug is measured experimentally. metabolites / products of the decomposition of the drug may not be known or may be very difficult to quantitate. Hence, The rate of a reaction is determined experimentally by measuring the disappearance of drug A at given time intervals.

Order of a reaction If C is the concentration of drug A, the rate of decrease in C (of drug A) can be expressed by a general expression as function of time, t as: dC/dt=-kCn Where k = rate constant and n = order of the reaction. If n = 0 then the reaction is called a zero-order reaction, if n = 1 then the reaction is called a first-order reaction. if n = 2 then the reaction is called a second order reaction.

If a reaction is: aA + bB Product and if the reaction rate = k [A] a [B]b then the reaction is said to be (a + b) order.

Molecularity of a reaction over all reaction take place by several steps. Each step elementary step. order of each elementary step the number of reactant molecules taking part in that reaction, hence, the order of an elementary step called the molecularity of the reaction. Specific rate constant The constant k associated with a single step (elementary) reaction called a specific rate constant for that reaction. If the specific rate constant of an elementary reaction is changed by some factors (like temperature, light, catalyst, solvents etc.) overall reaction rate will also change.

Zero-Order Reactions

If the concentration of drug A is decreasing at a constant time interval t. then the rate of disappearance of drug A is expressed as: dC/dt= -ko The term k0 is the zero-order rate constant and is expressed in units of concentration / time [e.g. (mg/ml)/ min).] C = k0 t + C0 where C0 is the concentration of drug at t= 0. Half life of the reaction: At t = t1/ 2 C = C0. Replacing t and C in above eq. C0. = k0 t1/ 2 + C0. or, t1/ 2 = c0/2ko Graphical representation

Fig: Plot of Conc vs. time

Fig. Rate vs. time

1st Order Reactions

In first order reaction the rate of reaction is proportional to the concentration of the drug remaining and can be expressed as: dC/dt=- kC1 dC/C= - k.dt C = C0 e k t log C = -kt/2.303 + log C0 Half life of the reaction t1/2 = 0.693/k Graphical representation

INFLUENCE OF TEMPERATURE AND OTHER FACTORS ON REACTION RATE Influence of temperature The speed of many reaction increases about two to three times with each 100 C rise in temperature. The effect of temperature on a rate constant of a reaction is given by the equation, first suggested by Arrhenius, k is the specific reaction rate, Ea A is a constant known as the Arrhenius factor or k A e RT Frequency factor Ea is the energy of activation Ea 1 R is the universal gas constant log k log A 2.303 R T T is the absolute temperature A plot of log k vs 1/T yields a slope equal to Ea / 2.303 R from which the value for the energy of activation ( Ea) and Arrhenius factor (A) can be calculated.

So Ea = Slope x 2.303 R and A = 10 intercept

Influence of light (Photoreaction)

Light energy (like heat) provide the activation energy necessary for a reaction to occur. The energy unit of light radiation is photon = equivalent of 1 quantum of energy. The photochemical reaction rate depends on the wavelength of light, intensity of light and the number of photons actually absorbed by the material. Examples: Ergosterol, under UV light, transforms into Vitamin D. Oxidation of benzaldehyde by light. Adriamycin, furosemide, menadione, nifedipine, sulfacetamide, theophylline etc. undergoes photo-degradation. Study of photo reactions are required to prepare suitable packaging material for the product e.g. color-glass bottles or paper box or aluminium foil etc.

Influence of solvent
Reactant (solvent ) Product The following facts are found: If polarity of product > polarity of reactant then reaction rate increases if the solvent is more polar. If polarity of product < polarity of reactant then reaction rate increases if the solvent is less polar.

Influence of catalytic species

The rate of a reaction is influenced by the presence of a catalyst. Equillibrium constant k forward K k reverse
Catalyst : a substance that influences the rate of a reaction but itself remain unchanged chemically. increases both forward and backward reaction rate, hence cannot change K. does not affect the yield of the product also. Only makes the reaction faster. Negative catalyst: reduces the rate of reaction. e.g. Phosphoric acid reduces the reaction rate of H2O2 H2O + O2. Inhibitor: A substance that reduces the rate of reaction and itself gets changed chemically. Homogeneous catalysis: If the catalyst and the reactants remain in the same phase. e.g. Hydrochloric acid catalyses the hydrolysis of sugar. Heterogeneous catalysis: If the catalyst and the reactants are in separate phases. e.g. Platinum powder is suspended in reaction medium of hydrogenation reaction. Catalyst poison: Substances those reduces the action of catalyst. e.g. Copper acts as catalyst in hydrogenation of ethylene. Carbon monoxide acts as poison of copper. Promoters: Substances those increases the activity of a catalyst. e.g. Ferric ion (Fe3+) acts as catalyst in decomposition of hydrogen peroxide. Cupric ion (Cu++) act as promoter to ferric ion.

ACCELERATED STABILITY STUDY

Accelerated stability testing: Instabilities in modern formulations are often detectable only after considerable storage periods under normal conditions. To reduce the time required to obtain information, various tests that involve storage of the products under conditions that accelerate decomposition have been introduced. Objectives of accelerated stability tests: the rapid detection of deterioration in different initial formulations of the same product this is used in selecting the best formulation from a series of possible choices; the prediction of shelf life, which is the time a product will remain satisfactory when stored under expected or directed storage condition; and the provision of rapid means of quality control, which ensures that no unexpected change has occurred in the stored product. All these objectives based on obtaining a more rapid rate of decomposition by applying to the product a storage condition that places a higher stress or challenge to it when compared with normal storage conditions.

Common high stresses or challenges: (a) Temperature An increase in temperature causes an increase in the rate of chemical reactions. The products are therefore stored at room temperatures greater than room temperature. The nature of the product often determines the range covered in the accelerated test. Samples are removed at various time intervals and the extent of decomposition is determined by analysis. (b) Humidity Storage of the product in atmospheres of high humidity will accelerate decomposition that result from hydrolysis. Marked acceleration will be obtained if a naked product (i.e. not enclosed in a container) is subjected to these tests. This type of stability tests are useful in determining the degree of protection that should be afforded by the container. (c) Light A source of artificial light is used to accelerated the effect of sunlight or sky light. the source should emit a similar distribution of radiant energy to that in sunlight because photochemical reactions involve the absorption of light of definite wavelengths. Day light fluorescent lamps provide a satisfactory source.

THE PREDICTION OF SHELF-LIFE: Say, the room temperature = 250C

Method 1: Prediction from Arrhenius plot: Concentration of undecomposed drug is plotted against time (hr) at various temperature above room temperature (250C) The stability constants at various temperatures are plotted in Arrhenius plot (i.e. log k vs 1/T). From the Arrhenius plot the stability constant at room temperature i.e. (k determined by extrapolation.
25)

is

Let us assume that when the drug is 10% decomposed it is to be said that the product has expired. i.e. at time t = 0 hour drug concentration remaining = 100% at time = t hour drug concentration remaining = 90%
Now we have to calculate the time t.

If the product is kept at room temperature (250C) then the following equation from 1st order kinetics may be used: log C = log Co (k25 /2.303) x t or, t = (2.303 / k25) = (2.303/k25) log (Co / C) = (2.303/k25) log (100/90) Since k25 value is known, therefore t can be calculated.

Method -II: Simplified techniques for stability prediction:

Free and Blythe describe such technique for liquid products where the decomposition behaves according to the general kinetic laws. In this case log(% of drug remaining) is plotted against time (in days). From the graph the time for the potency (concentration) to fall to 90% of the original value (i.e t90% ) are read at different temperature. Then the log (t90%) is plotted against (1/T) and the time at 250C gives the shelf life of the product (in days). Expiry time = Time required for 90% degradation at room temperature (i.e. 250C) = t25.

REFERENCES
1. SARANJIT SINGH, UNDERSTANDING ICH HARMONIZATION PROCESS. THE EASTERN PHARMACIST, 60 (474), 21 (1997). 2. SARANJIT SINGH, ICH GUIDELINES THE LATEST DEVELOPMENT. THE EASTERN PHARMACIST, 60 (479), 41 (1997). 3. SARANJIT SINGH, AN UPDATE ON ICH PROCESS. THE EASTERN PHARMACIST, 61 (487), 43 (1998). 4. SARANJIT SINGH, DRUG STABILITY GUIDELINES FOR INTERNATIONAL REGISTRATION OF PHARMACEUTICLAS, PHARMATIMES, 28 (8), 29 (1997).

5.

6.

7.

8.

W. R. FAIWEATHER, T. Y. D. LIN AND R. KELLY, REGULATORY DESIGN AND ANALYSIS ASPECTS OF COMPLEX STABILITY STUDIES, J. PHARM. SCI. 85, 1322 (1995) J. D. HAYNES, WORLD-WIDE VIRTUAL TEMPERATURES FOR PHARMACEUTICAL PROCESS STABILITY TESTING. J. PHARM. SCI. 60, 927 (1971) W. GRIMM, EXTENSION OF THE INTERNATIONAL CONFERENCE ON HARMONIZATION TRIPARTITE GUIDELINE FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS TO COUNTRIES OF CLIMATIC ZONES III & IV. DRUG DEV. IND. PHARM. 24, 313 (1998) SARANJIT SINGH, DRUG STABILITY TESTING LABORATORY: TIME TO CHANGE THE PRIMITIVE LOOK. THE EASTERN PHARMACIST, 37 (435), 53 (1994)

9. W. R. YOUNG, ACCELERATED TEMPERATURE PHARMACEUTICAL PRODUCT STABILITY DETERMINATIONS. DRUG DEV. IND. PHARM., 16, 551 (1990) 10. J. T. CARSTENSEN, 1995,DRYG STABILITY PRINCIPLES AND PRACTICES, 2ND ED., MARCEL DEKKER, NEW YORK. 11. P. WESSELS, M. HOLZ, F. ERNI, K. KRUMMEN AND J. OGROKA, STATISTICAL EVALUATION OF STABILITY EVALUATION OF STABILITY DATA FOR PHARMACEUTICAL PRODUCTS FOR SPECIFICATION SETTING, DRUGDEV. IND. PHARM., 24 313 (1998) 12. ICH GUIDELINES ARE AVAILABLE AT http:/www.fda.gov/guidance

13. ICH Q1B PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS (Nov. 1996) 14. ICH Q1C STABILITY TESTING FOR NEW DOSAGE FORMS (Nov. 1996) 15. ICH Q3A IMPURITIES IN NEW DRUG SUBSTANCES (JAN 1996) 16. ICH Q3B IMPURITIES IN NEW DRUG SUBSTANCES (NOV 1996) 17. ICH Q5C QUALITY OF BIOTECHNOLOGICAL PRODUCTS; STABILITY TESTING OF BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS (JULY 1996)

18. ICH Q6A SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: CHEMICAL SUBSTANCES (DEC 2000) 19. ICH Q6B SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES AND NEW DRUG PRODUCTS: BIOTECHNOLOGICAL / BIOLOGICAL PRODUCTS (AUGUST 1999)