MODULE 5: MANUFACTURING PHARMACY 2.

Production Department
 Manufactures product according
I. INTRODUCTION
to schedule
 Includes warehousing and
A. MANUFACTURING
storage
 Large scale production drug product
 Preparation, processing, packaging,
3. Quality Assurance Department
labeling, repacking, and changing the
 Assures all operation meet the
container, wrapper or label of any
required standards of safety and
drug product
efficacy
MANUFACTURING ACTIVITIES  Ensures compliance CGMP
 Conducts quality audit and
1. Primary Manufacturing
monitoring
 Manufacture of APIs and
 Cooperates with regulatory
excipient
agencies
2. Secondary Manufacturing
 Prepare SOP (Standard
 Manufacture of finished dosage
Operating Procedure)
forms
3. Tertiary Manufacturing
4. Quality Control Department
 Packaging, labeling or repacking
 Test compliance of RM, PM and
of bulk finished product
finished product
4. Toll Manufacturing
 Conduct sampling of materials
 An arrangement whereby a
competent company  Performs IPQC and
manufactures the products for environmental testing
another company
5. Marketing Department
B. DEPARTMENT IN A MANUFACTURING  Studies current market trends,
PLANT consumer behavior and product
status in the market
1. Research and Development  Advertisement and promotion
Department
 FORMULATES new product 6. Regulatory Department
 Reformulate existing product  Ensures compliance of the
 Does chemical pharmaceutical company and its product with all
and physiological research pertinent regulations & law
about drugs and their marketing
 Facilities
o Library  LTO initial: 2yrs, Renew: 3yrs
o Animal house  Certificate Product Registration
o Pilot plant (CPR)

1
 7. Engineering Department  Theoretical yield: Actual yield
 Install, maintain and repairs (not written ≠ not happen)
equipment and premises
 Ensures safety (employee) 6. Standard Operating Procedures
(SOPs)
8. Medical department  Step-by-step instructions for
 Concerned w/ the physical performing operational task or
examination and medical activities
treatment of employee
 Perform clinical studies 7. Manufacturing Order
 Publishes house organ/ paper  Gives instruction to the
(Clinical Research) production department of
manufacturing product
C. TERMS TO REMEMBER
8. Overage
1. Batch  Addition of an active in an
 A specific quantity of product unstable preparation to
having uniform character and compensate for drug loss during
quality produced during a single manufacturing/ manufacture
manufacturing process
2. Lot 9. Quarantine
 Specific identified portion of a  Designated area for holding of
batch incoming components prior to
acceptance testing and
3. Batch/ lot number qualification for use (Yellow
 For identification and traceability Label)
of a single batch/ lot  Green = Passed
 Red = Failed (double lock)
4. Master Formula
 Contains the formulation, 10. Validation
manufacturing procedures specs,  Documented evidence that a
QA requirement and labeling of a system does what is it supposed
finished product to do
 (3 batches)
5. Master Batch Record/ Batch  HVAC system (Heating
Manufacturing Record Ventilation Aircon)
 Ensures the batches were  Cleaning
properly made and Q.C. test was
performed

2
 II. PACKAGING, LABELING AND STORAGE c. Hermitic
OF DRUGS  Impervious to air or any other gas
(Parenteral)
A. PACKAGING
 Economic way of protecting,
d. Light-Resistant
preparing, identifying and
 Protect from photochemical
containing drug product
degradation (amber bottle = 100%
 Composed of a container and its
protection against light)
closure
TYPES OF PACKAGING e. Child resistant
 Difficult for children under 5 yrs.
1. Primary Packaging
of age
 Immediate container
 Press down and turn
 Direct contact w/ the product
 Align the arrows
 Affect stability
 Latch tap
 May be used for administration
 Pharm. Coil:
f. Tamper resistant
o Cotton in the drug product
 Uses an indicator which if
o To prevent rattling
breached or missing can provide
 Desiccant – prevent absorption
evidence that tampering has
of moisture
occurred
o Shrink seal/ wrap
2. Secondary Packaging
o Breakable cap
 Outer packaging
o Tape seal
 Encloses 1 or more primary o Bottle seal
packaging o Aerosol – only true tamper
 Not always present e.g. box, resistant, packaging
inserts
2. According to Quality Held
B. CLASS OF CONTAINERS
a. Single Unit
1. According to protection ability
 Hold a single dose only
a. Well closed container
 Non-resealable
 Protect from extraneous solid
 No-antimicrobial agent
 Water: SWFI or WFI
b. Tight
 USP limit: 1,000 mL
 Protect from extraneous solid,
 E.g ampule, pre-filled syringe
liquid or vapors

3
b. Multiple-unit  TYPE 3 SODA LIME GLASS
 Holds more than a single dose  Low resistance
 reseal able  For reconstituted by dry solid
 w/ antimicrobial agent and non-aqueous liquids
 water BWFI  NP:
 USP limit 30 mL o General purpose soda lime
glass
3. According to material used o For oral solid and liquid &
dosage form and external
a. Glass preparation
 Most widely used b. Plastic
 Major component SiO2  Organic polymer of HMW
 Adv:  Adv:
o Strength and rigidity o Durability
o Inertness o Light weight
o Barrier protection o Low cost
 Disadv:  Disadv:
o Fragility o Permeability
o Heavily o Environmental
o Leaching of alkali (+buffer) o Leaching of additives

TYPES OF GLASS TYPES OF PLASTIC

 TYPE 1 HIGHLY RESISTANT  THERMO PLASTIC

BOROSILICATE  Soft when heated and hard
 Highly resistance when cooled
 For buffered and non-buffered  Flexible and squeezable
aqueous parenteral solution (water bottle)
 Powdered glass
 THERMOSET
 TYPE 2 TREATED SODA-LIME GLASS  Permanently hard
 Surfaced it is treated w/ SO2 →  Rigid (monoblock)
dealkalized
 For buffered acidic aqueous
solution
 Water attack test

4
Polymer for Plastic C. LABELING (A.O. 55)

No. Polymer Description

 Label
1 Polyethylene For beverage
o Display of written, printed or
Terephthalate
(PET) graphic matter on the
2 High-density Hard immediate container (Principal
Polyethylene thermoset for Display Panel (POP) 40% -
(HOP) solid dosage most shown front part)
form
3 Polyvinyl -For blister  Labeling – material
chloride pack o All label and other written
-Least (printed or graphic matter
resistant to upon any item or its
permeation container)
4 Low density Thermoplastic
Polyethylene for squeeze
 PRINCIPAL DISPLAY PANEL
(LOP) bottles and
medicine (POP)
dropper
5 Polypropylene -High temp 1. Name of product (generic
(PP) resistance and brand name)
-For auto  Helvetica medium,
clave material universe medium – font
if BN has a special font
c. Foils, Films and Laminates
2. Dosage form and strength
 Low film cost, flexibility, heat-
sealability decoration
3. Pharmacologic category
 Ex: strip & blister pack, sachets,
liners for large container
4. Rx symbol in case of
prescription drug (Rx 1/5 of
d. Rubber
label)
 Ex:
o Stopper for vial
5. Name and address of manuf,
o Bulb for pipet
trader (reg. owner) or
o Plug for syringes
distributor (importer – from
other country → local,
e. Metal
exporter – from local →
 Aluminum (inert) international, whole saler –
 Tin (lighter, cheap) local source, local distribution)
 Ex: collapsative/ collapsible tube
aerosol can, crimp for vials

5
 6. Net content 2. Diluent/ filler
 Other info:  Inert substance added to
1. Formulation increase tablet size which is
2. Indication practical for compression
3. Contraindication,  Lactose
precaution, warning o Stearic acid (check)
4. Directions for use  ≠ mg stearate (most
5. Batch/ lot number common lubricant
6. Expiration & Mfg.  ≠ anime drugs
date & cosmetic = 36  ≠strong oxidizers
months’ shelf life  Sucrose and flucose
7. Registration number  Starch
(DR#)  Dibasic CaHPO4
8. Storage condition  Anhydrose/ spray-bried
lactose (free-flowing)
D. STORAGE CONDITIONS  Microcrystalline cellulose
(MCC) – Avicel ® (Freely-
1. Cold: nmt 8© flowing – direct compression)
a. Freezer – 20 to -10©
b. Refrigerator – 2-8© 3. Binder
 Imparts cohesiveness to
2. Cool: 8-15© powders causing them to form
granules
3. Room temp: temp prevailing in o Starch paste (common
the area binder wet granulation)
o Acacia
4. Controlled room temp: 20-25© o Tragacanth
o Gelatin
5. Warm: 30-40© o Sucrose
6. o Cellulose
7. Excessive heat: >40©  CMC –
carboxymethylcellulose
III. MANUFACTURING OF TABLETS  HPMC
o PVP
A. TABLET COMPONENT
4. Disintegrant
1. APIs  Facilitate the break-up of
 Excipients → consider tablet when in contact with
compatibility w/ the API(s) water in GIT

6
  MOA: swelling (starch paste), 7. Colorants
wicking (avicel ® MC) Classes:
 TYPES: a. Dyes
o Internal – added prior to  Water soluble
granulation colorants used as
o External – added prioir to solutions
compression b. Lakes
 Water-insoluble dye
5. Super disintegrant that have been
 Newer class of disintegrants absorbed on hydrous
which are effective at much oxide usually alumina
lower levels used as dry powders
o Sodium starch glycolate – (external use)
o Croscarmellose Na FD&C DYES
o Crospovidone
 Blue no.1 – brilliant blue
 Blue no. 2 – indigoine
6. Antifrictional/ Flowactivator
(indigo)
 Hydrophobic powders added
 Green no. 3 – fast green
prior to compression to
 Red no. 40 – allura red
reduce friction and improve
flow properties  Red no. 3 – erthrosine (pink)
 Included at concentration <1%  Yellow no. 5 – tartrazine
(yellow)
 Roles:
o LUBRICANT – facilitates  Yellow no. 6 – sunset yellow
(orange)
ejection from die cavity
o ANTI-ADHERENT – reduces
sticking to the punch faces 8. Flavors
or die walls a. Salty – cinnamon, orange,
o GLIDANT – enhance flow cherry, butterscotch
o Mg stearate – most
common 3 roles b. Bitter – chocolate, cherry,
o Purified talc – anti- raspberry, mint
adherent/ lubricant
o Colloidal talc – glidant c. Sour – raspberry, lemon, fruity
o Colloidal SiO2 (Cab-O-Sil®)
– glidant d. Oily – mint, lemon, orange
o Mg & Ca silicate – glidant
o PEG & lauryl sulfate – e. Unpleasantly sweet – vanilla,
hydrophilic lubricant fruity

7
 9. Sweeteners ISSUES:
 Artificial sweeteners
 Weighing accuracy
a. Sucralose – 1000x
 Dust control (negative pressure
airflow (solid), (+) pressure-
b. Saccharin – 500x
sterile)
 Lot control of each ingredient
c. Na Saccharin – 300x (magic
sugar)  Material movement

d. Acesulfame K – 180-200x  MILLING

 Particle size reduction, sizing,
e. Aspartame – 180-200x crushing, grinding
pulverization
f. Na cyclamate – 30x  OBJECTIVE: easier and more
uniform mixing
 (SuSaNa AcAsNa) EQUIPMENTS:
 Nela charade G. Puno (FDA
director General)
 Francisco Doque (DOH) 1. CUTTER MILL
 Cute particles using knives
 For fibrous material
B. PROCESS IN TABLET & MANUFACTURE
DISPENSING→ MILLING → MIXING→ 2. EDGE RUNNER MILL
GRANULATION→ TABLETING→ COATING  Crushes the materials by 2
rotating wheels
 COMPRESSION (principle
 DISPENSING involve)
 First-step in any
manufacturing process 3. HAMMER MILL
 Weighing and measuring  Use a high speed rotor to
 OBJECTIVE: Accuracy of which swinging hammer are
weight → uniform dose fixed
 IMPACT (PE)
METHODS:

 Hand scooping and weighing 4. FLUID ENERGY MILL

 Weighing w. material lifting  Use air w/ very high pressure
assistance  IMPACT
 Automated dispensaries

8
 5. ROLLER MILL b. Fixed shell mixer
 Consist of rotating cylindrical i. Ribbon blender
rolls  Helical shaped
 FRICTION  Not commonly used

6. BALL MILL ii. Sigma blade mixer

 Consist of a rotating cylindrical  Preferred for mixing acid
roll filled with balls material

 MIXING iii. Planetary mixer

 Process of blending material  Baking
together into 1 mess
 OBJECTIVE: obtain dosage iv. Vertical impeller mixer
unit each of which contains  Screw shaped
the same amount of API &
2. CONTINUOUS
UNIFORM DOSE
 High volume products
EQUIPMENTS:
 Materials enter through the
1. BATCH TYPE MIXER charging port to the discharge nozzle
 All ingredients are loaded
together, mixed and
 GRANULATION
discharged as a single type
 Powder size enlargement
2 types:  OBJECTIVE: ↑ flowability and
↑ compressibility
a. Tumbling mixer/ Rotating Shell
i. Drum type blenders TYPES:
 Cylindrical-shaped
a. Good granules
 Horizontal axis
 Passed through sieve # 20
 Poor crossflow – remedy:
but not through sieve # 40
baffles, put mixture slanted
b. Fine granules
(45°)
 Pass through sieve # 40
 Limited to 10%
ii. Double cone blender
 To fill interparticulate spaces
 Good crossflow
METHODS:
iii. V-shell blender
1. Wet granulation
 Twin-shell blender
 Addition of liquid binder to
 Solid-solid blending
powder
 Alternately combines and
 Most common method
draw apart the materials
9
  Cohesive of powder  Disadvantage: dusty and
 Disadv: uneven colored
o Labor intensive
PROCESS:
o Time consuming
o Not for moisture or heat- a. Slugging – formation of slugs
sensitive drug → large flat tablet (1inch)
 Oscillating
WET GRANULATION STEPS
granulation
1. Blending of dry ingredients b. Roller compaction –
2. Addition of liquid binder formation of sheets
3. Screening the damp mass (sieve no.  Chilsonator roller
6 or 8) compactor (machine)
4. Drying the granulation (alter drying
moisture content: 0.5-1%)  TABLETING
5. Screening the dry granules (sieve no.  Compression of tablet
12-20 (90%)) component within a die cavity
6. Addition of lubricant and external by the pressure exerted by
disintegrant the movement of 2 punches
 Under wet → too soft
 Over wet → too hard
PARTS OF TABLETING MACHINE
 Moisture content → 31-35%
 Sieve no. 6 or 8 1. Hopper – holds the material
2. Feed shoe/ teeth frame – transfer
2. Fluid bed granulation the material into the die
 Can accomplish both dry 3. Die – defines the size and shape of
mixing and wet granulation the tablet
efficiently and in much less 4. Punches – compress the material w/
time compared to traditional in the die
method 5. Cam tracks – guide the movement
of punches
3. Dry granulation
 Double compression or pre- TYPES OF TABLETING MACHINE
compression method
 Powder mixture is  SINGLE STATION
compacted into large pieces  Involves compression of the
and subsequently broken upper punch only
down into granules  MULTIPLE STATION
 For moisture and heat  Involves movement of both
sensitive material punches

10
REQUIREMENTS 5. Sticking
 Adhesion to die wall
1. Flowability – facilitates transfer
6. Picking
 Flow problem
 Adhesion to punch surfaces
o Arching/ bridging
(pinholes)
 Arch-shaped obstruction
7. Double impression
forms above the hopper
 Due to free rotation of the
outlet
punches w/ engraving on the
o Rat-holing
faces
 Discharge takes place only
8. Mottling
above the hopper outlet
 Uneven color distribution
2. Compressibility – form a stable,
 COATING
compact mass when pressure is
 Application of coating
applied
material to a moving bed of
DIRECT COMPRESSION solid w/ concurrent use of
heated air
 Tablet processing w/o granulation
 Require a very critical selection of EQUIPMENT
excipients → good flowability and
1. Standard coating pan
compressibility
 Consist of a rotating circular
 Ex: KCl, NaCl, and Na Br
metal pan w/ ducts
 Diluents: anhydrous lactose/ avicel
 Ex: Pellegrini Pan –
immersion tube/ sword
TABLET DEFECTS: system
a. Pan pouring
1. Capping
 Problem: surface erosion
 Partial or complete
 For viscous solution
separation of the top or
b. Pan spraying
bottom crown
 More efficient → allows
2. Lamination
control
 Separation into 2 or more
2. Perforated coating pan
distinct horizontal layers
 Exhausting is through the
3. Chipping
perforation
 Removal of small portion
 Ex: Accela-cota pan,
(tablet edges)
Driacoater, Glatt coater
 Very dry granulation
3. Fluid bed coater
4. Cracking
 Air-suspension coating or
 Fine cracks on the surface
wurster process
 Due to concave punches

11
2 TYPES OF COATING 3. SMOOTHING
 Smoothes out the sub coated
1. Sugar-coating
surface
 Oldest method
 Agent = 60-70% syrup
 Disadvantage
solution
o Large increase in weight
(MT 50%)
4. COLOR COATING
o Time consuming
 Critical step → color &
o Require expertise
elegance
STEPS OF SUGAR COATING  AGENT: 60-70% syrup +
colorant
 Sealing
 STEPS:
 Subcoating
o 4.1 Grossing – develops
 Smoothing
color
 Color coating
o 4.2 Heavy syruping – build
 Polishing
up color
o 4.3 Regular syruping – final
1. SEALING
color
 Water proofing
 Strengthens tablet core 5. POLISHING
 AGENTS:  Produces gloss/ shine
o Shellac  AGENTS:
o Cap or PVAP (cellulose o Beeswax
acetate phthalate) o Carnauba wax
(polyvinyl acetate o Candelila wax
phthalate) o Hard paraffin wax
o Zein
2. FILM COATING
2. SUBCOATING
 ADV:
 Round off the tablet edges o Minimal increase in weight
 Most critical step (thin polymer)
 Steps that adds most weight o Easier and faster (single step)
(↑ 50-100%)  Film coating component
 Agent: alternate layer of gum
(acacia/ gelatin) ↑ dusting 1. Film former
powder → to prevent from  Smooth, thin films
sticking  Ex: cellulose, methacrylate,
PVA, PVP

12
 2. Plasticizer 7. Wrinkling
 Flexibility and elasticity  Due to improper drying/ film
 Ex: castor oil, glycerin, former defect
phthalate esters 8. Orange peel
 Rough, non-glossy film
3. Surfactant surface
 Spreadability  Inadequate spreading
 Ex: polyoxyethylene sorbitan
derivation (TWEEN) IV. CAPSULES
 (SPAN: sorbitan ester)
 (cleaning & polishing) A. HARD GELATIN CAPSULE (HGC)
 HGC shells are manufactured in a
4. Allotting substance separate operation from filling
 Water solubility/ permeability o PIN METHOD/ RECIPROCATING DIE
 Ex: PEG METHOD: Most common

5. Glossant
 Luster or shine STEPS IN FILLING HGC
 Ex: beeswax  Supply (incorporation of raw
material capsule filling machine –
6. Volatile solvent/ vehicle hopper)
 Ex: alcohol + acetone o Capsule filling machine
COATING DEFECTS  Lily
 Parke davig
1. Mottling  Farmatic
 Uneven color distribution  Macofar
2. Sweating  Rectification
 Oily film or droplet of liquid  Separation
3. Bridging  Filling (Tamping and disclosing)
 Marking or obscured  Joining/ closing – cluger or spindle
4. Blooming dosing, stroking in or dribbling in
 White spots on the surface accogel process (powders)
or dull film  Finishing
 Under humid condition o Pan-polishing
5. Flaking o Cloth dusting (caps rub w/
 Due to rapid drying cloth)
6. Blistering o Brushing
 Reduced adhesion of film

13
 SPECIAL TECHNIQUE 1. INCORPORATION METHOD
 Used of ointment roller mills to
1. Sealing
mix heat sensitive ointment
a. Gelatin banding
bases
 Seals w/ a band of gelatin
 Water removable base
b. Heat welding
 Water soluble base
 Fuses cap to body through
double wall thickness
2. FUSION
 Thermal coupling
 Use of steam – jacketed kettles
c. Thermal coupling
to melt anhydrous ointment
 Uses liquid wetting agent to
bases and cooling gradually
lower melting point
until congested
2. Imprinting
 Constant stirring while cooling
 Empty capsules
3. Coating
VI. MANUFACTURE OF LIQUID DOSAGE
 Modifies solubility (ex: shellac,
FORM
CAP, salol (phenyl salicylate)
 Enteric absorption
A. EQUIPMENT
B. SOFT GELATIN CAPSULE
1. Mixing tank
 Formea, filled and seated in single
 Usually made of stainless steel,
operation methods
jacketed and have built in
1. Plate process
agitation system
 Oldest method which
 GRADES (stainless steel)
was gelatin sheets
o SS 304
2. Rotary die process
o SS 316 – most inert
 Uses gelatin ribbons
brought together 2. Mixer
between 2 rotating a. Mechanical stirrer
dyes
 Mixers w/ various
3. Reciprocating die process
impellers mounted on
 Uses different filling shafts
method b. Colloid mill
 For comminution of solids
V. MANUFACTURE OF SEMI-SOLID
or dispersion of suspension
DOSAGE FORM
c. Homogenizer
 Compresses the liquid w.
A. OINTMENTS
high pressure by a strong
spring mechanism
 Rotor and stator

14
 d. Ultrasonifier b. Antioxidants
 Uses ultrasonic energy to  TRUE antioxidants
produce emulsion o Read w/ free radicals
 Limited output, more o Ex: vit. E, BHT – Butylated
expensive Hydroxy Toluene, BHA
Butylated Hydroxy Anisole,
B. COMPONENTS akyll gallates

1. API’s  Reducing agent

2. Solvent or vehicle o Ex: Vit. C, Sulfites
3. Buffers
4. Viscosity enhancer  Antioxidant synergist
5. Humectants – o React w. heavy metals
(↑stability = ↑palatability) o Ex: EDTA, citric acid,
6. Colorants: flavors, tartaric acid
sweeteners and perfumes
C. MANUFACTURING PROCEDURE
7. Stability enhancers
 Dispensing
1. Stability Enhancers  Mixing
 Storage and aging
 Titration
a. Preservatives  Filling
 Prevent microbial growth
 Paraben (endocrine 2. MIXING
destructors  Dissolution of solutes
 Methyl paraben – molds  ↑ solubility
 Propyl paraben – yeast &  Speed of agitation
inhibit bacteria  Temperature
 Benzyl acid  Particle size
 Benzoic acid and Na,  pH
Benzoate  Complexation C
 Sorbic acid & K sorbate
 Chlorbutanol 3. Storage and aging
 Benzalkonium Cl  Optional step
 Thimerosal & phenyl  Improves flavor or odor of volatile
mercuric acid oils

15
4. Filtration
 TYPES: 2. Wetting agent
o Parallel – passes thru 1 filler  Displaces air from crevices of
medium hydrophobic solids to allow
o Series – 2 or more filter media penetration of H2O
 Ex: glycerin, PPG, PEG, syrup
 Filter media
o Filter paper/ cloth – non-sterile 3. Flocculating agents
products  Decrease Zeta potential
o Membrane filter – sterile causing aggregation to avoid
product formation of cake (optional)
o QC TEST: Bubble point test  Ex: NaCl, KCl
 Caking – formation of
 METHODS cement like substance at the
o Gravity – used in the lab. (small bottom of the suspension
scale)  Deflocculated = ideal
o Vacuum – large scale
o Pressure – large scale FORMATION
1. Precipitation method
5. Filling  By organic solvent
 METHODS  By changing pH
o Gravimetric – large container  By double decomposition
and high viscosity
o Volumetric – constant volume 2. Dispersion method
using piston action  Common method
o Constant level – container is  Suspension are wetted first
used to control the fill before dispersing into the
vehicle
D. SUSPENSION
FORMULATION: F. EMULSIONS
TYPES

1. Suspending agent: 1. Natural

 Viscosity enhancers  Acacia, tragacanth, cellulose,
 Ex: acacia, tragacanth, agar, pectin, gelatin, wool fat
cellulose, bentonite, magma,
veegum, agar, carrageenan, 2. Finely divided solid
gelatin  Bentonite, mg(OH)2, Al(OH)3,
Mg Trisilicate

16
  2. Creaming
3. Synthetic surfactant  ↑ internal phase
 Most common
3. Breaking/ cracking
a. Anionic – effective at basic  Separation into a layer due
pH to coalescence of internal
 Ex: soap, alkyl SO4, phase
sarcosinates, SLES (sodium  Irreversible
lauryl ethyl sulfate)
4. Phase inversion
b. Cationic effective at acidic pH  w/o → o/w or vice versa
 Anti-microbial agent  irreversible
 Ex: benzalkonium Cl,
cetremonium Cl IV. MANUFACTURE OF STERILE DOSAGE
FORMS
c. Amphoteric soap – both
anionic and cationic A. Sterilization method
 Ex: betaine, lecithin
1. Moist heat
d. Non-ionic – not affect by pH  Autoclave or steam under
 Span ® (lipophilic) – pressure
sorbitein ester  MOA: protein coagulation
 Tween ® (hydrophilic) –  BI: Bacillus Stearothermophilus
polysorbate (PEG)
 Acetyl alcohol 2. Dry heat
 Cocamide DEA  Oven (160-170© for 2-4 hours)
 MOA: oxidant
CONSIDERATION:
 BI: Bacillus subtilis
 Emulsion are unstable
 Internal phase = 40-60% 3. Membrane filtration
 Oil phase → high grade mineral oil  For heat-labile solution
 Ideal mixing temp→ 70-77©  MOA: physical separation
 If perfume is to added:
o o/w → 43-45© 4. Gas
o w/o → near RT  Plastic container
 Ethylene oxides or B-
INSTABILITIES
propiolactone
1. Sedimentation  MOA: alkylation
 ↓ internal phase  BI: Bacillus subtilis

17
 5. Ionizing radiation 2. Buffer area
 Gamma or cathode rays  For staging of supplies &
 MOA: DNA mutation equipment (class 10,000)
 BI: Bacillus pumilus
3. Compounding area (critical
site)
B. DEPYROGENATION  Class 100/ ISO class 5
(highest)
OVEN SETTING
 Laminar air flow hood –
 180© for 4hrs vertical(preferred) or
 250© for 45mins horizontal
 600© for 1min  Barrier isolator – for
hazardous material
 NMT 100,000 particles (>0.5
C. STERILE PRODUCTION AREA um) per cubic foot of air

 Clean rooms 4. Aseptic filling area

 Rooms in which the conc. of  Packaging (class 100)
airborne particles is
controlled 5. Quarantine area
 Positive pressure airflow  For staging prior to testing
 HEPA filters – removes
99.97% of particles (≥ 0.3 um) 6. Finishing area
from the air (high efficiency
particulate air) D. MANUFACTURING PROCEDURE
o Parts: pre-filter,
blower, electro static 1. DISPENSING & CLEANING
precipitator
 QC test: Dioctyl Phthalate test 2. COMPOUNDING
 Airlock – space with  Sterile solid
interlocked doors  Spray drying (not heat labile
product)
 PARTS  Freeze drying (if aqueous
solution through sublimation)/
1. Ante-room lyophilization
 For cleaning & wearing of
PPE (class 100,00/ ISO class 3. FILTRATION
8)  Sterile solution
 Personal protecting o Clarification – 2-3um
equipment (PPE) o Cold filtration – 0.2-0.3um

18
4. FILLING
 Sterile solids – net weight
filling
 Sterile liquids
o Volumetric filling – most
common
o Gravimetric filling

5. SEALING
 Vials – siliconization or
halogenization
 Ampule
 Tip/ Bead sealing – melt the tip
to form a bead
 Pull sealing – melt below the
tip then pull away (commonly
use)

------END----

19