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Module 5 – Manufacturing Pharmacy Page 1 of 10 RJAV 2022

MODULE 5│PHARMACEUTICS 2

MANUFACTURING PHARMACY
MANUFACTURING PHARMACY Drug Manufacturer

I. INTRODUCTION TO MANUFACTURING 1. Manufacturer – involved in production of drugs products

(preparatory processing, compounding, formulating, filling,
A. MANUFACTUIRNG packaging, repackaging, altering, ornamenting, finishing, labeling)

• large-scale production of drug products’ preparation, 2. Packer – involved in packaging of bulk drug product to its
processing, packaging, labeling, repacking, changing immediate container
wrapper, label or container of any drug products
3. Repacker – involved in repackaging of finished product into
Stages of Manufacturing smaller quantities in a separate container and/ or secondary
packaging

1 2 4 Trader – Registered owner of drug product and formulation but

Dispensing Processing 3 Packaging subcontracts manufacturing
of Raw of Dosage Filling & - Procures RM and PM
Materials Forms Repacking
- Provides monographs and QC protocols

Drug Distributor
Manufacturing Activities
1. Importer – imports RM, API, and/or finished products for
Primary Manufacturing – manufacture of raw material (APIs and wholesale distribution to other licensed established
Excipients)
2. Exporter – exports RM, API, and/ or finished products for
Secondary Manufacturing – manufacture of finished dosage form wholesale distribution to establishments outside the country

Tertiary Manufacturing – packaging, labeling, and repacking of 3. Wholesaler – procures RM, API, and/ or finished
bulk finished product products from a local licensed establishment for local
distribution in wholesale basis
Toll Manufacturing – an arrangement whereby a
competent company manufactures products for another C. DEPARMENTS IN MANUFACTURING COMPANY
company
1. Research and Development Department
B. TYPES OF DRUG ESTABLISHMENTS • formulates new products
• Stages of Drug Development
AO 56 s.1989 1) Discovery and Development
• Revised Regulations for the Licensing of Drug 2) Preclinical Research
Establishments and outlets 3) Clinical Research
4) FDA Review
Drug
Establishments 5) Post-market Surveillance
• involved in process development and scale-up
• prepares Master formula
Drug Drug
Drug Trader Drug Importer Drug Exporter
Manufacturer Wholesaler
Master formula – contains the formulation,
specifications, manufacturing procedures, QA
AO 2014-0034 requirements, and labeling of a finished product
• Rules and Regulations on the Licensing of Establishments
Engaged in the Manufacture, Conduct of Clinical Trial, • justifies overages in the formula
Distribution, Importation, Exportation, and Retailing of Drug
Products, and Issuance of Other Related Authorization Overages – addition of an excess amount of API in
an unstable preparation
Manufacturer
• improves existing products
Packer
Drug 2. Production Department
Manfacturer • deals with all stages of manufacturing batches of finished
Repacker drug products

Trader Batch – specific quantity of product intended to have

uniform character and quality, produced during the
Drug Establishments

Importer same single cycle of manufacture

Drug Distributor Exporter Lot – specific identified portion of a batch

Drugstore Wholesaler • Plans the production according to MO

RONPD
Manufacturing Order (MO) – gives instructions to
manufacture a product
Sponsor
• accomplish the BMR to ensure that batches were properly
made and tests were conducted
CRO
Batch Manufacturing Record (BMR) – document
containing the details of the manufacture of each
batch

Module 5 – Manufacturing Pharmacy Page 2 of 10 RJAV 2022

3. Warehouse Department f. Mannitol and xylitol
• stores materials and finished products • Used in chewable tablets
• holds incoming components in the quarantine area • Negative heat of solution

Quarantine – status of materials which are isolated 2. Binder

physically while a decision is awaited on their release, • Imparts cohesiveness to powders causing them to from
rejection, or reprocessing granules

• involved in purchasing and logistics Inadequate binder Too much binder

4. Quality Assurance Department • Soft granules • Too hard granules
• assures that all operations meet required standards for • Too much fines • Difficulty in screening
safety and efficacy, ensures compliance to cGMP • Inadequately hard tablets • Hampered disintegration &
• conducts quality audit and monitoring dissolution (↓ BA)
• prepares SOPs
a. Starch paste
Standard Operating Procedures (SOP) – step-by- • Binder of choice for wet gran
step instructions for performing operational tasks or
activities b. Acacia & Tragacanth
• Natural guns

5. Quality Control Department c. Gelatin

• tests compliance of raw materials, packaging materials, and • Protein substance
finished products to specifications
• conducts sampling of materials to be tested d. Sucrose
• performs IPQC and environmental testing • Can be used as powder or syrup

6. Marketing Department e. Cellulose Derivatives

• studies current market trends, consumer behavior and • Methyl cellulose
product status in market • Ethyl cellulose
• promote and advertisement • Carboxymethyl cellulose
• Hydroxypropyl methyl cellulose
7. Regulatory Department
• ensures compliance of company and its products with all f. PVP
pertinent regulations and laws about drugs and their • Binder for chewable tablets
marketing
3. Disintegrant
8. Engineering Department • Facilitates the breakup of a tablet when in contact with
• installs, maintains and repairs of equipment and premises aqueous medium
• conducts validation and qualification

Validation – action of proving and documenting that

any process, procedure or method actually and
consistently leads to the expected results
Qualification – action of proving that premises,
systems or equipment work correctly and actually
lead to expected results • MOA:
• Swelling – starch paste
• ensures safety • Wicking – MCC
• Release of gas – effervescent tablets
9. Medical Department
• concerned with physical examination and medical treatment 4. Superdisintegrant
of employees • Newer class of disintegrants which are effective at much
• performs clinical studies lower levels
• publishes house organ/paper • Hydroscopic

II. MANUFACTURING OF SOLID DOSAGE FORMS a. Sodium Starch Glycolate (Explotab®, Primojel®)
• Cross link starch polymer
A. FORMULATION COMPONENTS
b. Crospovidone
1. Diluent (Filler/ Bulking Agent) • Cross link polyvinylpyrrolidone
• inert substance added to increase tablet size or fill the
capsule body c. Croscarmellose Na
• Cross link cellulose derivative
a. Lactose
• Most common 5. Antifrictional Agents (Flow Activators)
• No reaction with most drugs • Fine powders added prior to compression to reduce friction
• Monohydrate, anhydrous, and spray-dried and improve flow properties
• Mostly hydrophobic and added at low concentration
b. Sucrose and Dextrose
• Used as sweetener Lubricant Antiadherent Glidant
Reduces friction Reduces sticking to Reduces friction
c. Microcrystalline Cellulose (Avicel®) between the tablet die walls and picking among particles to
and die wall to by punches enhance the flow
• Good flow and very compressible
facilitate ejection from
• Disintegrates rapidly in water die cavity

d. Starch a. Stearates (Mg, Ca, Na)

• Used as diluent, binder and disintegrant • lubricant, antiadherent and glidant
• Modified Starch: Sta-Rx 1500®, Cellutab®
b. Purified Talc
e. Dibasic calcium Phosphate • lubricant and antiadherent
• Only inorganic salt used as diluent
Module 5 – Manufacturing Pharmacy Page 3 of 10 RJAV 2022
c. Colloidal Talc 1. Dispensing
• glidant • first step in any manufacturing process
• weighing and measuring
d. Colloidal SiO2 (Cab-O-Sil®) • Objective: accuracy of weight → uniform dose
• glidant
Methods:
e. Silicates (Ca and Mg)
• glidant • hand scooping and weighing
• weighing with material lifting assistance
f. PEG and SLS • automated dispensaries
• hydrophilic lubricants
6. Colorant Issues:
• disguises off-color drugs and improves appearance
• weighing accuracy
Dyes Lakes • dust control (dust collecting assistance)
Synthetic organic colorants Dyes adsorbed on an inorganic • lot control of each ingredient
oxide • material movement (WH → DA → PA)
Water-soluble Water-insoluble
Used in solution form Used in fine dispersion or 2. Milling
suspension form
• particle size reduction
• aka sizing, crushing, grinding and pulverization
FD&C Designation Name Color
• Objective: easier and more uniform mixing
Blue No. 1 Brilliant Blue FCF Blue
Blue No. 2 Indigotin Indigo
Methods and its Equipment:
Green No. 3 Fast Green FCF Turquoise
Red No. 3 Erythrosine Pink
Red No. 40 Allura Red AC Red a. Cutting
Yellow No. 5 Tartrazine Yellow • material is cut by means of sharp blades
Yellow No. 6 Sunset Yellow FCF Orange • Cutter Mill – cuts particles using knives; for fibrous materials

7. Flavorant b. Compression
• masks the unpleasant taste of the drug • material is crushed by application of pressure
• End Runner Mill – mortar rotates
a. Salty • Edge Runner Mill – 2 rotating wheels
• cinnamon, orange cherry, butterscotch
c. Impact
b. Bitter • material is hit by an object or it strikes a stationary phase
• chocolate, cherry, raspberry, mint • Hammer Mill – 4 or more hammers hinged on a shaft

c. Sour d. Attrition
• raspberry, lemon, fruity • material is crushed in between rubbing surfaces
• Roller Mill – 2 metal cylindrical rolls rotating
d. Oily
• mint, lemon, orange e. Combined
• Utilizes both impact and attrition methods
e. Unpleasantly sweet • Ball Mill – hollow cylinder containing balls
• vanilla, fruity • Fluid Energy Mill – uses air with very high pressure

8. Sweetener 3. Mixing
• masks the unpleasant taste of the drug • blending materials together into one mass
• Objectives:
Nutritive Non-nutritive • uniform dose
Sugar Alcohols Artificial • even appearance
• Sucrose • Mannitol • Sucralose – 1,000x • avoid segregation
• Fructose • Xylitol • Saccharin – 500x
• Dextrose • Sorbitol • Na Saccharin – 300x Equipment:
• HFCS • Erythritol • Acesulfame K – 180-200x
• Aspartame – 180-200x a. Batch Type Mixer
• Na cyclamate – 30x • all ingredients are loaded together, mixed for a long period,
and discharged as a single batch
B. UNIT OPERATIONS • Rotating Shell/ Tumbling Mixers
• Drum Type Blenders
Tablets HGC • cylindrical-shaped
• rotates horizontally
Dispensing Dispensing • poor cross flow
• remedy: Baffles Slantea
• Double Cone Blender
Milling Milling • conical shaped at both ends
• better cross flow
• Twin-shell/ V-Shell Blender
Mixing Mixing • alternately combines and draws the ingredients
apart
Granulation • solid-solid blending
Granulation
• Fixed Shell Mixers
• Ribbon Blender
Tableting Filling • consists of through-like shell with mounted spiral
or helical blades
• Sigma Blade Mixer
Coating Sealing • consists of double through shaped shell with 2
sigma shaped blades fitted horizontally
• Planetary Mixer

Module 5 – Manufacturing Pharmacy Page 4 of 10 RJAV 2022

• Paddles moves around its own axis and around
the central axis
• Vertical Impeller Mixer
• Screw type impellers rotating inside a conical shell

b. Continuous Mixer
• agitates and moves materials through equipment, mixing
them in one quick pass
• for high volume products
• materials continuously travel from the charging port to the
discharge nozzle

4. Granulation
• powder size enlargement to granules
• Objective: ↑ flowability and compressibility
Types:

a. Good Granules
• pass through sieve #20 but not through sieve #40 Processes:
b. Fine Granules Slugging
• pass through sieve #40 • formation of slugs
Methods: Roller Compaction
• formation of sheets
a. Wet Granulation
• most common method Equipment:
• addition of liquid binder to powders that forms larger
agglomerates a. Chilsonator roller Compactor
• not for moisture-sensitive and heat labile materials • used to compress powder into thin sheets

b. Oscillating granulator
• used to crushed slugs or sheets into granules

C. MANUFACTURING OF TABLETS

Tableting – compression of materials within a die cavity by the

pressure exerted by the movement of 2 punches

Parts of Tableting Machine:

1. Hopper – holds the materials to be compressed

2. Feed Shoe – transfers materials into die

3. Die – defines size and shape of the tablet

4. Punches – compress materials within the die

5. Cam Tracks – guide the movement of punches

Blending of dry ingredients
Types of Tableting Machine:
Addition of liquid binder Single Station Multiple Station
involves compression of the upper involves movement of both
punch only punches
Screening the damp mass (sieve # 6 or 8)
Requirement of Tableting:

Drying granulation (moisture cnntent: 0.5-1%) 1. Flowability – facilitates transfer

• Problems:
• Arching/Bridging – arch-shaped obstruction forms above
Screening the dry granules (sieve # 12 or 20) hopper outlet
• Rat-Holing – discharge takes place only above hopper
outlets
Addition of running powder
2. Compressibility – forms a stable, compact mass when
*Moisture Content: 31-35%; Underwet – too soft; Overwet – too hard pressure is applied

Fluid Bed Granulation Direct Compression

• easier and faster than the traditional process • tablet processing without granulation
• materials are suspended in air while the liquid binder is • require a very critical selection of excipients →good
sprayed flowability and compressibility; (ex. KCl, NaCl, NaBr;
• diluents: anhydrous/ spray-dried lactose, Avicel®)
2. Dry Granulation
• double compression on pre-compression method
• powder mixture is compacted into large pieces and crushed
subsequently broken down into granules
• for moisture and heat-sensitive materials

Module 5 – Manufacturing Pharmacy Page 5 of 10 RJAV 2022

Tablet Defects 3. Fluid Bed Coater
• air suspension coating or Wurster process
Capping
Types of Coating:
Due to tableting
Lamination
process a. Sugar Coating
• oldest method
Cracking • involves successive coating of sucrose-based solution
• Disadvantages:
• large increase in weight (>50%)
Sticking • time-consuming
Tablet Defects

• requires expertise
Due to excipients Picking Steps:
Color
Sealing Subcoating Smoothing Polishing
coating
Chipping

1. Sealing
Due to Machine Double Impression • waterproofing
• separates tablet core from water
Due to more than 1
Mottling • Sealcoating agents
factor • shellac
• cellulose acetate phthalate (CAP)
Due to tableting process: • polyvinyl acetate phthalate (PVAP)
• zein
a. Capping
• partial or complete separation of top or bottom crown (air 2. Sub-coating
entrapment) • rounds off the edges and builds up the tablet size
• most critical step
b. Lamination • Sub-coating agents
• separation into 2 or more distinct horizontal layers (air • alternate layers of sticky binder (acacia or gelatin) and
entrapment) dusting powder

c. Cracking 3. Smoothing
• in concave tablets; rapid expansion of tablets • smoothes out the subcoated surface
• Smoothing agents
Due to excipients: • 60-70% syrup

d. Sticking 4. Color coating

• adhesion of material to die wall or face of the punch • Critical step → color and elegance
(excessive moisture) • Color coating agent
• 60-70% syrup + colorant
e. Picking • Steps
• adhesion of material to the design embedded on the punch • Grossing – develops color
tip (excessive moisture) • Heavy Syruping – builds up color
• Regular Syruping – final color
f. Chipping
• removal of small portion of tablet edges (lack of binder) 5. Polishing
• produces gloss/shine
Due to Machines: • Polishing agents
• beeswax,
g. Double Impression • carnauba wax,
• 2 engravings on the surface (due to free rotation of punches • candelila wax
with engraving on faces) • hard paraffin wax
• blending of dry
Due to more than 1 factor:
b. Film Coating
h. Mottling • involves deposition of thin film of polymer around the tablet
• uneven color distribution (due to different color material or core
improper mixing) • Advantages:
• minimal increase in weight (2-3%)
Coating – application of coating material to a moving bed of • easier and faster
solids with concurrent use of heated air
Components:
Methods: Film Former
• produces smooth, thin films
• Pan Pouring – for viscous solutions • examples:
• problem: surface erosion • Non-enteric: celluloses, methacrylate; PVA; PVP
• Pan Spraying – increases efficiency of coating process • Enteric: shellac, CAP, PVAP, salol

Coating Equipment: Plasticizer

• produces flexibility and elasticity
1. Standard Coating Pan • examples:
• consists of a rotating circular metal pan with ducts • castor oil
• (ex. Peilegrini Pan; immersion tube/ sword system) • glycerin

2. Perforated Coating Pan Surfactant

• heated air is exhausted through the perforations in the drum • enhances spreadability of the fil
• (ex. Accela-Cota Pan; Driacoater; Giatt Coater) • example:
• polysorbates (Tween)

Module 5 – Manufacturing Pharmacy Page 6 of 10 RJAV 2022

Alloying Substance • Pin Method/ Reciprocating Die Method – most common
• provides water solubility/ permeability to the film method of manufacturing
• example:
• PEG Steps in filling HGCs:

Glossant Rectification
• Provides luster or shine to the tablets without separate orienting empty shells properly with bodies facing forward
polishing operation
• example: Separation
• beeswax
separation of caps from the bodies
Volatile Solvent/ Vehicle
• allows the spread of the other components over the tablets Filling
• example: dosing of fill material into the body
• alcohol + acetone

Coating Defects: Joining/ Closing

replacement of caps and closing of capsule shells
Mottling
• uneven color distribution
Ejection
• due to poor mixing, uneven spray patterns, or migration of
additives during drying ejection of filled capsules

Sweating Finishing
• oily film or droplets of liquid dedusting and cleaning of surface
• due to humid conditions

Special Techniques:
Bridging
• markings are obscured 1. Sealing
• markings are obscured • Gelatin Banding – seals with a band of gelatin
• due to coating solution filling in the logo of the tablet • Heat Welding – fuses cap to body through double wall
thickness
Erosion • Thermal Coupling – uses liquid wetting agent to lower
• removal of coating from the tablet surface due to friction melting point between cap and body then bonds
among themselves
2. Coating
Cratering • modifies solubility characteristics
• craters appear exposing the tablet surface • (ex. shellac; cellulose acetate phthalate; salol)
• due to disruption of coating at the crown when the surface is
more porous ii. Soft Gelatin Capsules (SGC)
• formed, filled and sealed in a single operation
Blistering
• reduced adhesion and detachment of the film Methods:
• due to entrapment of gases underneath the film
1. Plate Process – oldest method which uses gelatin sheets
Blooming
• fading or dulling of the film 2. Rotary Die Process – uses gelatin ribbons brought together
• due to high concentration and low MW of plasticizer between 2 rotating dies

Blushing 3. Reciprocating Die Process – uses gelatin ribbons brought

• whitish specks or haziness of the film together between 2 rotating dies
• due to precipitation of polymer at high temperature
III. MANUFACTURING OF SEMISOLID DOSAGE FORM
Twinning
• 2 tablets stick together A. MANUFACTURING OF OINTMENTS
• due to inappropriate tablet shape or tracky coating
formulation Methods of Manufacturing

Orange Peel 1. Incorporation

• Rough, non-glossy film surface • the components are mixed until a uniform preparation is
• due to inadequate spreading) attained
• remedy: add polysorbate surfactant • use of ointment roller mills (to mix heat-sensitive ointment
bases), Unguator® Electric Mortar and Pestle
Flaking
• Type I – due to thermal expansion of tablet cores caused by 2. Fusion
over drying • the components are combined by melting together and
• Type II – due to core swelling caused by excessive moisture cooled with constant stirring until congealed
uptake • use of stem-jacketed kettle, ointment roller mill

Delayed Distribution B. MANUFACTURING OF GELS

• associated with the exposure of tablet cores to coating
process conditions rather than a direct effect of the applied Gelling Agents
coating • substances which when added to water or an aqueous
mixture, increase its viscosity
D. MANUFACTURING OF CAPSULES
Types of Gelling Agents:
i. Hard Gelatin Capsules (HGC)
• HGC shells are manufactured in a separate operation from 1. Natural Polymers: alginic acid, gelatin, starch, acacia,
filling tragacanth, Mg Al silicate, bentonite

Module 5 – Manufacturing Pharmacy Page 7 of 10 RJAV 2022

2. Semisynthetic Polymers: cellulose derivatives, sodium starch parabens; methyl – molds (short)
glycolate propyl – yeasts and bacteria (short)

3. Synthetic Polymer: carbomer, polyvinyl alcohol b. Antioxidants

Carbomer – swells in water at basic pH (Carbopol®); neutralized: • prevent oxidation of the active components, fats, and oils
methanol amine
Classification of Antioxidants
Manufacturing Parameters
• the drug and other additives are dissolved in the liquid • True Antioxidants: react with free radicals; alpha tocopherol
vehicle before the gelling agent is added (vit. E), BHT, BHA, alkyl gallates
• Temperature – hot water is preferred for gelatin and PVA • Reducing Agents: ascorbic acid (vit. C), sulfites
and cold water is used for other gelling agents • Antioxidant Synergists: react with heavy metals; EDTA, citric
• Duration of Swelling – 24 to 48 hours acid, tartaric acid
• Removal of Entrapped Air – position the propeller at the
bottom of the container IV.1. MANUFACTURING OF SOLUTIONS

C. FILLING AND PACKAGING A. METHODS

• Usually filled In jars, tubes or syringes 1. Simple Solution

• Jars – plastic or glass • prepared by dissolving the solute in most of the solvent,
• Tubes – plastic laminate or metal mixing until dissolved, then adding sufficient solvent to bring
• Syringes the solution up to the proper volume
• Ointments prepared by fusion should be poured while still • Ex: Calcium Hydroxide Topical Solution, USP
soft directly into the containers
2. Solution by Chemical Reaction
IV. MANUFACTURING OF LIQUID DOSAGE FORMS • prepared by reacting 2 or more solutes with each other in a
suitable solvent
A. EQUIPMENT • Ex: Aluminum Subacetate Topical Solution, USP

1. Mixing Tank – jacketed to allow heating or cooling of contents; 3. Solution by Extraction

Made of stainless • for drugs of vegetable or animal origin
• Grades: • extracted with water or other solvents
• SS 304 – 18% Cr and 8% Ni • Ex: Belladona Extract, USP
• SS 316 – 16% Cr, !0% Ni and 2% Mo; most inert
2. Mixers B. STEPS

Types of Mixers: 1. Dispensing

• weighing and measuring of raw materials
a. Mechanical Stirrer 2. Mixing
• mixers with various impellers mounted on shafts • dissolution of solute in solvent
• problem: vortex formation → remedy: buffers, slanted (45°) • Methods to hasten dissolution
• Vigorous agitation
b. Colloid Mill • Application of heat
• for comminution of solids and dispersion of suspensions • Particle size reduction
• Use of solubilizer and chelating agents
c. Homogenizer 3. Storage and Aging
• compresses liquid with high pressure by a strong spring • for solutions with high amounts of volatile oils; enhances
mechanism odor and flavor
• for emulsification 4. Filtration
• process of separating liquids from solids w/ the use of filter
d. Ultrasonifier medium
• user ultrasonic energy to produce emulsion • Filter Medium – resists the flow of solid materials while
permitting the passage of liquid
B. COMPONENTS • Filter paper
• Membrane filter - sterile products; Bubble Point Test →
1. APIs to test efficiency of membrane filter
2. Solvent or Vehicle • Cotton filter
3. Buffers • Glass-wool filter
4. Viscosity Enhancers • Sintered-glass filter
5. Humectants • Types:
6. Colorants, Flavors, and Fragrances • Parallel Filtration – passes through and filter medium
7. Stability Enhancers • Series Filtration – 2 or more filter media

Stability Enhancers: 5. Filling

• Methods:
a. Preservatives • Gravimetric – large containers and high viscosity
• prevent microbial growth • Volumetric – constant volume using piston action
• effective at low concentration against all possible • Constant-Level – container is used to control fill
microorganisms
IV.2. MANUFACTURING OF EMULSIONS
Classification of Preservatives
A. EMULSIFYING AGENTS
• Alcohols: ethanol, propylene glycol, chlorobutanol, phenyl
alcohol Classification:
• Acids: benzoic acid, sorbic acid
• Esters: parabens 1. Carbohydrate Materials: tragacanth, acacia, agar, pectin,
• Quaternary Ammonium: benzalkonium chloride, cetrimide, chondrus, xanthan, carrageenan
cetylpyridinium chloride
• Organic Mercurial: thimerosal, phenylmercuric nitrate 2. Protein substances: gelatin, egg yolk, casein

Module 5 – Manufacturing Pharmacy Page 8 of 10 RJAV 2022

B. METHODS
3. Finely Divided Solids: colloidal clay, bentonite, Mg(OH)2,
Al(OH)3; 1. Dispersion
• Finely divided solid drug is wetted first before dispersion in
4. HMW Alcohols: glyceryl monostearate, stearyl alcohol, cetyl the liquid vehicle
alcohol, cholesterol 2. Precipitation
• Finely divided solid drug is reacted with another substance
5. Synthetic Surfactants: • Ex: Milk of Magnesia
• Anionic
• effective at basic pH V. MANUFACTURING OF STERILE DOSAGE FORMS
• ex. soaps; alkyl SO4; sarcosinates
• Cationic A. STERILE PRODUCTIO AREA
• effective at acidic pH
• ex. benzalkonium Cl; cetypyridinium Cl Clean Rooms
• Amphoteric • room in which concentration of airborne particles are
• both anionic and cationic controlled
• ex. betaine; lecithin • Filtered air supplied
• Non-Ionic • positive pressure air flow
• not affected by pH • HEPA filter – removes 99.97% of particles (≥ 0.3 µm)
• Span® – sorbitan esters [lipophilic] from air
• Tween® – polysorbates [hydrophilic • Diocylphthalate Test – QC test for HEPA filter
• Airlocks for entry – space with interlocked doors
HLB Systems
• Stands for hydrophilic-lipophilic balance Classification of Clean Rooms
• Used to categorize surfactants based on the substance’s
polarity US Customary ISO WHO GMP Max no. of particles
• Values range between 1 and 40 per ft3 (≥ 0.3 µm)
• Materials that are highly polar or hydrophilic have been Class 100 ISO 5 Grade A 100
assigned higher numbers Class 1,000 ISO 6 Grade B 1,000
Activity HLB Value Class 10,000 ISO 7 Grade C 10,000
Antifoaming 1-3 Class 100,000 ISO 8 Grade D 100,000
W/O Emulsifier 3-6
Wetting Agent 7-9 B. STERILE MANUFACTURING OPERATIONS
O/W Emulsifier 8-18
Detergent 13-16 Categories
Solubilizer 15-20
1. Terminal Sterilization
B. INSTABILITIES OF EMULSIONS • Prepared, filled and sterilized
• Method of choice whenever possible
1. Creaming – the upward movement of dispersed globules 2. Aseptic Processing
(↑ internal phase) • Components are sterilized separately and assembled

2. Sedimentation – the downward movement of dispersed globules Sterilization Methods

(↓ internal phase)
1. Moist Heat
3. Phase Inversion – an o/w changes to a w/o emulsion or vice • autoclave or steam under pressure (121°C, 15psi, 15-20
versa (w/o ↔ o/w) minutes)
• MOA: protein coagulation
4. Flocculation/ Aggregation – the dispersed globules come • BI: Bacillus stearothermophirus
together but do not fuse 2. Dry Heat
• oven (160-170°C for 2-4 hours)
5. Coalescence – complete fusion of droplets • MOA: oxidation
• BI: Bacillus subtilis
6. Breaking/ Cracking – complete separation of oil and water 3. Membrane Filtration
• membrane filters (0.22 µm); for heat-labile solutions
IV.3. MANUFACTURING OF SUSPENSIONS • MOA: physical separation
• BI: Brevudimonas diminuta
A. FORMULATION 4. Gas
• ethylene oxide, formaldehyde or β-propiolactone
1. Suspending Agents • MOA: alkylation
• Viscosity-increasing agents used to reduce sedimentation • BI: Bacillus subtilis
rate of particles in a vehicle 5. Ionizing Radiation
• Ex: tragacanth, acacia, celluloses, bentonite, magma, • gamma or cathode rays
veegum, agar, carrageenan, gelatin, kaolin) • MOA: DNA mutation
2. Wetting Agents • BI: Bacillus purnilus
• Displace air from cervices of hydrophobic solids to allow
penetration of water Depyrogenation
• Ex: surfactants, glycerin, PPG, PEG, syrup • Oven Settings
3. Flocculating Agents • 180°C for 4 hours
• Reduce the electrical barrier between the particles of the • 250°C for 45 minutes
suspensoid and forming a bridge so as to link them together • 650°C for 1 minute
(decrease zeta potential causing aggregation to avoid
formation of cake) Steps in preparing Sterile Dosage Forms:
• Ex: Electrolytes (NaCl, KCl), surfactants and Polymers
4. APIs 1. Cleaning
5. Liquid Vehicle • Manual cleaning and sterilization of equipment
6. Buffers • Sanitation of clean rooms
7. Preservatives • Sterilization of components for aseptic processing
8. Colorants, Flavors and Fragrances 2. Product Preparation
• Critical process → Class 100

Module 5 – Manufacturing Pharmacy Page 9 of 10 RJAV 2022

Advantages Disadvantages
• Solutions: dissolution, tonicity adjustment, preservation and - low cost - permeable
filtration - not breakable - low heat resistance
• Dry Solids: spray-drying or freeze-drying (lyophilization) - light weight - not as clear as glass
- chemically inert - poor physical stability
3. Filtration
• Methods b. Multiple Unit
• contains multiple doses and packaged in resealable
• Clarification – 2-3 µm particles
containers
• Cold Filtration – 0.2 -0.3 µm particles
4. Filling • with antimicrobial agent; water: BWFI; USP limit: 30
mL
• Methods
• Gravity Filling – hand-operated • vials
• Pressure filling – semi-automatic
3. According to Material Used
• Vacuum Filling – fully automated
5. Sealing
• Ampoule Sealing a. Glass
• most widely used, made up of inorganic compounds
• Tip-Seal (Bead-Seal) – made by melting the tip of the
neck o an ampoule to form a bead (major component: SiO2)
Advantages Disadvantages
• Pull-Seal – made by heating the neck of a rotating
- rigid and transparent - high cost
ampoule below the tip and pulling the softened glass - impermeable - fragile
away - chemically resistant - relatively heavy
- can be easily sterilized - prone to leaching
VI. PACKAGING AND STORAGE OF DRUG PRODUCTS
Types of Glass
A. PACKAGING I Highly Resistant Borosilicate (Pyrex, Borosil)
Boron – decrease coefficient of expansion
•an economic way of protecting, preparing, identifying, and II Treated Soda Lime Glass
containing the drug products III Soda Lime Glass; Dry Powder Packaging
• composed of container and closure IV/NP General Soda Lime Glass
Types of Packaging: b. Plastic
• organic polymers of HMW
Primary Packaging
• in direct contact with product Types of Plastic:
• immediate container
• affects stability 1. Thermoplastic – soft when heated and hard when
• may provide means of administration cooled; flexible and squeezable
• ex. bottles, caps, liners, filler, desiccant 2. Thermoset – permanently hard; rigid

Secondary Packaging Types of Polymers for Plastic

• outer packaging (not always present)
• encloses primary packaging No. Plastic Use
• ex. carton box, sticker label, inserts, conjugated box 1 Polyethylene Terephthalate - for beverages

2 High-density Polyethylene - hard thermoset for solid

B. CLASSIFICATION OF CONTAINERS
dosage forms
3 Polyvinyl Chloride - for blister packs
1. According to Protection Ability 4 Low-density Polyethylene - thermoplastic for squeeze
bottles and medicine
a. Well-Closed droppers
• protects content from extraneous solids 5 Polypropylene - for autoclave containers
b. Tight
• protects contents from extraneous solids, liquids, c. Metal
and vapors • Used in aerosol cans and collapsible tubes
• protects from deliquescence, efflorescence, d. Foils, Films and Laminates
evaporation • Used in blister packs and strip packs
c. Hermetic e. Rubber
• impervious to air or any other gas • Used in vial stoppers and syringe plugs
d. Light-Resistant f. Paper
• protects from photochemical degradation • Used for divided powders
• amber bottles
e. Child-Resistant C. STORAGE CONDITIONS
• difficult for children under 5 years of age to open
• press down and turn 1. Cold – NMT 2 to 8°C
• squeeze and turn a. Refrigerator – 2 to 8°C
• alight the arrows b. Freezer – -20 to -10°C
• latch top
f. Tamper-Resistant 2. Cool – 8 to 15°C
• uses an indicator which if breached or missing can
provide evidence that tampering has occurred 3. Room Temperature – temperature prevailing in the area
• shrink seal/ wrap
• breakable caps 4. Controlled Room Temperature – 20 to 25°C
• tape seal
• bottle seal 5. Warm – 30 to 40°C
• aerosol → only true temper-resistant packaging
6. Excessive Heat – >40°C
2. According to Quantity Held

a. Single Unit
• contains a single dose only and packaged in non-
resealable containers
• no antimicrobial agent; water: WFI or SWFI; USP
limit: 1000 mL
• ampoules, prefilled syringes

Module 5 – Manufacturing Pharmacy Page 10 of 10 RJAV 2022