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
contract manufacturers
1. Research and Development Department

!
B. TYPES OF DRUG ESTABLISHMENTS ~• formulates new products >Formulation:
M• Stages of Drug Development
evaluation of
AO 56 s.1989 1) Discovery and Development dry unit.
stability, followed by the
• Revised Regulations for the Licensing of Drug 2) Preclinical Research
Establishments and outlets 3) Clinical Research developmentof anappropriate
4) FDA Review drug delivery system
Drug
Establishments 5) Post-market Surveillance
• involved in process development and scale-up
Drug Drug
- • prepares Master formula
-

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
↑• justifies overages in the formula
Engaged in the Manufacture, Conduct of Clinical Trial,
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
~• ⑧
accomplish the BMR to ensure that batches were properly
made and tests were conducted
CRO
Batch Manufacturing Record (BMR) – document

C
containing the details of the manufacture of each
batch computation of% yield;deviations,
I

or Master Batch Record

Module 5 – Manufacturing Pharmacy Page 1 of 9 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
La
sugar alcohols
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
Cmoisture content:31-35%.
- • 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 &
-•

~•
conductsC
prepares SOPs ⑳
quality audit and monitoring
-
-
-
·underwet dissolution (↓ BA)
-
overwet -

a. Starch paste
-
-

Standard Operating Procedures (SOP) – step-by-

step instructions for performing operational tasks or
• - Binder of choice for wet gran ⑳
activities b. Acacia & Tragacanth
~
• Natural guns
I

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 -
-
- -

binder
6. Marketing Department e. Cellulose Derivatives act as a

• studies current market trends, consumer behavior and • Methyl cellulose -

3
~
alternative to gelatin
• Ethyl cellulose
-

product status in market

-

- • promote and advertisement • Carboxymethyl cellulose

• Hydroxypropyl methyl cellulose
7. Regulatory Department
f. PVP Polyvinylpyrrolidine
• ensures compliance of company and its products with all
-

pertinent regulations and laws about drugs and their • Binder for chewable tablets
-

starch, clays, celluloses

marketing
-

-
3. Disintegrant Alginates, Gums, Ion-exchange resin
⑳
-

8. Engineering Department • Facilitates the breakup of a tablet when in contact with ↳ Polacritin
-• installs, maintains and repairs of equipment and premises aqueous medium ④ Potassium
~ • conducts validation and qualification ⑧
2 Lamberlite)
- -

Validation – action of proving and documenting that

-

any process, procedure or method actually and

-

Disintegration Aggregation
consistently leads to the expected
-
results
Qualification – action of proving that premises,
systems or equipment work correctly and actually - E
lead to expected results • MOA:
r Internal
addition: External ->
o
• Swelling – starch paste Internal
body:External ->

~• ensures safety • Wicking – MCC ca silicate ,

I n

• Release of gas – effervescent tablets

9. Medical Department
- • concerned with physical examination and medical treatment 4. Superdisintegrant
of employees • C Newer class of disintegrants which are effective at much

G
-
-

-
• performs clinical studies lower levels
~
• publishes house organ/paper • Hydroscopic

II. MANUFACTURING OF SOLID DOSAGE FORMS a. Sodium Starch Glycolate (Explotab®, Primojel®)

O
-

• Cross link starch polymer

- -

A. FORMULATION COMPONENTS -

b. Crospovidone
• Cross link polyvinylpyrrolidone

is
1. Diluent (Filler/ Bulking Agent)
• inert substance added to increase tablet size or fill the n
capsule body c. Croscarmellose Na
• Cross link cellulose derivative
a. Lactose -> incompatiblew/soxidizers, anine drugs alricants
• 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
↳ granulation ↳ • Mostly hydrophobic and added at low concentration
wet
Dry granulation (a 4%
b. Sucrose and Dextrose
• Used as sweetener Lubricant Antiadherent Glidant
Reduces friction
- Reduces- sticking to
& Reduces friction

flowability
>
e

c. Microcrystalline Cellulose (Avicel®) between the tablet

- -
O and⑳
die walls picking
-
among particles to
and die wall to by punches ↓punches enhance the flow
• Good flow and very compressible
-

facilitate⑳
ejection from
• Disintegrates rapidly in water die cavity
Running powders
*
-
lubricant-external disintegrant
d. Starch
-
dbd
a. Stearates (Mg, Ca, Na)
• Used as diluent, binder and disintegrant •
- - -

lubricant, antiadherent and glidant -> stearic acid

• 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 2 of 9 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
--sodium lauryl sulfate • automated dispensaries
• hydrophilic lubricants
6. Colorant Issues:
• disguises off-color drugs and improves appearance
~ iron oxide Ale03 • weighing accuracy
Dyes (F.DSC) for internal prep. Lakes (DSC) -> for external prop. • 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 •
• End Runner Mill – mortar rotates
⑳
material is crushed by application of pressure

a. Salty • Edge Runner Mill – 2 rotating wheels

• cinnamon, orange cherry, butterscotch
c. Impact
b. Bitter • material isI
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 between⑳ rubbing surfaces
• Roller Mill – 2 metal cylindrical rolls rotating
d. Oily
• mint, lemon, orange e. Combined
• Utilizes both⑧
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 -
zero calories • uniform dose Mottling Uneven
color distribution
-

Sugar Alcohols Artificial to 1i

• even appearance
49
↳a calories
provides
• Sucrose • Mannitol • Sucralose – 1,000x
-
• avoid segregation
• Fructose • Xylitol • Saccharin – 500x
Equipment:
-

• Dextrose • Sorbitol • Na Saccharin – 300x

-

• HFCS • Erythritol • Acesulfame K – 180-200x

It
• Aspartame – 180-200x (nurrasweets a. Batch Type Mixer
• Na cyclamate – 30x (magic sugar) • all ingredients are loaded together, mixed for a long period,
leastsweet and discharged as a- single batch
B. UNIT OPERATIONS • Rotating Shell/ Tumbling Mixers
• Drum Type Blenders
Tablets HGC • cylindrical-shaped
• rotates horizontally
(45%)
Dispensing Dispensing • poor cross flow o slanted
• remedy: Baffles Slantea -or
-
ensures cross-mixing
• 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-ethrough-like shell with mounted spiral
or helical blades~Used for said Materials
• Sigma Blade Mixer 2 Greek letter shaped blades
-

Coating Sealing • consists of double through shaped shell with 2

sigma shaped blades fitted horizontally
• Planetary Mixer

Module 5 – Manufacturing Pharmacy Page 3 of 9 RJAV 2022

7) Flavorant

Flavoring Techniques:

a) Blending
-

fruit
flavors +
sour taste

bitter taste & sour

-

salty, sweet
+

-
saltasourness & increases sweetness
-

Vanillin, MSG S benzaldehyde

b) Overshadow
-
addition offlavor whose intensity
is longer stronger
than the
obvious faste

Ex:methyl salicylate, oleoresins

glycyrrhiza,
-

c) Physical
-

emulsification oils
of

effervescence
viscosity offluids
-

-
tablets
coating of
-formulation of insoluble comp

6) chemical

absorption ofd rug on substrate

-

-formation a
of complex

e) physiological
-taste
b uds be anestuisized by menthol / mint
may

DOH
Dr. Ted Herbosa secretary
-

Samuel Zacate FDA Dir. General

Dr. -
 • Paddles moves around its own axis and around
the central axis
• Vertical Impeller Mixer
• Screw type impellers rotating inside a⑧
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:

90% a. Good Granules

• pass through sieve #20 but not through sieve #40 Processes:

10% b. Fine Granules Slugging

• pass through sieve #40 -
• &
formation of slugs -
large flattablers
Methods: Roller Compaction
produ • formation of sheets
a. Wet Granulation -produces granules ofthe bestquality
• 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

-
E

3. Die – defines size and shape of the tablet

-
-
-

4. Punches – compress materials within the die

-

API, diment, internal disintegrant,

~
5. Cam Tracks – guide the movement of punches
Blending of dry ingredients #

* moisture content:31-35% 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:
-

0
Drying granulation (moisture cnntent: 0.5-1%) 1. Flowability – facilitates transfer
• Problems:
quanules
good
• 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
I
-
- internal disintegrant
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

Direct Compression
~use for some crystalline substances
Fluid Bed Granulation
• easier and faster than the traditional process • ⑳
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
Disadv:
Dusty tablets

Module 5 – Manufacturing Pharmacy Page 4 of 9 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 • Sealcoating agents
Mottling
factor • shellac (pharmaceutical glaze]
• 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 –>
n
-
-
builds up color
• Regular Syruping – final color
f. Chipping
- -
- -

•
8
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: ~ disintegrates in the
stomach
• problem: surface erosion • Non-enteric: celluloses, methacrylate; PVA; PVP
• Pan Spraying – increases efficiency of coating process • Enteric: shellac, CAP, PVAP, salol aka phenyl salicylate
->

G disintegrates in small intestine

the

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
phthalate esters
2. Perforated Coating Pan ⑧
Surfactant
• heated air is exhausted through the perforations in the drum • enhances0 spreadability of the filM
• (ex. Accela-Cota Pan; Driacoater; Giatt Coater) • example: ~tubig" "Sebo"
-

• polysorbates (Tween) SPAN- lipophiliz

La more hydrophilic
-

Module 5 – Manufacturing Pharmacy Page 5 of 9 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
• =e
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 /polishing
• due to humid conditions Lacloth dusting

18go-infilling -
due partially spray-dried
accumulation
to of material
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 "Pumps"
• 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 -

Blushing
-
low MW of plasticizer
modern E between 2 rotating dies

3. Reciprocating Die Process – uses gelatin ribbons brought

• whitish specks or haziness of the film
-
process 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 /Film Cracking -
• Type I – due to thermal expansion of tablet cores caused by 2. Fusion
over drying • the components are combined by⑧ 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 /Delayed Dissolution B. MANUFACTURING OF GELS

• associated with the exposure of tablet cores to coating
-

coating
E
process conditions rather than a direct effect of the applied
-
-

-
Gelling Agents
• substances which when added to water or an aqueous
mixture,⑧
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,
↳
O
- -

filling pin method tragacanth, Mg Al silicate, bentonite

B
Module 5 – Manufacturing Pharmacy Page 6 of 9 RJAV 2022
(Weeg um)
 2. Semisynthetic Polymers: cellulose derivatives, sodium starch -
parabens; methyl – molds (short)
glycolate propyl – yeasts and bacteria (short)
-
crimoges)
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 BHT
-

butulated hydroxy toluene;BHA- ""anisole

• 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 ⑧
(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 Go chelating agents

-

• 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 ↳ Lime water
-

-
undergreen termwater
u

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
↳ a1283 acetic acid
+

(1:2.35) aka Burrow's solution

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

promotes
• SS 316 – 16% Cr, !0% Ni and 2% Mo;⑳ most inert (menstrum: alcohol + H20

2. Mixers B. STEPS
-

higher curosion
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
• O
problem: vortex formation → remedy: buffers, slanted (45°)
affle,
•
•
Methods to hasten dissolution
Vigorous agitation
b. Colloid Mill • Application of heat -> endothermic ren

• for comminution of solids and dispersion of suspensions - •

•
Particle size reduction
Use of solubilizer and chelating agents
c. Homogenizer 3. Storage and Aging ~aromatic waters & spirits
•
mechanism
⑳
compresses liquid with high pressure by a strong spring • for solutions with high amounts of volatile oils; enhances
odor and flavor
-

• for emulsification 4. Filtration

• process of separating liquids from solids w/ the use of filter
d. Ultrasonifier has limited outeut
->
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 21time passage)
7. Stability Enhancers • Series Filtration – 2 or more filter media

Stability Enhancers: 5. Filling

weightnot
volume
• Methods: ~based on
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 - -

Luide
spectrum IV.2. MANUFACTURING OF EMULSIONS
Classification of Preservatives
(noteffective in spores(
MoA: protein
denaturation & distrupts cell membrane
A. EMULSIFYING AGENTS
• Alcohols: ethanol, propylene glycol, chlorobutanol, phenyl
alcoholMor: bacteriostatic by alteration ofcell membrace inhibits spore formers Classification:
- -

• Acids: benzoic acid, sorbic acid by increasing H+ ion concentration. colloids olw emulsions
~D from hydrophilic
-
- -

MUA: •
memb
Esters: parabens alkyl-

para hydroxybenzoic acid

esters of
1. Carbohydrate Materials: tragacanth, acacia, agar, pectin,
Co cytolysis •· Quaternary Ammonium: benzalkonium chloride, &
cell
-

distrupts
-
cetrimide,
-
chondrus, xanthan, carrageenan
1) methylparaben -
cetylpyridinium chloride MOA: distrupts cell Ccationic surfactants)
memy.
Imolds
• Organic Mercurial: thimerosal, phenylmercuric nitrate 2. Protein substances: gelatin, egg yolk, casein
2) Cpropylparaben MOA: attacks SHgroups arupts
yeast& bacteria enzymating to revertible protein precipitation (a produce Olw emulsions

Module 5 – Manufacturing Pharmacy Page 7 of 9 RJAV 2022

 a film;o/wemulsions
a forms B. METHODS
3. Finely Divided Solids: colloidal clay, bentonite, Mg(OH)2,
Al(OH)3; 1. Dispersion
~as thickeners & stabilizers for of w • 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
Let • Finely divided solid drug is reacted with another substance
5. Synthetic Surfactants: • Ex: Milk of Magnesia
• Anionic (t PH > 8
• effective at basic pH V. MANUFACTURING OF STERILE DOSAGE FORMS
• ex. soaps; alkyl SO4; sarcosinates ;SLS/SLES
• Cationic (1) PH3-7(acidic) A. STERILE PRODUCTIO AREA
• effective at acidic pH
• ex. benzalkonium Cl; cetypyridinium Cl Squaternary ammonium) Clean Rooms
• Amphoteric L • room in which concentration of airborne particles are
• both anionic and cationic controlled
• ex. betaine; lecithin ("no tears") • Filtered air supplied ~ outward direction
& CO29midopropyl betaine
• Non-Ionic choche-10 • Opositive pressure air flow
• not affected by pH ~ sorbital mono oleate •
High Efficiency
&
HEPA filter – removes 99.97% of particles (≥ 0.3 µm)
• Span® – sorbitan esters [lipophilic] Air from air
↳CLASS
"Selo" 100 for critical
areas
-- -
Particulate
•+Ubig" Tween® – polysorbates [hydrophilic higher HLB
-
-

• Diocylphthalate Test – QC test for HEPA filter

polyoxyefnyiere
-

L sorbitan der. • Airlocks for entry – space with interlocked doors

HLB Systems
↑
• Stands for hydrophilic-lipophilic balance HLB, more hydrophilic 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 SLS-40 HLB value &per ft3 (≥ 0.3 µm)
• Materials that are highly polar or hydrophilic have been Class 100 ISO 5 Grade A 100 highest
assigned higher numbers Class 1,000 ISO 6 Grade B 1,000
A Activity CAWWODS) HLB Value Class 10,000 ISO 7 Grade C 10,000
Antifoaming surfactants
-
- . . . -

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 microemulsions
-
15-20
1. Terminal Sterilization
B. INSTABILITIES OF EMULSIONS • Prepared, filled and sterilized
it
• Method of choice whenever possible
·Y
1. Creaming – the upward movement of dispersed globules 2. Aseptic Processing
reversi
E
(↑ internal phase) 0/w • Components are sterilized separately and assembled

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

(↓ internal phase)
w/O
1. Moist Heat /steam sterilization
irreversible3. Phase Inversion – an o/w changes to a w/o emulsion or vice •
000
autoclave or steam under pressure (121°C, 15psi, 15-20
versa (w/o ↔ o/w) Cminutes)
• MOA: protein coagulation
-
-

4. Flocculation/ Aggregation – the dispersed globules come • BI: Bacillus stearothermophirus

G
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 & Filtration
3. Membrane

.
↳ irreversible • membrane filters (0.22 µm); for heat-labile solutions
IV.3. MANUFACTURING OF SUSPENSIONS • MOA: physical separation ↳ QC test:Bubble Pointtest
• BI: Brevudimonas diminuta
-

A. FORMULATION 4. Gas Co Pseudomonas "

• ethylene oxide, formaldehyde or β-propiolactone

1. Suspending Agents Stoke's Equation
-

• 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 - wavelength,energy
te

veegum, &>
agar, carrageenan, gelatin, kaolin) • MOA: DNA mutation
2. Wetting Agents magnesium aluminum silicate • BI: Bacillus purnilus
17

C
• Displace air from cervices of hydrophobic solids to allow
-
-

penetration of water Depyrogenation

• Ex: surfactants, glycerin, PPG, PEG, syrup • Oven Settings
3. Flocculating Agents -

preventcaking in suspension • 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
(decreaseX zeta potential causing aggregation to avoid
formation of cake) Steps in preparing Sterile Dosage Forms:
• Ex: Electrolytes (NaCl, KCl), surfactants and Polymers
4. APIs PS Velocity p. Disadv:
zeta
1. Cleaning
5. Liquid Vehicle Deflocculated * Slower * prone to caking • Manual cleaning and sterilization of equipment
6. Buffers Flocculated ④
• Sanitation of clean rooms
7. Preservatives faster unpleasantappearance
• Sterilization of components for aseptic processing
8. Colorants, Flavors and Fragrances 2. Product Preparation
• Critical process → Class 100

Module 5 – Manufacturing Pharmacy Page 8 of 9 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 parenteral
resistance
leaching;ideal
to for all

Types of Glass high

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 -teared w/ SO2 a high hydrolytic resistance
-

containing the drug products III Soda Lime Glass; Dry Powder Packaging In for non-ap. inj;low to average
-

hydrolytic
• composed of container and closure IV/NP General Soda Lime Glass notsuitable ->
containers as resistance

Types of Packaging: b. Plastic for parenterals

• 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
moisture
• may provide means of administration ~prevents cooled; flexible and squeezable
• ex. bottles, caps, liners, filler, desiccant silica
-
a gels 2. Thermoset – permanently hard; rigid
La
coil/cotton preventrattling
- a
tablets
of

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 topical solutions
(PET)
2 High-density Polyethylene - hard⑳ thermoset for solid
B. CLASSIFICATION OF CONTAINERS CHDPE) dosage forms
3 Polyvinyl Chloride CPUCS - for blister packs infusion sets
1. According to Protection Ability
;

4 Low-density Polyethylene -&thermoplastic for squeeze

(LDPE) bottles and medicine
a. Well-Closed droppers
• protects content from extraneous solids 5 Polypropylene CPP) - for autoclave containers
-

b. Tight 2121.2

• 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 (most biologicals)
• alight the arrows b. Freezer – -20 to -10°C (Sputnik & modernal
• latch top c. Ultra cold--80 to
(Pfizer)
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 9 of 9 RJAV 2022