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Margarita M.

Gutierrez, RPh, MHPEd (ongoing)

University of the Philippines- College of Pharmacy
 The complete set of activities to produce a
drug that comprise production and quality
control from dispensing of materials to the
release for distribution of the finished
 the manufacture,
preparation and
processing of a
drug product in a
large scale
 the making by
physical, chemical,
biological or any
other procedure of
any article that
meets the definition
of drugs
 the manipulation,
sampling, testing or
control procedures
applied to the final
product or any
other part of the
 the packaging, repacking or changing the
container, wrapper or label of any drug
package in preparation for its distribution
from the manufacturer to the final user
 mass production of
drug products
 small scale
preparation of drug

 prescription order

 specific for a
particular patient
 Any organization or company involved in the
manufacture, importation, repacking and/or
distributions of drugs or medicines
 any establishment engaged in operations
involved in the production of drugs

 A056 s 1989
 IRR of RA 9711
a. Ethical Manufacturers
◦ prescription drugs

b. Proprietary / Generic Manufacturers

◦ branded / generics

c. Biologicals Manufacturers
◦ vaccines, toxoids, antisera, biotech products
d. Veterinary Products Manufacturers
◦ animal drugs

e. Medicinal Chemical Manufacturers

◦ active ingredients, excipients

f. Toll / Contract Manufacturers

◦ produce drugs for other companies
 Imports or exports raw materials, active
ingredients or finished products for its own
use or for wholesale distribution on whole
sale basis

 IRR 9711
 registered owner of the drug product but
subcontracts toll manufacture of such
products to a licensed manufacturer

 May also engage in distribution and or

marketing of products

 AO56
 RA 9711
 Procures raw materials , active ingredients
and or finished product from local
establishment or for local distribution on
wholesale basis

 RA 9711
 develops new or existing products

 3 facilities:
◦ a. library
◦ b. animal house
◦ c. pilot plant
 manufacturing of drug products
 “heart & soul” of a drug manufacturer
 sampling, testing, assaying of drugs
 promotes
maximum volume
of sales of products
 locates, installs, repairs and maintains
 ensure plant and personnel safety
 purchases, receives and inventories supplies
 physical and medical
examination of
employees and

 clinical studies

 prepares product
inserts and literature

 publishes company’s
newsletter / organ
 Current Good Manufacturing Practices

 Chapter 21 of the Code of Federal

Regulations Part 211
 were first promulgated by the US Food and
Drug Administration (FDA) in 1963; and
finalized in 1979
 Part of quality assurance which ensures that
products are consistently produced and
controlled to the quality standards
appropriate to their intended use

 - WHO 2007
 System of quality assurance aimed at
ensuring that products are consistently
manufactured to a quality appropriate for
intended use and is concerned with
manufacturing and quality control process
and procedures

 AO43 s 1999
 Part of quality assurance which ensures that
medicinal products are consistently produced
and controlled to the quality standards
appropriate to their intended use.
AO43 1999- adoption of the 1st edition of the
current GMP guidelines by FDA

AO2012-0008- adoption and implementation

of the PIC/s GMP as the standard on the

FDA MC 2012- Philippine FDA mandated all

drug manufacturers to ensure strict and full
compliance to the newly adopted PICS
 I. Quality management
 II. Personnel
 III. Premise and equipment
 IV. Documentation
 V. Production
 VI. Quality control
 VII. Contract manufacture and analysis
 VIII. Complaints and product recall
 IX. Self inspection
 1. All manufacturing processes are clearly
defined, systematically reviewed in the light
of experience and shown to be capable of
consistently manufacturing medicinal
products of the required quality and
complying with their specification
 2. Critical steps of manufacturing process
and significant changes to the process
 3. All necessary facilities for GMP are
provided including
 A. appropriately qualified and trained
 B.adequate premises and space
 C. Suitable equipment and services
 D. Correct materials, containers and labels
 E. Approved procedures and instruction
 F. Suitable storage and transport
 4. Instructions and procedures are written in
an instructional form in an unambiguous
language specifically applicable to the
facilities provided
 5. Operators are trained to carry out
procedures correctly
 6. Records are made, manually and or by
recording intriments, during manufacture
which demonstrates that all the step required
by the defined procedures and instructions
were in fact taken and that the quantity and
quality of the product was as expected.

 Any significant deviations are fully recorded

and investigated
 7. Records of manufacture including
distribution which enable the complete
historyof a batch to be traced are retained in
a comprehensible and accessible form
 8. the distribution (wholesaling) of the
products minimizes any risk to their quality

 9. A system is available to recall any batch of

product from sale or supply
 10.complaints about marketed products are

 The cause of quality defects investigated and

appropriate measures taken in respect of the
defective products and to prevent
 an economical means of providing
presentation, protection, preservation,
identification, information, containment,
convenience and compliance for a drug
 device that holds a drug and is or may be in
direct contact with the drug
1. Primary Container
◦ aka: Immediate
◦ direct contact
◦ direct effect on the
◦ bottle, cap, cap
2. Secondary
◦ external to the
primary container
◦ adds physical
◦ cartons, boxes,
 protects against
extraneous solids
and loss of drug
under ordinary
conditions of
handling, shipment,
storage and
 protects from
extraneous solids,
liquids or vapors,
from loss of drug and
from efflorescence,
deliquescence or
evaporation and loss
of drug under
ordinary conditions
of handling,
shipment, storage
and distribution
 impervious to air or
any other gases
under ordinary
conditions of
handling, shipment,
storage and

 generally sterile
 protects the
contents from

 amber, opaque,
 designed to hold a
quantity of drug
intended for
administration as a
single dose

 sterility is not
assured after

 ex. ampul, prefilled

 contains more than
a single dose of the

 ex. vial
Type General Description Uses Test

I highly resistant for parenterals Powdered Glass

borosilicate glass

II treated soda lime for parenterals Water Attack


III soda lime glass for parenterals Powdered Glass

NP general purpose other products Powdered Glass

soda lime glass except
 does not apply to a
single material but
rather to a vast
number of
materials each
developed to have
desired features
Advantages: Disadvantages:
 lightweight  permeability
 flexibility  leaching
 resistance to  sorption
impact  transmission of
 alteration of
container upon
 two types:
◦ thermoplastic – squeezy
◦ thermoset – firm & rigid
Polyethylene (PE)
• cannot be

• low-density (LDPE)
 droppers & sprays

• high-density
 solid oral prepns
Polyethylene Terephthalate
• for beverages
• APETG (amorphous PET
• PETG (PET glycol)
• have transparency and luster
• gamma radiation sterilization
Polypropylene (PP)
• autoclavable

Polyvinyl Chloride
• rigid & good clarity
• blister packaging
 aluminum, tin &

 vial caps, ointment

 synthetic ones are preferred because of their
more definite compositions as compared to
natural rubber

 stoppers for vials

 Sachet
 Seals
 Strips
 blisters
 one that is difficult
for most children
under 5 years of
age to open or gain
access to the
contents or obtain a
harmful amount of
the contents
 uses an indication or barrier to entry that is
distinctive by design, or must employ an
identifying characteristic which if breached or
missing can reasonably be expected to
provide visible evidence to consumers that
tampering has occurred
 film wrappers  bottle seals
 blister/strip packs  tape seals
 bubble packs  breakable caps
 shrink seals/bands  sealed tubes
 foil  sealed cartons
 paper or plastic  aerosol containers,
pouches  cans
Term Condition
Cold Place not exceeding 8ºC
a. Freezer cold place that is thermostatically
controlled at -25ºC to -10ºC

b. Refrigerator cold place that is thermostatically

controlled between 2ºC to 8ºC

Cool any temperature between 8ºC to 15ºC

Room Temperature temperature prevailing in a working

(usually 20ºC to 25ºC)
*Controlled Room 20ºC to 25ºC or 15ºC to 30º
Warm 30ºC to 40ºC
Excessive Heat above 40ºC
 inserted to the cap
to effect a hermetic
 for more positive seal surface
 for tamper-evidence
 multiple-dose vials, syringes and gasket
 to prevent damage during shipping
 to absorb moisture
 contains essential information about the

aka: - chartula
drug used: non-potent potent
preparation: block & divide geometric dilution,
preferably weighing

dose: not individual individual

packaging: wide mouth plastic paper

or glass bottles, - white bond
sifter cans, aerosol - glassine
containers - vegetable parchment
- waxed
1. cutting / shearing mill
2. End runner mill- Compressing
3. Hammer mill, vibration mill- Impact
4. Ball mill and pin mill- Impact andattrition
5. Roller mill- compression attrition
 Tumbling mixer/blender-
 y cone, rotating cube, double cone,
oblique cone, twin she’l or v mixer

 High speed mixer granulator

 Fluid bed mixer

 Agitator mixer – ribbon and planetary mixer

 liquid is sprayed on suspended powders
 Shear granulators
 High speed mixers/granulators
 Spray driers
 Spheronizers/pelletizers
 A multistep process used to make uniformly
sized spherical paricles

 Primarily used to produce multiparticulates

for controlled release application
 Fluid bed dryers
 Vacuum ovens
 Microwave dryers
 Spray dryers
 Freeze dryers
 particles are aggregated using high pressure

 for drugs that do not compress well after wet

granulation or those that are sensitive to
 types:
a. roll-compaction method
b. slugging method
 powders are rolled into dense sheets
 sheets are granulated using a mechanical
 sieve granules to obtain desired size
 Sluggers + hammermill
 Roller compactors
1. fluidity / flowability

2. compressibility
1. alteration of particle size and size
◦ use larger particles
◦ reduce the amount of fines
2. alteration of particle shape or texture
◦ the more spherical and smoother the particles,
the more flowable

3. alteration of surface forces

◦ reduce/increase electrostatic charges
◦ reduce moisture content
4. alteration of process conditions

5. use of flow activators

◦ use glidants, lubricants and antiadherents
 G- glidants- improve flowability of granules

 A- antiadherent- prevents the adherence of

granules to the punch

 L - lubricant- to avoid wear and tear of punch

and dies
 gelatin shells are
manufactured in a
separate process
(dipping pegs made
of manganese
bronze in a melted
gelatin mixture)
 has 2 parts: body
and cap/head

 shell composed of:

◦ gelatin
◦ water
◦ sugar
◦ colorants
◦ 0.15% sulfur dioxide
◦ titanium dioxide
 Diluent
 Glidant
 Lubricant
 Wetting agent
 Disintegrant
 Stabilizer
 has 6-10% moisture

 rendered plastic-
like with the
addition of
(glycerin or
 oblong, oval, spherical, tube, pearl,
 methods:
◦ plate process
◦ rotary or reciprocating die process
 partial hydrolysis of
collagen from

 types: Gelatin A & B

 for elasticity & flexibility
 glycerin, sorbitol
 FD&C
 0.15% sulfur dioxide
 titanium dioxide
 glidants
 lubricants
 surfactants

…may also be employed

1. Preparation of formulation
2. Filling
3. Sealing
4. Cleaning & Polishing
 measure of gelatin capsule’s rigidity

 HGC= 200-250g

 SGC= 150g
 a solid dosage form
which may or may
not contain
substances with or
without diluents
and prepared either
by molding or

 most widely-used
dosage form
 Single punch/eccentric press- 200 tablet per

 Rotary, multi station press- 10000 tablets per

◦ for storing of materials for
Feed shoe
◦ for distribution of materials
into the die
◦ for compaction
◦ determines the hardness of
the tablet
◦ determines the size & shape
of the tablet
Cam tracks
◦ for guiding the movement of
the punches
 used to bring up the weight of the tablet

 add the necessary bulk to the formulation

 ex. lactose, starch, cellulose derivatives,

mannitol, sucrose, sorbitol
 added to promote adhesion among the
particles of the formulation

 ex. starch, gelatin, methylcellulose, NaCMC,

HPMC, sugar solution, polyvinylpyrrolidone

 Glucose > Acacia >Gelatin > Simple syrup >

 promote the break-up of the tablet when it
comes in contact with water in the GI tract

 opposite effect of a binder

 types: internal (before granulation) external

(during tableting)
 ex. starch, gums,
clays, cellulose,
alginates, surfactants

 croscarmellose
 crospovidone
 sodium starch
glycolate (Explotab®)
 improve the flow properties of granules by
reducing the friction among particles

 ex. talc, corn starch, colloidal silica, calcium

silicate, calcium phosphate, Zn, Mg, and Ca
 reduce the friction between the different
parts of the tablet press particularly the
punches and dies

 ex. talc, magnesium stearate, and calcium

 reduce sticking, or adhesion of the tablet
granulation or powder to the faces of the
punches or die walls

 ex. colloidal silica, corn starch, sodium lauryl

sulfate, stearates
 adsorb fluids and moisture, keep products

 ex. magnesium oxide, magnesium carbonate,

bentonite, silicon dioxide
 for aesthetic purposes
and product

 can be
◦ natural
◦ synthetic
 FD&C – food, drug & cosmetics
 D&C – drug & cosmetics
 external D&C – external use only
 Dyes – water soluble
 Lakes – water insoluble
 oils or dry powders are used in formulations

 color, odor and flavor must complement one

Drug Flavor

Sweet honey, mixed fruits, berries, maple,

Bitter chocolate, anise, cherry mint, nut, fennel

Sour citrus, rootbeer, anise, cherry,

strawberry, licorice
Salty butterscotch, maple, peach, melon,
Metallic grape, lemon, lime

Alkaline chocolate, cream, vanilla, mint

 sucrose
◦ sugar cane
◦ sugar beet
◦ sugar maple
 honey (Apis mellifera)

 stevia (Stevia
 saccharin – has bitter aftertaste

 aspartame* – methylester dipeptide of

phenylalanine &
aspartic acid

 acesulfame K – used more in confectionary

*contraindicated to phenylketonurics
 successive addition of sucrose-based
solutions to a tablet core
1. Pan Coating – most widely-used
2. Pan Spraying
3. Pan Suspension
1. Sealing / Waterproofing
2. Subcoating
3. Syruping / Smoothing
4. Finishing
5. Polishing
 to protect the tablet core from water in
subsequent steps

 ex. shellac, phthalic anhydride

 improves the bond between the seal coat and
sugar coat
 to round-off the contour
 builds-up standard size
 gelatin, acacia solution
 to finalize the rounding-off of tablet

 substeps:
a. Grossing – for color base
b. Heavy Syruping
c. Regular Syruping
 employs “jogging” (quick on-off)
 to attain final smoothness
 for sheen or gloss
 ex. beeswax, carnauba wax
 the process of placing a thin, skin-tight
coating of a plastic-like material over a tablet

 adv: no significant increase in tablet size and

weight unlike sugar-coating

 about 2-5% increase in thickness only

 1.functional
 2. non-functional coat
 produces smooth, thin film

 examples:
◦ cellulose acetate phthalate
◦ hydroxypropyl methylcellulose (HPMC)
 provides water-solubility / permeability

 ex. polyethylene glycol (PEG)

 imparts plasticity / elasticity to the coat

 ex. castor oil

 enhances spreadability of films during

 ex. Spans & Tweens

 enhance appearance

 ex. TiO2, FD&C

 improve palatability

 ex. vanillin, saccharin

 provides luster

 ex. beeswax
 vehicle that evaporates rapidly used for
spreading the components
 ex. alcohol-acetone mixture
 designed to resist dissolution in the stomach
but dissolve in the less acidic environment of
the small intestines (pH 4.8 or greater)

 ex. shellac, HPMC

 a capsule
composed of hard
gelatin shell
hundreds of tiny
beads/pellets of
drugs for modified
 Compaction of  Use specially
granular material designed tableting
around an already equipment
preformed tablet
 separation of the top layer
 separation of a small portion observed on the
edge of the tablet
 separation into several layers
 removal from the top layer of the tablet
 adhesion of the material to the die wall
 migration of color
 migration of plasticizer

 It is a common film-coating defects

characterized by the dull film developing on
the surface of the coat due to exceedingly
humid conditions during the manufacture of
the product.
 migration of other ingredients

 – presence of mottled areas on the coat which

indicates the migration of plasticizers, dyes
or other additives in the coating formulation
 formation of oil films or droplets of liquids
 reduced adhesion of film from tablet
 filling-in of the score line or intended logo by
the film
 roughness of tablet surface

 caused by the rapid or inadequate solution

distribution after each application of coating
 when coating material is easily from the
product in sheets or large flakes after
 homogenous one-phase system consisting of
2 or more components

 most commonly used liquid dosage form

 Mixing tank

 Mixers

 Propeller
 Turbine
 Inline

 Clarification system
 consider solubility & stability
 consider clarity, toxicity, viscosity,
compatibility, palatability

 water – best solvent

 used in combination with the solvent to
increase solubility of the solute

 examples:
◦ ethanol
◦ sorbitol
◦ glycerin
◦ propylene glycol
◦ polyethylene glycol
 surfactants (Tweens)
 improves pourability and to some extent,

 sugar, PVP, cellulose derivatives

 controlling pH to maintain solubility and
 most common: pH 4-7
 citric, lactic, glutaric
 benzoic acid and its salts
 parabens
 chlorobutanol
 benzyl alcohol
 thimerosal
 benzalkonium chloride
 charge the solute to the solvent

 agitate with the use of mixers until solution is

 heat may be employed to increase solubility

 ensure complete solution before further

 solutes in small concentrations (such as dyes
and intensely colored materials) must be
predissolved prior to mixing with the whole
 to allow complete blending of all the
 aim for 3-5 microns or less

 filter media:
◦ cellulose nitrate
◦ polyamide
◦ polyvinylidene chloride
◦ nylon
Gravity filtration
◦ slow

Vacuum filtration
◦ very large quantities

Pressure filtration
◦ fast, to achieve highly polished product
Parallel filtration
◦ one type of filter

Series filtration
◦ more than one filter
 Perforated basket centrifuge- crystalline

 Tubular bowl centrifuge-sedimentation

Gravimetric filling
◦ for mobile and frothy solutions

Vacuum filling
◦ for viscous solutions

Pressure filling
◦ for viscous solutions
 liquid dosage forms containing finely divided
drug particles distributed somewhat
uniformly throughout a vehicle in which the
drug exhibits a minimum degree of solubility
flocullated Deffloculated
definition Loose aggregates of Particles are
particles (granule separate entities
like) (powder like)
Sedimentation rate faster slower

Sediment faster slower

hard cake (-) Absent (+) present
Appearance (unsightly) Cloudy appearance
Supernatant liquid +
 Aka suspensoid 3-5mcm
 should be insoluble
 must be uniformly dispersed
 aqueous or non-aqueous
 displaces the air from crevices of drug
 glycerin, sorbitol solution, syrup
◦ acacia, tragacanth, veegum, cellulose derivatives

◦ bentonite, kaolin

◦ agar, gelatin, pectin, gelatinized starch
 Buffer
 Sweetening agent
 Flavoring agent
 Colorant
 Preservative
1. Caking
2. Partial solubility of the active ingredient
3. Polymorphism of the active ingredient
 are dispersed systems in which the dispersed
phase is composed of small globules of a
liquid distributed throughout a vehicle in
which it is immiscible
 acts as the bridge between the 2 immiscible
 stabilizer of the internal phase
 retards coalescence of the globules
 Natural
◦ gelatin, egg yolk, acacia, tragacanth, cellulose

 Finely Divided Solids

◦ bentonite, kaolin

 Synthetic
◦ Tweens, Spans, SLS, SLES
 protects the emulsified lipids which are
susceptible to oxidation

 ex. BHA, BHT, tocopherol, ascorbic acid,

 should be effective for both phases
 reduces the evaporation of moisture from the

 ex. glycerin, sorbitol, propylene glycol

1. Oil phase containing oil-soluble ingredients
is heated at about 5-10ºC above the
melting point of the ingredient with the
highest melting point.

2. Aqueous phase is heated to the same

3. The two phases are mixed.

4. Volatile ingredients are added at the lowest

temperature as possible (usually 45-55ºC).

5. Adjust the final weight when emulsion

reaches 35ºC.
 creaming
 breaking
 phase inversion
 parenterals
 ophthalmics
 biologicals
 sterile preparations
several layers of
tissue or mucous
 Parenteral
◦ Intravenous
◦ Intraarterial
◦ Intracardiac
◦ Intramuscular
◦ Subcutaneous
◦ Intradermal/intracutaneous
◦ Intraarticular (intrasynovial
◦ Intrathecal
◦ Intraspinal
◦ Epidural
 best quality
 maximum safety
 highest level of
 strictest quality
1. solutions ready for injection

2. dry soluble products ready to be combined

with a solvent prior to use

3. suspensions ready for injection

4. dry insoluble products ready to be
combined with a vehicle prior to use

5. emulsions ready for injection

6. liquid concentrates ready for dilution prior

to use
 Should be carried out in clean areas, entry to
which should be through airlocks for
personnel and/or for equipment and
 An area with defined environmental control of
particulate and microbial contamination,
constructed and used in such a way as to
reduce the introduction ,generation, and
retention of contaminants within the area
 An enclosed space with two or more doors,
which is interposed between two or more

 Differing cleanliness

 Control the airflow between rooms

Maximum permitted number of particles
At rest At operation
0.5um 5um 0.5um 5 um
A 3520 20 3520 20
B 3520 29 352000 2900
C 352000 2900 352000 29000
D 3520000 29000 Not Not
defined defined
 easy to clean, safe, sterile

 5 sections
◦ Materials support area
◦ Compounding area
◦ Aseptic filling area
◦ Quarantine area
◦ Finishing area
 Carrying out less critical stages of the
manufacture of sterile
 surfaces should be continuous
 class 10,000 environment

 nmt 10,000 particles or 0.5 um or larger are

present in per cubic ft.)
 Hair and where relevant beard should be

 General protective suit and appropriate shoes

and overshoes should be worn

 Appropriate measures should be taken to

avoid any contamination coming from outside
and clean areas
 Hair and where relevant beard should be

 A single or two piece suit gathered at the

wrist and with high neck and appropriate
shoes or overshoes should be worn should
shed virtually no fibers or particulate matter
 Local zone for high risk operations

 Filling zone, stopper, aseptic connections

 Lac with HEPA

 Background environment of grade A
 Headgear should totally enclose hair and where relevant
beard and mustache; it should be tucked into the neck of
the suit

 A face mask should be worn to prevent the shedding of


 Appropriate sterilized, nonpowdered rubber or plastic

gloves and sterilized and disinfected footwear should be

 Trouser legs should be tucked inside the foot wear

 Protective clothing should shed no fibers or particulate

 most stringent control
 stainless steel cabinets and counters
 continuous surfaces
 class 100 environment

 (SS 304, SS 316 the best)

 “heart” of production area

 laminar air flow (LAF) with HEPA filter (High

Efficiency Particulate Air)

 99.95% efficiency
 Used to test efficiency of heap filter:
◦ DOP (dioctylphtalate test)
 storage while waiting for QC results
a. Active drug
b. Solvent / Vehicle
◦ aqueous
 water for injection

◦ water miscible
 glycerin
 ethanol
 propylene glycol
 PEG 400 & 600
◦ vegetable oils
 corn oil
 peanut oil
 sesame oil
 cottonseed oil

◦ non-vegetable oils
 benzyl benzoate
 ethyl oleate
 isopropyl myristate
c. Other Excipients
◦ buffer
 citrates
 acetates
 phosphates

◦ preservative
 chlorobutanol
 benzyl alcohol
 parabens
◦ chelating agent

◦ tonicity adjusting agent

 NaCl
 boric acid
 NaNO3
 KNO3
 dextrose
d. Containers
◦ bottle, vial, ampule, cartridge, bag

◦ glass, plastic

◦ single-dose (limit: 1000 mL)

◦ multiple-dose (limit: 30 mL)

e. Closures / Stoppers
 Cleaning
 Compounding
 Filtering
 Filling
 Sealing
◦ for ampules: pull / tip sealing
◦ check using leaker’s test
 Sterilization
 Steam
◦ autoclave (121ºC, 15-30 mins, 15psi)

 Dry Heat
◦ oven (160-170ºC, 2-4 hrs)
◦ 6500C in 1 minute, 2500C in 45 minutes, and 1800C
in 4 hours

 Gas
◦ ethylene oxide
 Ionizing Radiation

 Bacterial Filtration
◦ membrane filters

 Tyndallization
◦ intermittent steam sterilization exposing material
to 100ºC for 30 min or at 80ºC for 1 hr for 3
consecutive days
 environment:
◦ blood agar plate
◦ RODAC contact plates (Replicate Organism
Detection and Counting)

 product: sterility tests, pyrogen tests

 1. tip seal method ( aka bead seal)
 Not so efficient, long

 2. pull seal
 More efficient