MANUFACTURING
PHARMACY
ADELLE RAE C. CAÑA, RPH, MPH
Pharmaceutical manufacturing
The complete set of activities to produce a
product that comprise production and quality
control from acquisition of all materials through
processing and subsequent packaging to the
release for distribution of the finished product
(AO 153 s. 2004)
EXTEMPORANEOUS
PHARMACY COMPOUNDING
small scale production
DRUG OUTLETS
DRUG ESTABLISHMENT
any organization or company involved in the
manufacture, importation, repacking and, or
distribution of drugs or medicines.
Types of Drug Establishment:
1. Drug manufacturer
2. Drug trader
3. Drug distributor
◦ Importer
◦ Exporter
◦ wholesaler
DEPARTMENTS:
1. R & D
•Formulates and develops new products
•Improve the company's existing products
•Conducts
chemical/pharmaceutical/physiological
researches (ex. toxicity testing)
2. PRODUCTION
- Manufactures drug products
according to schedules
3. QC/QA
◦ Assures that all operations in the
manufacture of drug products will
meet the standard of quality
involving purity, safety, and efficacy
◦ Ensures compliance to cGMP
4. MARKETING
- Advertisement of drug products
- Monitors product status, market
trends and consumer behavior
5. ENGINEERING
- Installs, maintains and repairs
equipment & facilities
- Ensures the safety of the plant &
personnel
6. PURCHASING
- Purchases raw materials, and
other things needed for the
production and of the company
7. MEDICAL
- Annual/quarter physical
examination of the personnel
- Conducts clinical studies
8. REGULATORY AFFAIRS
- Product registration (FDA)
OTHER TERMINOLOGIES:
BATCH
- Specific quantity having uniform
characteristic & quality
- Produced in a single cycle of
manufacture
LOT
- Portion of a batch
BATCH / LOT NUMBER
- Combination of letters and numbers
- Traceability & identification purposes
MASTER RECORD
-Document containing the product
formulation, specification, manufacturing
procedures, QA requirements & labeling
MANUFACTURING ORDER
- Standard document which gives
instructions to production department in
manufacturing drug product
STANDARD OPERATING PROCEDURE
(SOP)
- Step-by-step procedure in performing
operational task
MANUFACTURING OVERAGE/AVERAGING
- addition of an active in an unstable preparation to
compensate the loss during manufacture
QUARANTINE
- yellow sticker (QC testing : P or F)
- green sticker (go)
- red sticker (rejected)
VALIDATION
- written documentation which proves that a company
does what it has supposed to do
DRUG OUTLET
means pharmacy, and other business establishments
which sell drugs or medicines
DRUG PRODUCT
Is the finished product form that
contains the active ingredients,
generally but not necessarily in
association with inactive agents
ACTIVE INGREDIENT
Is the chemical component responsible for the claimed therapeutic
effect of the pharmaceutical product
GOOD MANUFACTURING PRACTICE
(GMP)
Part of QA which ensures that
medicinal products are
consistently produced and
controlled to the quality
standards appropriate to their
intended use and as required by
the marketing authorization or
product specification and is
concerned with both production
and quality control. (PIC/s 2009)
- A quality assurance system aimed at
ensuring that products are
consistently manufactured, packed,
repacked or held to a quality
appropriate for the intended use. It is
thus concerned with both
manufacturing and quality control
procedures. (AO 153 s. 2004)
- It is the system of quality assurance aimed at ensuring that products are
consistently manufactured to a quality appropriate for their intended use. It is
thus concerned with both manufacturing and quality control processes and
procedures. (AO 43 S. 1999)
GMP Regulations In The Philippines
- AO 43 s. 1999 (adoption of the 1st edition of the
CGMP guidelines by BFAD)
- AO 153 S. 2004 (updated cGMP that is important and
urgent "tool" to push forward local industry
competitiveness and profitability
- AO 2012-0008 (adoption and implementation of the
PIC/s GMP as the standard on the manufacturer
-FDA MC 2012 (Philippine FDA mandated all drug
manufacturers to ensure strict and full compliance to the
newly adopted PICs
PIC
• Means Pharmaceutical Inspection Convention
PIC/s
• Means Pharmaceutical Inspection Co-operation
Scheme
• Focused on the following:
- GMP → manufacturing
- GDP → distribution
Chapters of PIC/S GMP (March 2014)
“QUA-PE-PRE-DOC-PRO-QUA-CO-CO-SE”
I. Quality management
II. Personnel
III. Premises and Equipment
IV. Documentation
V. Production
VI. Quality Control
VII. Contract Manufacture and Analysis
VIII. Complaints and Product Recall
IX. Self Inspection
PRODUCTION
CONTRACT MANUFACTURE
AND ANALYSIS
SELF INSPECTION
II. PACKAGING, LABELING
CONTROL, AND STORAGE
Packaging
- an economical means of
providing presentation,
protection, preservation,
identification, information,
containment, convenience, and
compliance for a drug product
Container
a.) Primary container
- aka "immediate container"
- has the direct contact with the drug product
- inert (non-reactive)
- ex. Bottles
b.) Secondary container
- encloses 1° container
- for marketing purposes
- ex. standard folding carton
c.) Tertiary container
- encloses 2° container
- ex. corrugated boxes
TYPES OF CONTAINERS
1. According To Protection Ability
◦WELL – CLOSED
◦TIGHT
◦HERMETIC
•2. According To Quality Method
- SINGLE UNIT
- MULTIPLE UNIT
3. According To Material
◦ Glass
◦ Type I = “highly resistant borosilicate glass”
◦ Type II = “treated soda lime glass”
◦ Type III = “ soda lime glass”
◦ Type NP = “general purpose soda lime glass”
◦ Plastic
◦ Polyethylene
◦ Polypropylene
◦ Polyethylene terephthalate
◦ Polyvinyl chloride
◦ Foils, films, and laminates
◦ Rubbers
◦ Metallic containers
Pharmaceutical
Excipients
Definition: non-drug adjuncts in a formulation to aid
stability, concentration and protectivity to final dosage
forms.
Purpose of Excipients:
• Provide bulk to the formulation.
• Facilitate drug absorption or solubility and other
pharmacokinetic considerations.
• Aid in handling of “API” during manufacturing.
• Provide stability and prevent from denaturation.
Commonly-used Excipients:
Surfactants Diluents
Emulsifying Agents Disintegrants
Suspending Agents Lubricants
Flocculating Agents Anti-adhesives
Wetting Agents Adbsorbents
Dispersants Antioxidants
Sweetening Agents Preservatives
Binders
ANSEL’S CHAPTER 4
(Table 4.3) and
APPENDIX A for
Definitions of
Selected Drug
Categories
Surfactants :
❖ Reduces the interfacial tension between the dispersed phase and
dispersion medium and are defined as surface-acting agents.
❖ Also known as surface active agents.
❖ Properties of a surfactant :
a. A surfactant must contain a lipophilic region.
b. A surfactant must contain a hydrophilic region.
c. In a surfactant, both hydrophilic and lipophilic region must be balanced.
❖ Types of surfactants: Based on the hydrophilic region
1. Anionic surfactant ( the hydrophilic region negatively charged i.e. an anion)
Example: Sodium lauryl sulfate: used as an excipient on some dissolvable
aspirins.
2. Cationic surfactant ( hydrophilic region is positively charged i.e. a
cation)
Example: Cetyltrimethylammonium bromide: is effective antiseptic agent
against bacteria & fungi.
3. Nonionic surfactant
Example: Tween 80 (polyoxyethylene sorbitol monooleate): is an
excipient used to stabilize aqueous formulations of medications for parenteral
administration.
4. Amphoteric surfactant
Example: Lecithin acts as wetting, stabilizing agent and a choline
enrichment carrier, helps in emulsifications and encapsulation and is good
dispersing agent.
Emulsifying Agents :
❖Maintains the stability of the dispersed phase and the dispersion medium in
emulsion.
❖Classified as:
a. Anionic
b. Cationic
c. Ampholytic
d. Nonionic
Suspending Agents :
❖Increases the viscosity of the continuous phase.
❖Examples:
• Methylcellulose
• Carboxymethylcellulose
• Gelatin
• Hydroxyproplymethyl cellulose
• Clays e.g. veegum and bentonite
Flocculating Agents :
❖Employed in pharmaceutical formulation in the form of electrolytes,
polymers, or surfactants.
❖Efficacy of electrolytes in flocculate particle normally depends on the valence
of the ion.
❖Examples:
• NH+4
• K+
• Na+
• Li+++
• Cl-
• Mg++
Wetting Agents :
❖Reduces the interfacial tension and increase the interaction between the
solid particles of the dispersed phase and the dispersion medium.
❖Examples:
• Surfactants
Dispersants :
❖Discourages the suspended particles to break the energy barrier and form
aggregates.
❖Examples:
• Darvan
• Daxads
• Maraspearses
Antioxidants :
❖ Protects the formulation from oxidative degradation.
❖ Excipients that enhance the effects of antioxidants by only their presence
are defined as synergist.
❖ Ideal Properties of an antioxidant :
• Effective at a low, nontoxic concentration
• Stable and effective under normal conditions of use, over a wide pH and
temperature range
• Soluble at the required concentration
• Compatible with a wide variety of drugs and pharmaceutical excipients
• Free from objectionable odor, objectionable taste
• Colorless in both the original and oxidized form
❖ Types of antioxidants:
1. Water soluble antioxidants
Examples: sodium bisulfate, sodium metabisulfite, sodium thiosulfate, thiourea
2. Oil soluble antioxidants
- are used in parenteral solutions whose solvents are fixed oils.
Examples: tocopherol, ascorbylpalmitate, butylatedhydroxy-anisole,
butylatedhydroxytoluene
3. Synergists
Examples: citric acid, lecithin, glycerin, phosphoric acid, polyethylene glycol,
propylene glycol
Preservatives :
❖ Prevents microbial growth and prohibit large-scale chemical changes in
the formulation.
❖ Ideal Properties of a preservative:
• Exert a wide spectrum of antimicrobial activity at low inclusion levels
• Maintain activity throughout product manufacture, shelf life and usage
• Not compromise the quality or performance of product, pack or delivery
system
• Not adversely affect patient safety or tolerance of the product
❖ Examples:
• Methyl & Ethyl parabens
• Propylparaben
• Benzoic acid and its salts
• Sorbic acid and its salts
Diluents :
❖ Inactive solid ingredients that can be mixed with medication to bring up
the weight of a tablet for it to be easily compressed.
❖ Examples:
A. Disaccharides
1. Dextrose – occurs as odorless, sweet-tasting, colorless crystals or as a white crystalline or
granular powder.
2. Lactose – occuring as white to off-white crystalline particles or powder, anhydrous
lactose is widely used in direct compression tableting applications as a tablet-and-capsule
diluent, filler and binder.
3. Sucrose – obtained from sugar cane, sugar beet, and other sucrose sources, sugar occurs
either as colorless crystals, as crystalline masses or blocks, or as a white crystalline
powder.
– odorless, has sweet taste and good stability at room temperature and at
moderate humidity.
Uses of Sucrose Concentration (% w/w)
Syrup for oral liquid formulations 67
Sweetening agent 67
Tablet binder (dry granulation) 2-20
Tablet binder (wet granulation) 50-67
Tablet coating (syrup) 50-67
4. Mannitol – white, odorless, crystalline powder, or free-flowing granules, almost
as sweet as glucose, and half as sweet as sucrose and imparts a cooling
sensation in the nouth.
– odorless, has sweet taste and good stability at room temperature and
at moderate humidity.
5. Sorbitol – odorless, white or almost colorless, crystalline, hygroscopic
powder.
– available in a wide range of grades and polymorphic forms, such
as granules, flakes, or pellets that tend to cake less than the powdered form
and have more desirable compression characteristics.
– has pleasant, cooling, sweet taste.
Uses of Sorbitol Concentration (%)
Humectant 3-15
IM Injections 10-25
Moisture control agent in tablets 3-10
Oral solutions 20-35
Oral suspensions 70
Plasticizer for gelatin and cellulose 5-20
Prevention of “cap locking” in syrups and
15-30
elixirs
Substitute for glycerin and propylene glycol 25-90
Tablet binder and filler 25-90
Toothpastes 20-60
Topical emulsions 2-18
B. Disaccharides
1. Starch – odorless, tasteless, fine, white, to off-white powder.
– consists of very small spherical or ovoid granules or grains whose size and shape
are distinctive for each botanical variety.
2. Modified starch – exhibits the same appearance as starch, and manifests the same
chemical and microbiological properties, also sharing common uses with starch as a
diluent, disintegrant, and a viscosity-increasing agent.
3. Microcrystalline cellulose – purified, partially depolymerized cellulose that occurs as a
white, odorless, tasteless, powder composed of porous particles, it is stable, physically
and chemically, in ambient conditions.
Uses of Microcrystalline Cellulose Concentration (%)
Adsorbent 20-90
Anti-adherent 5-20
Capsule binder/diluent 20-90
Tablet disintegrant 5-15
Tablet binder/diluent 20-90
C. Inorganic Compounds
1. Dibasic Anhydrous Calcium Phosphate – white, odorless, tasteless, powder or crystalline
solid occuring as triclinic crystals.
2. Dibasic Dihydrate Calcium Phosphate – like the anhydrous type in apperance and use,
except that it occurs in monoclinic crystals.
3. Tribasic Calcium Phosphate – white, odorless, and tasteless poweder is an anticaking
agent, buffering agent, and tablet-and-capsule diluent.
4. Calcium Sulfate – white or off-white, fine, odorless, and tasteless powder or granules.
5. Calcium Carbonate – odorless and tasteless white powder or crystals.
Binder :
❖ Holds together a tablet’s ingredients before compression.
❖ A binder should be compatible with other products of formulation and
add sufficient cohesion to the powders.
❖ Commonly-used binders:
• Acacia
• Tragacanth
• Starch
• Gelatin
• Polyvinylpyrrolidone
• Polyacrylamide
• Sugar
• Hydroxypropylcellulose
• Sodium carboxymethylcellulose
Disintegrants :
❖ Breaks down compressed tablets into finer particles in the presence of G.I.
media.
❖ Ideal Properties of a preservative:
• Good hydration capacity
• Poor solubility
• Poor gel formation capacity
❖ Examples:
• Cellulose
• Starch
• Clay
• Alginic acid
Sweetening agents :
❖ Makes a product sweet to help mask bitter or unpalatable taste in
medication.
❖ Examples:
• Glucose
• Cane sugar (although easily available and is inexpensive, it can promote
microbial growth and requires large quantity to produce sweetness)
• Sorbitol
• Glycerine
• Saccharin sodium (ideal for diabetic patients, has less calories per serving, and
requires less quantity to produce sweetness, however it is expensive and may
cause cancer.
Glidants :
❖ Excipients that improves the flow property of granules from hopper into
the die cavity.
❖ Examples:
• Talc
• Cornstarch
• Colloidal silica
• Zn, Mg, and Ca stearate
• Calcium silicate
• Calcium phosphate
Lubricants :
❖ Excipients that reduce interaction between particles and dye during
compression and ejection cycles.
❖ Commonly-employed lubricants:
• Boric acid
• Na, Mg, Zn, and Ca salts of stearates
• Sodium lauryl sulfate
• Stearic acid
• PEG 4000
• PEG 6000
• Waxes
• Vegetable oils
Anti-adhesives :
❖ Inert excipients that prevent the adhesion of the tablet surface to the die
walls and punches, thereby eliminating the “picking” or “sticking” of the
tablets.
❖ Commonly-used anti-adhesives:
• Colloidal silica
• Cornstarch
• Sodium lauryl sulfate
• Magnesium stearate
Adsorbents :
❖ Adsorb fluids and moisture and keep pharmaceutical products dry.
❖ Used in formulations containing large amounts of liquid, eutectic
mixtures, oil soluble durgs, or essential oils.
❖ List of commonly-employed adsorbents:
1. Silica – submicroscopic fumed silica with a particle size of about 15 nm, is a light, loose,
bluish-white, odorless, tasteless and amorphous powder.
2. Magnesium oxide – occurs as a fine, white, odorless powderl; and comes in cubic crystal
structure.
3. Magnesium aluminum silicate – occurs as an off-white to creamy white, odorless,
tasteless, soft, slippery small flakes, or as a fine, micronized powder, it is added in 10-50%
concentrations.
4. Kaolin – graying-white, unctuous powder, free from gritty particles, with an earthy or
claylike taste.
5. Magnesium carbonate – similar to kaolin, has a slightly earthy taste, and occurs as light,
whte friable masses or as a bulky, white powder.
Reference:
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… If you fail,
never give up because
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… End is not the end,
in fact
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remember N.O means
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