Manuf Slides

INTRODUCTION TO
MANUFACTURING
PHARMACY
Module 1
Definition of Terms ↑ chemical
substance
• Drug – any article for use in PREVENTION, DIAGNOSIS, CURE, MITIGATION, -
and TREATMENT of diseases humans and other animals.

- -
-
• Active Ingredient – any component that is intended to furnish pharmacological

activity or other direct effect in the diagnosis, cure, mitigation, treatment of human
and other animals
• Excipient – purpose is to make drugs more appealing and more efficacious
• Dosage Forms – formulation containing a specific quantity of API’s in combination

with or without more excipients
classifications
:
# Two of Dosage Forms
① Route of Administration
> Oral
> Parenteral
② Physical Form
> solid
> liquid
-gas
ingredient i
anactive
who
O posage form
Definition of Terms
• Drug Product – finished dosage form that contains a drug substance,
generally, but not necessarily, in association with active ingredients
• Drug Delivery System – used for more uniform release of drug and for
targeted release
• Reasons for Formulating Dosage Forms:

 Improve appearance
 Improve palatability
 Ease of administration
 Improve stability
 Improve solubility
Manufacturing Pharmacy
• “Industrial Pharmacy” – refers to pharmaceutical research and
manufacturing companies which provide medicines in pre-fabricated or
ready-to-take form.
• Deals with the technology of various official and non-official products

manufactured in a semi-commercial and commercial scale.
Other Definition of Terms
 Batch – specific quantity of product intended to
have uniform character and quality produced
during a single manufacturing process
 Lot – specific identified portion of a batch
 Batch/Lot Number – for identification and
traceability of a single batch/lot
 Master Formula – contains formulation,
manufacturing procedures, specifications, QA
requirements and labeling of a finished product
 Master Batch Record/Batch Manufacturing
Record – ensures that batches were properly
made and QC tests were performed; actual
yield
 Standard Operating Procedures (SOPs) –
step-by-step instruction for performing an
operational task or activity
 Manufacturing Order – give instructions to
production department to produce product
• Overage– addition of an API in an unstable
preparation to compensate for loss during
manufacture
• Quarantine – designated area for holding of
incoming components prior to acceptance testing
and qualification for use
• Validation– documented evidence that a system
does what it is supposed to do
Introduction to the Organizational
Structure
Basic Elements of an Organization
• Divisionof Responsibility – the types of work
must be identified and grouped logically on
related elements
• Delegationof Authority – authority must be
defined and delegated to avoid negligence of duty
• Determination of Interrelationship among
Functions – it must be defined to promote
harmonious teamwork
Basic Tools in an Organization
Organization Planning
• the
process of creating a plan for a company or
organization that outlines its goals and objectives,
as well as the strategies and actions necessary to
achieve them
Organizational Chart
• Lists
all important positions and functions of
each division or department
Position Description
• Clearly
defines the authority, duty, or
responsibility of the areas in the chart
Organizational Manual
• It
combines the chart and position
description
 Top management
 Company philosophy
 Objectives of the company
 Policies, rules and regulations of the company
 Benefits and privileges of the personnel
Basic Levels of Top Management and
their Functions
Handles general
management /
administrative work
Level III
Level I Level II
Establishes objectives; Level III
determines basic policies
and general course of the
business Management of the
major department and
specific divisions of the
company
Importance of an Organizational
Chart
• Can analyze organizational problems like
overlapping of functions
• Canassess strength and weakness in functions
and personnel
• Canplan changes in the structure if not
applicable
Drawbacks in the Organizational
Chart
• Can’t reveal company objectives and policies
• Can’t indicate delegated authority
• Reveals little about working relationships
An Organizational Chart of a Typical
Manufacturing Company
General
Manager
Personnel Finance Marketing Technical Plant

Department Department Department Department Department
Manufacturing Activity
• Primary Manufacturing
 API or excipient manufacturing
• Secondary Manufacturing
 Finished dosage forms
• Tertiary Manufacturing
 Packaging, labeling, or repacking of bulk
finished product
Departments of Manufacturing
Company
• Research and Development Department
 Formulates new product
 Improves existing product
 Does chemical pharmaceutical, physiological
research (drug discovery, clinical trials)
 Requires facilities such as library, a pilot plant,
and an animal house
Three Stages of Research
1. Preliminary Stage – consists of chemical
literature review
2. Applied Research Stage – chemical studies,
pharmacological studies, development of
manufacturing process and cost of research
3. Clinical Research Stage – manufacturing
requirements, research on label, review of basic
information, product control, patent
application and cost of clinical trial
Company
• Production Department – manufactures products
according to schedule; warehousing (inventory control)
and storage
• Quality Assurance Department – assures that all
operations meet required standards for safety and
efficacy; ensures compliance to cGMP; conducts quality
audit and monitoring; cooperates with regulatory
agencies; prepares SOPs
• Quality Control Department – tests compliance of raw
materials, packaging materials, and finished products;
conducts sampling of materials to be tested; performs
IPQC and environmental testing
Company
• Marketing Department – studies current market trends,
consumer behavior and product status in market;
promote and advertisement
 Regulatory Department – ensures compliance of company
and its products with all pertinent regulations and laws
about drugs and their marketing
 Engineering Department – installs, maintains and
repairs of equipment and premises; safety
 Medical Department – concerned with physical
examination and medical treatment of employees;
performs clinical studies; publishes house organ/paper
Types of Drug Establishments
• Drug Manufacture
the process of industrial-
scale synthesis of pharmaceutical drugs as part of
the pharmaceutical industry.
Types of Drug Manufacturer
• Ethical Drug Manufacturer
• Proprietary / Generic Manufacturer
• Biologicals Manufacturer
• Veterinary Products Manufacturer
• Medicinal Chemicals Manufacturer
• Toll or Contract Manufacturer
Ethical Drug Manufacturer
Proprietary / Generic Drug
Manufacturer
Toll or Contract Manufacturer
Veterinary Drug Manufacturer
Different Drug Establishments
• Drug Distributor /Importer
any establishment that imports raw materials, active
ingredients, and/or finished products for its own distribution or
for wholesale distribution to other establishments or outlets
• Drug Trader
any establishment which is a registered owner of the
drugs product, procures the materials and packaging
components and provides the production monographs, quality
control standards and procedures, but subcontracts the
manufacture of such products to a licensed manufacturer
Different Drug Establishments
• Drug Supplier
includes manufacturers, importers, and
traders of drugs.
References:
• Ansel, Howard, Loyd V. Allen. Jr., “Ansel’s Pharmaceutical Dosage Forms
and Drug Delivery Systems” 10th ed., Wolters Kluwer
Current Good Manufacturing
Pharmacy
Standards for cGMP
regulations are established by the Food and

Drug Administration (FDA)
1962 –first GMP regulations under the

provisions of the Kefauver-Harris Drug
Amendments
• 1902 - Development of the Biologic Control Act
• 1906 - Development of the Pure Food and Drug Act
• 1938 - Federal Food, Drug and Cosmetic Act
• 1941 - Initiation of GMP
• 1944 - Development of Public Health Services Act
• 1962 - Kefauver-Harris Drug Amendments released
A Timeline of • 1963 - Establishment of GMPs for Drugs
GMP • 1975 - CGMPs for Blood and Components Final Rule
• 1976 - Medical Device Amendments
• 1978 - CGMPs for Drugs and Devices
• 1979 - GLPs Final Rule
• 1980 - Infant Formula Act is passed
1941 Initiation
of GMP
• Sulfathiazole tablets
contaminated with phenobarbital
• 1941 - GMP is born

1962 Kefauver-
Harris Drug
Amendments
• Thalidomide tragedy
• “Proof of efficacy” law
cGMP for Finished Pharmaceuticals
GENERAL PROVISIONS ORGANIZATION AND BUILDINGS AND FACILITIES EQUIPMENT CONTROL OF COMPONENTS
PERSONNEL AND DRUG PRODUCT
CONTAINERS AND
CLOSURES
PRODUCTION AND PROCESS PACKAGING AND LABELING HOLDING AND

CONTROLS CONTROL DISTRIBUTION
cGMP for Finished Pharmaceuticals
Laboratory Controls Records and Reports Returned and Salvaged

Drug Products
Batchwise control: The use of validated in-process sampling and
testing methods in such a way that results prove that the
process has done what it purports to do for the specific batch
concerned
Certification: Documented testimony by qualified authorities

that a system qualification, calibration, validation, or revalidation
General
has been performed appropriately and that the results are
acceptable
Provision Compliance: Determination through inspection of the extent to

which a manufacturer is acting in accordance with prescribed
regulations, standards, and practices
Component: Any ingredient used in the manufacture of a drug

product, including those that may not be present in the finished
product
General Provision
Quality audit: A documented activity performed in accordance with established

procedures on a planned and periodic basis to verify compliance with the procedures to ensure quality
Quality control unit: An organizational element designated by a firm to be responsible

for the duties relating to quality control
Representative sample: A sample that accurately portrays the whole
Reprocessing: The activity whereby the finished product or any of its components
is recycled through all or part of the manufacturing process
General Provision
Strength: The concentration of the drug substance per unit dose or volume
Verified: Signed by a second individual or recorded by automated equipment
Process validation: Documented evidence that a process (e.g., sterilization) does

what it purports to do
Validation protocol: A prospective experimental plan to produce documented

evidence that the system has been validated
Organization and
Personnel
• deals with the responsibilities of the quality

control unit, employees, and consultants.
• The regulations require that a quality control unit
have the authority and responsibility for all
functions that may affect product quality.
• This includes accepting or rejecting product
components, product specifications, finished
products, packaging, and labeling.
• Adequate laboratory facilities shall be provided,
written procedures followed, and all records
maintained.
Buildings and
Facilities
• the regulations in this section include the design,
structural features, and functional aspects of
buildings and facilities.
Equipment
• Each piece of equipment must be of appropriate
design and size and suitably located to facilitate
operations for its intended use, cleaning, and
maintenance.
• Standard operating procedures must be written
and followed for the proper use, maintenance,
and cleaning of each piece of equipment, and
appropriate logs and records must be kept.
• Written procedures describing in sufficient detail the receipt,
Control of identification, storage, handling, sampling, testing, and approval or
rejection of components and drug product containers and closures
Components, • Each container or grouping of containers for components or drug
Containers, and product containers, or closures shall be identified with a distinctive
code for each lot in each shipment received. This code shall be used
Closures in recording the disposition of each lot. Each lot shall be
appropriately identified as to its status
Production and Process
Control
• Written procedures are required for production

and process controls
• All product ingredients, equipment, and drums
or other containers of bulk finished product
must be distinctively identified by labeling as to
content and/or status.
Production and Process Control
• In-process controls are of two general types:

(a) those performed by production personnel at
the time of operation and
(b) those performed by the quality control
laboratory personnel
Packaging and
Labeling Control
• Written procedures shall incorporate the
following features:
• Prevention of mix-ups and cross-
contamination
• Identification and handling of
unlabeled DPs
• Identification by lot or control
number for traceability to
manufacture
• Examination of materials for
suitability and correctness before
production
• Inspection of the packaging line prior
to use
Expiration Dating
• this type of manufacturing date code shows a

pre-determined date after which a product is no
longer ideal to be used or consumed. It indicates
the anticipated shelf life, especially of perishable
products
Tamper-
Evident
Packaging
Package Type Tamper Protection
Film Wrapper Sealed around product and/or product container; film must be cut or torn to
remove product.
Blister/strip pack Individually sealed dose units; removal requires tearing or breaking individual
compartment
Bubble pack Product and container sealed in plastic, usually mounted on display card; plastic
must be cut or broken open to remove product
Shrink seal, band Band or wrapper shrunk by heat or drying to conform to cap; must be torn to
open package
Bottle seal Paper or foil sealed to mouth of container under cap; must be torn or broken to
reach product
Examples of Tamper-Evident Packaging

Package Type Tamper Protection
Tape seal Paper or foil sealed over carton flap or bottle cap; must
be torn or broken to reach product
Breakable cap Plastic or metal tearaway cap over container; must be
broken to remove
Sealed tube Seal over mouth of tube; must be punctured to reach
product
Sealed carton Carton flaps sealed; carton cannot be opened without
damage
Aerosol container Tamper-resistant by design
Examples of Tamper-Evident Packaging

Records and Reports
• Production, control, and distribution records must be

maintained for at least a year following the
expiration date of a product batch.
• Complete master production and control records for
each batch must
be kept.
• Records of written and oral complaints regarding a
drug product must also be maintained, along with
information regarding the internal disposition of each
complaint.
• All records must be made available at the time of
inspection by FDA officials
Returned and Salvaged Products
RETURNED DRUG PRODUCTS MUST BE IDENTIFIED BY DRUG PRODUCTS THAT MEET SPECIFICATIONS MAY RECORDS FOR ALL RETURNED PRODUCTS MUST BE
LOT NUMBER AND PRODUCT QUALITY DETERMINED BE SALVAGED OR REPROCESSED MAINTAINED AND MUST INCLUDE THE DATE AND
THROUGH APPROPRIATE TESTING. REASONS FOR THE RETURN; QUANTITY AND LOT
NUMBER OF PRODUCT RETURNED; PROCEDURES
EMPLOYED FOR HOLDING, TESTING, AND
REPROCESSING THE PRODUCT; AND THE PRODUCT’S
DISPOSITION.
Activity
• Provide examples of drugs that
have been demonstrated to
interact with their container and
describe the type of interaction.
• Compare and contrast a label
from a prescription drug product
with that of a non-prescription
product label and a dietary
supplement label
Module 2.
Dosage Form Design
Preformulation of Drugs
(Lesson 2A)
PHARMACEUTICAL MANUFACTURING (with Regulatory

Pharmacy, Quality Assurance and cGMP)
Pharmaceutical and Formulation
Considerations

General Considerations
Before formulating a drug substance into a dosage form:
• Desired product type
• Desired features
Loading…
• Pilot plant studies and production scale-up

Early Stage Preformulation Studies
At various stages during the development of a new medical product
the candidate drug must be formulated into a dosage form that is
appropriate for the intended study
• in vitro screening
• pre-clinical in vitro laboratory safety tests
• in vivo efficacy and safety studies in relevant animal species
• first-in-human studies
• initial volunteer/patient studies and full-scale clinical trials

Early Stage Preformulation Studies
Loading…

Preformulation Studies at Various Stages
of Development

Preformulation Studies
Early Stages of New Formulation
Preformulation is the stage of development during which the
physicochemical properties of the drug substance are characterised and
established.
• Knowledge of the relevant physicochemical and biopharmaceutical
properties determines the appropriate formulation and delivery method
for Pre-Clinical and Phase 1 studies.
• Studies to collect basic information on the physical and chemical
characteristics of the drug substance

Purposes of Preformulation Studies
• to evaluate the characteristics of candidate drugs
• To evaluate potential formulation excipients, and their interactions
with drug substances, in order
• to select appropriate formulation ingredients
• To assess the effect of possible conditions of preparation, manufacture
and storage on stability
• To understand the potential pharmacokinetics of a drug in humans and
animals
• to use alternative equipment or technologies
• to predict the stability PHARMACEUTICAL
of the formulation during manufacture, transport
MANUFACTURING (with Regulatory
and storage so as to determine Pharmacy,the
Quality shelf life
Assurance and cGMP)of the marketed product
Physical Description
• Purity of a chemical substance
• Chemical properties
• Physical properties
• Biologic properties

Microscopic Examination
It gives an indication of:
• particle size
• Size range of the raw material
• Crystal structure

Heat of Vaporization
• Important in the operation of implantable pumps delivering
medications and also in aerosol dosage forms
Loading…

Melting Point Depression
• Defines the purity of a drug substance
• Compatibility of various substances before inclusion in the
same dosage form

The Phase Rule
• Phase diagram
• Used for determining miscibility / solubility, coacervation
regions, gel-forming regions for multicomponent mixtures

Particle Size
Greatly affects the formulation and its efficacy
Absorption
Dissolution rate
Bioavailability
Content uniformity
Taste
Texture
Color
stability
Polymorphism
• Pertains to the crystal and amorphous forms of the product
Changes in crystal characteristics - influence bioA and chemical
and physical stability, create implications in dosafe forms process
functions
Ways to determine crystal properties:
o Hot stage microscopy
o Thermal analysis
o Infrared spectroscopy
o X-ray diffraction
Solubility
• Aqueous system solubility = therapeutic efficacy
Solubility and Particle Size
• small increases in solubility can be accomplished by
particle size reduction
Solubility and pH
• pH adjustment enhances solubility

Dissolution
• Time it takes for the drug to dissolve in the fluids at the
absorption site
• Rate-limiting step in absorption
• Determines the rate at which a drug substance becomes available
to the organism
• It may be increased by decreasing drug particle size

Modern Preformulation Studies
• It include an early assessment of passage of drug molecules across
biologic membranes
• Biologic membrane therapeutic response
• Biologic membrane - acts as llipid barrier to most drugs, permits
the absorption of lipid-soluble substances

Partition Coefficient
• Measure of a molecules’s lipophilic character – preference for
the hydrophilic or lipophilic phase
Distribution of the drug between two immiscible liquids –

equilibrium wil be reached at a constant temperature

Partition Coefficient
Applications:
• Extraction of crude drugs
• Extraction of drugs from biologic fluids for therapeutic drug
monitoring
• Absorption of drugs from dosage forms (ointments, suppositories
and transdermal patches)
• Distribution of flavoring oil in emulsions

pKa / Dissociation Constants
• Measures the extent of ionization of drug substances
• It has an important effect on the formulation and pharmacokinetic
parameters of the drug
• Extent of dissociation is highly dependent on the pH of the medium
containing the drug – extent of absorption, distribution, and
elimination

Membrane Permeability
• Passage of drug molecules across biological membranes to produce a
biologic response
• Lipid-soluble membranes – passive diffusion
• Llipid-insoluble membranes - other transport mechanisms
• Basic physicochemical studies – pKa, solubility and dissolution rate =
ABSORPTION

Drug and Drug Product Stability
Product formulation:
• To reduce or prevent deterioration caused by hydrolysis, oxidation,
and other processess.
5 types of Stability:
1. Chemical stability
2. Physical stability
3. Microbiologic stability
4. Therapeutic stability
5. Toxicologic stability
Drug and Drug Product Stability
Chemical Stability:
• Active ingredient must retain its chemical integrity and labeled
potency within the specified limits
• Important for selecting storage conditions (temperature, light,
humidity)
• For selecting the proper container for dispensing
• Anticipating interctions during mixing of drugs and dosage forms

Stability Testing
• Must be done in every stage of product development –
quality of product
• Assurance of stability is vital to its safety and
effectiveness during the course of its shelf-life and use
• Accelerated stability testing

Drug Instability
• May be detected through changes in physical appearance, color, odor,
taste, or texture of the formulation

Pharmaceutical Ingredients
and Excipients

Pharmaceutical Excipients
• Excipient - derived from the Latin excipere, meaning
‘to except’, which is simply explained as ‘other than‘.
• “Pharmaceutical excipients are substances other than

the active pharmaceutical ingredient (API) that have
been appropriately evaluated for safety and are
intentionally included in a drug delivery system.”

Pharmaceutical Excipients
Loading…

Ideal Excipient Properties

Roles of Excipients

Flavoring Pharmaceuticals
• Applies primarily to liquids intended for oral administation
• Addition of flavoring agents to liquid medication can mask the
disagreeable taste.
• Color must have a psychogenic balance with the taste, and the odor
must also enhance that taste
• Age of the patient should also be considered in the selection of the
flavoring agent

Flavors for Pharmaceuticals

Flavors for Pharmaceuticals

Sweetening Pharmaceuticals
• In addition to sucrose, a number of artificial
sweeteners have been used in foods and
pharmaceuticals.
Issues on Safety? Toxicity?
• Saccharin – not metabolized; excreted by
the kidneys unchanged
• Cyclamates - metabolized and processed
in the digestive tract; excreted by the
kidneys
• Aspartame - breaks down into amino acids
(phe and aspartic acid) + Pharmacy,
methanol
Quality Assurance and cGMP)
• Phe – leads to phenylketonuria or PKU

Health Hazards
Aspartame
• allergic symptoms such as hives and swelling in sensitive individuals
(diketopiperazine)
• sudden increase in brain phenylalanine levels
• Aspartame has seizure-promoting activity
Saccharin
• leads to increased body weight and obesity by interfering with
fundamental homeostatic and physiological processes
Coloring Pharmaceuticals
• Used in pharmaceutical preparations for aesthetics
• Certain substances have inherent colors which were thought of a
colorants
• Synthetic coloring agents were first prepared from principles of
coal tar (pix carbonis)
Safety? Toxicity?
• FD&C Red No.2 (amaranth) – caused cancer in rats
• FD&C Red No.4 – maraschino cherries
• FD&C Yellow No.5 (tartrazine) – allergic reactions
• Dyes and lakes - used to color coated tablets, pharmaceutical
suspensions and other dosage forms
• Selection of dyes must be done on the basis of their physical and
chemical properties – *solubility in the vehicle to be used for liquid
formulations
*pH and pH stability of the preparation to be
colored


Preservatives
• A preservative is a substance that prevents or inhibits microbial
growth and extends the shelf life of the drug products.
• Preservatives must be employed in pharmaceutical preparations in
specified concentrations
• Influence of the preservative on the comfort of the patient must be
considered
• Testing of preservatives
Examples: sodium benzoate, EDTA, sorbic acid, and parabens

Preservatives

Official Monographs

USP / NF
USP stands for U- United
S – States
P – Pharmacopeia
NF stands for N – National

F - Formulary

USP / NF
USP–NF Components
• USP–NF is a combination of two compendia, the United States
Pharmacopeia (USP) and the National Formulary (NF).
• Monographs for drug substances, dosage forms, and compounded
preparations are featured in the USP.
• Monographs for dietary supplements and ingredients appear in a
separate section of the USP. Excipient monographs are in the NF.

USP / NF
Monographs
• A monograph includes the name of the ingredient or preparation; the
definition; packaging, storage, and labeling requirements; and the
specification.
• The specification consists of a series of tests, procedures for the tests,
and acceptance criteria.
• These tests and procedures require the use of official USP Reference
Standards.
• Medicinal ingredients and products will have the stipulated strength,
quality, and purity if they conform to the requirements of the
monograph and relevant general chapters.
Sample Monograph of Raw Material

Sample Monograph of
Finished Products

Importance of the monographs
• provides detailed parameters used to determine key quality attributes
of drugs and medicines
• marketed legally in any given country.
• to ensure that a medicine meets the relevant, internationally-accepted
quality standards, regulators perform analytical testing of medicines,
along with other regulatory functions, such as inspection,
pharmacovigilance and registration.
Source: www.who.int/bulletin/volumes/96/6/17-205807/

Batch Manufacturing Records

What is a Batch Manufacturing Record (BMR)?
• written document of the batch being manufactured
• It contains the actual data of the step by step manufacturing
process of the batch
• It includes all stages of the manufacturing process from
issuance of the raw materials and packaging materials to the
final packaging of the finished product

Parts of a BMR
1. Batch Record
2. General Instruction for Manufacturing
3. Equipment cleaning record
4. List of materials with the weights and quantities of each
5. Manufacturing process
6. Yield
7. History of changes

References
Ansel, Howard, Loyd V. Allen, Jr., “Ansel’s Pharmaceutical Dosage
Forms and Drug Delivery Systems” 10th ed., Wolters Kluwer.
Shargel, Leon and Andrew Yu. “Applied Bopharmaceutics and
Pharmacokinetics”, Appleton & Lange: Norwalk, Connecticut.
Trevor M. Jones, CHAPTER 1:Preformulation Studies ,
in Pharmaceutical Formulation: The Science and Technology of
Dosage Forms, 2018, pp. 1-41
https://www.pharmaexcipients.com/pharmaceutical-excipients-some-definition/

Manufacture of Pharmaceutical Products
Requirements in the Manufacture of

Pharmaceutical Products

Pilot Plant Scale-Up

What is a pilot plant scale-up?
• It is a simulation of the processes involved in the production of drug
products in a large scale scenario.
Objectives:
• to facilitate the transfer of a product from the laboratory into
production Loading…
• to successfully develop a product that is capable of being processed
and packaged on a large scale.

1. Reporting responsibilities - important departments involved
2. Personnel requirements - qualifications required for a
position in a pilot plant organization
3. Space requirements
- Administration and Information Processing
- Physical testing area
- Standard pilot plant equipment floor space
- Storage area
4. Review of the formula
1. Raw materials
2. Relevant processing equipment
3. Production rates
4. Process evaluationLoading…
5. Preparation of master manufacturing procedures
6. GMP considerations
7. Transfer of analytic methods to Quality Assurance

Dosage Form Design
Pharmaceutical Unit Operations

and Equipment

Unit Processes in
Pharmaceutical Production

UNIT PROCESSES
► MILLING
► DRYING
► MIXING
► GRANULATION
► FILTRATION
► CLARIFICATION
► PACKAGING

Size Reduction
The process of reducing larger size solid unit masses to
smaller size unit masses by mechanical means.

Size Reduction
Principal Means of Size Reduction
Cutting or shearing
Compressing
Impact
Attrition
Mesh – the number of linear opening per square inch
Size is conveniently expressed in terms of Mesh

Size Reduction
Factors in Choosing a Mill
► Properties of feedstock : hardness, physical nature, water
content, production of heat during milling
► Specification of productLoading…
Milling equipment is classified into:
► Coarse - 20-mesh
► Intermediate - 200 – 20 mesh
► Fine - <200-mesh

Milling Equipment
Mill Feedstock Type Action Product Size

Cutting mill Fibrous, wet Cutting and 4 – 80 mesh
mass, dry some attrition
powder
Hammer mill Non-abrasive Impact and 10 – 325 mesh
to mod. some attrition
Abrasive,
brittle and dry
Ball or rod mill Mod. Hard and Attrition and 5 – 100 µm
abrasive impact

Milling Equipment
Hand screen Raw mats, wet Shear and

and dry attrition
granulation
Roller mill Soft materials

Colloid mill Used in
preparation of
suspension and
emulsions

Milling Equipment
Oscillating Dry granulation Attrition and 10 -50 mesh
granulator shear
extruder Wet shear

granulation
Fluid energy Moderately Attrition and 5 – 30 µm

mill or hard and friable impact
micronizer mats.

Size Reduction
Ball Mill - One of the
oldest and safest methods
of grinding of a wide
range of materials of
hardness up to 8 scale.

Size Reduction
► The colloid mill is useful for

milling , dispersing,
homogenizing and breaking down
of agglomerates in the
manufacture of food pastes,
emulsions, coatings, ointments,
creams, pulps, grease etc.

Granulation
Oscillating Granulator is
extensively used wherever
tablets or pellets are produced.
Fluid-Bed Dryer - Fluid bed

dryer that offers better methods
of drying products than the
conventional methods of tray
drying.

Factors Influencing Milling
The properties of a solid determine its ability to resist size reduction and
influence the choice of milling equipment.
► Hardness of the material
► Physical Nature of the material
► Presence of Water (5%)
Three Basic Parts of a Mill:

► Feed chute - delivers the material
► Grinding mechanism - rotator or stator
► Discharge chute

DRYING
The process of removing water (or other liquid) from a solid or
semisolid mass by evaporative process.
Factors in Choosing a Drying Equipment

► Nature of the product
► cost

DRYING
Examples of Drying Equipment
► Tray dryer
► Vacuum dryer
► Infrared dryer
► Radiofrequency dryer
► Fluid bed dryer

Tray Dryers

MIXING
Mixing is a unit operation that aims to treat two or

more components, initially in an unmixed or
partially mixed state, so that each unit (particle or
molecule etc.) of the components lies as nearly as
possible in contact with a unit of each of the other
components.

FLUIDS MIXING
A] Flow Characteristics – create forces of shear
Viscosity = the rate of shear stress to the shear
rate
Rate of shear – the derivative of velocity with respect to

the distance measured normal to the direction of flow.
B] Mixing Mechanisms
• Bulk Transport
• Turbulent Mixing
• Molecular Diffusion
BULK TRANSPORT
► Analogous to the convective mixing of powders

► Involves the movement of a relatively large amount of material from
one position in the mix to another, e.g. Due to a mixer paddle
► Tends to produce a large degree of mixing fairly quickly, but leaves
the liquid within the moving material unmixed.

TURBULENT MIXING
► Arises from the haphazard movement o molecules when forced to

move in a turbulent manner
► The constant changes in speed and direction of movement means that
induced turbulence is a highly effective mechanism for mixing.
Video: https://www.youtube.com/watch?v=PaCQRw9bW5Y

MOLECULAR DIFFUSION
► Analogous to diffusive mixing in powders

► Occurs with miscible fluids wherever a concentration gradient exists
and will eventually produce a well-mixed product

SOLIDS MIXING
- Considers important the particle size, particle shape and
particle distribution
Mixing Mechanisms
Convection mixing
Shear mixing
Diffusion mixing

Convection Mixing
► Arises when there is the transfer of relatively large groups
of particles from one part of the powder bed to another
► Inversion of the powder bed using blades or paddles or
screw element , in which large mass of material moves from
one place to another
Video: https://www.youtube.com/watch?v=2ORXmEPzAyA

SHEAR MIXING
► Occurs when a ‘layer’ of material moves/flows over another ‘layer’.

► May be due to the removal of a mass by convective mixing creating
Loading…
an unstable shear/slip plane, which causes the powder bed to collapse.
► May also occur in high-shear mixers or tumbling mixers

DIFFUSION MIXING
► occurs when a random motion of particles within a powder bed

causes them to change position relative to one another.
► Has a potential to produce a random mix, generally results in a low
rate of mixing.
Video: https://www.youtube.com/watch?v=Mmrk3ZgHCWw

Classification of Mixing Equipment
1] Batch Type
a. rotation of the entire body with no agitator
- barrel - double cone
- cube - slant double cone
- v-shaped
Videos: https://www.youtube.com/watch?v=Mmrk3ZgHCWw
https://www.youtube.com/watch?v=S_HNlHBJezc
https://www.youtube.com/watch?v=CEdsJ1e7hL0
b. rotation of the entire mixer body with rotating agitator

- v-shaped - slant double cone
- double cone
c. stationary body with rotating agitator
- ribbon
- planetary
- sigma blade
- conical screw
Videos:
https://www.youtube.com/watch?v=Mmrk3ZgHCWw
https://www.youtube.com/watch?v=uap5RVB2Dng
https://www.youtube.com/watch?v=GyTCqqK_xGE
https://www.youtube.com/watch?v=Qb2p0H54IDM

d. stationary body with a rotating mixing blade
and high-speed agitator blade
- barrel - bowl
Video: https://www.youtube.com/watch?
v=18ypfMT7Rvo

Rapid Granulator Mixer - Rapid Mixer Granulator is
designed to achieve excellent mixing and consistent
granules at lower operating cost along with higher
productivity.
Video: https://www.youtube.com/watch?v=GNG80jlxk48
https://www.youtube.com/watch?v=mT1lwRikKrg

e. stationary body with moving air as
agitator
- fluid bed dryer
- fluid bed granulator
Video: https://www.youtube.com/watch?v=x4-
bERhp4rI
2] Continuous Type
zigzag

Granulation
The process in which powder particles are made to adhere to form larger
particles called granules.
Primary Reasons for Granulation

► To prevent segregation of the constituents in the powder mix
► To improve the flow properties of the powder mix
► To improve the compression characteristics of the mix.

Other Reasons
► The granulation of toxic materials will reduce the
hazard of generation of toxic dust which may arise when
handling powders.
► Materials which are slightly hygroscopic may adhere
and form a cake if stored as a powder.
► Granules occupy less volume per unit weight.
Methods of Granulation
► Dry Granulation
► Wet Granulation

Particle Bonding Mechanisms
5 Primary Bonding Mechanisms between Particles
► Adhesion and cohesion forces in immobile liquid
films,
► Interfacial forces in mobile liquid films,
► Solid bridges,
► Attractive forces between solid particles,
► Interlocking bonds

Adhesion and Cohesion
► Presence of sufficient amount of liquid in a powder causes a
decrease in interparticulate distance and increase in contact area
between the particles.
Interfacial Forces in Mobile Films
► During wet granulation, liquid is added to the powder mix and is
distributed as films around and between the particles.
Solid Bridges
These can be formed by:
► Partial melting
► Hardening binders
► Crystallization of undissolved substances

Mechanisms of Granule Formation
Dry Methods – adhesion of particles takes place

because of applied pressure.
Wet Methods – liquid added to dry powders has to be

distributed through the powder by the mechanical
agitation produced in the granulator.

Pharmaceutical Granulation Equipment
Wet Granulators
► shear granulators
► High speed mixer/granulator
► Fluidized bed granulator
► Spray dryer - https://www.youtube.com/watch?
v=6Jj4RkvgH0c
► Spheronizer/pelletizer - https://www.youtube.com/watch?
v=_noO6YpA5hA

Dry Granulators
► Sluggers
► Roller compactors
Videos:
https://www.youtube.com/watch?v=IxQCtDrqxzQ
https://www.youtube.com/watch?v=yCwqABwoVUA

Questions:
1. What is the difference between mixing and blending processes?
2. When mixing two or more solids together, what do you think are
the factors that might affect the mixing of the powders?

Filtration
The process of separating liquids from solids through the use of a
porous substance with the purpose of obtaining optically
transparent liquids.

Clarification
The process by which finely divided solids and colloidal materials
are separated from liquids without the use of filters.
Filtering Equipment:
► Filter press - https://www.youtube.com/watch?v=IOwnTwUYNAg
► Centrifugal filter
► Vacuum filter - https://www.youtube.com/watch?v=M4qpgX9Falc

Question:
• As a production pharmacist, what GMP measures can you
apply when performing the different manufacturing
processes?

Packaging
Container – device that holds a drug and is, or may be in direct contact
with the drug.
Primary Package System - composed of those package components
that actually come in direct contact with the product or which have a
direct effect on the product shelf-life.
Secondary Package System - includes other outer packaging forms
such as cartons, corrugated shippers, pallets, labels, leaflets

Functions of a Package
► To provide presentation
► To provide containment
► For communication
► For convenience
► For legal compliance
► For protection and preservation against atmospheric,
physical and chemical hazards

Classification of Containers
► Well-closed container
► Tight container
► Hermetic container
► Light Resistant container
► Child-Resistant
► Tamper- Resistant
Factors in Choosing a Package

► Physical and chemical characteristics of the product
► Protective needs
► Marketing requirements
Qualities of an Ideal Packaging Material
► Must protect the product from environmental conditions

► Must not react with the product
► Must not impart tastes and/or odors
► Must be nontoxic
► Must be BFAD approved
► Must meet tamper-resistant requirements
► Must be adaptable to high-speed packaging equipment

Materials Used as Packaging Materials
► Glass (Type I Highly Resistant Borosilicate)

(Type II Treated Soda-Lime)
(Type III Soda-Lime)
(Type NP General Purpose Soda-Lime)
► Plastic
► Metal
► Rubber
► Paper and Board

Materials Used as Packaging Materials
• Plastic
• Advantages: durability; light weight; low cost
• Disadvantages: permeability; environmental; leaching of
additives
• Types of Plastic:
• Thermoplastic – soft when heated and hard when cooled;
flexible and squeezable
• Thermoset – permanently hard; rigid
Polymers of Plastic
No, Plastic Use
1 Polyethylene terephthalate For beverages
Hard thermoset for solid

2 High-density polyethylene
dosage forms
3 Polyvinyl chloride For blister packs
Thermoplastic for squeeze

4 Low-density polyethylene bottles and medicine
droppers
5 Polypropylene High temperature resistance

• Foils, Films and Laminates – low cost; flexibility; heatsealability;
decoration
• Metal – aluminum; tin;
Basic Designs of Closures
► Screw, threaded, or lug
► Crimp-on or crown
► Press-on or snap
► Roll-on
► Friction
Variations on the Basic Design of Closures
► Safety (child-resistant, tamper-evident, tamper-
resistant)
► Vacuum
► Linerless
► Dispenser applicators
Liner - a material that is inserted in a cap to effect a
hermetic seal between the closure and the container
Inner Seal - a material added for a more positive seal

surface and to provide tamper-evidence
Coil - a material inserted into the container to prevent

damage during shipping
Desiccant - a material used to counteract moisture

brought to the container system brought by the coil.

LABELLING
• Label – display of written, printed or graphic matter on immediate
container
• Labelling Material – all labels and other written, printed or graphic
matter
• (1) upon any item or any of its containers or wrappers;
• (2) accompanying any such items
Labelling
• Principal Display Panel
• Name of Product – generic and brand name (helvetica medium; universe
medium)
• Dosage Form and Strength
• Pharmacologic Category
• Rx Symbol – prescription drugs
• Name and Address of Manufacturer Trader or Distributor
• Net Content
• Other Info – formulation; indications; contraindications; precaution;
warnings; directions for use; batch/lot number; registration number (OR#);
storage conditions
Storage Conditions
STORAGE CONDITION TEMPERATURE (DEGREE CELSIUS)
COLD NMT 2-8

FREEZER -10 -20
REFRIGERATOR 2-8
COOL 8-15
ROOM TEMP TEMP PREVAILING IN AREA
CONTROLLED ROOM TEMPERATURE 20-25
WARM 30-40
EXCESSIVE HEAT >40

References
Ansel, Howard, Loyd V. Allen, Jr., https://www.youtube.com/watch?
v=Qb2p0H54IDM
“Ansel’s
https://www.youtube.com/watch?
Pharmaceutical Dosage Forms
v=18ypfMT7Rvo
and Drug Delivery
ystems” 10th ed., Wolters v=x4-bERhp4rI
Kluwer. https://www.youtube.com/watch?
Shargel, Leon and Andrew Yu. v=Mmrk3ZgHCWw
“Applied https://www.youtube.com/watch?
v=S_HNlHBJezc
Biopharmaceutics and
Pharmacokinetics”, Pharmacy, Quality Assurance and cGMP)
v=CEdsJ1e7hL0
Activity
• Gather any available medicine from your medicine cabinet and
samples of packaging materials.
• Identify the materials used in and describe the functions of the
packaging material in each medicine.

Manufacture of Pharmaceutical
Liquids

Manufacture of Liquid Dosage
Forms

EQUIPMENT
• Mixing Tanks – usually made of stainless steel, jacketed and have
built-in agitation system
• Grades: SS 304; SS 316 – most inert
Loading…
• Mixers o Mechanical Stirrer – mixers with various impellers mounted
on shafts; problem: vortex formation remedy: buffers, slanted
(45degree)
• Colloid Mill – for comminution of solids or dispersion of suspensions
• Homogenizer – compresses liquid with high pressure by a strong spring
mechanism
• Ultrasonifier – user ultrasonic energy to produce emulsion

COMPONENTS
• APIs
• Solvent of Vehicle
• Buffers
• Viscosity Enhancers
• Humectants
• Colorants, Flavors, and Sweeteners, Perfumes
• Stability Enhancers

Component
• Stability Enhancers:
• Preservatives – prevent microbial growth
• ex. parabens; methyl – molds (short); propyl – yeasts and bacteria (short); benzyl alcohol;
benzoic acid and Na benzoate; sorbic acid and K sorbate; chlorobutanol; benzalkonium
Loading…
Cl; thimerosal and phenylmercuric NO3
• Antioxidants – prevent oxidation

• True Antioxidants – react with free radicals; (ex. vit. E; BHT; BHA; alkyl gallates)
• Reducing Agents – (ex. vit. C; sulfites)
• Antioxidant Synergists – react with heavy metals; (ex. EDTA; citric acid; tartaric acid)

ADVANTAGES
• Completely homogenous dosing
• Immediate availability for absorption
• Flexible
• Easy to swallow
• Reduce gastric irritation

DISADVANTAGES
• Bulky
• Inabilty to mask taste
• Degrade more rapidly
• Can interact with other constituents

Solutions
Dispensing Mixing Storange and Aging Filtration Filling

Solution: Filtration
• Types:
• Parallel – passes thru and filter medium
• Series – 2 or more filter media
• Filter Media:
• Filter Paper/Cloth: non-sterile products
• Membrane Filter – sterile products; Bubble Point Test -> to test efficiency of
membrane filter
• Methods: gravity; vacuum; pressure

Solutions: Filling
• Methods:
• Gravimetric – large containers and high viscosity
• Volumetric – constant volume using piston action
• Constant-Level – container is used to control fill

Suspensions
• Formulation
• Suspending Agents – viscosity enhancers
• Wetting Agents – displace air from cervices of hydrophobic solids to allow
penetration of water
Loading…
• Flocculating Agents – decrease zeta potential causing aggregation to avoid the
formation of cake

Suspensions
• Formation
• Precipitation Method – by organic solvents; by changing pH; by double
decomposition
• Dispersion Methods – suspensions are wetted first before dispersing into
vehicle

Emulsions
• Types:
• Natural
• Finely divided solids
• Synthetic Surfactants
• Anionic – effective at basic pH
• Cationic – effective at acidic pH
• Amphoteric – both anionic and cationic
• Non – ionic – not affected by pH

Emulsions
• Considerations
• Emulsions are unstable
• Internal Phase – 40% - 60%
• Oil Phase – high grade mineral oil
• Ideal Mixing Temperature – 70-72°C
• If perfume were to be added:
• o/w (40-45 degree Celsius)
• w/o (near room temperature)

Emulsions
• Instabilities
• Sedimentation
• Creaming
• Breaking/ Cracking
• Phase Inversion

Tablet Components
Manufacture of Tablets • Activated Pharmaceutical Ingredients

(API) – choice of
excipients should consider compatibility
with API
• Diluent/Filler – inert substance added
to increase tablet size
which is practical for compression; (ex.
lactose; sucrose and
glucose; starch; dibasic CaHPO4;
anhydrous/spray-dried
Tablet Components
Tablet Components
• Super disintegrant – 2-4%; newer class of
• Binders – imparts cohesiveness to disintegrants which are effective at much lower
powders causing them to form granules levels
• Disintegrant – facilitates breakup of a • Anti-frictional/Flow Activators – hydrophobic
tablet when in contact with water in the powders added prior to compression to reduce
GIT
friction and improve flow properties; included
• MOA: swelling – starch paste; at concentrations < 1%\
wicking – Avicel®
• Lubricant – facilitates ejection from die
• Types: internal – added prior to cavity
granulation; external - added prior to
compression • Anti-Adherent – reduces sticking to punch
faces or die walls
• Double Disintegrant – divide
disintegrant into 2 portions • Glidant – enhances flow
COLOR
FD&C DESIGNATION NAME
Blue No. 1 Brilliant blue FCF Blue
Blue No. 2 Indigotine Indigo
Green No. 3 Fast Green FCF Turquoise
Red No. 3 Erythrosine Pink

Tablet Components • Colorants
• Dyes – water-soluble colorants used as Red No. 40 Allura Red AC Red
solutions (ex. FD&C dyes)
• Lakes – water-insoluble dyes that have
Yellow No. 5 Tartrazine Yellow
been absorbed on hydrous oxide usually
alumina, used as dry powders
Yellow No. 6 Sunset Yellow FCF Orange
• Flavors
• Salty – cinnamon; orange;
Tablet Components
cherry; butterscotch
Tablet • Bitter – chocolate; cherry; • Sweeteners
raspberry; mint • Artificial Sweeteners
Components • Sour – raspberry; lemon; fruity • Sucralose – 1000x
• Oily – mint; lemon; orange • Saccharin – 500x
• Unpleasantly Sweet – vanilla; • Na saccharin – 300x
fruity • Acesulfame K – 180-200x
• Aspartame – 180-200x
• Na cyclamate – 30x
Process in Tablet Manufacture
Dispensing Milling Mixing Granulation Tableting Coating

Dispensing – particle size reduction, sizing, crushing, grinding.
Equipment:
• Cutter Mill – cuts particles using knives; for fibrous
materials
– first step in any manufacturing process; weighing and measuring
Milling
• Edge Runner Mill – crushes materials by 2 rotating
wheels
• Methods: • Hammer Mill – uses a high speed rotor to which
swinging hammers are fixed
• hand scooping and weighing
• Fluid Energy Mill – uses air with very high pressure
• weighing with material lifting assistance
• Roller Mill – consists of rotating cylindrical rolls
• automated dispensaries
• Ball Mill – consists of a rotating cylindrical roll
• Issues: weighing accuracy; dust control (dust collecting assistance); filled with balls
lot control of each ingredient; material movement
– process of blending materials together into one mass

Equipment:
• Batch Type Mixer – all ingredients are loaded together, mixed and
– powder size enlargement to
discharged as a single batch
• Rotating Shell/Tumbling Mixers
granules
• Drum Type Blenders – cylindrical-shaped; horizontal axis;
poor cross flow; remedy: Baffles Slantea • Types:
Mixing •
•
•
Double Cone Blender – good cross flow
V-Shell Blender – twin-shell blender; solid-solid blending;
alternately combines and draws apart materials
Fixed Shell Mixers
Granulation • Good Granules – pass through
sieve #20 but not through sieve
#40
• Ribbon Blender
•
•
Sigma Blade Mixer
Planetary Mixer
• Fine Granules – pass through
• Vertical Impeller Mixer sieve #40
• Continuous Mixer – for high volume products; materials travel from charging
port to discharge nozzle blending materials together into one mass
Methods:
• Wet Granulation – addition of liquid binder to powders; most • Fluid Bed Granulation – can accomplish both dry mixing and wet
common method granulation efficiently and in much less time compared to traditional
• Steps: method
• Dry Granulation – double compression on pre-compression method;
powder mixture is compacted into large pieces and subsequently
broken down into granules; for moisture and heat-sensitive materials
Addition of
Blending of Dry
Ingredients
Addition of
Liquid Binder
Screening Damp
Mass
Drying
ganulation
Screening Dry
granules
lubricant and
external
• Processes:
lubricant
• Slugging – formation of slugs; breakdown slugs -> granules: oscillating granulator
• Roller Compaction – formation of sheets; chilsonator roller compactor
• Types of Tableting Machine:
– compression of tablet components within a die • Single Station – involves movement of both punches
cavity by pressure exerted by movement of 2 • Multiple Station – involves movement of both punches
punches • Requirement of Tableting:
• Flowability
• Flow Problems:
Tableting Parts of Tableting Machine:

• Hopper – holds materials
• Feed Shoe – transfers materials into die
Tableting • Arching/Bridging – arch-shaped
obstruction forms above hopper outlet
• Rat-Holing – discharge takes place only
above hopper outlets
• Die – defines size and shape of tablet • Compressibility – forms a stable, compact mass when
pressure is applied
• Punches – compress materials within die
• Direct Compression – tablet processing without
• Cam Tracks – guide movement of punches granulation; require a very critical selection of
excipients -> good flowability and compressibility
• Capping – partial or complete separation of top or – application of coating material to a moving bed of solids with
bottom crown concurrent use of heated air
• Lamination – separation into 2 or more distinct • Equipment:

horizontal layers • Standard Coating Pan – consists of a rotating circular
Tablet • Chipping – removal of small portion (tablet edges)

metal pan with ducts (ex. Peilegrini Pan; immersion
tube/sword system)
• Cracking – fine cracks on surface; cause: deep concave
punches
Coating • Methods:
• Pan Pouring – for viscous solutions; problem: surface
Defects • Sticking – adhesion to die wall

• Picking – adhesion to punch faces (pinholes)
• Double Impression – due to free rotation of punches
•
erosion
• Pan Spraying – increases efficiency
Perforated Coating Pan – exhaustion is through the
perforations (ex. Accela-Cota Pan; Driacoater; Giatt
Coater)
with engraving on faces
• Fluid Bed Coater – air suspension coating or Wurster
• Mottling – uneven color distribution process
Coating
• Types of Coating:
• Sugar Coating – oldest method
• Steps
Colar
Sealing Subcoating Smoothing Polishing
Coating
• Sealing – water proofing; strengthens tablet core; agents: • Film Coating – minimal increase in weight (2-3%);
shellac, cellulose acetate phthalate (CAP), polyvinyl acetate easier and faster
phthalate (PVAP), zein
• Components:
• Subcoating – rounds off tablet edges; most critical step; step
that adds most weight (50-100%); agents: alternate layers of • Film Former – smooth, thin films; (ex. celluloses,
gum and dusting powder methacrylate; PVA; PVP
• Plasticizer – flexibility and elasticity; (ex. castor
Steps Coating
• Smoothing – smoothes out subcoated surface; agents: 60-70%
syrup solution oil, glycerin, phthalate; esters)
• Color Coating – critical step color and elegance; agent: 60- • Surfactant – spreadability; (ex. Polyonyethylene
70% syrup + colorant sorbitan derivatives)
• Grossing – develops color • Alloying Substance – water
• Heavy Syruping – builds up color solubility/permeability; (ex. PEG)
• Regular Syruping – final color • Glossant – luster or shine; (ex. beeswax)
• Polishing – produces gloss/shine; agents: beeswax, carnauba • Volatile Solvent/Vehicle – (ex. alcohol and
wax, candelila wax, hard paraffin wax acetone)
Manufacture of Tablets
• Mottling – uneven color distribution
Wet Granulation Dry Granulation Direct Compression
• Sweating – oily film or droplets of liquid
1. Milling 1. Milling 1. Milling
• Bridging – markings are obscured
Coating • Blooming – white spots on surface or dull film

• Flaking – due to rapid drying
2. Mixing
3. Preparation of Binder
4. Mixing with Blender
2. Mixing
3. Slugging
4. Screening of Slugs
2. Mixing
3. Compression
4. Dedusting
• Blistering – reduced adhesion of film
Defects • Wrinkling – due to improper drying/film former
defect
5. Coarse Screening 5. Mixing w/ disintegrant and
lubricant
5. Tablet Coating
• Orange Peel – rough; non-glossy film surface 6. Drying of moist granules 6. Compression
(due to inadequate spreading); remedy: add 7. Screening 7. Dedusting
polysorbate surfactant
8. Mixing w/ disintegrant and 8. Tablet Coating
lubricant
9. Compression
HARD GELATIN CAPSULES

• HGC shells are manufactured in a separate operation from filling
• Pin Method/Reciprocating Die Method – most common method
Manufacture of • Steps in filling HGCs:
Capsules
Supply Rectification Separation Filling Joining/Closing Finishing
• Encapsulating Machines: Lilly; Parke-Davis; Macofar; Farmatic • Special Techniques:
• Methods: Anger/Spindle Dosing; Tamping and Disc Dosing; Accogel • Sealing
• Gelatin Banding – seals with a band of gelatin
Process dry powders to SCG
• Heat Welding – fuses cap to body through double wall thickness
• Finishing – cleaning and polishing; (methods: pan polishing; cloth • Thermal Coupling – uses liquid wetting agent to lower melting point between cap and
dusting; brushing) body then bonds
• Imprinting – empty capsules
• Coating – modifies solubility characteristics (ex. shellac; cellulose acetate
phthalate; salol)
Capacity Empty Gel Caps
SOFT GELATIN CAPSULES

• formed, filled and sealed in a single operation
• Methods:
• Plate Process – oldest method which uses gelatin sheets
• Rotary Die Process – uses gelatin ribbons brought
together between 2 rotating discs
• Reciprocating Die Process – uses different filling method
• Processes of Manufacture:
• Dipping
• Spinning
Gelatin • Drying
• Stripping
Preparation • Cutting
• Joining
• Finished capsule has a moisture
content between 13-16%
OINTMENTS AND PASTES
Manufacture of Semi- • Methods:
• Incorporation – use of ointment roller mills to mix heat-
Solid Dosage Forms sensitive ointment bases
• Fusion – use of stem-jacketed kettler to melt anhydrous
ointment bases and cooling gradually until congealed
CREAMS GELS
• The consistency and rheologic character depend on whether • Gelling Agents:
the emulsion is a W/O or O/W type and on the nature of the • Alginic acid
• Celluloses
solids in the internal phase.
• Colloidal SiO2
• Tragacanth
• Mg Al silicate
• Manufacture: Prepared as emulsions. • Carbomer – swells in water at basic pH (Carbopol®); neutralized: methanolamine
• Prepared by either a fusion process or a special procedure necessitated by the gelling
characteristics of the gallant.
Manufacture of Suppositories
Suppositories • Hand molding - the simplest and oldest method of preparing a
suppository; Method is employed for small scale production
• Compression molding - the cold compression method is simple and
Four methods used in preparing suppositories: results in a more elegant appearance; It avoids the possibilities of
sedimentation of insoluble solids in the base
• Hand molding
• Compression molding • Pour molding - The most commonly used method for producing
• Pour molding suppositories in both small and large scale
• Automatic molding machine • Automatic molding - Automatic molding method employed in large
scale production
Manufacture and Packaging of
Transdermal Drug Delivery
Systems
Basic Types of transdermal Dosing System

Definition
• Transdermal delivery systems are designed to support the Those that control Those that allow
passage of drug substances from the surface of the skin,
through its various layers, and into the systemic circulation. the rate of drug the skin to control
delivery to the the rate of drug
skin. absorption
Technology of Transdermal Technology of Transdermal

Delivery Systems Delivery Systems
1. Monolithic systems 2. Membrane controlled transdermal system
incorporate a drug matrix layer between backing and are design to contain a drug reservoir, usually in liquid
frontal layers. The drug matrix layer is composed of a polymeric or gel form, a rate controlling membrane, and backing,
material in which the drug is dispersed. The polymer matrix adhesive, and protecting layers
controls the rate at which drug is released for percutaneous
absorption.
Drug in Adhesive Patches
Drug in Adhesive Patches
• A system in which the drug is • Components of the Patch:
incorporated directly into the adhesive, • Liner: Protects the drug during storage and is removed prior touse
rather than into a separate layer. • Drug
• Usually used for smaller molecular • Adhesive: Serves to bind the components of the patch to theskin
weight compounds. • Membrane: Controls the release of the drug from the reservoirin
• These can be either a single layer or certain types of patches
multi-layer. • Backing: Protects the patch from the outer environment.
Schematic Drawing of the Matrix (Drug-in-Adhesive) type of patch. Reservoir Patches
Schematic Drawing of the Reservoir type of patch. Transdermal Scopolamine

• Scopolamine - Transderm - Scop
• Four layered patch:

(1) backing layer of aluminized polyester film,
(2) drug reservoir of scopolamine, mineral oil, and polyisobutylene,
(3) a microporous polypropylene membrane for rate delivery of
scopolamine, and
(4) adhesive
Iontophoresis and Sonophoresis Other Transdermal Therapeutic Systems
• This is used to treat Attention Deficit

Iontophoresis involves the delivery of charged chemical compounds Daytrana Hyperactivity Disorder (ADHD) in
across the skin membrane using an applied electrical fie children six to12 years of age.
Sonophoresis, or high-frequency ultrasound, is also being studied • Iontophoretic patches use a tiny
to enhance transdermal drug delivery Iontophoretic electrical current to promote flow of the
Patch drug (usuallycharged) through the skin.
Transdermal Vaccine
Technology
• Microneedles Patches
are currently being explored as mechanisms to deliver
Manufacture and Packaging
vaccines and larger macromolecules.
of Pharmaceutical Aerosols
Pressure Filling apparatus

• Consists of a pressure burette capable of
metering small volumes of liquefied gas
Small –scale under pressure into an aerosol container
Manufacture of Cold Filling apparatus

Pharmaceutical • Simpler than the pressure filling apparatus;
Can be used with metered valves Ad well as
Aerosols with non-metered valves
Compressed Gas Filling apparatus

• Capable of filling aerosols that contain
compressed gases under high pressure
Large –scale Manufacture of Pharmaceutical
Packaging Containers for Aerosols
Aerosols
• Containers
• Containers must be able to withstand pressures as high as 140 to 180 psig at 130⁰F.
A. Metal
A. Tinplated Steel
A. Side-seam (3-pc)
B. 2-pc or drawn
C. Tin free steel
B. Aluminum
A. 2-pc
B. 1-pc (extruded or drawn)
C. Stainless Steel
B. Glass
A. Uncoated glass
B. Plastic-coated glass
Aerosol Valve Assembly
Aerosol Valves
- it is capable of being easily opened and closed, and capable of
delivering the content in the desired form
In pharmaceuticals, the valve is expected to deliver a given
amount of medication
Actuators
Manufacture of
Sterile Dosage Forms
Sterilization Methods DEPYROGENATION
Method MOA BI 180°C for 4

Moist Heat – autoclave or steam
under pressure (121°C. 15psi, 15-
Protein Coagulation Bacillus stearothermiphirus
hours
20 mins)
Dry Heat – oven 160-170°C, 2-4
hours
Oxidation Bacillus subtillis 250 °C for 45
Membrane Filtration – for heat- Physical Separation minutes
labile solutions
Gas – ethylene oxide of beta-
propriolactone
Alkylation Bacillus subtiillis
650 °C for 1
Ionizing Radiation – gamma or minute
cathode rays
Sterile Production Area

• Clean Rooms – room in which concentration of airborne particles is
controlled; positive pressure air flow
• HEPA filter – removes 99.97% of particles (≥ 0.3 μm) from air;
Diocylphthalate Test – QC test for HEPA filter
• Airlock – space with interlocked doors
• Parts:
• Ante Room – for cleaning and wearing of PPE (class 100,000/ISO class
8 – NMT 100,000 particles [≥ 0.5 μm] per cubic foot of air)
Sterile Production Area

ISO CLASS PARTICLES PRESENT PER CUBIC FOOR OF AIR
3 1
4 10
5 100
6 1000
7 10,000
8 100,000
MANUFACTURING PROCEDURE
• Buffer Area – for staging of supplies and
equipment (class 10,000)
Sterile • Compounding Area – (class 100)

• Laminar Air Flow Hoods – vertical or
Production horizontal flow

• Barrier Isolators – for hazardous materials Dispensing
Area • Aseptic Filling Area – packaging; (class 100)

• Quarantine Area – for staffing prior to testing
and Cleaning Compounding Filtration Filling Sealing
• Finishing Area
MANUFACTURING PROCEDURE
• Dispensing and Cleaning
• Compounding – Sterile Solids: Spray Drying; Freeze Drying/Lyophilization
• Filtration – Sterile Solutions: Clarification – 2-3μm; Cold Filtration – 0.2-
0.3μm
• Filling
• Sterile Solids – Wet Weight Filling
• Sterile Liquids – Volumetric Filling – most common; Gravimetric Filling
• Sealing
• Vials – siliconization or halogenization
• Ampules
• Tip/Bead Sealing – melt tip to form a bead
• Pull Sealing – melt below tip then pull away

Manuf Slides

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Manuf Slides

Uploaded by

Copyright:

Available Formats

INTRODUCTION TO

• Drug – any article for use in PREVENTION, DIAGNOSIS, CURE, MITIGATION, -

and TREATMENT of diseases humans and other animals.

• Active Ingredient – any component that is intended to furnish pharmacological

• Excipient – purpose is to make drugs more appealing and more efficacious

• Dosage Forms – formulation containing a specific quantity of API’s in combination

• Reasons for Formulating Dosage Forms:

• Deals with the technology of various official and non-official products

Personnel Finance Marketing Technical Plant

regulations are established by the Food and

1962 –first GMP regulations under the

• 1941 - GMP is born

PRODUCTION AND PROCESS PACKAGING AND LABELING HOLDING AND

Laboratory Controls Records and Reports Returned and Salvaged

Certification: Documented testimony by qualified authorities

Provision Compliance: Determination through inspection of the extent to

Component: Any ingredient used in the manufacture of a drug

Quality audit: A documented activity performed in accordance with established

Quality control unit: An organizational element designated by a firm to be responsible

Representative sample: A sample that accurately portrays the whole

Verified: Signed by a second individual or recorded by automated equipment

Process validation: Documented evidence that a process (e.g., sterilization) does

Validation protocol: A prospective experimental plan to produce documented

• deals with the responsibilities of the quality

• Written procedures are required for production

• In-process controls are of two general types:

• this type of manufacturing date code shows a

Examples of Tamper-Evident Packaging

Examples of Tamper-Evident Packaging

• Production, control, and distribution records must be

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

Distribution of the drug between two immiscible liquids –

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

• “Pharmaceutical excipients are substances other than

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory

PHARMACEUTICAL MANUFACTURING (with Regulatory