Manufacturing Pharmacy

 Deals with the technology of various official and non-official products manufactured in a semi- commercial
and commercial scale.
 Relates to the practice of pharmacy in some hospitals and to the large-scale production carried out in
modern pharmaceutical plants.

Industrial Pharmacy
 Refers to the pharmaceutical research and manufacturing companies providing pharmacists with medicines
in prefabricated form.

Elements of an Organization
 Organization – is a mechanism for determining and assigning duties to people so that they can work
together effectively.
 Business Organization - is a combination of people, money and machines so coordinated that they can fulfill
an economic objective.

Basic Elements of an Organization

(1) Division of Responsibility
 Responsibility must be delegated.
 The company objectives must be. determined and the organizational plan must be consulted with the aim of
achieving them.
 The type of work must be identified and grouped logically on related elements.

(2) Delegation of Authority

 Authority again must be defined and delegated to avoid negligence of duty.
 Authority means power or right to give commands, enforce obedience and make final decisions.

(3) Determination of Interrelationship among Functions of each of the Components of an Organizational Plan
 This interrelationship must be clearly defined to promote harmonious teamwork.

Basic Tools in an Organization

(1) First Basic Tool
 Is the Organization Planning
 This is interpreted in a Chart

Characteristics of a Chart
(1) An organizational chart lists all important positions and functions of each division or department.
(2) An organizational chart is a means of quickly showing the shape or structure of the company to
employees and other interested parties outside the company.

Importance of a Chart
(1) Can analyze organizational problems like overlapping of functions.
(2) Can assess strength and weaknesses in functions and personnel.
(3) Can plan changes in the structure if not applicable.

Drawbacks in the Organizational Chart

(1) Can not reveal company objectives and policies.
(2) Can not indicate delegated authority.
(3) Reveals little about working relationships.

(2) Second Basic Tool

 Is Position Description.
 This will clearly define the authority, duty or responsibility of the areas in the chart.

(3) Third Basic Tool

 Is Organizational Manual.
  Also called Management Guide which combines the Chart and Position Description.
 Description materials about the organization to give all levels of management a clear understanding of the
organizational plan, top management, philosophy & objectives of the company.

Three Basic Levels of Top Management & Their Functions

 Level I – consists of Board of Trustees or Board of Directors, the functions are:
(1) To protect & make the most effective use of company's assets.
(2) Establishes objectives & determines the basic policies & general course of the business.
(3) Represents & safeguards stockholders' interests.

 Level II – consists of the President, the function being general management or administrative
 includes the active planning, direction, coordination & control of the business within the scope of
policies established & authorized by the Board or Level I.

 Level III - consists of the Vice President, General Managers

 The function includes management of the major departments of the company.
 They are fully responsible & accountable to the President or Level II for the success of their
respective operations.
 Embraces the topmost level of executives concerned with a particular division of the company.

Forms of Organizational Structure

(1) Functional Structure Groups
 Appropriate for a small company or one with closely related products.
 All production is grouped under one head, all sale under one head & all financial activities under one head.
 It is flexible, facilitates coordination & encourages specialization.

(2) Divisionalized Structure

 Combines into one unit all different kinds of work necessary to accomplish a specific result.
 The kinds of work necessary may be grouped on a geographical basis or commonly on a product basis.

"Line"
 Constitutes the framework for the organizational structure
 Functions are those that have direct responsibility to accomplish the objectives of the enterprise.
 Functions have the power or authority to initiate & carry through other primary activities necessary to reach
the stated goals of the company.
 Identified as "Chain of Command" from the top to the bottom of the organization.

“Staff"
 Constitutes work functions or as organization components that are required to supply information and
service to the "line” components.
 Technical Director’s Department

Research & Product Development Division Quality Control Division

Types: Stages: Sections:

Chemical Preliminary Specs & Assay Dev.
Biological Applied Research Central Release
Pharmaceutical Clinical Research Chemical Control
Plant Inspection
Biological- Micro

Stages of Research
Preliminary stage

 Market research
 Literature review
 Patent research
 Raw material evaluation
Applied research stage

 Chemical studies
 Pharmacological studies
 Development of manufacturing process
 Cost of research
Clinical research stage

 Manufacturing requirement
 Research on label
 Review of basic information
 Product control
 Contract with therapeutic trial committee
 Patent application
  Cost of clinical trial

QC Division
Purpose of establishing Specification

 Conform to appropriate standards of identity, purity, potency, quality, physiological bioavailability

& therapeutic activity
 Meet government rules & regulation
 Prevent potential hazard to public health
I. SPECS & ASSAY DEV.
A. Raw materials specs
Usual criteria/standards:

 Description
 Solubility
 Identification
 Melting point
 Loss on ignition (LOI)
 Residue on ignition (ROI)
 Specific rotation
 Refractive index
 Specific gravity
 Assay
Adding such critical features as:

 Particle size
 Crystal shape
 Surface tension
 Viscosity
 Irritation
 Foreign substance
 Allergenic substances
 Toxicity
B. Features to be considered before containers specs are set:
1. Physical changes
2. Moisture & gaseous permeability
3. Compatibility
4. Toxicity & safety
Containers include:

 Glass
 Plastic
 Metal
 Rubber materials
FINISHED PRODUCT SPECS
Usual criteria:

 Description
 Identification
 Moisture content
 pH
 Specific gravity
 Alcohol content
 Hardness
 Disintegration time
 Weight variation
 Sterility
 Pyrogenicity
 Safety
 Assay
Adding critical features:

 Dissolution rate
 Content Uniformity
 Related foreign substances
 Irritation
 Microbial content
 Stability
2 MAJOR KINDS OF IMPURITIES

 Product Specific Impurities – appears as by-products/ degraded products of the drug substance &
excipients used in the formulation
 Product Unspecific Impurities – are introduced externally into the product during processing
Factors to be considered in the development of Specs:
1. Physical, chemical, biological characteristics
2. Dosage form characteristics
3. Appropriate test methods
4. Acceptable tolerances
Purposes of varying/changing Assay Methods:
1. Accuracy
2. Rapid
3. Reduction
4. Increase in the number of samples tested
II. CENTRAL RELEASE SECTION
1. Examine meticulously the records
2. Investigate customer complaints/ inquiries
3. Maintain complete & accurate records
III. CHEMICAL CONTROL SECTION
 1. Test and assay
2. Stability studies
IV. INSPECTION & CHECKING SECTION
1. Inspect & sample every shipment
2. Examine every shipment
3. Examine & check all operations
4. Sample retention
V. BIOLOGICAL- MICROBIOLOGICAL CONTROL SECTION
1. Perform & evaluate
2. Sterility

PLANT DEPARTMENT

A. Production Control: consists of 3 sections

1. Purchasing-purchases requisitioned items for the company, both from local and imported sources

2. Inventory-watches closely and records all materials used in production, controls the stock of both raw materials
and finished products. This section, therefore is in charge of checking stocks periodically

3. Planning and Scheduling-coordinates with marketing on what products are required for supply and then plans
and schedules the manufacturing order (M.O). the production department manufactures the quantity schedule at
the time limit allowed.

B. Warehouse Division: consists of 5 sections

1. Raw Material - consists of 3 subdivisions

a Quarantine area

b. Approved for use area

c. Rejected area

Quarantined materials are labeled "QUARANTINED" this implies that the materials are subject to tests and assays
by Quality Control and are not to be used.

Approved for use materials are labeled with a green label withhold letters "APPROVED FOR USE". The materials
from the quarantine area found to conform with standards and specifications are transferred to the approved for
use area replacing the Quarantine label with the green label

Rejected materials are those found to be substandard and are transferred from the Quarantine area to the
Rejected area replacing the Quarantine label with Red label containing the bold letters REJECTED These materials
are either returned to supplier or destroyed.

2. In-Process - this section consists of the products which have been bottled or stripped, packed but not yet labeled
or packed into boxes or cartons because they are awaiting Quality Control tests and assays and final disposition.

3. Finished Product - this area contains the products packaged and finished and are ready for distribution and sale
4. Returned Goods - inasmuch as returns cannot be avoided, goods returned are stored in a section of the
Warehouse pending disposition by Quality Control

5. Dispensing is an area in the Warehouse where raw materials for use in production are weighed and/ or
measured. The supervisor here should be pharmacist who understands and knows the chemicals, their properties
and cautions in handling them. A checker is required in this area to avoid errors. Quality Control inspectors do
routine checks on all these areas of the Warehouse

C. Engineering and Maintenance Section: takes charge of the care and maintenance of all machines used in the
Plant Department including electric lines, water lines, repair of defective equipment.

D. Manufacturing of Pharmaceuticals

The general procedure for manufacturing product is as follows:

1. The parent company abroad or Research department locally prepares the Master
Formula then passes on to its subsidiary for product manufacture.
The Master Formula consists of seven information such as the

a. Name of the Product

b. Potency of the active ingredient

c. Batch size, amount of yield

d. List of ingredients and specifications and code numbers

e. Quantity of each ingredient

f Signature of competent people who prepared it

2. The Quality Control head is in charge of the preparation of the Master Formula if the Master Formula sent
is not the actual amount to be manufactured.
3. Production Control prepares the Manufacturing Order (M.O) based upon the Master Formula of a
required batch size. The M.O has additional information as to schedule date of production and M.O
number
4. The M.O in duplicate copies is prepared, one goes to Warehouse (dispensing) and the original to the
Production. Together with the M.O is the Finishing Order (FO) which contains a list of packaging materials
with the corresponding quality necessary for the batch size indicated in the M.O.
5. The Dispensing Pharmacist weighs and/or measures the ingredients and transfers them to the respective
manufacturing area and/or Packaging section
6. The corresponding manufacturing section compounds the product using the standard procedure for which
they are provided with a copy. The product while being processed is checked, tested and assayed by Quality
Control
7. The compounded product is transferred to the Packaging Section where it is bottled in case of
liquids/parenterals and some tablets or stripped in case of tablets or capsules
8. the Packaging Section transfers the packaged product to the Warehouse, in-process area pending release
by Quality Control
9. If approved by Quality Control, the bottled or stripped tablets are labeled and packed in cartons by
Packaging Section
10. These are then transferred to the Warehouse finished Product Section for distribution or sale
As soon as the M.O. is received by the Manufacturing head, he supervises the preparation of the product, the
equipment necessary, materials, theoretical yield and labor time to be spent to meet the target date.

In manufacturing of pharmaceuticals in large scale, the preparations are classified, and respective sections are
assigned to do a definite class of product.

I. TECHNICAL DIRECTOR'S DEPARTMENT

A. Research and Product Development Division

Three Types of Research

(1) Chemical

(2) Biological

(3) Pharmaceutical

Three Stages of Research

(1) Preliminary Stage consists of market research, literature review, patent search raw material evaluation and

(2) Applied Research Stage consists of chemical studies, pharmacological studies, development of manufacturing
process and cost of research

(3) Clinical Research Stage - consists of manufacturing requirements, research on label, review of basic information,
product control, contract with therapeutic trial committee. patent application and cost of clinical trial

After all researches have been accomplished, the product is submitted to the FDA or DDB evaluation and approval
for release to the public.

B. Quality Control Division

(1) Specification and Assay Development Section:

Specification Development Function

Specifications and procedures designed to test product quality consist of a series of statements and
methods of evaluating the physical, chemical and biological characteristics of the raw materials and the dosage
forms

The main purpose of establishing specification is to ensure that the characteristics of the finished dosage
forms:

(a) conform to appropriate standards of identity, purity, potency, quality, physiological availability and
therapeutic activity

(b) meet government rules and regulations

(c) prevent potential hazard to public health

Specifications developed are for raw materials and containers and finished products.
1. RAW MATERIALS AND CONTAINERS SPECIFICATIONS:

A. Raw Materials

IMPORTANCE

Since the quality of a finished medicament may often depend on the quality of the raw materials used in the
manufacturing operations, the establishment of specifications for raw materials is an important function. Such
specification are developed jointly by scientists involved in research, product development and quality control

The usual criteria or standards are :

Description

Identification

melting point

loss on ignition

residue on ignition

solubility

specific rotation

specific gravity

refractive index

assay

Adding such critical features as

particle size

crystal shape

surface tension

viscosity

irritation

foreign substance

allergenic substance

toxicity

The raw material specifications, therefore are also used in the procurement of drug substance, excipients, reagents,
packaging and printed materials

The specifications set forth as the standard should be realistic and practical to meet the actual needs and the ability
to produce at the established quality level for each product.
B. Containers

Specifications for containers are meaningful only if they have been selected on the basis of tests performed on the
product in the containers.

The following are to be considered before containers specifications are set

1. Physical changes of containers upon prolonged contact with the product

2. Moisture and gaseous permeability of the container

3 Comparability between container and product

4. Toxicity and safety considerations

Containers include glass, plastics, metal and rubber materials

2. FINISHED PRODUCT SPECIFICATIONS

It is necessary to develop and improved specifications for quality characteristics of the finished product

The specifications are developed jointly by quality control, research, Product Development, Sales and Marketing,
Production and Management individuals.

Usual criteria:

 Description
 Identification
 Moisture content
 pH
 Specific gravity
 Alcohol content
 Hardness
 Disintegration time
 Weight variation
 Sterility
 Pyrogenicity
 Safety
 Assay
Adding critical features:

 Dissolution rate
 Content Uniformity
 Related foreign substances
 Irritation
 Microbial content
 Stability

All specifications should include at least those requirements whenever applicable, of the government and official
compendia

Specifications for a product are developed not only to assure quality but to detect and identify impurities
Two major kinds of Impunities

1. Product Specific Impurities - which appear as by-products or degraded products of the drug substance and
excipients used in the formulation

2. Product Unspecific impurities which are introduced externally in to the product during processing

Factors to be considered in the development of specifications dosage forms or finished products

1. ascertain which physical, chemical and biological characteristics of dosage forms are critical which are important,
which are helpful and which are not particularly important but useful

2. decide which dosage form characteristics shall be established as the criteria for evaluating routine production
batches

3 establish appropriate test methods for evaluating selected criteria

4. determine the acceptable tolerances for each of the dosage form characteristics

Assay Development Function

Assay methods used to test many raw materials and finished products are published in the USP/NF For those raw
materials and finished products not described in either of these compendia, it is necessary for the manufacturer to
develop his own methods of testing

Purposes of varying or completely changing assay methods are

1 greater accuracy in testing

2. more rapid results, thus

3. contribute to reduction in cost of operation

4. increase in the number of samples tested without increase in cost or time especially with the growing use of
automation in testing

II. CENTRAL RELEASE SECTION

The functions are

1. to examine meticulously the records resulting from the exercise of Quality Control functions throughout all steps
of manufacturing and packaging for completeness and accuracy and to assume responsibility for their safekeeping
and storage

2 to investigate customer complaints or inquiries on product quality since this section has an easy access to records
of manufacturing and packaging operations

3. to maintain complete and accurate records of the receipt and distribution of every of raw material and finished
product

4 to keep retention samples in locked areas under similar conditions comparable to the market conditions

5. to properly record and handle finished products returned by pharmacies and hospitals
III. CHEMICAL CONTROL SECTION

The functions are:

1. to test and assay every lot of raw materials, in-process products and every lot of finished products

2. to conduct stability studies

IV. INSPECTION AND CHECKING SECTION

The functions are

1. to inspect and sample every shipment of raw materials received and every lot of finished goods for distribution

2. to examine every shipment of packaging material

3. to examine and check all manufacturing operations, including in-process filling and labeling as well as periodic
examination on the quality of stocks in the warehouse

4. to sample retention or reserved samples withdrawn from the packaging line for finished products and from the
Warehouse for raw materials

Retention samples are portions of the materials or finished products taken from the same lot tested and assayed
and are kept in locked areas under the same conditions comparable to market conditions. These are used for
additional tests if necessary

The quantity of reserved samples includes at least 2 labeled containers of the final dosage form or 2 times the
quantity required for testing These samples are to be retained for at least 2 years after distribution or 2 years after
expiry date, whichever is shorter.

V. BIOLOGICAL-MICROBIOLOGICAL CONTROL SECTION

The functions are:

1. to perform and evaluate microbiological and pharmacological assays

2. to do sterility, pyrogenicity, bacteriological, irritation and safety or toxicity tests

A number of raw materials and finished products require biological assays even though chemical tests may be
required for other components of the formulation

Biological tests are required for biological products, parenteral and eye preparations

It is essential that the staff in a biological testing laboratory should be well-trained and experience since many of the
procedures are complex and biological interactions are in many cases misunderstood. A high degree of skill and
judgement is required to perform and evaluate biological test
Description of the Quality Control Organization

in the organization of Quality Control, the Director of Quality Control is the individual directly responsible for the
quality of drug products in a manufacturing company he should report directly and only to the President, Vice
President or Technical Director as the case may be and should be on the same level as the Production Manager. His
decisions on quality should be subject only to review by the highest level of management

Quality Control is a staff function as a service department supporting but not subordinate to production
supervision

Responsibility for quality is shared by all but the Quality Control has ultimate jurisdiction over the lease of every
product manufactured and/or filled and packaged

ESSENTIALS OF QUALITY CONTROL

in prescription compounding in a pharmacy or drugstore, the quantities of medicaments prepared are usually small
and all the work is carried out by pharmacist herself

This prescription compounding requires skill and integrity, but the control involved is relatively small. Therefore,
the problem associated here is not as great as in large-scale pharmaceutical operations or production.

In the manufacture of drugs by an industrial firm, the variety and complexity of operations make it necessary to
assign to a separate and independent group of scientists within each company the responsibility for controlling the
quality of the final product. This group of qualified scientists that examine and check each lot of each product during
and upon completion of manufacturing operations for identity, purity, uniformity of drug content is collectively as
Quality Control

In any industry, Quality Control, is one of the major elements of the operations and as fundamental to success
both from the ethical and commercial point of view.

It is certain that existence of defective products in the market can put down sales very quickly as well as reputation
of a company.

Definition of Terms

1 Total Quality Control (RPS statement from Pharm. Manufacturers Association) or Control of Quality as it applies
to the drug industry is the organized effort within an establishment to design, produce, maintain and assure the
specified quality in each unit of product distributed

(a) Organized effort should establish specifications for product acceptance, should provide procedures and methods
for achieving conformance with such specifications

(b) To design the specified quality means that the ultimate objective of a program for the total control of quality is
the attainment of perfection in meeting specs for a product of high quality

(c) To assure the specified quality means that a program is designed to guarantee or promise the professional user or
ultimate consumer that

 every lot of a product conforms to specifications

 each dose distributed will fulfill the representations in the labeling
 the product distributed will meet all legal requirements
 and the product will meet all additional standards adopted by the management of the firm
2. Quality means:

(a) A combination of attributes or characteristics designed and manufactures into a product which determines the
degree of acceptability of the product

(b) In reference to medicinal and related products, it is the sum of all factors which contribute directly or indirectly to
the safety, effectiveness and acceptability of the product

(c) As to market-oriented definition of quality, three major elements are considered such as:

1. Functional Element - the product meets consumers' specs in point of use (safe and effective as to therapeutic
action)

2. Aesthetic Element - the product possesses an attractive design

3. Technological Properties - the product can withstand surrounding conditions

3. Quality Control and Quality Assurance

In some establishments the two terms refer to the same thing. In others, they consider quality assurance as a tool of
Quality Control were random spot checking instead of 100% examination of the work processes and product is
performed by the inspector with the prime purpose of giving the worker a sense of responsibility and active
participation in the inspection function of the production organization.

According to RPS, the terms Quality Control and Quality Assurance are often used interchangeably depending on
the structure of the specific company, there is continuing trend to separate and define their functional
responsibilities.

Quality Control can be broadly defined as the

 day-to-day control of quality within the company,

 a department staffed with scientists and technician responsible for the acceptance or rejection of incoming
materials and packaging components
 for the myriad of in-process tests and inspections to assure that systems are being controlled and
monitored and
 finally, for approval or rejection of completed dosage forms.

Quality Control, therefore, includes not only the analytical testing of the finished products but also assessment of
all operations beginning with the receipt of materials and continuing throughout the production and packaging
operations, finished product testing, documentation. surveillance and distribution

Quality Assurance may be defined as the responsibility of an organization to determine that systems, facilities and
written procedures are both adequate and followed in order to assure that products are controlled and will meet,
in the final dosage form, all applicable specifications

Quality Assurance naturally then become an oversight function often auditing operations to determine that
procedures and systems are suitable and if not, to recommend the required changes. Higher management looks
toward the Quality Assurance unit in order to develop some level of comfort" as to how well they are doing in
meeting company standards and applicable government regulations.

Therefore, to assure and control the attributes of product quality, there must be continuing search for the causes of
defects and their subsequent prevention. These defects are determined during the entire production operation,
from the raw materials to the finished products

Quality must be built into the product during research, development and production.
4. Documentation

During the course of producing a pharmaceutical product, numerous documents and records are generated. Each
batch is assigned a specific code or lot number.

All documentation relating to a specific code is referred to as a "batch record" which will include data on each
significant phase of production, control and distribution. The batch record provides a historical blueprint of every
step beginning with the receipt of chemical raw materials and packaging components and continuing through each
in-process stage. Recording charts or computer printouts of significant operations such as autoclaving, drying, air
particulate monitoring. lyophilizing, etc. all become part of the batch history. After the batch has been completed,
including final analytical and physical testing and additional step should be completed prior to approving the lot for
distribution.

When the batch has been released, accurate shipping records must be maintained showing the batch distribution.
With these records, it is then possible to trace the batch to the market place which will facilitate, if the need arose,
recalling the product (batch) from the market place

Sources of Quality Variations

The diversity of drugs and dosage forms produced, the size and complexity of the operations and the equipment
employed differ from company to company. Serious errors can occur anywhere from the receipt of raw materials at
the different stages of manufacturing and packaging of the product to the final acceptance of a product

The risk of error increases as the number of raw materials involved becomes greater the process becomes more
complex and the operation becomes larger.

General sources of variations and Examples

1. materials

a. variations between suppliers of the same substance

b. variations between batches from the same supplier

c variation within a batch

2.machines

a variation of equipment for the same process

b. difference in adjustment in equipment

c. aging and improper care

3.methods

a. inexact and inadequate procedures

b. negligence by chance

4. men

a. improper working conditions

b. inadequate training and understanding

c. dishonesty and fatigue

Sources of Quality Control Functions

The fundamental aims of Quality Control and Good Manufacturing Practices are identical. Both embrace the idea
of building high quality into a product by the use of good raw materials and adherence to a rigid set of
manufacturing controls at every step of the production cycle

It is important to note that product quality must be built into the product and not merely tested in it.

For the total quality control and assurance system function effectively, certain basic operational rules should be
established and should always prevail

1. Control decisions must be based solely on considerations of quality of the product

2. The operation must adhere rigidly to the established standards or specs as determined through systemic
inspection and sampling / testing and should constantly strive for improving the levels of the current standards or
specs

3. The facilities, personnel, funds and environment necessary to perform their responsibility effectively should be
adequately provided

4. The Control decisions should be independent administratively and they must not yield or be overruled by
production or marketing under any circumstances. The Control decisions should be subjected to review only by the
highest level of management in time of major disagreement

The Control decisions involve both the health of the consumer and reputation of the manufacturer

1. Material Control

The materials to be controlled are those that appear as a physical part of the final dosage including the package

these materials are as follows

1. Drug substance or Active ingredient or therapeutic ingredient-must meet specs that have been previously
established for it

2. Excipients are components of the finished dosage form other than therapeutic ingredient. These materials are
considered as inert since they may influence the quality of the product due to the interaction with the drug
substance affecting the physical properties of the dosage form as well as its influence to the production process

3. Packaging and Printed Materials include the primary container components such as closures and containers and
secondary components such as labels, inserts and cartons

As in raw materials, complete specs should be provided for these materials, such as for thickness, impact strength
and light transmission

For the labels, experienced proofreaders should carefully inspect the printing Further precautions against label mix-
ups is also essential

Bar marks are found in specifications areas in the label and carton for identification purposes

In general, upon receipt of the material the Quality Control inspector performs appropriate visual examinations
Should he find that the packing of the raw material is defective then outright rejection is made and no more
sampling is done

Another point of importance is the practice of FIFO in raw materials and components meaning, first in-first out, a
system where the first materials and components approved for use should be the first to be used in production

2.Control of Manufacturing Practices

The Food, Drug and Cosmetic Act empowered the BFAD to inspect drug manufacturing sites in which drugs are
processed, manufactured, packaged or stored for compliance with accepted standards of operations, practices and
sanitation

The successful application of Good Manufacturing Practice is complex but possible if there is proper planning and
control

It should be kept in mind that GMP is an aid and not a substitute for a good total quality assurance program

To comply with BFAD requirements as to the scope of Quality Control function, Administrative Order of 1974 by the
Ministry of Health was issued for CGMP which are as follows:

I. Definitions:

a. Components (raw materials) ingredients intended for use in the manufacture of drugs including those that may
not appear in the finished product

b. Batch - a specific homogenous quantity of a drug produced according to a single M.O. (Manufacturing Order)
during the same cycle of manufacture

c. Lot - a batch or any portion of a batch of a drug produced by a continuous process; an amount of drug produced in
a unit of time or quantity in a manner that assures its uniformity and in either case is identified by a distinctive lot
number and has uniform character and quality: within specified limits

d. Lot number or Control number any distinctive combination of letters or numbers or both by which the complete
history of the manufacture, control, packaging and distribution of a batch or lot of a drug is determined

e. Active ingredient- any substance of a drug which is intended to furnish pharmacological activity or other effect in
the diagnosis, cure, mitigation, treatment or prevention of diseases or to affect the structure or any function of the
body of man or animal

f. Strength - the concentration of a known active drug substance in the formulation (w/w. w/v or unit dose/volume
basis) and potency, that is the specific ability or capacity of the product as indicated by appropriate laboratory tests
or by adequately controlled clinical data expressed in terms of units by reference to a standard

II. Current Good Manufacturing Practices (CGMP)

1. Buildings and Equipment used in the manufacture, processing, packaging, labeling, storage. or control of drugs
should be of suitable design, size, construction and location and maintained in an orderly manner

The building shall provide adequate space for the orderly placement of materials and equipment to maximize any
risk of mix-ups or cross-contamination between the drugs, excipients, packaging, labeling and other printed supplies
from the time they are received to the time the products are released. Adequate lighting, ventilation, dust control,
temperature and humidity should also be provided

The equipment should have their surfaces inert, non-reactive, non-absorptive so that the identity, purity and quality
of the drug substance and other components will not be affected

2. Personnel
a. The personnel responsible for directing the manufacturing and control of the drug shall be adequate in number
and background of education and experience and should have a thorough understanding of the operations which
they perform

b. Personnel having direct contact with the drug shall have periodic health checks and shall be free from
communicable disease and open lesions on the exposed surface of the body

3. Control of Records. These records are the master formula records and batch production records

Master Formula records for each product shall be prepared and shall include:

 name of the product, description of the dosage form and its strength
 Complete list of ingredients, each one designated by whole names and code number
 The quantity by weight or volume of each ingredient regardless of whether it appears in the finished product
 The standards and specifications of each ingredient
 Theoretical yield at various stages in the processing
 Batch size
 Manufacturing and control instructions, specs, precautions and special notations to be followed
 A detailed description of the closures, containers, labeling, packaging and other finishing materials

Batch Production Record - Manufacturing Order (M.O.) and Finishing Order (F.O.)

These records should be prepared, maintained and controlled for each batch of product produced

The batch records shall include:

a. An accurate reproduction of the appropriate master formula record checked and endorsed by a competent,
responsible individual

b. Records of each step in the manufacturing, processing, packaging, labeling, testing and controlling of the batch
including the dates, individual major equipment and lines employed in process lab. Control test results and the
endorsement of the individual actively supervising or checking each step in the operation

c. A batch number that permits determination of all laboratory control results in the batch and all lot or control
numbers appearing on the package of the drug from such batch

d. A record with complete investigative history of any mix-ups, errors and unsatisfactory drug products found
during and after drug manufacturing and distribution. Said record shall indicate the evaluation and action

4. Manufacturing Control

a. To assure the uniformity and integrity of products, there shall be adequate in-process controls such as checking
the lots and disintegration time of tablets, the fill of liquids

b. Certifiable antibiotics and insulin are to be withheld from distribution until released by Quality Control

c. Until the certification certificate from BFAD is actually received

d. Other drugs shall be withheld from distribution until released by Quality Control

e. in-process batches of drugs found unacceptable shall be held until disposition has been determined

f. Material tickets for each substance and excipient are written and issued by the Production Control Department to
the Material Dispensing Area where the orders are filled and verified

g. IPQC (In-process Quality Control) is adopted for two reasons:

1. To monitor all the features of a product that may affect its quality
2. To prevent errors during processing

Only the most commonly practiced methods of in-process controls shall be discussed:

1. For Parenteral products, the IPQC are

a. Checking the bulk solution before filling, for drug content, pH, color, clarity and completeness of solution

b. Checking the filled volume of liquid or the filled weight of sterile powders for injection in the final container at pre-
determined intervals during filling

c. Testing for leakage of flame-sealed ampoules

d. Examining the sterility indicator placed in various areas of the sterilizer

2. For Solid Dosage Forms

a. Determination of the drug content of the formulation

b. Checking of the weight variation of tablets and capsules at appropriate intervals

c. Checking the disintegration time, hardness, friability of tablets at the beginning, middle and end of production

3. For Semisolid Preparations

a. Checking for homogeneity and uniformity of drug content prior to filling operations

b. Checking physical parameters at intervals

c. Checking or testing for filling weight during the filling operations

The above bulk finished products are held in quarantine and labeled as "in-process products" until released for
packaging by Quality Control

5. Packaging Controls

Packaging and labeling operations shall be adequately controlled for the following reasons:

1. To assure that only those products that have met the standards and specs established in the M.F (Master Formula)
shall be distributed

2. To prevent mix-ups between drugs during the filling, packaging and labeling operations

3. To identify the finished product with a lot number or control number

Practices and Procedures in the Packaging Section

1. At some prior to completing the manufacture of a product, a packaging record (F.O) bearing an identification
number is issued to the packaging section. This record specifies the packaging materials to be used, operations to
be performed and the quantity to be packaged

2. Prior to the start of a packaging operations, the Quality Control inspector and packaging supervisor must check
and verify the line to ensure that it has been thoroughly cleaned and that all materials from the previous packaging
order have been completely removed

6. Finished Good Warehouse Control and Distribution Records Control

It is the function of Quality Control to do periodic inspection and checking of finished foods in the Warehouse.
Records on the warehouse stocks and distribution should be maintained for the following reasons

1. For inventory control

2. To facilitate recall, if necessary, records on distribution shall contain

a. Name and address of the buyer or consignee

b. Date and quantity shipped

c. Name, lot number of the drug

FIFO should also be followed in the finished goods in the warehouse

7. Stability

Quality assurance of the product does not stop at the release of the product. There shall be assurance of the stability
of components of the drug preparations in the course of processing and finished drugs. Stability studies are
undertaken by Quality Control to confirm the shelf-life stability of the product as indicated by the expiry date which
in turn should appear on the label of the product

To assist in assuring the stability of the dosage form during transport and storage, an indication of the proper storage
condition should appear on the label

The FDA requires that the stability of drugs be determined by reliable, meaningful and specific test methods.

8. Product Complaint

Occasionally complaints are received by a manufacturer about products distributed

The complaints may be :

 Adulteration
 Misbranding
 Deterioration
 Counterfeit

The action taken often times ranges from recall of the product with the same lot number if verified to be
substandard or changed with new stocks if no reasonable defects are confirmed

Quality Control tests the returned or complained product against the retention samples of the same lot number so
that evaluation would be faster

9. Returned Goods
A certain fraction of distributed products inevitable returned for one reason or another

Upon receipt of the goods, each item is listed in an appropriate form (Returned Goods Receipt) giving the following
data:

1. Name of the product

2. Control number or lot number

3. Name and address of the sender

4. Date of return

5. Reason for return and estimated condition of the product

The returned product should be analyzed by physical, chemical or biological methods and store, pending issuance of
a credit and a decision for disposal

It is the responsibility of Quality Control to recommend recall of products that are unsatisfactory

An effective system for product recall requires a careful system of record keeping at all levels of product distribution
from manufacturer to ultimate consumer

Ex List name of product for distribution, size, control number, quantity and name of consignee or buyer

WAREHOUSING

Organization and Management

 Organization
 Responsibilities

Personnel

 Hygiene

Quality Management

 Systems and Procedures

Premises and Facilities

 Storage Areas
 Storage Conditions
 Monitoring of Storage Conditions Receipt of Incoming Products
 Stock Rotation and Control
 Rejected and Returned Products
 Counterfeits

Self-inspection

Cold Chain

 Handling of Cold Chain Products

GOOD WAREHOUSE PRACTICES

ORGANIZATION

 The organization to which a warehouse belongs must be an entity appropriately authorized to perform the
intended functions in terms of applicable legislation and which can be held liable for its activities
 There should be arrangements in place to ensure that management and personnel are not subject to
commercial, political, financial and other pressures or conflicts of interests that may have adverse effects on
the quality of services provided

RESPONSIBILITIES

 Individual responsibilities should be clearly defined and understood by concerned individuals.

 Written job descriptions must be provided to each personnel
 Managerial and technical personnel must have the authority and resources needed to carry out their duties
and to set up and maintain a quality management system, as well as to identify and correct deviations from
the quality management system
 Safety procedures relating to all relevant aspects Including safety of personnel and property, environmental
protection and product integrity should be in place

PERSONNEL

 There must be sufficient personnel to carry out all the tasks for which the Warehouse is responsible. They
should have the ability and the experience appropriate to their responsibility of ensuring that
pharmaceutical products and materials are stored and distributed properly.
 Personnel handling hazardous pharmaceutical products and materials such as highly active, toxic, infectious
or sensitizing products should be given specific training. Likewise, these personnel should be provided with
protective garments as necessary

HYGIENE

 Personnel in the warehouse should wear working or protective garments suitable for the activities that they
perform
 All personnel should be trained in and observe high levels of personal hygiene and sanitation
 First aid procedures and equipment for dealing with emergencies involving personnel should be available
 Procedures and conditions of employment for employees and other personnel having access to
pharmaceutical products and materials must be designed and administered to minimize the possibility of
such products coming into unauthorized possession

SYSTEMS and PROCEDURES

 Defined procedures and adequate systems must be in place to ensure traceability and assure confidence in
the quality of pharmaceutical products and materials. There should be written procedures for the
traceability of the products.
 Approved Standard Operating Procedures for all administrative and technical operations performed must be
in place.

STORAGE AREAS

 Must be off-limits to unauthorized persons.

 With sufficient capacity to allow the orderly storage of the various categories of materials and products
namely: starting and packaging minerals, intermediates, bulk and finished products, quarantined products,
and release, rejected, returned or recalled products
 Storage areas should provide adequate lighting to enable all operations to be carried out accurately and
safely
 Where special storage conditions are required on the label (e.q. temperature, relative humidity), these
should be provided, checked, monitored and recorded.
  Pharmaceutical products should be stored off the floor and suitably spaced to allow cleaning and inspection.
Pallets should be kept in a good state of cleanliness and repair.
 Storage areas should be clean, and free from accumulated waste and vermin
 A written sanitation program should be available indicating the frequency of cleaning and methods to be
used to clean the premises ad storage areas.
 There should be a written pest control program. The pest control agents used should be safe and there
should be no risk of contamination of the materials and pharmaceutical products.
 Receiving and dispatch bays should protect materials and products from the weather. Reception areas
should allow containers of incoming materials to be cleaned, if necessary, before storage.
 Areas holding quarantined products must be clearly marked and their access restricted to authorized
personnel only.
 Rejected, expired, recalled or returned pharmaceutical products and materials must be segregated physically
(Or by electronic means) from other stocks. The materials or products and areas concerned should be
appropriately identified in marked.
 The first expired/first out (FEFO) principle should be followed for pharmaceutical products. When no expiry
dates exist, the first in/first out (FIFO) principle should be applied.

FEFO- Warehousing and distribution procedure that ensures stuck with the earliest expiry date is issued/used and
/or Distributed before an identical stock with a later expiry date is issued/ used an or distributed.

FIFO-warehousing and distribution procedure that ensures stock that is received first is issued/used and/ Or
distributed before a newer and identical stock is issued/ used an or distributed.

 Rejected materials and pharmaceutical products should be identified and controlled under a quarantine
system designed to prevent their used until a final disposition has been made.
 Narcotic drugs should be stored in compliance with international conventions and national laws and
regulations on narcotics.

NARCOTICS- A drug derived from opium or opium-like compounds, with potent analgesic effects associated with
significant alteration of mood and behaviour and with a potential for dependence and tolerance following
repeated administration.

 Broken or damaged items should be withdrawn and segregated from usable stocks.

STORAGE CONDITIONS

 Storage conditions for pharmaceutical products should be in compliance with the labelling (Based on the
results of stability testing)

Normal storage conditions

 Storage in dry, well-ventilated premises at temperatures of 15° to 25° C or depending on climate conditions
up to 30° C.
 Drug products that must be stored under defined conditions require appropriate storage instructions.
 Unless otherwise specifically stated (e.g. Continuous maintenance of cold storage) deviation may be
tolerated only during short term interruptions, for example during local transportation.

MONITORING STORAGE CONDITIONS

 Recorded temperature monitoring data should be available for review. The equipment used for monitoring
should be checked at suitable predetermined intervals and there is also of such checks should be recorded
and retained.
 All monitoring records should be kept for at least the shelf life of the stored product plus one year, or as
required by regulations.
 Temperature mapping should show uniformity of the temperature across storage facility. it is recommended
that temperature monitors be located in areas that are most likely to show fluctuations.
 Equipment used for monitoring should be calibrated at defined intervals.
RECEIPT OR INCOMING PRODUCTS

 On receipt, each delivery should be checked against the relevant purchase order.
 The delivery should be examined for uniformity of containers and if necessary, should be subdivided
according to suppliers batch number should the delivery be comprised of more than one batch.
 Each container should be physically verified by the label description, batch number, type of pharmaceutical
product and quantity.
 Each container should be carefully inspected for possible contamination, tampering and damage.
 When there is a suspect container, the entire delivery should be quarantined for further in firm the entire
delivery should be quarantined for further investigation.

STOCK ROTATION AND CONTROL

 Periodic stock rotation should be performed by comparing the actual and recorded stocks.
 All significant stock discrepancies should be investigated as a check against inadvertent mix-ups and/or
incorrect issue
 Damaged containers should not be issued unless the quality of the product has been shown to be
unaffected.
 Where possible, this should be brought to the attention of the person responsible for quality control.
 If necessary further tests should be done to check for quality compliance. Any action taken should be
documented.

REJECTED AND RETURNED PRODUCTS

 Rejected and returned pharmaceutical products from the distributor should be segregated physically or by
other equivalent (e.g. electronic) system and placed in quarantine, in order to avoid confusion and prevent
re-distribution until a decision has been taken with regard to their disposition.
 Returned goods may only be considered as saleable stocks after a thorough evaluation of the integrity and
quality has been completed.
 The return to saleable stocks of returned goods should be approved by the authorized responsible person
following a satisfactory quality evaluation.
 Where any doubt arises over the quality of a product, it should be considered unsuitable for re-issue or re-
use
 Any stock re-issued should be so identified and recorded
 Returned goods should be transported in accordance with relevant storage and other requirements.
 Proper and safe transport of rejected and waste materials should be made.
 Pharmaceutical products should be destroyed where necessary in accordance with international and
national and local requirements regarding disposal of such products, and with due consideration to the
protection of the environment.
 Records of all returned and /or destroyed pharmaceutical products and materials should be kept

COUNTERFEIT

 Any counterfeit or suspected counterfeit medicines found in the distribution network should be segregated
immediately from other pharmaceutical products
 Counterfeit or suspected counterfeit products should be clearly labelled as not foe further distribution or
sale.
 Cases of counterfeit or suspected counterfeit should be reported to the appropriate national and/or
international regulatory bodies.

SELF-INSPECTION

 Self-inspection should be conducted to monitor the implementation and compliance with the principles of
Good Warehousing Practices and to propose corrective measures.
 Self-inspections should be conducted in an independent and detailed way by a designated, competent
person.
  All self-inspections should be recorded.
 Reports should contain all observations made, and where applicable, proposals for corrective measures.
Actions taken should also be recorded.

COLDCHAIN

What is COLD CHAIN?

 It is an uninterrupted flow of specific

thermal profile through out the
manufacturing, packaging and
distribution of a temperature
sensitive product.

Production/Filling (Bulk product)

Labeling/Packaging (Packaged product) Local Warehouse (Packaged
product) Customers

Stability data provide a “safety net”

Excursions below 2° C +2° C +8° C Excursions above 8°C

 Covered by stability data- Allowed Excursions (temperature range, duration and freeze/thaw cycles) vary per
product. Stability data proves no loss of product quality.
 Beyond the maximum permissible temperatures, the issue has to be raised to the manufacturer for
evaluation of the stability data of the specific lot/batch.
 Only an EXPERT STATEMENT can release the product for further use.

EQUIPMENT TO MAINTAIN COLD CHAIN

Storage to distribution

COLD ROOM

+2°C to 8° C environment

BIOREF

+2°C to 8° C environment

TEMPERATURE LOGGING DEVICES

 Programmable devices which can measure, record and store temperature readings at regular intervals
 Used for temperature monitoring during storage inside the cold room.

ICE BRICKS AND VALIDATED STYRO BOXES

  An insulated container that can be lined with frozen ice packs. Styro boxes can be used to store
temperature-sensitive products during brown-outs.
 Coolants used transporting temperature sensitive products for a longer period of time.
 Container which can maintain +2°C to +8° C during transport.

HANDLING OF COLD CHAIN PRODUCTS

Maintain COLD CHAIN all the way:

 Cold boxes must be placed in cool or shaded areas.

 Avoid placing cold boxes in trunks of cars.
 Use well frozen ice packs. Check for leaks.
 Avoid direct contact of the product to the ice packs. Put clean paper separators around products to avoid
freezing and to keep product from moisture.

Causes of BREAK in COLD CHAIN

 Lack of awareness resulting to mishandling of temperature-sensitive products.

 Poor or unavailable cold chain storage and transport equipments.
 Poor or fluctuating electricity supply; brown-outs
 Absence of temperature monitoring devices.

How to maintain COLD CHAIN

BIOREF

 Avoid storing too much products. Allow air to circulate by having enough spaces in between boxes of
products.
 Ideally, store temperature-sensitive products that can be consumed in a month or less.
 Do not keep expired products.
 Monitor temperature daily.
 Ensure that the 2°C to 8° C is maintained all the time.
 Keep a calibrated thermometer inside the bioref near the products stored.
 Do not store food, beverages and drinking water together with temperature-sensitive pharmaceutical
products.
 Do not open door more that necessary. Ensure that door is properly closed at all times.

COLD CHAIN shipments

 Receive cold chain products in a cool room. Ideally, the refrigerators for storing cold chain products are near
the receiving/checking area.
 Upon receipt of cold chain products, check and inspect immediately, without unnecessary delay.
 Place inside the refrigerator or cold storage immediately the cold chain products received.
 Ensure that refrigerator’ or cold storage doors are securely closed after opening.

Lack of adherence to COLD CHAIN maintenance may result to:

 Lack of product effectiveness

 Potency of product may be lost

COLD CHAIN maintenance is a VERY DANGEROUS ISSUE

 Temperature affects the stability of a product

 If stability is affected, potency and safety of the product are compromised
 Patient’s health even life, will be endangered.

Who are responsible for COLD CHAIN maintenance?

We are responsible for maintaining COLD CHAIN while temperature-sensitive products are:
 Stored in our cold rooms, biorefs, refrigerators…
 Found in our warehouses, hospitals, clinics, health centers, pharmacies and drugstores.