GOOD MANUFACTURING PRACTICES (GMPs) IN

PHARMACEUTICAL INDUSTRY
by
Ayesha Bibi
Pharm-D Student
https://www.linkedin.com/in/ayesha--bibi
 Table of Contents
1. Introduction……………………………………………………4
2. Aim of GMPs…………………………………………………..4
3. Importance of GMPs………………………………………….4
4. GMP Principles………………………………………………..5
5. GMP Guidelines/Regulations…………………………………7
5.1 Organization and Personnel……………….……......7
5.2 Building and Facilities…………………………...…8
5.3 Contamination and its Control……………………...9
5.4 Equipment……………………………..…….….....10
5.5 Materials Control…………………………...…...…11
5.6 Controls of Production and Process……………..…12
5.7 Control of Packaging and Labeling………………..13
5.8 Holding and Distribution……………………...…...14
5.9 Laboratory Controls…………………………..…....15
5.10 Records and Reports………………………..…..….15
5.11 Returned and Salvaged drug products………..…....16
5. QA/GMP/QC Relationship………………………….....….....16
6. Conclusion……………………………………………….........17
7. References……………………………………………….........18
 Good Manufacturing Practices Industrial Pharmacy

Good Manufacturing Practices (GMPs)

Introduction:
Good manufacturing practices are the sets of the principles, regulations, codes (law or official
standards), guidelines and procedures and part of quality assurance system which must be
followed by the manufacturers to ensure that the products that are consistently produced are of
quality standard and appropriate for their intended use (safe and effective) and cover the
manufacturing and testing of pharmaceutical dosage form and active pharmaceutical ingredients
(APIs), diagnostics, foods, various other pharmaceutical products and medical devices.

Good manufacturing practice is that part of quality assurance which ensures that products are
consistently produced and controlled to the quality standards appropriate to their intended use
and as required by the marketing authorization.

Aim of GMPs:
The aim of GMP is diminishing risks that cannot be controlled by testing of product. Some of these
are:

• Contamination and cross-contamination

• Mix-ups (confusion) e.g. due to mislabeling

Importance of GMPs:
Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug
products by requiring that manufacturers of medications adequately control manufacturing
operations. This includes establishing strong quality management systems, obtaining appropriate
quality raw materials, establishing robust operating procedures, detecting and investigating
product quality deviations, and maintaining reliable testing laboratories.
GMPs are aimed primarily at diminishing the risks inherent in any pharmaceutical production.
Such risks are essentially of two types: cross-contamination (in particular of unexpected
contaminants) and mix-ups (confusion) caused by, for example, false labels being put on
containers.
The approval process for drug marketing applications includes a review of the manufacturer’s
compliance with the GMPs or CGMPs.

GMP Principles:
Good manufacturing practice guidelines provides guidance for manufacturing, testing, and quality
assurance in order to ensure that drug product is safe for human consumption. Many countries
have enforced laws that pharmaceutical and medical device manufacturer must follow GMP

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procedures, and have created their own GMP guidelines that correspond with their legislation. All
guidelines follow a few basic principles or requirements:

1. Hygiene:
Pharmaceutical manufacturing facility must maintain a clean and hygienic manufacturing area.

2. Contamination control:
Controlled environmental conditions in order to prevent cross contamination of drug product from
other drug or extraneous particulate matter which may render the drug product unsafe for human
consumption.

3. Quality Management:
The manufacturer shall establish and implement an effective pharmaceutical quality assurance
system, involving the active participation of the management and personnel involved.
4. Process validation:

Manufacturing processes are clearly defined and controlled. All critical processes are validated to
ensure consistency and compliance with specifications. Manufacturing processes are controlled,
and any changes to the process are evaluated. Changes that have an impact on the quality of the
drug are validated as necessary.

5. Documentation:
Instructions and procedures are written in clear and unambiguous language. Operators are trained
to carry out and document procedures.
6. Quality control:
The quality control department shall have at its disposal one or more quality control laboratories
appropriately staffed and equipped to carry out the necessary examination and testing of starting
materials, packaging materials and intermediate and finished products testing.
7. Record keeping:
Records are made, manually or by instruments, during manufacture that demonstrate that all the
steps required by the defined procedures and instructions were in fact taken and that the quantity
and quality of the drug was as expected. Deviations are investigated and documented. Records of
manufacture that enable the complete history of a batch to be traced are retained in a
comprehensible and accessible form.

8. Computerized system:
A system is available for recalling any batch of drug from sale or supply.

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9. Monitoring:
Complaints about marketed drugs are examined, the causes of quality defects are investigated, and
appropriate measures are taken with respect to the defective drugs and to prevent recurrence.
10. Self-inspections:

The manufacturer shall conduct repeated self-inspections as part of the quality assurance system
in order to monitor the implementation and respect of good manufacturing practice and to propose
any necessary corrective measures. Records of such self-inspections and any subsequent corrective
action shall be maintained.

11. Necessary provisions:

• All necessary resources are provided, including:
• Appropriately qualified and trained personnel
• Adequate premises and space
• Suitable equipment and services
• Appropriate materials, containers and labels
• Approved procedures and instructions
• Suitable storage and transport
• Adequate personnel, laboratories and equipment for in-process controls

GMP Guidelines/Regulations:
The cGMP regulations establish requirements for all aspects of pharmaceutical manufacture. They
apply to domestic and to foreign suppliers and manufacturers whose bulk components and finished
pharmaceutical products are imported, distributed, or sold in this country. To ensure compliance,
the FDA inspects the facilities and production records of all firms covered by these regulations.

The Code of Federal Regulations (CFR) contains:

(a) Requirements for the “Current Good Manufacturing Practice for Finished
Pharmaceuticals” and (b) additional cGMP requirements for biologic products, (c)
medicated articles, and (d) medical devices.

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The regulations in 21 CFR, part 211, contain the minimum GMP requirements for the preparation
of finished pharmaceutical products for administration to humans or animals. These are:

Organization and Personnel:

Responsibilities of Quality Control Unit:

• There shall be a quality control unit (QCU) that shall have the responsibility and authority to
approve or reject all product components, product specifications, drug product containers, in-
process materials, packaging materials, labeling, and drug products and the authority to review
production records to assure that no errors have occurred, or, if errors have occurred, that they
have been fully investigated.
• Adequate laboratory facilities shall be provided, written procedures followed, and all records
maintained.
• The QCU shall have the responsibility for approving or rejecting all procedures or
specifications impacting on the safety, identity, strength, quality, and purity of the drug
product.

Personnel Qualifications:
a) Each person engaged in the manufacturing, processing, packing, or holding of a drug
product shall have education, training, and experience, or any combination thereof, to
enable that person to perform the assigned functions.
b) Training shall be in the particular operations that the individual performs and in CGMP as
they relate to the individual’s functions.
c) There shall be an adequate number of qualified personnel to perform and supervise the
manufacture, processing, packing, or holding of each drug product.
Personnel Responsibilities:

a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product

shall wear clean clothing appropriate for the duties they perform. Protective apparel, such
as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products
from contamination.
b) Personnel shall practice good sanitization and health habits.
c) Only personnel authorized by supervisory personnel shall enter those areas of the buildings
and facilities designated as limited access areas.
d) Any person shown at any time (either by medical examination or supervisory observation)
to have an apparent illness or open lesions that may adversely affect the safety or quality
of drug products shall be excluded from direct contact with the product. All personnel shall
be instructed to report to supervisory personnel any health conditions that may have an
adverse effect on drug products.

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Buildings and Facilities:

1. Any building used in the manufacture, processing, packing, or holding of a drug product shall
be of suitable size, construction, and location to facilitate cleaning, maintenance, and proper
operations.
2. Any such building shall have adequate space for the orderly placement of equipment, receipt
and storage of materials to prevent mix-ups between different components, drug product
containers and closures, labeling, in - process materials, or drug products (materials) and to
prevent contamination during following procedures:
a) Identification, storage and withholding from using the materials pending the
appropriate sampling, testing, and release for manufacturing or packaging.
b) Holding rejected materials and storage of released materials
c) Manufacturing and processing operations
d) Packaging and labeling operations
e) Quarantine storage before release of drug products
f) Aseptic processing, which comprise:
• Floors, walls, and ceilings of smooth, hard surfaces that are easily cleanable
• Temperature and humidity controls
• An air supply filtered through high-efficiency particulate air (HEPA) filters
• A system for monitoring environmental conditions
• A system for cleaning and disinfecting the room and equipment
3. Operations relating to the manufacture, processing, and packing of penicillin must be
performed in facilities separate from those used for other drug products.
Lighting: Adequate lighting shall be provided in all areas.

Air-handling systems:
Adequate ventilation should be provided. In areas where air contamination occurs during
production, there shall be adequate exhaust systems or other systems adequate to control
contaminants. Air-handling systems for the manufacture, processing, and packing of penicillin
shall be completely separate from those for other drug products for human use.
Plumbing:

Potable water should be supplied free from defects that could contribute to contamination of any
drug product. Drainage must be of adequate size. Where connected directly to a sewer, an air break
or other suitable mechanical device must be provided to prevent back-siphonage.
Sewage and refuse:
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed
of in a safe and sanitary manner.

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Washing and toilet facilities:

Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air
driers or single-service towels, and clean toilet facilities easily accessible to working areas.
Sanitation:

The building should be maintained in a clean and sanitary condition.

Written procedures assigning responsibility for sanitation and describing in sufficient detail the
cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and
facilities are required.

Written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents,
and cleaning and sanitizing agents are required and must be followed.

Contamination and Contamination Control:

The word “contamination” covers a range of different substances. Simply, it is stuff in the wrong
place, or where it should not be. It can be classified into two main types:

1. Living/Viable Contamination:

The term is for the most part taken to allude not to such macro-organisms, but rather to
microorganisms — such things as microbes, molds and parasites, yeasts, and viruses. Even with
dry items taken orally, for example, tablets and containers, there have been instances of difficult
sickness in patients taking items contaminated with bacteria. Some molds (which can develop on
tablets) produce a few extremely harmful substances. It is significant consistently to recollect that
individuals taking meds are typically doing so on the grounds that they are now sick, and
subsequently their protection from disease likely could be lower than ordinary.

2. Nonliving Contamination:

These can further be classified into two main groups:

o Active contamination
o Inert (or inactive) contamination

By “active” is meant chemically, or physiologically active, or having some activity when

introduced into the human (or animal) body.
In addition, there is another form of contamination that must be guarded against when making
products for injection. These are pyrogens (or bacterial endotoxins).
Control of Contamination:

The control of contamination is a major issue in the design, construction, and layout of a
manufacturing facility, and indeed in QA/GMP as a whole. Much depends on people and the way

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they behave, and the protective clothing they wear. Other important control measures are the
application of well-planned and proven cleaning and disinfection procedures.
• Cleaning and Disinfection (Cleaning is quite simply the removal of dust, dirt, debris, and
residues.)
• Disinfection (A disinfectant is a chemical substance, or combination of substances, which,
when applied to surfaces will kill microorganisms, with the exception of some bacterial
spores.)
✓ A wide range of substances are used as disinfectants. They may be single substances, like
alcohols or phenols, and there are a number of commercially available mixtures.
1. Ethanol
2. Phenols
3. Formaldehyde
4. Isopropanol etc. are used as disinfectants.
✓ Many manufacturers use different disinfectants over a period of time, on an alternating, or
rotating, basis. The reasoning behind this is to prevent the development of disinfectant-
resistant strains of microorganisms.
• Cleaning and Disinfection in Processing Area: Routine cleaning and disinfection in clean
rooms and other processing areas should be regularly carried out in accordance with an
established program, following a standard written procedure. That is, cleaning and disinfection
is not something to be done just when it seems like a good idea, or when time permits.

Equipment:
Design, size and location:

Equipment shall be of appropriate design, adequate size, and suitably located to facilitate
operations for its intended use and also for its cleaning and maintenance.
Construction:

Equipment should be constructed so that surfaces should not be reactive, additive, or absorptive
so as to alter the safety, identity, strength, quality, or purity of the drug product beyond official
requirements.
Any substance required for operation such as lubricants or coolants shall not come into contact
with drug products, containers, and so on.
Cleaning and maintenance:

Equipment and utensils should be cleaned, maintained, and sanitized at appropriate intervals.
Written procedures must be established and followed for cleaning and maintenance of equipment
and utensils used in the processing of a drug product.

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Automatic, Mechanical and Electronic Equipment:

All these types of equipments, including computers or related systems, must be routinely
calibrated, inspected, or checked according to a written program designed to assure proper
performance.

Input to and output from such systems should be checked for accuracy. A backup file of data
entered into a computer-related system must be maintained.

Filters:
Filters for liquid filtration used as a part of the manufacture, processing, or packing of injectable
drug products intended for human use must not release fibers into such products. Fiber - releasing
filters may not be used unless it is not possible to manufacture the product without the use of such
a filter.

Materials Control:
Basic requirements:

There shall be written procedures describing in sufficient detail the receipt, identification, storage,
handling, sampling, testing, and approval or rejection of components and drug product containers
and closures.
Drug product containers or closures shall be identified with a distinctive code for each lot in each
shipment received. This code shall be used in recording the disposition of each lot. Each lot shall
be appropriately identified as to its status (i.e., quarantined, approved, or rejected).

Storage of untested materials:

Upon receipt each container of components must be visually examined for appropriate labeling
and any damage or contamination to the component container. Components must be stored under
quarantine until they have been tested as appropriate and released for use.
Testing of materials:

Each lot of components shall be withheld from use until it has been sampled, tested, and released
by the quality control unit.

Representative samples must be taken from every receival of every component. The selected or
representative samples are tested.

If a lot of components meets the written specifications, it may be approved and released for use.
Any lot of such material that does not meet such specifications must be rejected.

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Using of approved materials:

Components, drug product containers, and closures approved for use shall be rotated so that the
oldest approved stock is used first.
Re-examination of approved materials:

Components must be retested and/or reexamined after storage for a long period of time or after
exposure to the atmosphere, heat, or other condition that might adversely affect the component.

Rejected materials:
Rejected components should be identified and controlled under a quarantine system designed to
prevent their use in manufacturing or processing.
Product containers and closures:

These shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength,
quality, or purity of the drug beyond the official requirements.

Container closure systems shall provide adequate protection against foreseeable external factors
in storage and use that can cause deterioration or contamination of the drug product.

Drug product containers and closures shall be clean and, where indicated by the nature of the drug,
sterilized, and processed to remove pyrogenic properties.

Controls of Production and Process:

Written instructions:
Written procedures should comprise of following:

The batch shall be formulated with the intent to provide not less than 100% of the labeled or
established amount of active ingredient.

Components for drug product manufacturing shall be weighed, measured, or subdivided as

appropriate. If a component is removed from the original container to another, the new container
shall be identified with the relevant information.

Testing of in-process materials and final products:

In order to assure batch uniformity and integrity, it is imperative to follow procedures that describe
the in-process material tests conducted on samples taken according to procedure. Procedures
should be written to monitor the output and to validate the performance of those manufacturing
processes that may be responsible for causing variability in the product being manufactured. Some
of these tests are:

• Dissolution time
• Weight variation (tablets and capsules)
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• Disintegration time
• Content uniformity
• Clarity of solution
• pH of solution
Microbiological contamination control:
Written procedures, designed to prevent objectionable microorganisms in drug products shall be
established and followed.

Control of Packaging and Labeling:

Criteria for materials testing and use:

Labeling and packaging materials shall be representatively sampled, and examined or tested upon
receipt and before use in packaging or labeling of a drug product.

Outdated labels, labeling, and other packaging materials must be destroyed. Labels and other
labeling materials for each different drug product, strength, dosage form, or quantity of contents
must be stored separately with suitable identification. Access to the storage area must be limited
to authorized personnel.
Use of gang-printed labels is prohibited. If cut labeling is used, the labeling operation includes one
of the following:

• Use of visual inspection

• Use of electronic or electromechanical equipment
• Dedication of a labeling and packaging line
Tamper-evident packaging:

An OTC product (with the exception of a dermatological, dentifrice, insulin, or lozenge product)
intended for retail sale is considered adulterated or misbranded or both if it is not packaged in a
tamper-resistant package.
Requirements for tamper-resistant packaging:

• A tamper - evident package must have one or more indicators or barriers to entry which, if
breached or missing, can reasonably be expected to provide visible evidence to consumers
that tampering has occurred.
• Any two-piece hard gelatin capsule covered by this regulation must be produced using an
acceptable tamper-evident technology.

Labeling:
In order to alert consumers to the specific tamper-evident feature used, each retail package of
an OTC drug product is required to bear a statement that is written on the package and placed

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such that it is not affected when tamper-evident feature is breached and identifies the type of
tampered packaging.
Labeling statement refers to the identifying characteristic of the tamper-evident feature. For
example, the labeling statement on a bottle with a shrink band could say, “For your protection,
this bottle has an imprinted seal around the neck.”

Inspection of final product:

Packaged and labeled products must be examined during finishing operations to provide assurance
that containers and packages in the lot have the correct label. A representative sample of units
should be collected at the end and should be visually examined for correct labeling. Results of
these examinations must be recorded in the batch production records.

Expiration date:
All packaged drug products must carry an expiration date that has been determined from
appropriate stability testing.
Expiration dates must be related to the recommended storage conditions stated on the label as
determined by stability studies.
If the drug product is to be reconstituted at the time of dispensing, its label must carry expiration
information for both the reconstituted and un-reconstituted forms.

Holding and distribution:

Warehouse procedures:

Written instructions expressing the warehousing of drug products followed. These procedures
should include:

• Quarantine of drug products before release by the quality control unit.

• Storage of drug products under appropriate conditions of temperature, humidity, and light
so that the quality of the drug products is not affected.
Distribution procedures:

Written instructions describing the distribution of drug products must be followed. These
procedures should include:

• A procedure that assures the distribution of the oldest approved stock first. Deviation from
this procedure is acceptable if it is temporary and appropriate.
• A system for documenting distribution so that distribution of each lot of drug product can
be readily determined to facilitate its recall if required.

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Laboratory Controls:
Basic requirements:

Laboratory controls include:

• Determination of conformance to written specifications and a description of sampling and

testing procedures for in-process materials and drug products. Such samples shall be
representative and properly identified.
• The calibration of instruments, apparatus, gauges, and recording devices at suitable
intervals in accordance with an established written program containing specific directions,
schedules, limits for accuracy and precision.
Testing of stability:
There must be a written testing program designed to assess the stability characteristics of every
drug product. The results of such testing must be used to determine appropriate storage conditions
and expiration dates.

The written program must include

• Sample size and test intervals

• Storage conditions for sample retained for testing.
• Testing of the product in the same container-closure system as the one in which the product
is to be marketed.
An adequate number of batches of each drug product must be tested to determine appropriate
expiration date. All sampling and testing plans must be described in written procedures that include
the method of sampling and the number of units to be tested.

The statistical quality control criteria must include acceptance levels and/or rejection levels.
Accelerated studies, combined with basic stability information on the components and drug
product in its container-closure system may be used to project a tentative expiration date.
Specific requirements for samples:

For each batch of ophthalmic ointment, there shall be appropriate testing to determine
conformance to specifications regarding the presence of foreign particles and harsh or abrasive
substances.
For each batch of controlled release dosage form, there shall be appropriate laboratory testing to
determine conformance to the specifications for the rate of release of each active ingredient.

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Records and Reports:

Basic requirements:

Any production, control, or distribution record that is associated with a batch of a drug must be
retained for at least one year after the expiration date of the batch, for OTC drug products that do
not have expiration dates, three years after complete distribution of the batch.

Records must be available for inspection where the activities described therein occurred.
Equipment cleaning and use record:

A written record of major equipment cleaning, maintenance, and use shall be included in individual
equipment logs that show the date, time, product, and lot number of each batch processed.

Records of materials:
Records must include:

• The identity and quantity of each shipment of materials. Also required are the identity of the
supplier, the date of receipt, and name and location of the prime manufacturer if different from
the supplier.
• The disposition of rejected materials.
• The results of any test or examination performed and any conclusions derived from these
results.

Returned and Salvaged drug Products:

Returned drug products (e.g., from wholesalers) must be identified by lot number and product
quality determined through appropriate testing. Drug products that meet specifications may be
salvaged or reprocessed. Those that do not, along with those that have been subjected to improper
storage (e.g., extremes in temperature), shall not be returned to the marketplace. Records for all
returned products must be maintained and must include the date and 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.

QA/GMP/QC Relationship:
Quality Assurance embraces GMP and includes such additional factors as original product design
and development, and GMP in turn includes Quality Control. Quality assurance is the sum total of
the organized arrangements made with the object of ensuring that medicinal products are of the
quality required for their intended use. Quality Control is that part of Good Manufacturing Practice
which is concerned with sampling, specifications and testing, and with the organization,
documentation and release procedures which ensure that the necessary and relevant tests are

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actually carried out and that materials are not released for use, nor products released for sale or
supply, until their quality has been judged to be satisfactory.

Conclusion:
Good manufacturing practice is that part of quality assurance which ensures that products are
consistently produced and controlled to the quality standards appropriate to their intended use
and as required by the marketing authorization. Good manufacturing practice guidelines
provides guidance for manufacturing, testing, and quality assurance in order to ensure that drug
product is safe and effective for human consumption.

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References:
1. The FDA and Worldwide CGMPs by Jose Rodriguez-Perez
2. Good Manufacturing Practices for Pharmaceuticals by Sidney H. Willig
3. Good Pharmaceutical Manufacturing Practices by John Sharp
4. Pharmaceutical Manufacturing Handbook by SHAYNE COX GAD
5. Good Manufacturing Practices for Pharmaceuticals by Joseph D. Nally
6. Pharmaceutical Quality Management System by Adnan S. Chaudhary

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