CURRENT GOOD MANUFACTURING PRACTICES

Prepared by:
Meghna.M
Registration No: 190609003
M Pharm Semester 1

Guide:
Dr. Swapnil J Dengale
Assistant Professor – Senior Scale

DEPARTMENT OF PHARMACEUTICAL QUALITY

ASSURANCE
MANIPAL COLLEGE OF PHARMACEUTICAL
SCIENCES
MAHE, MANIPAL

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 CONTENTS
SL/NO CONTENT PAGE NO
1 Introduction 3

2 General provisions 3

3 Organisation and personnel 4

4 Buildings and facilities 5

5 Equipment 8

6 Control of components and drug 10

product containers and closures

7 Production and process controls. 12

8 Packaging and labeling control 13

9 Holding and distribution 15

10 Labeling controls 16
11 Records and reports 18

12 Returned and salvaged drug products 21

13 References 22

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 CURRENT GOOD MANUFATURING PROCEDURES
INTRODUCTION
Good manufacturing practices required in order to conform to the guidelines
recommended by agencies that control the authorization and licensing of
manufacture and sale of food and beverages, cosmetics, pharmaceutical products
dietary supplements and medical devices. Pharmaceutical quality affects everyone.
The food and drug administration (FDA) regulates the quality of pharmaceuticals
very carefully The main regulatory standard for ensuring pharmaceutical quality is
the Current Good Manufacturing Practices (cGMP.)It contains regulations
regarding the design, monitoring, control and maintenance of manufacturing
process and facilities. To follow cGMP includes strong quality management
systems, using the quality raw materials, implementing robust operating
procedures, meticulously screening and investigating product quality deviations
and maintaining reliable testing laboratories.(1)

The regulations set in parts 211 and 226 contain the minimum current good
manufacturing practice of methods to be followed in and the facilities or controls
to be used for the manufacture, process, packaging or holding of a drug to assure
that such drug meets required criteria to act with its safety and has the identity and
strength and meets the quality and purity characteristics that it purports is
represented to posses.

Any kind of failure to comply with this regulation set in this part shall render the
drug to be adultered under section 501(a)(2)(B)of the act and in such case the drug
and the person who is responsible for the failure in the compliance shall be subject
to regulatory action.(2)

GENERAL PROVISIONS

 This sections deals with the drugs manufactured for humans and animals
 This requirement will not be enforced for OTC drugs products even if all the
products and all the ingredients are ordinarily marketed and considered as
human foods and also which products follow the legal drug definition by
virtue of its intended use.

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ORGANISATION AND PERSONNEL

1. Responsibilities of quality control unit

(a) A quality control unit must be a part of the facility organization.
(b) This unit is given the full responsibity and authority to review the
production records and approve and reject the drug product containers,
closure, process material, packaging material and labeling the drug
product.
(c) Adequate laboratory facilities must be available for testing the above
mentioned materials.
(d) Any process or specification affecting the identity, strength, quality and
purity can be approved or rejected by the quality control unit.
(e) Responsibilities and procedure to be followed by the unit must be written
and must be followed.
2. Personal Qualification
(a) Each and every person to be involved in the manufacture, process and
packaging of the drug product must have best knowledge, training and
experience in the same field to be able to perform their duties. The
employees must be trained to work according to cGMP and its training
must be conducted by qualified individuals and must assure that the
workers remain familiar with the instruments and procedures around
them.
(b) Persons who give supervision to the other works must be educated
trained and experienced to perform their assigned function and thus can
ensure good product with at most safety, identity, strength, quality and
potency.
(c) There is a need for adequate number of qualified personnel to perform
the tasks.
3. Personnel Responsibilities
(a) Protective apparel must be worn and the clothes should be clean and
white and appropriate for the duty undertaken.
(b) Personnel should practice good sanitation and health habits.
(c) In the limited access area only the authorized personnel can enter.

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 (d) Any worker with apparent illness or open lesions are not allowed to come
in direct contact with the product, components or containers as it can
adversely affect the quality of the product.
4. Consultants should have sufficient knowledge, education and training to
advise on the manufacture, processing, packaging or holding of drug
products and also experience to advise on the subject for which they are
retained. The manufacturer must maintain eh record of name and address
and qualification of any consultants and the type of service they provide.
5. Training
(a) The manufacturer should provide training to the personnel in accordance
with the written program me whose duties take them in to the
manufacturing areas.
(b) Training related to the GMP and the duties assigned to them. Continuous
training should be given and practically it should be assessed.
(c) Personnel working in areas where contamination is a hazard.
(d) The concept of quality assurance and all measures.
(e) Visitors or untrained personnel should no be taken to to the production
and quality control unit.
(f) Consultant and quality staff should be qualified for the services they
provide.

BUILDINGS AND FACILITIES

1. Design and construction features

(a) The buildings should be of suitable size, in good location to facilitate
cleaning and proper operations.
(b) Adequate space should be present for the placement of equipment and
materials to prevent any mix ups between the compounds, drug products
packaging materials and to prevent any sort of contamination.
(c) The movement of components and products in the building should be
organized in such a way that is causes no contamination.
(d) Operations should be performed with in specified area having good
control system to prevent any contamination and mix ups during the
following procedures:

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 (i) Receipt, identification, storage, and withholding from use of
components, drug product containers, closures and labeling,
sampling testing and release for packaging.
(ii) Holding rejected materials.
(iii) Storage of released components, drug product containers, closures
and labeling.
(iv) Storage in process materials.
(v) Manufacturing and processing operations.
(vi) Packaging and labeling operations
(vii) Quarantine storage before release of drug products.
(viii) Storage of products.
(ix) Control and laboratory operations.
(x) Aseptic processing, which includes:
Floors, walls and ceilings
Temperature and humidity controls
HEPA filters under positive pressure
Environment monitoring system
Cleaning and disinfecting room and to provide aseptic area
2. Adequate lighting should be provided
3. Heating ventilation and air conditioning
(a) Adequate ventilation in required areas
(b) Equipment to control air pressure, MO, dust, humidity, temperature
during the production of product
(c) During air supply it should be filtered
(d) Air handling systems for manufacture of penicillin should be separate
from other products.
4. Plumbing
(a) Continuous positive pressure system should be used for the supply of
potable water and free from defects that would contribute to
contamination of drug product
(b) Potable water should meet the standards prescribed in the
Environmental Protection Agency Primary drinking water regulations
defined in 40 CFR Part 141.
(c) Adequate sized drainage should be there.

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5. Adequate washing facilities should be provided which includes hot and cold water,
soap, detergent air driers, clean toilet facilities which are easily accessible.
6. Sanitation
(a) Clean and sanitary condition should be maintained for the building used for
manufacture, process, packaging and holding of products.
(b) Disposal of trash and organic waste matter should be on time.
(c) The cleaning schedules, methods equipment and materials used for cleaning
the building and other facilities should be described in detail and record
should be maintained.
(d) Written procedures for the use of rodenticides, insecticides, fungicides,
fumigating agents and cleaning and sanitizing agents are required and to be
followed. These procedures must be designed in such a way that it should
prevent contamination. No agent should be used unless it is registered and
used in accordance with the federal insecticide, fungicide, and rodenticide
act (7 USC 135)
7. All the buildings used for GMP related purposes must be maintained in a good
state of repair.(3)
8. Layout

Pharmaceutical plant layout is the allocation of space and the arrangement of

machines, furniture and other important administration and necessary services
needed in a production process within a factory building to perform the various
unit operations involved in the manufacturing process of dosage forms in a cost
effective manner and with the least amount of handling in processing the product
from the receipt of raw material through the distribution of the finished product.

Features

 There should be adequate floor space for machines installation and

utilization
 The machines should be properly arranged to facilitate minimum material
handling is necessary for low cost processing.
 The layout should facilitate smooth and continuous flow of production
process from one point to another without any form of delay
 It must incorporate adequate health, safety and security features such as first
aid box, fire extinguisher, emergency exit and access point

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  A good layout should allow effective supervision, coordination and control
of the production processes
 There should be room for adjustment and modifications whenever the need
arises.(4)

Circular flow of layout

EQUIPMENT

1. It should be of appropriate design, adequate size and location should also

facilitate operations for its intended use, cleaning and maintenance.
2. Equipment construction
(a) The instrument should be constructed in such a way that the surfaces that
come in contact with the components should not be reactive, additive, or
absorptive to prevent changes in safety purity strength etc.
(b) Substances like lubricants or coolants should not come in contact with the
drug products containers to alter the safety, identity, quality purity beyond
the established limits.
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3. Equipment cleaning and maintenance
(a) Equipment and utensils should be cleaned, maintained properly and
sanitized at every interval of the procedure to prevent malfunctions that
would alter the drug product beyond the limits.
(b) Procedures for cleaning of equipment and utensils used for drug process
should be written and these must include but are not limited to the
following:
(i) Responsibility for cleaning and maintaining equipment should be
assigned.
(ii) Maintain cleaning schedules including sanitization.
(iii) A detailed description of methods, equipment and materials used for
cleaning and maintenance operations and also operations of
assembling and reassembling the equipment as part of cleaning
procedure.
(iv) Removal of previous batch identification.
(v) Clean the instruments should be protected from contamination prior to
use.
(vi) Inspection of all instruments before use.
(vii) Records should be kept for maintenance, cleaning, sanitizing and
inspection of all the processing equipment.
4. Automatic, mechanical and electronic equipment
(a) All such equipment including computers and related systems should be
routinely calibrated, inspected or checked according to written procedure
to assure proper performance. It should be maintained for all such
practices.
(b) Appropriate controls should be done to assure that changes in master
production and control records are made only by authorized personnel. A
back up file of data entered into the computer must be maintained except in
cases of calculations done in connection with laboratory analysisare
eliminated by computerization. In such cases there should be a written
record of the program.
5. The filters used as a part of manufacture, process or packaging of injectable
must bot release fibers into such products. Filters which release fiber s may not
be used unless it is impossible to manufacture the product. In such case non

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 fiber releasing filters of 0.22microm maximum must be used after fiber
releasing filter.

CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS

AND CLOSURES

. 1. General Requirements
(a) The receipt, identification, storage, handling, sampling testing, and
approval or receipt of product components, containers and closures should
have written procedures. And all the procedures must be followed.
(b) All the components must be stored in such a way that to prevent
contamination.
(c) Bagged and boxed components should be stored off the floor with much
space for cleaning and inspection.
(d) There should be a distinctive code or lot number for every container of
compounds for each receiver of that product. Even if the next receiver is
the same vendor lot number it must be a new identified number by the
pharmaceutical manufacturer.
. 2. Receipt and storage of untested components

(a) On receipt of each container of components must be visually examined for

appropriate labeling and any damage.

(b) Components must be stored under quarantine until they have been tested and
found to be appropriate and released for use

3. Testing and approval or rejection of component

Unless it is sampled tested and released by the quality control unit the components
cannot thus they are kept withheld.

Representative samples must be taken from each receive of every component. The
number or amount of component to be sampled should be based on component
appearance, statistical confidence levels, the past history of the supplier, and the
quantity needed to analyze and reserve samples if required.

(a) Sampling procedures

(i) Clean the containers properly

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 (ii) The containers should be opened, sampled, and resealed in a manner
designed to prevent contamination of the sample and remaining contents of the
container.

(iii) Sterile equipment and aseptic sampling techniques should be used.

( iv) Containers from which samples have been taken must be marked to
show that samples have been removed.

(b) Examination and testing of samples

(i)For verification of identity ach sample should be tested.

(ii) Each component should be tested for its purity strength tocomply with
then written specifications.

(iii) Microscopically examination if needed

(iv) Each lot of a component that is liable to contamination with dirt

insect infestation, or other extraneous adulterant should be examined
against established specifications for such contamination.

(vi)A component that is subject to microbial contamination that is

contrary to its intended use should be subjected to microbiological tests before
use.

. (vii) Rotate the approved containers such that old one in the stock is used first
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PRODUCTION AND PROCESS CONTROLS.

1. Written procedures and procedure deviations

2. (a) Written procedures for production and process control must be written
and followed and should be designed to assure that the drug products have
the identity, strength, quality, and purity they are represented to possess.
(b)When following the above identified procedures, all actions must be
documented at the time of performance. Any deviations must be recorded
and justified.
3. At the end of each phase of the process, manufacturing, packaging
calculations of actual yield and practical yield.
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 4. Equipment identification

(a) All compounding and storage containers, processing lines, and major
equipment used during the production of a batch of a drug product must be
properly identified. This is done at all times to indicate their contents and the phase
of processing of the batch.

(b)Major equipment should be identified by a distinctive identification that

shall be recorded in the batch production record to indicate the specific equipment
used.

5. Sampling and testing in process control

(a) It is very necessary to write and follow up the procedure that describe
in process and other examinations to ensure batch uniformity. This is
done mainly to input and validate the procedure.

It should include the following control procedures.

(i) Tablet or capsule weight variation.

(ii) Disintegration time.
(iii) Adequacy of mixing or blending to assure uniformity and
homogeneity.
(iv) Dissolution time and rate.
(v) Clarity of solutions.
(vi) pH of solutions.

(b) In process control must be developed from previous acceptable

product average and process variability data and it must be consistent with the drug
product final specifications and

(c) In process materials must be approved for continued use or rejected by

the quality control unit before production continues. They must be tested for
identity, strength, quality, and purity.

(d) Rejected in process materials should be kept controlled in quarantine

designed system to prevent its use in manufacturing process.

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 6. Time limits should be set up for the production process and it should ensure
good quality of the product. This can be sometimes compromised if it doesn’t
affect the quality of the product.

7. Control of microbial contamination

(a) Appropriate procedures are designed to prevent growth of

microorganisms should be written and followed .

(b) If sterilization is a part of any procedure described in (a) above, this

procedure must be validated.

8. Reprocessing

(a) Written procedures describing any system used to reprocess batches that do
not conform to the established standards must be written and followed.

(b) It should be performed only with the review and approval of Quality
control unit

PACKAGING AND LABELING CONTROL

1. Follow written procedures which are approved in describing the receipt,

identification, storage, handling, sampling, examination, and/or testing of
labeling and packaging materials.
2. Rejection of materials which do not follow the acceptance criteria.
3. Maintain records of each receive of each different label and packaging
material indicating receipt, examination or testing, and whether accepted or
rejected.
4. Labels and other labeling materials for each different drug product,
strength, dosage form, or quantity of contents must be stored separately
with suitable identification.
5. Outdated labels, labeling, and other packaging materials must be
quarantined and destroyed.
6. Monitor the printing instruments which are used to imprint labeling upon
the drug product.

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Issuance of labeling

1. Strict control should be exercised over the issuance of labeling for use in
drug product labeling operations.
2. Labeling materials issued for a batch must be carefully examined for
identity and conformity to the labeling specified in the batch production
record.
3. All excess labeling bearing control number must be destroyed.
4. Written procedures should describe the control procedures used for the
issuance of labeling.
5. Tamper - evident packaging requirements for OTC human drug products

Labelling
1. labeling to alert the consumers should bear the statement:
(a) Identifies all tamper- evident features and any capsule -sealing
technologies.
(b) Is prominently placed on the package.
(c) Is placed that it will be unaffected if the tamper - evident feature of
the package is breached or missing.

Drug product inspection

1. Packaged and labeled products must be examined during finishing

operations to assurance that containers and packages in the lot have the
correct label.
2. Any one of the sample is taken and then collected for checking the
completion of finishing operations.

Expiration date

1. All the packaged drug product must contain the expiry date on the label
that is determined from the stability test

2. Based on the storage condition the expiry date is stated on the label.

3. Homeopathic drug products are exempt from the requirements of this

section.

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 4. If the drug product is to be reconstituted at the time of dispensing, its
label must carry expiration information for both the reconstituted and
unreconstituted forms

5. Allergenic extracts that are labeled “ No U.S. Standard of Potency ” are

exempt.

HOLDING AND DISTRIBUTION

1. Warehousing procedures
(a) Drugs should be kept in quarantine before release.
(b) The drugs should be stored t appropriate conditions of temperature
humidity and light to prevent contamination and maintain the
quality.
2. Distribution procedures
(a) A written procedure that assures the distribution of the oldest
approved stock first. Deviation from this procedure is acceptable
if it is temporary and appropriate.
(b) Documentation system for distribution so that distribution of each
lot of drug product can be readily determined to facilitate its recall
if required.

LABORATORY CONTROLS

1. General requirements
(a) The establishment of any standards, sampling plans, test processes,
or other laboratory control mechanism required must be drafted by the
appropriate organizational unit and reviewed and approved by the
quality control unit. It must be documented at the time of
performance and if any deviation it should be documented and must be
justified.
(b) Written specifications should under conformance for the acceptance
of each lot within each shipment of raw materials. The specifications

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 should include a description of the sampling and testing procedures
used. Samples must adequately identified..
(c) Instruments, apparatus, gauges, and recording devices should be
calibrated at specified intervals in accordance with the established
written program containing specific directions, schedules, limits for
accuracy and precision, and provisions for remedial action in the event
that the limits are not met. No such devices should be used if it doesn’t
meet the standards.
2. Testing and release of distribution
(a) Laboratory testing is done to establish the conformance with the
final specifications. Testing include identity and strength of each
active ingredient and also sterility and pyrogen testing are required
on short - lived radiopharmaceuticals.
(b) Batch that should be tested for objectionable microorganisms should
be tested appropriately.
(c) Sampling and testing plans must be described in written procedures
that include the method of sampling and the number of units to be
tested.
(d) Quality control unit adequately check to assure that the batch meets
the acceptance criteria for sampling and testing to meet all the
specification.
(e) The accuracy, sensitivity, specificity, and reproducibility of test
methods used must be established and documented. Validation and
documentation must be accomplished in accordance with this
regulation.
(f) Drug products that don’t meet the standard specification must be
rejected.
3. Stability Testing
(a) Written testing program must be designed to assess the stability
characteristics of every drug product. The result of the tests
determine the storage conditions and expiry date
It include:
(i) Sample size and test intervals based on statistical criteria should
be examined.
(ii) Storage conditions of samples.
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 (iii) Testing of the product in the same container- closure system as
the one in which the product is to be marketed
(iv) Drug products must be tested for reconstitution at the time of
dispensing as well as after they are reconstituted.
(b) An adequate number of batches of each drug product must be
tested to determine appropriate expiration date. A record of such
data must be maintained. Accelerated stability studies and basic
stability information determine the expiration date.
(c) Allergenic extracts that are labeled “No U.S. Standard of Potency ”
are exempt from the requirements of this section.
(d) Requirements of homeopathic drugs:
(i) Written assessment of stability based on testing or examination
of the drug product for compatibility of the ingredients, and
marketing experience with the drug product to indicate that
there is no degradation of the product for the normal or
expected period of use.
(ii) Evaluation of stability should be same as with container
closure system.
4. Special testing requirements
(a) To establish conformance with the claim to be sterile and pyrogen
free appropriate laboratory testing should be done. The procedures
should be written and then followed.
(b) Appropriate testing to determine conformance to specification
regarding the presence of foreign particles and harsh or abrasive
substances is mandatory for ophthalmic preparations.
(c) In case of sustained release drugs also there should be defined
laboratory testing to indicate its drug release and should be written
and followed.
5. Animals used in testing components, in process materials, or drug
products must be maintained and controlled in a manner that assures their
fitness for their intended use. Adequate record should be maintained for
the history of their use.

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RECORDS AND REPORTS

1. General requirements
(a) 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 OR, for OTC drug products that do not
have expiration dates, three years after complete distribution of the
batch.
(b) In case of records of containers, closures, labeling also these should be
retained for the same time.
(c) In case of any inspection these retained records should be easily
accessible.
(d) These retained copies should be original or photocopies of the original.
(e) Procedures must be established to assure that the responsible officials
of the firm are notified in writing of any investigations conducted
under Sections 211.198, 211.204, or 211.208 of any recalls, reports of
inspectional observations issued by the FDA, or any regulatory actions
relating to GMP brought by the FDA.
2. In individual equipment logs equipment cleaning and maintenance should
be recorded
3. Component, drug product container, closure, and labeling records must
include the following:
(a) The identity and quantity in each shipment of each lot of components,
drug product containers, closures, and labeling. The identity of the
supplier, the supplier’s lot number, the receiving code, the date of
receipt, and name and location of the prime manufacturer is also
required if different from the supplier.
(b) Recording of all the tests result and conclusions is mandatory.
(c) Documentation of the examination and review of labels and labeling
for conformance with established specifications.
(d) Rejected and disposed materials should be recorded.
4. Master production and control records.
(a) Prepare batch production and control records for each batch of drug
product produced including complete information about the
production and control of that batch. These records must include:

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 (i) The master production record should be complete and its copy is
checked for accuracy then dated and signed.
(ii) Documentation in each significant step of manufacture,
processing, packaging, and holding of the batch was
accomplished as prescribed, including:

(a) Dates.
(b) Identity of individual major equipment used. This includes
packaging lines.
(c) Complete and specific identification of each batch of component or
in - process material used.
(d) Weight and measures of components used in the course of
processing.
(e) In - process and laboratory control results.
(f) Inspection of the packaging and labeling area before and after use.
(g) Documentation of the actual yield and the percentage of theoretical
yield that this represents at critical stages of processing.
(h) Complete labeling control records, including specimens or copies of
all labeling used.
(i) A description of drug product containers and closures.
(j) Any sampling performed.
(k) Identification of the persons performing and directly supervising or
checking significant steps in the operation.
(l) Any investigations conducted.
(m) Results of examinations made.

5. Laboratory records
(a) It should include all the data needed to assure its specificatins and meet
the standard. This include sexamination of the following:
(i) Detailed description of the sample when received for testing with its
identification of source.
(ii) Descrption of the method used for testing the sample with the location
of data that establish the methods used in the testing of the sample
and should meet proper standards of accuracy and reliability as
applied to the product tested.
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 (iii) Record of the sample weight used for teting.
(iv) A complete record of the result obtained with graphs, charts etc.
(v) A record of all calculations performed in the sample testing
procedure.
(vi) A statement of how the result is compared with the standard
specifications to meet the standards of identity, strength quality and
purity.
(vii) The initials or signature of the person who performed each test and
the date the tests were performed and also the secod person who
shows that the original records are verified.
(b) Complete records of testing and standardization of laboratory reference
standards, reagents, and standard solutions must be maintained and also
for the periodic calibration of equipment.
7. Complaint files

(a)Follow the written procedures for the handling of all oral and written
complaints regarding the drug product. It should be easily revived by the quality
control unit of any complaint involving the failure of a drug product to meet any of
its specifications and in case of investigation.

(b) The written complaint should be maintained in a file. The written

reports should be maintained for atleast one year after the expiration date of the
product or one year after which the complaint has been received. In case of OTC
drugs it should be maintained for 3 years as its expiry date is not certain. It should
include:

(i) The name and strength of the drug product, lot number, name of
complainant, nature or complaint, and reply to the complainant.

(ii) In case of investigation conducted the record must contain

information of the findings of investigation and follow up.

(iii) If no investigation is conducted it should state why the

investigation was not necessary.

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RETURNED AND SALVAGED DRUG PRODUCTS

Returned products must and held. If in conditions the returned drug products have
been held, stored, or shipped before or during the return or the condition of the
drug product, its container, carton, or labeling is a result of storage or shipping
casts doubt on the safety, identity, strength, quality, or purity of the drug product,
the returned drug product must be destroyed unless examination testing or other
investigation proves the drug product meets appropriate standards. The record has
to be maintained also.

Drug product salvaging

Drug products subjected to improper storage conditions, including changes in

temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural
disasters, fires, accidents, or equipment failures, must not be salvaged and must be
returned to the marketplace. Salvaging can be done only if :

 Evidence from laboratory tests and assays that the drug products meet all
applicable standards of identity, strength, quality, and purity
 Evidence from inspection of the premises that the drug products and associated
packaging were not subjected to improper storage conditions as a result of the
disaster or accident.(3)

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REFERENCES

1. https://www.fda.gov/.../current-good-manufacturing-practices-cgmps
2. PP Sharma. How to practice GMPs- A treatise on GMPs, 6 Edition. Delhi:
Vandana Publications; 1991.
3. Shayne Cox Gad. Pharmaceutical Manufacturing Handbook, Regulations
and Quality : New Jersy : John willey and sons;
4. https://manoxblog.com/2018/03/29/pharmaceutical-plant-layout.

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