TOPIC: cGMP as per WHO

PRESENTED BY: Dhruvi Parmar GUIDED BY: Khushbu Thakor

M.PHARM: 1ST SEM DATE: 04th Oct 2019

DEPARTMENT OF PHARMACEUTICAL QUALITY ASSURANCE

SMT. B. N. B. SWAMINARAYAN PHARMACY COLLEGE, SALVAV
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 CONTENTS
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1. DEFINITION 12. SELF-INSPECTION, QUALITY

2. HISTORY AUDITS AND SUPPLIERS’
3. PRINCIPLE OF GMP AUDITS AND APPROVAL
i. PERSONNEL
4. QUALITY RISK MANAGEMENT
ii. TRAINNING
5. PRODUCT QUALITY REVIEW
iii. PERSONAL HYGIENE
6. GMP FOR PHARMACEUTICAL iv. PREMISES
PRODUCTS v. EQUIPMENT
7. SANITATION AND HYGIENE vi. MATERIALS
8. QUALIFICATION AND vii. DOCUMENTATION
VALIDATION 13. GMP IN PRODUCTION
9. COMPLAINTS 14. GMP IN QUALITY CONTROL
10. PRODUCT RECALLS
11. CONTRACT PRODUCTION,
ANALYSIS AND OTHER
ACTIVITIES
 DEFINATION
 The World Health Organization(WHO) is a specialized
agency of the United Nations that is concerned with
international public health. It was established on 7 April
1948, and is headquartered in Geneva, Switzerland.
 WHO defines Good Manufacturing Practices(GMP) as
“that part of Quality Assurance which ensures that products
are consistently produced and controlled to the quality
standard appropriate to their intended use and as required
by the marketing authorization.”
 The Current Good Manufacturing Practices(CGMP)
regulations for drugs contain minimum requirements for the
methods, facilities, and controls used in manufacturing,
processing, and packing of a drug product
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 HISTORY
YEAR DESCRIPTION

In 1903 Harvey W. Wiley, a chemist with the US Department of Agriculture and

crusader for safer products, established a volunteer "Poison Squad."
In 1906 Upton Sinclair published The Jungle, a graphic exposure of the meatpacking
industry. This book pushed Congress to pass the Pure Food and Drug Act of
1906 but they refused to take action and over 100 people (mostly children)
death occurred.
In 1937 The S.E. Massengill Company developed a liquid form of Sulfanilamide
used for treating streptococcal infections. They soon found out that many
people who took this drug were dying terrible deaths.
In 1938 The Federal Food, Drug, and Cosmetic Act was passed and the
requirement for the drug manufacturers was to show that a drug is safe before
marketing it.
Thalidomide Frances Oldham Kelsey was a PhD in pharmacology working for FDA. The
Incident tranquilizer and painkiller thalidomide was also used in pregnant women for
morning sickness which leads to severe deformities of the babies..
In 1962 The Drug Amendments of 1962 tightened control over prescription drugs,
new drugs and investigational drugs. The Drug Amendments of 1962
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formalized Good Manufacturing Practices
 PRINCIPLE:
 The manufacturer must assume responsibility for the quality
of the pharmaceutical products to ensure that they are fit for
their intended use, comply with the requirements of the
marketing authorization and do not place patients at risk due
to inadequate safety, quality or efficacy.
 Quality management is a wide-ranging concept covering all
matters that individually or collectively influence the quality
of a product. It is the totality of the arrangements made with
the object of ensuring that pharmaceutical products are of the
quality required for their intended use. Quality management,
therefore, incorporates GMP and other factors, including
those outside the scope of this guide, such as product design
and development.

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 QUALITY RISK MANAGEMENT:
 QRM is a systematic process for the assessment,
control, communication and review of risks to the
quality of the medicinal product. It can be applied both
proactively and retrospectively.
 QRM should ensure that:
o The evaluation of the risk to quality is based on scientific
knowledge, experience with the process and ultimately
links to the protection of the patient;
o The level of effort, formality and documentation of the
QRM process is commensurate with the level of risk

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 PRODUCT QUALITY REVIEW:
a) a review of starting materials and packaging materials used for the product,
especially those from new sources and in particular the review of supply
chain traceability of active substances;
b) a review of critical in-process controls, and finished product results;
c) a review of all batches that failed to meet established specification(s) and
their investigation;
d) a review of all significant deviations or non-conformances, the related
investigations and the effectiveness of resultant CAPAs taken;
e) a review of all changes made to the processes or analytical methods;
f) a review of dossier variations submitted, granted or refused;
g) a review of the results of the stability monitoring programme and any
adverse trends;
h) a review of all quality-related returns, complaints and recalls and the
investigations performed at the time;
i) a review of adequacy of any other previous corrective actions on product
processes or equipment;
j) post-marketing commitments for new dossiers and variations to the dossiers;
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GMP FOR PHARMACEUTICAL PRODUCTS:
 GMP is that part of quality management which ensures that products are
consistently produced and controlled according to the quality standards
appropriate to their intended use and as required by the marketing
authorization, clinical trial authorization or product specification. GMP is
concerned with both production and QC.
 Under GMP:
a. All manufacturing processes are clearly defined, systematically reviewed
for associated risks in the light of scientific knowledge and experience,
and shown to be capable of consistently manufacturing pharmaceutical
products of the required quality that comply with their specifications;
b. Qualification and validation are performed;
c. All necessary resources are provided, including:
i. sufficient and appropriately instructions,
qualified and trained personnel, vi. suitable storage and transport,
ii. adequate premises and space, vii. adequate personnel, laboratories
iii. suitable equipment and services, and equipment for in-process
iv. appropriate materials, containers controls;
and labels,
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v. approved procedures and
 d. instructions and procedures are written in clear and unambiguous
language, specifically applicable to the facilities provided;
e. procedures are carried out correctly and personnel are trained to do so;

SANITATION AND HYGIENE:

 A high level of sanitation and hygiene should be practised in
every aspect of the manufacture of medicines. The scope of
sanitation and hygiene covers personnel, premises, equipment
and apparatus, production materials and containers, products for
cleaning and disinfection, and anything that could become a
source of contamination to the product. Potential sources of
contamination should be eliminated through an integrated
comprehensive programme of sanitation and hygiene
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 QUALIFICATION AND VALIDATION:
 The key elements of a qualification and validation programme of
a company should be clearly defined and documented in a
validation master plan
 Qualification and validation should not be considered as one-off
exercises. An ongoing programme should follow their first
implementation and should be based on an annual review.
 The commitment to maintain continued validation status should
be stated in the relevant company documentation, such as the
quality manual or validation master plan.
 The responsibility for performing validation should be clearly
defined.
 Validation studies are an essential part of GMP and should be
conducted in accordance with predefined and approved
protocols.
 A written report summarizing the results recorded and the
conclusions reached should be prepared and stored.

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 COMPLAINTS:
 Principle: All complaints and other information concerning
potentially defective products should be carefully reviewed
according to written procedures and the corrective action
should be taken.
 A person responsible for handling the complaints and
deciding he measures to be taken should be designated. If
this person is different from the authorized person, the latter
should be made aware of any complaint, investigation or
recall.
 Special attention should be given to establishing that the
product that gave rise to a complaint was defective.
 Complaints records should be regularly reviewed for any
indication of specific or recurring problems that require
attention and might justify the recall of marketed products.

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 PRODUCT RECALLS:
 Principle: There should be a system to recall from the market, promptly and
effectively, products known or suspected to be defective.
 The authorized person should be responsible for the execution and
coordination of recalls. He or she should have sufficient staff to handle all
aspects of the recalls with the appropriate degree of urgency.
 The distribution records should be readily available to the authorized person,
and they should contain sufficient information on wholesalers and directly
supplied customers (including, for exported products, those who have
received samples for clinical tests and medical samples) to permit an effective
recall.
 The progress of the recall process should be monitored and recorded. Records
should include the disposition of the product. A final report should be issued,
including a reconciliation between the delivered and recovered quantities of
the products.
 The effectiveness of the arrangements for recalls should be tested and
evaluated from time to time.
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CONTRACT PRODUCTION, ANALYSIS:
 Principle: Contract production, analysis and any other activity
covered by GMP must be correctly defined, agreed and
controlled in order to avoid misunderstandings that could result
in a product, or work or analysis, of unsatisfactory quality.
The contract giver :
o The contract giver should provide the contract acceptor with all the
information necessary to carry out the contracted operations
correctly in accordance with the marketing authorization and any
other legal requirements. The contract giver should ensure that the
contract acceptor is fully aware of any hazards associated with the
product, work or tests that might pose a risk to premises, equipment,
personnel, other materials or other products.
o The contract giver should monitor and review the performance of
the contract acceptor including the implementation of any needed
improvements and their effectiveness.

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 The contractor acceptor:
o The contract acceptor must have adequate premises, equipment,
knowledge, experience and competent personnel to satisfactorily
carry out the work ordered by the contract giver. Contract
manufacture may be undertaken only by a manufacturer who holds a
valid manufacturing authorization.
o The contract acceptor should refrain from any activity (including
unauthorized changes outside the terms of the contract) that may
adversely affect the quality of the product manufactured and/or
analysed for the contract giver
The contract:
o The contract must clearly state the way in which the authorized
person, in releasing each batch of product for sale or issuing the
certificate of analysis, exercises his or her full responsibility and
ensures that each batch has been manufactured in, and checked for,
compliance with the requirements of the marketing authorization.
o Technical aspects of the contract should be drawn up by competent
persons with suitable knowledge of pharmaceutical technology,
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analysis and GMP.
 SELF-INSPECTION, QUALITY
AUDITS and SUPPLIERS’ AUDITS :
 Principle: The purpose of self-inspection is to evaluate the
manufacturer’s compliance with GMP in all aspects of
production and QC.
 Items for self-inspection:
a) personnel; i) sanitation and hygiene;
b) premises including personnel j) validation and revalidation
facilities; programmes;
c) maintenance of buildings and k) calibration of instruments or
equipment; measurement systems;
d) storage of starting materials and l) recall procedures;
finished products; m) complaints management;
e) equipment; n) labels control;
f) production and in-process o) results of previous self-
controls; inspections and any corrective
g) QC; steps taken.
15 h) documentation;
  Self-inspection team
o Management should appoint a self-inspection team consisting of experts in
their respective fields who are familiar with GMP. The members of the team
may be appointed from inside or outside the company.
• Frequency of self-inspection
o The frequency with which self-inspections are conducted may depend on
company requirements but should preferably be at least once a year. The
frequency should be stated in the procedure.
• Self-inspection report
o A report should be made at the completion of a self-inspection. The report
should include:
(a) self-inspection results;
(b) evaluation and conclusions;
(c) recommended corrective actions.
• Quality Audit:
o It may be useful to supplement self-inspections with a quality audit. A
quality audit consists of an examination and assessment of all or part of a
quality system with the specific purpose of improving it. A quality audit is
usually conducted by outside or independent specialists or a team
designated by the management for this purpose. Such audits may also be
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 i. PERSONNEL
 Principle: The establishment and maintenance of a satisfactory system
of QA and the correct manufacture and control of pharmaceutical
products and active ingredients rely upon people.
 Key personnel:-
Key personnel responsible for supervising the production and quality
unit(s) for pharmaceutical products should possess the qualifications
of a scientific education and practical experience required by
national legislation. Their education should include the study of an
appropriate combination of:
a) chemistry (analytical or organic) or biochemistry; (b)
b) chemical engineering;
c) microbiology;
d) pharmaceutical sciences and technology;
e) pharmacology and toxicology;
f) physiology;
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 ii. TRAINING
 The manufacturer should provide training in accordance
with a written programme for all personnel whose duties
take them into manufacturing areas or into control
laboratories (including the technical, maintenance and
cleaning personnel) and for other personnel as required.
 Continuing training should also be given, and its practical
effectiveness periodically assessed. Approved training
programmes should be available. Training records should
be kept.
 The concept of QA and all the measures which aid its
understanding and implementation should be fully
discussed during the training sessions.
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 iii. PERSONAL HYGIENE:
 All personnel, prior to and during employment, as appropriate, should
undergo health examinations. Personnel conducting visual inspections
should also undergo periodic eye examinations.
 Direct contact should be avoided between the operator’s hands and
starting materials, primary packaging materials and intermediate or
bulk product.
 To ensure protection of the product from contamination, personnel
should wear clean body coverings appropriate to the duties they
perform, including appropriate hair covering. Used clothes, if reusable,
should be stored in separate closed containers until properly laundered
and, if necessary, disinfected or sterilized.
 Smoking, eating, drinking, chewing, and keeping plants, food, drink,
smoking material and personal medicines should not be permitted in
production, laboratory and storage areas, or in any other areas where
they might adversely influence product quality. .
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 iv. PREMISES
 Principle: Premises must be located, designed, constructed,
adapted and maintained to suit the operations to be carried
out.
A. ANCILLARY AREA
B. STORAGE AREA
C. WEIGHING AREA
D. PRODUCTION AREA
E. QUALITY CONTROL AREA

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 v. EQUIPMENT
 Equipment must be located, designed, constructed, adapted and
maintained to suit the operations to be carried out. The layout
and design of equipment must aim to minimize the risk of errors
and permit effective cleaning and maintenance in order to avoid
cross-contamination, build-up of dust or dirt, and, in general, any
adverse effect on the quality of products.
 Equipment should be installed in such a way as to minimize any
risk of error or of contamination.
 Production equipment should be thoroughly cleaned according to
a fixed schedule.
 Laboratory equipment and instruments should be suited to the
testing procedures undertaken.
 Washing, cleaning and drying equipment should be chosen and
used so as not to be a source of contamination.

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 vi. MATERIALS
 Principle: The main objective of a pharmaceutical
plant is to produce finished products for patients’ use
from a combination of materials (starting and
packaging).
 Materials include starting materials, packaging
materials, gases, solvents, process aids, reagents and
labelling materials.
A. STARTING MATERIALS
B. PACKAGING MATERIALS
C. WASTE MATERIALS

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 vii. DOCUMENTATION
 Principle: Good documentation is an essential part of the
quality assurance system and, as such, should exist for all aspects
of GMP. Its aims are to define the specifications and procedures
for all materials and methods of manufacture and control; to
ensure that all personnel concerned with manufacture know what
to do and when to do it; to ensure that authorized persons have
all the information necessary to decide whether or not to release
a batch of a medicine for sale; to ensure the existence of
documented evidence, traceability, and to provide records and an
audit trail that will permit investigation. It ensures the
availability of the data needed for validation, review and
statistical analysis. The design and use of documents depend
upon the manufacturer. In some cases some or all of the
documents described below may be brought together, but they
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will usually be separate.
 DOCUMENTS REQUIRED:
 Labels
 Specification and testing procedures
 Specification for starting and packaging materials
 Specification for intermediate and bulk product
 Specification for finished product
 Master formulae
 Packaging instruction
 Batch processing records
 Batch packaging records
 Standard operating procedure and records

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 GMP IN PRODUCTION:
 Principle: Production operations must follow clearly defined
procedures in accordance with manufacturing and marketing
authorizations, with the objective of obtaining products of the
requisite quality.
 Prevention of cross-contamination and bacterial contamination
during production:
o When dry materials and products are used in production, special
precautions should be taken to prevent the generation and
dissemination of dust. Provision should be made for proper air control
o Measures to prevent cross-contamination and their effectiveness should
be checked periodically according to SOPs.
o Production areas where susceptible products are processed should
undergo periodic environmental monitoring (e.g. for microbiological
and particulate matter, where appropriate).
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  Processing operations
o Before any processing operation is started, steps should be taken
to ensure that the work area and equipment are clean and free
from any starting materials, products, product residues, labels or
documents not required for the current operation.
o Any necessary in-process controls and environmental controls
should be carried out and recorded.
o Containers for filling should be cleaned before filling. Attention
should be given to avoiding and removing any contaminants such
as glass fragments and metal particles.
o Any significant deviation from the expected yield should be
recorded and investigated.
o Checks should be carried out to ensure that pipelines and other
pieces of equipment used for the transportation of products from
one area to another are connected in the correct manner.
o Pipes used for conveying distilled or deionized water and, where
appropriate, other water pipes should be sanitized and stored
according to written procedures that detail the action limits for
microbiological contamination and the measures to be taken.
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  Packaging operations
o When the programme for packaging operations is being set up,
particular attention should be given to minimizing the risk of
cross-contamination, mix ups or substitutions. Different products
should not be packaged in close proximity unless there is
physical segregation or an alternative system that will provide
equal assurance.
o Before packaging operations are begun, steps should be taken to
ensure that the work area, packaging lines, printing machines and
other equipment are clean and free from any products, materials
or documents used previously and which are not required for the
current operation. The line clearance should be performed
according to an appropriate procedure and checklist, and
recorded.
o The name and batch number of the product being handled should
be displayed at each packaging station or line.

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 GMP IN QUALITY CONTROL
 The independence of QC from production is considered
fundamental
 QC responsibilities include:
a. establishing, validating and implementing all QC procedures;
b. evaluating, maintaining and storing reference standards
for substances;
c. ensuring the correct labelling of containers of materials
and products;
d. ensuring that the stability of the active pharmaceutical
ingredients and products is monitored;
e. participating in the investigation of complaints related to the
quality of the product;
f. participating in environmental monitoring;
g. participation in QRM programmes
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  Control of starting materials and intermediate, bulk and
finished products :
o All tests should follow the instructions given in the relevant
written test procedure for each material or product. The result
should be checked by the supervisor before the material or
product is released or rejected.
o Samples should be representative of the batches of material
from which they are taken in accordance with the approved
written procedure.
• Test Requirements:
1. Starting and packaging materials
2. In-process control
3. Finished products
4. Batch record review
5. Stability studies

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 THANK YOU

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