PIC/S GMP MODULE 1

Pharmaceutical Quality System(PQS)

Outsources Activities
Self-Inspection
Prepared by: Quality Assurance (Compliance)
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Pharmaceutical Quality System

<PIC/S Chapter 1>

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 What is a Pharmaceutical Quality
System?
Definition:
A Pharmaceutical Quality System (PQS) is a systematic approach to ensure that pharmaceutical
products consistently meet quality standards throughout their lifecycle, from development to
manufacturing, distribution, and beyond.

PQS aims to ensure compliance with regulatory requirements, maintain product quality, and
continually improve processes.
 OBJECTIVES
The holder of a Manufacturing Authorization must ensure:

Medicinal products are fit for intended use

Compliance with Marketing Authorization or Clinical Trial Authorization

Patients are not at risk due to inadequate safety, quality, or efficacy

PQS
 Responsibilities and Commitment
 Quality objective responsibility: Senior management

 Participation and commitment from:

 Staff across departments PQS

 Suppliers
Others QA PD
QC LW
 Distributors
 Key Components of Pharmaceutical
Quality System
 Comprehensively designed and implemented

 Incorporates Good Manufacturing Practice (GMP) and Quality Risk Management

(QRM)
 Adequately resourced with competent personnel, suitable premises, equipment, and
facilities
 Key Topic of PQS
Content 1:

Pharmaceutical Quality System

(Quality Management)

Note: Term “Quality Assurance” was replaced with Pharmaceutical Quality System to align with ICH Q10
terminology. In PIC/S GMP PE009-17, the term: Quality Assurance, Quality Management and Pharmaceutical
Quality System are interchangeable.
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 Quality Management
Basic Concepts of Quality Management

1. Quality Management is wide-ranging of concept, which covers all matters,

which individually or collectively influence the quality of a product.
2. It is the sum total of the organized arrangements made with the objective
of ensuring that medicinal products are of the quality required for their
intended use.
3. Quality Management therefore incorporates Good Manufacturing Practice.
 Quality Management
Pharmaceutical Quality System should ensure:

DEVELOPMENT MANUFACTURING DEVIATION & CHANGE

• Production and control operations • Continual improvement is facilitated
• Product realization is are clearly specified & GMP through the implementation of quality
achieved by designing, adopted improvements appropriate to the
planning, maintaining and current level of process and product
continuously improve a • Arrangements are made for the
knowledge
system that allows consistent manufacture, supply and use of
delivery of products with the correct starting and packaging • Arrangements are in place for the
appropriate quality attributes. materials. prospective evaluation of planned
• A state of control is established changes and their approval prior to
• Product & process implementation taking into account
knowledge is managed and maintained by developing and
regulatory notification and approval
throughout all lifecycle stages using effective monitoring and
where required
control systems for process
• Medicinal products are performance and product quality • After implementation of any change, an
designed and developed with evaluation is undertaken to confirm the
application of Good • All necessary controls on
quality objectives were achieved and
Manufacturing Practice intermediate products and any
that there was no unintended
other in-process controls and
deleterious impact on product quality
validations are carried out
• An appropriate level of root cause
analysis should be applied during the
investigation of deviations
 Quality Management
Pharmaceutical Quality System should ensure:

BATCH RELEASE SUPPLY CHAIN & OUTSOURCED MANAGEMENT

ACTIVITIES RESPONSIBILITY
• Each batch is approved by
• Selection, monitoring of suppliers • Responsible to ensure an
Authorized Person prior
and for verifying that each delivery effective of PQS in place,
release.
is from the approved supply chain. adequately resourced
• Should take into account • Roles, responsibilities &
• Processes are in place to assure
the results of product & authorities are defined,
the management of outsourced
processes monitoring, communicated and
activities
investigation of deviations, implemented
& with a view to taking • Storage, distribution & handling of
preventive action to avoid medicinal products to ensure • Periodic Management Review
potential deviations quality is maintained throughout is required with involvement of
occurring in the future. their shelf life. senior management to identify
opportunity for improvement
SELF-INSPECTION/ AUDIT • Quality Manual should be
• Process to regularly evaluate the established.
effectiveness and applicability of
the PQS.
 Key topic of PQS
Content 2:

Requirements of GMP

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 GMP
Basic of Concepts of GMP

Good Manufacturing Practice (GMP) is part of Quality

Management which ensures products are consistently
produced and controlled to the quality standards
appropriate to their intended use and as required by the
Marketing Authorization, or product specification.

PRODUCTION

QUALITY CONTROL
 GMP
Basic Requirements of GMP

Clearly defined manufacturing Instructions and procedures

steps & systematically reviewed are written in clear,
unambiguous, directive form
Validation of critical steps in
manufacturing and any
significant changes
Operators trained to carry out
All necessary facilities for procedures correctly
GMP are provided (trained
personnel, adequate premise
& space, equipment & service, Records during manufacturing
correct material, container & to demonstrate steps required
label, approved procedures & were taken, and quantity and
instructions, suitable quality of product is as
transport and storage) expected
 GMP
Basic Requirements of GMP

Significant deviations are

fully recorded, investigated
and with appropriate CAPA System is available to recall
implemented any batch of product, from
sale or supply

Complete history of a batch,

including distribution,
should be retained & Product complaints are
accessible examined, investigated, and
appropriate measures are
taken to prevent
reoccurrence
Distribution of products
minimize any risk to their
quality, and takes into
account good distribution
practice
 Key topic of PQS
Content 3:

Requirements of Quality Control

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 Quality Control
Basic of Concepts of QC

Quality Control is that part of GMP which is concerned with

sampling, specifications and testing of materials (starting &
packaging materials) & product (intermediate and finished
product), and with the organization, documentation and
release procedures which ensure that the necessary and
relevant tests are 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.
 Quality Control
Basic Requirements of QC
Adequate facilities, trained personnel and The finished products contain active
approved procedures are available for ingredients complying with the
sampling & testing of starting material, specification, are of purity required, and
packaging material, Intermediate & are enclosed within their proper
finished products, & environment containers and correctly labeled
monitoring
Records are made of the results of
inspection are assessed against
Samples of starting & packaging materials, specification. Product assessment
intermediate, bulk & finished products are includes a review and evaluation of
taken by approved personnel and methods relevant production documentation and
an assessment of deviations from
specified procedures
Test methods are validated
No batch is released prior certification by
Records are made which demonstrate that an Authorized Person
all the required sampling, inspecting and
testing procedures were actually carried Sufficient reference samples of starting
out. Any deviations are fully recorded and materials and products are retained in
investigated final pack.
 Key topic of PQS
Content 4:

Product Quality Review

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 Product Quality
Review
Objective

To verify the consistency of the existing manufacturing

process, the appropriateness of current specifications for both
starting materials and finished product, to highlight any
trends and to identify product and process improvements.

Conducted & documented annually

Taking account previous reviews

 Product Quality
Review

Starting & packaging materials

Contractual agreements Critical in-process controls and
(Outsourced activities) finished product results

Qualification status of relevant Batches that fail to meet

equipment and utilities established specifications and
their investigation
Post-marketing
commitments for new & Information Deviations/non-
variations of Marketing reviewed conformances,
Authorizations. investigations, CAPA

Adequacy of previous product Changes to process

process or equipment corrective or analytical methods
actions
Marketing Authorization
Quality-related returns, complaints, variations submitted,
recalls and their investigations granted or refused
Stability monitoring program and
any adverse trends
 Assessment shall be made whether CAPA or revalidation required
 Quality reviews may be grouped by product type
 Technical agreement shall be in place to define responsibilities to produce
PQR if the manufacturer is not MAH
 Authorised person and MAH responsible to ensure PQR is performed in
timely manner and accurate
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Key topic of PQS

Content 5:

Quality Risk Management

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 Quality Risk
Management

Objective

Through the use of a systematic process, to allow for the

assessment, control, communication and review of
risks to the quality of the medicinal product.

Principle of Quality Risk Management is based on

scientific knowledge, experience with the process and
ultimately links to the protection of patient.
Level of effort, formality and documentation of QRM
process is commensurate with the level of risk.
Quality Risk
Management
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Outsourced Activities
<PIC/S Chapter 7>

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 Any activity covered by the GMP Guide that is outsourced should be appropriately
defined, agreed and controlled in order to avoid misunderstandings which could result in
a product or operation of unsatisfactory quality.

 There must be a written contract between the Contract Giver and the Contract
Acceptor which clearly establishes the roles and responsibilities of each party.

 Concerns on responsibilities of manufacturers towards Competent Regulatory

Authorities with respect to granting of manufacturing and marketing authorizations.
 General
 A written contract should be established that covers:

 Activities that outsourced

 Related products or operation
 Any technical arrangements made in connection with it

 Example: Laboratory testing for Ethylene Glycol (EG) and Diethylene Glycol (DEG) for Axcel Paracetamol 120mg Syrup
(Cherry)

Related product

Activity that outsourced

 Outsourced Activities

Contract Giver (CG) Contract Acceptor Contract

• Controlling & reviewing any
(CA)
• Specifies responsibilities and
outsourced activity communication process related
EXAMPLE
• Ensure all materials, to the outsourced activities.
• Responsible to ensure processes
are in place to assure the controls Contract manufacturing,
product and knowledge Testing
• Technical aspects drawn up by
of outsourced activities. Calibration services,
delivered Maintenance
to him/her are competent person related to the
• Responsible to assess the legality,
& Validation
suitable services associated
for its intended outsourced activities.
purpose.
with facilities, equipment &
suitability and competence of CA • Described clearly
• Shouldutilities
not subcontract to
• To ensure all products/ materials responsibilities of each party in
third party or make
delivered by the CA have been conducting each step in
unauthorized changes
processed in accordance with GMP outsourced activities.
without CG evaluation
and the Marketing Authorization . • All related records for
and approval
• Should monitor and review the outsources activities shall be
• May subject to inspection
performance of CA kept or available to CG.
by competent authority
• Responsible review & assess • Should permit CG to audit
related record and results outsourced activities performed
by CA or subcontractor.
 3

Self Inspection
< PIC/S Chapter 9>

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 Self Inspection
Objective
To monitor the implementation and compliance with Good
Manufacturing Practice principles and to propose necessary
corrective measures.

Verify the conformity with the principle of Quality Assurance

Personnel matters, premises, equipment, documentation,
production, quality control, distribution of the medicinal
products, arrangements for dealing with complaints and
recalls, and self inspection.
 Premise & Quality
Personnel Equipment Control

SCOPE OF INSPECTION Self-Inspection

Product
Distribution

Complaint &
Documentation
Recall
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CASE STUDY
of Non-conformities

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 GMP Audit Findings
• First case study, 2 samples.

• The procedure for deviations only made reference to deviations

based on manufacturing such as production activities, laboratory
and equipment which would have an impact on a batch or product.
It was therefore unclear how other deviations or incidents from
standard procedures such as utilities, and processes that were not
directly impacting on manufacturing processes would be handled.
 There was inadequate implementation of the CAPA procedure as
well as its monitoring with some CAPAs not being raised or
implemented despite a request for CAPA. It was also noted there
was a repeat deviation but in the deviation it was indicated that
CAPA was not required and there was no evidence that it was even
considered in the investigation of the deviation.

PHARMACEUTICAL QUALITY SYSTEM

 GMP Audit Findings
• Second case study, 4 samples

• The company does not carry out any quality and safety testing to
the batch manufactured products.
• Testing validation for raw material and preservative that has not
been carried out fully.
• Total Aerobic Microbial Count (TAMC) testing validation is not
complied to the British Pharmacopeia.
• There are weaknesses in finished goods testing procedure such as
Salmonella test procedure which does not comply to the
specification and requirement of British Pharmacopeia.

QUALITY CONTROL
 GMP Audit Findings
• Third case study, 4 samples.

• Manufacturing of registered products are carried out using

equipment and utilities that have not been fully qualified and
manufacturing process that are not validated.
• Company is found to have used split-air conditioning system in
manufacturing area.
• The design and cleanliness of HVAC has made the maintenance
activities ineffective.
• Handling and issuance of “punches and dies” of the company is
not satisfactory.

FACILITY & EQUIPMENT

 GMP Audit Findings
• Fourth case study, 3 samples.

• The procedure for PQR did not detail the need to conduct PQR for all
products manufactured but indicated that it was based on risk
assessment. It was however unclear as to how the risk assessment was
implemented.
• Critical in-process controls and equipment and utilities qualification
status are not considered; all evaluated result is placed into table form
without further discussion regarding the trending of achievement,
changes, investigation or corrective action which have been carried
out.
• Review of equipment qualification is not thorough. E.g. The re-
qualification of equipment that has been scheduled for 2015 was not
carried out according to the plan without any justification; equipment
qualification was not reviewed accordingly.

PRODUCT QUALITY REVIEW

 QUIZ

 Can you list out the areas which

Pharmaceutical Quality System
(PQS) should cover?

 Can you list out 3 basic requirements

of GMP?
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CONCLUSION

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 CONCLUSION

A robust and correctly implemented Pharmaceutical

Quality System (PQS) which incorporates Good
Manufacturing Practice (GMP) and Quality Risk
Management (QRM) is required to assure quality
objectives are met, of which should be fully documented
and its effectiveness monitored.
 REFERENCES

1. PIC/S GUIDE TO GMP FOR MEDICINAL PRODUCTS PART 1 (PE 009-17,

25 August 2023)
2. Analysis of Findings from GMP Inspectors of Pharmaceutical Facilities for
Year 2016-2017 (17 October 2018).
3. MCAZ GMP Inspection Report (29 August 2015)