A PROJECT REPORT

Submitted by:

BHOBE VINAYAK VASUDEV (22)

CHIMULKAR BHAGWANT VINAYAK (25)
CHOUDHARI HARSHAL SURESH (27)
DESHMUKH HRISHIKESH ARVIND (29)
NAIK GAUTAM SUBHASH (32)
MANIBHUSHAN NIDHI (47)

In partial fulfilment of the course work

Course Name:

PRODUCTION AND OPERATIONS

MANAGEMENT

XAVIER INSTITUTE OF MANAGEMENT &

2
ENTREPRENEURSHIP
BANGALORE – 560 100

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 APRIL 2008

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 ACKNOWLEDGMENT

We are really thankful to Mr. J. Philip, President of Xavier

Institute of Management and Entrepreneurship, for
including such an enriching Production Management project
in our curriculum.

The faculty of Production & Operation Management, Mr.

George Eshaw was of immense help during the whole
tenure of the project and his experience really came in as
welcome assistance.

We are really thankful to Mr. Reddy, the Production Manager

at Medreich Sterilab Limited, Bangalore for taking trouble to
introduce us to the different departments of his
organization.

We were really benefited by the experience views of Mr. K.

Ramamurthy, the Supervisor in Quality Control Department
as he gave us the idea about the different aspects involved
in tablet manufacturing and packaging quality processes.
He introduced us to the FDA quality standards and ICH
guidelines that are being used at Medreich along with the
concepts like Pharmaceutical Quality System and Quality
Risk Management.

Mr. R. Krishnan, one of the supervisors in liquid

manufacturing and quality control department explained us
various quality standards used for liquid manufacturing.

We are also thankful to all the technical and office staff for
helping us to complete the project.

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 CONTENTS

Sr.
Particulars Page No.
No.

1 Introduction – Medreich Today 1

2 Medreich Products 2

3 Quality Control Department 3

4 Pharmaceutical Quality Tests 5

5 Non - compendial Standards 6

Pharmaceutical Quality System –

6 7
Q10

7 Management Responsibility 10

Continual Improvement of
8 11
Performance
Continual Improvement of
9 13
Pharmaceutical Quality System

10 Quality Risk Management 14

2 Risk Management Methods and

11 17
Tools

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 1. Medreich Today
Medreich is an integrated technology
driven healthcare company. The company has
grown rapidly over the last decade. In 2006, its
estimated revenue is US$ 90 Million spread
over diverse business profiles including own
marketing in various geographies, strategic
alliances with giants like GlaxoSmithKline,
Pfizer, Sanofi Aventis, Wyeth and Adcock
Ingram and Formulation Development activity.
Medreich's employee strength globally is
in excess of 1500. Medreich fully understand
the need to cultivate a broad range of
capabilities to stay ahead of competition.
Medreich's HR policies aim to identify and
take advantage of the synergies that arise from
team work within the organisation as well as
the alliances and partnerships they have
forged.
Medreich's intent to be successful and
enduring organisation is being fulfilled by way
of developing an organisational culture that
supports learning and high performance
employee base.
Medreich support high level of employee
participation, flatter reporting structures and
strong bonds between the organisation and its
2 people. Because Medreich believe that
employee commitment is vital.
Medreich fully appreciate that our goal is
to win the customers' preference and create a

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 sustainable competitive advantage but its
substance and detail must come from the
minds of its people who are closest to the
action and who understand their markets, their
resources, and their strengths and weaknesses.
Medreich is in the process of upgrading
its Formulation Development and Regulatory
Services to sustain and extend the reach in
many more areas of excellence and develop a
competitive edge.
This Centre of Excellence besides housing
Formulation Development, Regulatory
Compliance & Documentation and Technology
Transfer under one roof will be capable of going
from product concept and design, to pilot and
commercial batch manufacturing according to
highest international standards. When
combined with the six manufacturing sites
already in the group, Medreich has lot to offer.
Medreich's manufacturing facilities
located in Europe and India cover a wide range
of Solid Oral Dosage forms like Tablets,
Capsules, Liquid Suspensions and Syrups, Dry
Powder for Suspensions and Dry Powder for
Injections.
Medreich’s manufacturing facilities with
Tablets and Liquid manufacturing follow cGMP
practices and are FDA approved.

2.

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 Complete Range of Products

1. Penicillins : Fleming Range, Promox

Range, Reichamox Range, Reichlin
Range, Reichlox Range, Ryflox / Klocin
Range
2. Cephalosporins : Axacef, Roxicef,
Zafalex, Zoxim, Zidim, Zoxon, Zotax
3. Quinolones : Cyplox / Proxacin, Olox /
Surflox / Norzol
4. Cardiovascular & Diabetic : Corstat,
Guamet, Glyzyl, Amédin, Carédin, Lipril /
Liprazid, Mapril / Euril, Telol
5. Antihistamines : Histacet / Cezine /
Lotin
6. OTC Respiratory : Mucodil / Tussex
7. Antimalarials : Malareich, Malafin /
Malafloq / Loquin, Chlomal / Chloroject /
Quinoral / Quininject, Malar-ACT, Armact
8. Anti-Ulcerants : Cetidine / Omizec /
Ulticer
2 9. Anti-Fungals : Lucon, Fungral
10. Analgesics : Uncle Joe Range,
Dicofen / Dymol, Ibex, Ridake / Myolieve,
Brumed, Paraflam

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 11. Vitamin Suppliments : Medvite
Gold / Pélé, Foliron, Bioferon
12. Other Anti-Infectives :
Trimezole / Trimoprim, Biozole / Tizol,
Rycin / Ryped / Xyclin, Tetrin / Elisca /
Evril

3. Q.C. & Q.A.& ANALYTICAL

DEVELOPMENT DEPARTMENT

Introduction:-
The basis objective of QUALITY
CONTROL & QUALITY ASSURANCE department
is to ensure compliance of all raw material,
packing material ,in process product & finished
products with established.
It ensures that GMP is adhered to
build quality into products during
manufacturing process. The quality control
department at Medreich has implemented
following important concepts, as per ICH
guidelines and FDA:
- Pharmaceutical Quality Systems
- Quality Risk Management
Other activities includes:-
 To regulatory requirement,
whenever applicable.
 To provide analytical support to
formulation, bulk drug & other
department.
 To ensure quality of contract
manufactured products through
audits & Q.A. activities ,
whenever possible.
 To investigate quality complaints
&recommend preventive action,
whenever applicable.
The Analytical development
department renders the service mainly to
formulation dept. & bulk drug development.
2 The Dept. is involved in designing analytical
methodologies for the evaluation of products &
their intermediates that under development.
The department also provide support to quality

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 assurance dept. in trouble shooting as & when
required. It helps quality control department to
carryout routine stability studies.
The major responsibility of this
department to ensure that GMP are adhered to
build development procedures in final analysis
into products during development stages.
The Department also assure
regulatory requirement when ever applicable. It
provides analytical support to product
development department, Bulk drug & other
dept. It ensures quality of manufactured
products through audits, whenever required. It
investigates quality complaints & recommends
preventive action, whenever applicable. Its job
is monitoring the stability of drug as well as
drug products.
In – Process Quality Control

The control of the tableting process in

production is concerned with the following :
I. Weight of tablet – Single pan electric balance.
II. Crushing strength – Controls friability and
disintegration time.
III. Tablet thickness – Very thick tablet affect
packaging particularly into blisters.
IV. Disintegration time.
V. Friability
As a part of Current Good Manufacturing
Practice (cGMP), the production run is
monitored under control chart. At regular
interval (10 – 15minutes) the operator must
sample specified number of tablets, weigh
them individually, check thickness, crushing
strength and all the properties as mentioned
above. The process can be automated and
interfaced with printer. Such data promotes
process improvement.

Laboratory & Quality Control Equipment &

Tablet Section
 Leak Test Apparatus
2  Six Stage Dissolution Rate Test Apparatus
 Microprocessor Based Tablet
Disintegration Machine
 Microprocessor control Programmable
counter

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  Friabilator
 Tablet Hardness Tester (Automatic)
 Tablet hardness tester (Automatic)
 Tablet Friability Tester
 Melting Point Apparatus
 Precision Melting Point cum – Boiling
point apparatus
 Automatic Tablet Counting Machine
 Disintegration Tester
 Tablet Dissolution Tester
 Melting Point Apparatus
 Room Dehumidifier / Inspection Tables

List of Equipment:-
NAME
NO QUANTITY CAPACITY MAKE
1. HPLC with auto 4 _ TSP,Datalab,spe
sample ctraphysics
2. Gas chromotography 1 _ Datalab
3. Gas chromotography 1 _ Shimadzu
4. FTIR 1 _ Jasco
5. Dissolution app. 2 _ Labindia
,Electrolab
6. UV 1 _ Shimadzu
spectrophotometer
7. Polarimeter 1 _ Jasco
8. Karl Fischer app. 2 _ Veego Labindia ,
9. Electronic balance 4 100 gm Mettler
10. ph meter 2 _ Shimadzu,Elder
11. D.T. app. 3 2Head Labindia, Veego
12. Friability app. 2 2 Drum Veego
13. Viscometer 1 _ Brookfield
14. Atomic absorption 1 _ sklar

4. PHARMACEUTICAL QUALITY
2 SYSTEM

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 Official Standards as per I.P. / B.P. / U.S.P.

PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED

Content of active
ingredients
For all tablets Disintegration
Uniformity of content
Labelling
Disintegration test
Uncoated tablet
Uniformity of weight
Disintegration test
Effervescent tablet
Uniformity of weight
BRITISH Coated tablet Disintegration test
PHARMACOPOEIA Uniformity of weight
Gastro resistant tablet Disintegration test
Modified release tablet Uniformity of weight
Tablet for use in mouth Uniformity of weight
Disintegration test
Soluble tablet
Uniformity of weight
Disintegration test
Dispersible tablet Uniformity of dispersion
Uniformity of weight
Uniformity of container
content
Content of active
Uncoated tablet ingredient
Uniformity of weight
Uniformity of content
INDIAN Disintegration test
PHARMACOPOEIA Enteric coated tablet
Disintegration test
Uniformity of dispersion
Dispersible tablet
Disintegration
2 Soluble tablet Disintegration test
Disintegration/ Dissolution
Effervescent tablet
/ Dispersion test

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 Bulk density /Tapped
density of powder
Powder fineness
Loss on drying
Physical tests Disintegration test
UNITED STATES Tablet friability
applicable to tablet
PHARMACOPOEIA Dissolution test
formulation
Drug release testing
Uniformity of dosage form
Container permeation test
Labelling of inactive
ingredients

5. Non – compendial standards

Measurement of mechanical properties is not

covered pharmacopoeial monograph. There are
also a number of tests frequently applied to
tablets for which there are no pharmacopoeial
requirement but will form a part of a
manufacturer’s own product specification.

Hardness tests/ Crushing strength

The test measures crushing strength property
defined as the compressional force applied
diametrically to a tablet which just fractures it.
Among a large number of measuring devices,
the most favored ones are Monsanto tester,
Pfizer tester, and Strong cobb hardness tester.
All are manually used. So, strain rate depends
on the operator. Heberlein Schleuniger,
Erweka, Casburt hardness testers are motor
driven.

Friability
(Official in USP)
The tablet may well be subjected to a tumbling
motion. For example, Coating, packaging,
transport, which are not severe enough to
break the tablet, but may abrade the small
particle from tablet surface. To examine this,
tablets are subjected to a uniform tumbling
2 motion for specified time and weight loss is
measured. Roche friabilator is most frequently
used for this purpose.

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 Tests for coated tablets
I. Water vapor permeability
II. Film tensile strength
III. Coated tablet evaluations:
i)Adhesion test with tensile-strength tester:
Measures force required toe peel the film from
the tablet surface.
ii)Diametral crushing strength of coated tablet:
Tablet hardness testers are used. This test
gives information on the relative increase in
crushing strength provided by the film and the
contribution made by changes in the film
composition.
iii) Temperature and humidity may cause film
defects. Hence studies are to be carried out.
iv) Quantification of film surface roughness,
hardness, & colour uniformity. Visual inspection
or instruments are used. Resistance of coated
tablet on a white sheet of paper. Resisilient
films remain intact, & no colour is transferred
to the paper; very soft coating are readily
“erased” from the tablet surface to the paper.

6. PHARMACEUTICAL QUALITY SYSTEM

- - Q10

Quality should be built into the

product, and

testing alone cannot be relied on to

ensure product quality.
2
6.1 Introduction
A new ICH tripartite guideline describes a
model for an effective quality management
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 system for the pharmaceutical industry,
referred to as the Pharmaceutical Quality
System.
ICH Q10 describes one comprehensive
approach to an effective pharmaceutical
quality system that is based on ISO concepts,
includes applicable Good Manufacturing
Practice (GMP) regulations and complements
ICH Q8 “Pharmaceutical Development” and ICH
Q9 “Quality Risk Management”. ICH Q10 is a
model for a pharmaceutical quality system that
can be implemented throughout the different
stages of a product lifecycle. Much of the
content of ICH Q10 applicable to manufacturing
sites is currently specified by regional GMP
requirements. ICH Q10 is not intended to
create any new expectations beyond current
regulatory requirements. Consequently, the
content of ICH Q10 that is additional to current
GMP requirements is optional.
Throughout this guideline, the term
“pharmaceutical quality system” refers to the
ICH Q10 model.
ICH Q10 demonstrates industry and regulatory
authorities’ support of an effective
pharmaceutical quality system to enhance the
quality and availability of medicines around the
world in the interest of public health.
Implementation of ICH Q10 throughout the
product lifecycle should facilitate innovation
and continual improvement and strengthen the
link between pharmaceutical development and
manufacturing activities.
6.2 Scope
This guideline applies to pharmaceutical drug
substances and drug products, including
biotechnology and biological products,
throughout the product lifecycle.
The elements of ICH Q10 should be applied in a
manner that is appropriate and proportionate
to each of the product lifecycle stages,
recognizing the differences among, and the
different goals of each stage (described later in
Section 3).
2 For the purposes of this guideline, the product
lifecycle includes the following technical
activities for new and existing products:
 Pharmaceutical Development

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 o Drug substance development;
o Novel excipient development;
o Formulation development
(including container/closure
system);
o Delivery system development
(where relevant);
o Manufacturing process
development and scale-up;
o Analytical method development.
 Technology Transfer
o New product transfers from
Development to Manufacturing;
o Transfers within or between
manufacturing and testing sites for
marketed products.

 Manufacturing
o Procurement of materials;
o Provision of facilities, utilities and
equipment;
o Production (including packaging
and labelling);
o Quality control and assurance;
o Release;
o Storage;
o Distribution (excluding wholesaler
activities).
 Product discontinuation
o Retention of documentation;
o Sample retention;
o Continued product assessment and
reporting.
6.3 Relationship of ICH Q10 to Regional
GMP Requirements, ISO Standards
and ICH Q7
Regional Good Manufacturing Practice
requirements, the ICH Q7 Guideline and ISO
Quality Management System Guidelines form
the foundation for ICH Q10. To meet the
objectives described below, ICH Q10 augments
2 GMPs by describing specific quality system
elements and management responsibilities.
ICH Q10 thereby serves as a bridge between
the regional requirements, helping industry and

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 regulators achieve harmonisation of the
pharmaceutical quality system throughout the
lifecycle of a product.
6.4 Relationship of ICH Q10 to
Regulatory Approaches
Regulatory approaches for a specific product or
manufacturing facility should be
commensurate with the level of product and
process understanding, the results of quality
risk management, and the effectiveness of the
pharmaceutical quality system. When
implemented, the effectiveness of the
pharmaceutical quality system can normally be
confirmed during a regulatory inspection at the
manufacturing site. Potential opportunities to
enhance science and risk based regulatory
approaches are identified in Annex 1.
Regulatory processes will be determined by
region.
6.5 ICH Q10 Objectives
i) Achieve Product Realisation
To establish, implement and maintain a
set of processes that provides a product
with the quality attributes appropriate to
meet the needs of patients, health care
professionals, regulatory authorities
(including compliance with marketing
authorisations) and internal customers.
ii) Establish and Maintain a State of Control
To develop and use effective monitoring
and control systems for process
performance and product quality, thereby
providing assurance of continued
suitability and capability of processes.
Quality risk management can be useful in
establishing the monitoring and control
system.
iii) Facilitate Continual Improvement
To identify and implement appropriate
product quality improvements, process
improvements, variability reduction,
innovations, and pharmaceutical quality
system enhancements, thereby
2
increasing the ability to consistently fulfil
quality needs. Quality risk management
can be useful to identify and prioritise
areas for improvement.

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 6.6 Enablers
Knowledge management and quality risk
management are enablers of ICH Q10 that
facilitate a consistent scientific approach to
achieve the objectives described in 1.5 above.
These enablers should provide the means for
science- and risk–based decisions related to
product quality.
i) Knowledge management
Knowledge should be managed from
development through the commercial life
of the product up to and including
product discontinuation. Knowledge
management is a systematic approach to
acquiring, analyzing, storing and
disseminating information related to
products, processes and components.
Sources of knowledge include, but are
not limited to, prior knowledge (public
domain or internally documented),
pharmaceutical development studies,
technology transfer activities, process
validation studies over the product
lifecycle, manufacturing experience,
continual improvement and change
management activities.
ii) Quality risk management
Quality risk management can provide a
proactive approach to identifying and
controlling potential risks to quality
throughout the product lifecycle. ICH Q9
describes a model for quality risk
management approaches within a
pharmaceutical context.
6.7 Design and Content Considerations
i) The pharmaceutical quality system
should be well structured and clear to
facilitate common understanding and
consistent application.
ii) The elements of ICH Q10 should be
2 applied in a manner that is appropriate
and proportionate to each of the product
lifecycle stages, recognizing the
differences among, and the different
goals of each stage.
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 iii) The size and complexity of the
company’s activities should be taken into
consideration when developing a new
pharmaceutical quality system or
modifying an existing one. While some
aspects of the pharmaceutical quality
system can be company-wide and others
site-specific, the effectiveness of the
implementation of the pharmaceutical
quality system is normally demonstrated
at the site level.
iv) Outsourced (contracted) activities should
be within the scope of the
pharmaceutical quality system.
v) Management responsibilities, as
described in Section 2, should be
identified within the pharmaceutical
quality system.
vi) The pharmaceutical quality system
should include the following elements:
process performance and product quality
monitoring, corrective and preventive
action, change management and
management review, as described in
Section 3.
vii) Key performance indicators should be
identified and used to monitor the
effectiveness of processes within the
pharmaceutical quality system as
described in Section 4.
6.8 Quality Manual
A Quality Manual or equivalent documentation
approach should be established and should
contain the description of the pharmaceutical
quality system. The description should include:
i) The quality policy (further described in
Section 2).
ii) The scope of the pharmaceutical quality
system.
iii) Identification of the processes within the
pharmaceutical quality system, as well as
their sequences, linkages and
interdependencies. Process maps and
2 flow charts can be useful tools to
facilitate depicting these in a visual
manner.

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 iv) Management responsibilities within the
pharmaceutical quality system, as
described in Section 2 of this document.

7. MANAGEMENT RESPONSIBILITY
Leadership is essential to establish and
maintain a company-wide commitment to
quality and for the performance of the
pharmaceutical quality system.
7.1 Management Commitment
i) Senior management has the ultimate
responsibility to ensure an effective
pharmaceutical quality system is in
place, and that responsibilities and
authorities are defined, communicated
and implemented throughout the
company.
ii) Management should:
(1) Participate in the design,
implementation and monitoring of
the pharmaceutical quality system;
(2) Demonstrate strong and visible
support for the pharmaceutical
quality system and ensure its
implementation throughout their
organization;
(3) Ensure a timely and effective
communication and escalation
process exists to raise quality issues
to the appropriate levels of
management;
(4) Define and communicate individual
and collective roles, responsibilities
and authorities of all organizational
units related to the pharmaceutical
quality system, and ensure
interactions are defined and
understood. An independent quality
unit/structure with authority to fulfil
certain pharmaceutical quality
system responsibilities is required by
regional regulations;
(5) Conduct management reviews of
2
process performance and product
quality and of the pharmaceutical
quality system;
(6) Advocate continual improvement;

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 (7) Commit appropriate resources.
7.2 Quality Policy
i) Senior management should establish a
quality policy that describes the overall
intentions and direction of the company
related to quality.
ii) The quality policy should include an
expectation to comply with applicable
regulatory requirements and should
facilitate continual improvement of the
pharmaceutical quality system.
iii) The quality policy should be
communicated to and understood by
personnel at all levels in the company.
iv) The quality policy should be reviewed
periodically for continuing effectiveness.

7.3 Quality Planning

i) As part of quality planning, senior
management should ensure the quality
objectives needed to implement the
quality policy are defined and
communicated.
ii) Quality objectives should be supported
by all relevant levels of the company.
iii) Quality objectives should align with the
company’s strategic plans and be
consistent with the quality policy.
iv) Management should provide the
appropriate resources and training to
achieve the quality objectives.
v) Key performance indicators that measure
progress against quality objectives
should be established, monitored,
communicated regularly and acted upon
as appropriate.
7.4 Resource Management
i) Management should determine and
provide adequate and appropriate
resources (human, financial, materials,
2 facilities and equipment) to implement
and maintain the pharmaceutical quality
system and continually improve its
effectiveness.

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 ii) Management should ensure that
resources are appropriately applied to a
specific product, process or site.
7.5 Internal Communication
i) Management should ensure appropriate
communication processes are
established and implemented within the
organization.
ii) Communications processes should
ensure the flow of appropriate
information between all levels of the
company.
iii) Communication processes should ensure
the escalation of certain product quality
and pharmaceutical quality system
issues to appropriate levels of
management in a timely manner.
7.6 Management Review
Senior management should be responsible for
pharmaceutical quality system governance
through management review to ensure its
continuing suitability and effectiveness.
Management should assess the conclusions of
periodic reviews of process performance and
product quality and of the pharmaceutical
quality system.
7.7 Oversight of Outsourced Activities
A pharmaceutical company can outsource
activities at all stages of the product lifecycle.
The pharmaceutical quality system, including
the management responsibilities described in
this section, extends to the oversight and
review of outsourced activities. Normally under
a contract, the contract giver should be
responsible for assessing the suitability and
competence of the contract acceptor to carry
out the work required. Responsibilities for
quality-related activities of the contract giver
and contract acceptor should be specified in a
written agreement.

8. CONTINUAL IMPROVEMENT OF PROCESS

2 PERFORMANCE AND PRODUCT QUALITY
Regional GMP requirements and the ICH Q7
guideline form the foundation of ICH Q10. This
section describes the four specific

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 pharmaceutical quality system elements that
augment this foundation. to achieve the ICH
Q10 objectives. It does not restate all regional
GMP requirements. The elements described
below might be, in part, required under
regional GMP regulations; however, the intent
is to enhance these elements in order to
promote the lifecycle approach to product
quality. These four elements are:
 Process performance and product
quality monitoring system;
 Corrective action and preventive
action (CAPA) system;
 Change management system;
 Management review of process
performance and product quality.
These elements should be applied in a manner
that is appropriate and proportionate to each of
the product lifecycle stages, recognizing the
differences among, and the different goals of
each stage. Throughout the product lifecycle,
companies should evaluate opportunities for
innovative approaches to improve product
quality.
The goals of each product lifecycle stage are
described below, followed by examples of how
each pharmaceutical quality system element is
applied to that product lifecycle stage.
8.1 Lifecycle Stage Goals
i) Pharmaceutical Development
The goal of pharmaceutical development
activities is to design a product and its
manufacturing process to consistently
deliver the intended performance and
meet the needs of patients, healthcare
professionals, regulatory authorities and
internal customers. Approaches to
pharmaceutical development are
described in ICH Q8. The results of
exploratory and clinical development
studies, which are outside the scope of
this guidance, are inputs to
pharmaceutical development.
2 ii) Technology Transfer
The goal of technology transfer activities
is to transfer product and process
knowledge between development and

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 manufacturing, and within or between
manufacturing sites to achieve product
realisation. This knowledge forms the
basis for the manufacturing process,
control strategy, process validation
approach and ongoing continual
improvement.
iii) Manufacturing
The goals of manufacturing activities
include achieving product realisation,
establishing and maintaining a state of
control and facilitating continual
improvement. The pharmaceutical
quality system should assure that the
desired product quality is routinely met,
suitable process performance is
achieved, the set of controls are
appropriate, improvement opportunities
are identified, and the body of knowledge
is continually expanded.
iv) Product Discontinuation
The goal of product discontinuation
activities is to effectively manage the
terminal stage of the product lifecycle.
For product discontinuation, a pre-
defined approach should be used to
manage activities such as retention of
documentation and samples and
continued product assessment (e.g.,
complaint handling and stability) and
reporting in accordance with regulatory
requirements.
8.2 Pharmaceutical Quality System
Elements
i) Process Performance and Product Quality
Monitoring System
Pharmaceutical companies should plan
and execute a system for the monitoring
of process performance and product
quality to ensure a state of control is
maintained. An effective monitoring
system provides assurance of the
continued capability of processes and
2 controls to meet product quality and to
identify areas for continual improvement.
The process performance and product
quality monitoring system should:

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 (1) Use quality risk management to
establish the control strategy that
can include parameters and
attributes related to drug substance
and drug product materials and
components, facility and equipment
operating conditions, in-process
controls, finished product
specifications, and the associated
methods and frequency of
monitoring and control. The control
strategy should facilitate timely
feedback / feed forward and
appropriate corrective action and
preventive action;
(2) Provide the tools for
measurement and analysis of
parameters and attributes identified
in the control strategy, e.g., data
management and statistical tools;
(3) Analyze parameters and
attributes identified in the control
strategy to verify continued
operation within a state of control;
(4) Identify sources of variation
affecting process performance and
product quality for potential
continual improvement activities to
reduce or control variation;
(5) Include feedback on product
quality from both internal and
external sources, e.g., complaints,
product rejections, non-
conformances, recalls, deviations,
audits and regulatory inspections
and findings;
(6) Provide knowledge to enhance
process understanding, enrich the
design space (where established),
and enable innovative approaches to
process validation.

9. CONTINUAL IMPROVEMENT OF THE

PHARMACEUTICAL QUALITY SYSTEM
2
This section describes activities that should be
conducted to manage and continually improve
the pharmaceutical quality system.

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 9.1 Management Review of the
Pharmaceutical Quality System
Management should have a formal process for
reviewing the pharmaceutical quality system
on a periodic basis. The review should include:
i) Measurement of achievement of
pharmaceutical quality system
objectives;
ii) Assessment of Key Performance
Indicators that can be used to monitor
the effectiveness of processes within the
pharmaceutical quality system, such as:
(1) Complaint, deviation, CAPA and
change management processes;
(2) Self-assessment processes
including audits;
(3) External assessments such as
regulatory inspections and
findings and customer audits.
9.2 Monitoring of Internal and External
Factors Impacting the
Pharmaceutical Quality System
Factors monitored by management can include:
i) Emerging regulations, guidance and
quality issues that can impact the
Pharmaceutical Quality System;
ii) Innovations that might enhance the
pharmaceutical quality system;
iii) Changes in business strategies and
objectives.
9.3 Outcomes of Management Review
and Monitoring
The outcome of management review of the
pharmaceutical quality system and monitoring
of internal and external factors can include:
i) Improvements to the pharmaceutical
quality system and related processes;
ii) Allocation or reallocation of resources
and/or personnel training; Revisions to
quality policy and quality objectives, as
appropriate; Timely and effective
2 communication of the results of the
management review and actions,
including escalation of appropriate issues
to senior management.

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 10. QUALITY RISK MANAGEMENT

1. SCOPE
This guideline provides principles and
examples of tools for quality risk management
that can be applied to different aspects of
pharmaceutical quality. These aspects include
development, manufacturing, distribution, and
the inspection and submission/review
processes throughout the lifecycle of drug
substances, drug (medicinal) products,
biological and biotechnological products
(including the use of raw materials, solvents,
excipients, packaging and labelling materials in
drug (medicinal) products, biological and
biotechnological products).
2. PRINCIPLES OF QUALITY RISK
MANAGEMENT
Two primary principles of quality risk
management are:
 The evaluation of the risk to quality
should be based on scientific knowledge
and ultimately link to the protection of
the patient; and
 The level of effort, formality and
documentation of the quality risk
management process should be
commensurate with the level of risk.
3. GENERAL QUALITY RISK
MANAGEMENT PROCESS
Quality risk management is a systematic
process for the assessment, control,
communication and review of risks to the
quality of the drug (medicinal) product across
the product lifecycle. A model for quality risk
management is outlined in the diagram (Figure
1). Other models could be used. The emphasis
on each component of the framework might
differ from case to case but a robust process
will incorporate consideration of all the
elements at a level of detail that is
2 commensurate with the specific risk.
Figure 1: Overview of a typical quality risk
management process

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 Initiate
Quality Risk Management Process

Risk Assessment

Risk Identification

Risk Analysis

Risk Evaluation
unacceptable

Risk Management tools

Risk Communication
Risk Control

Risk Reduction

Risk Acceptance

Output / Result of the

Quality Risk Management Process

Risk Review

Review Events

Decision nodes are not shown in the diagram

above because decisions can occur at any
point in the process. These decisions might be
to return to the previous step and seek further
information, to adjust the risk models or even
to terminate the risk management process
based upon information that supports such a
decision. Note: “unacceptable” in the flowchart
does not only refer to statutory, legislative or
regulatory requirements, but also to the need
to revisit the risk assessment process.
3.2 Initiating a Quality Risk
Management Process
Quality risk management should include
systematic processes designed to coordinate,
facilitate and improve science-based decision
making with respect to risk. Possible steps used
to initiate and plan a quality risk management
process might include the following:
 Define the problem and/or risk question,
including pertinent assumptions
identifying the potential for risk;
 Assemble background information and/
2
or data on the potential hazard, harm or
human health impact relevant to the risk
assessment;

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  Identify a leader and necessary
resources;
 Specify a timeline, deliverables and
appropriate level of decision making for
the risk management process.

3.3 Risk Assessment

Risk assessment consists of the identification
of hazards and the analysis and evaluation of
risks associated with exposure to those hazards
(as defined below). Quality risk assessments
begin with a well-defined problem description
or risk question. When the risk in question is
well defined, an appropriate risk management
tool (see examples in section 5) and the types
of information needed to address the
risk question will be more readily identifiable.
As an aid to clearly defining the risk(s) for risk
assessment purposes, three fundamental
questions are often helpful:
1. What might go wrong?
2. What is the likelihood (probability) it will
go wrong?
3. What are the consequences (severity)?

Risk identification is a systematic use of

information to identify hazards referring to the
risk question or problem description.
Information can include historical data,
theoretical analysis, informed opinions, and the
concerns of stakeholders. Risk identification
addresses the “What might go wrong?”
question, including identifying the possible
consequences. This provides the basis for
further steps in the quality risk management
process.
Risk analysis is the estimation of the risk
associated with the identified hazards. It is the
qualitative or quantitative process of linking
the likelihood of occurrence and severity of
2 harms. In some risk management tools, the
ability to detect the harm (detectability) also
factors in the estimation of risk.

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 Risk evaluation compares the identified and
analyzed risk against given risk criteria. Risk
evaluations consider the strength of evidence
for all three of the fundamental questions.
In doing an effective risk assessment, the
robustness of the data set is important because
it determines the quality of the output.
Revealing assumptions and reasonable sources
of uncertainty will enhance confidence in this
output and/or help identify its limitations.
Uncertainty is due to combination of
incomplete knowledge about a process and its
expected or unexpected variability. Typical
sources of uncertainty include gaps in
knowledge gaps in pharmaceutical science and
process understanding, sources of harm (e.g.,
failure modes of a process, sources of
variability), and probability of detection of
problems.
Example of Use of a Risk Assessment Tool
For example, a cross-functional team of experts
could work together to develop an Ishikawa
(fishbone) diagram that identifies all potential
variables which can have an impact on the
desired quality attribute. The team could then
rank the variables based on probability,
severity, and detectability using failure mode
effect analysis (FMEA) or similar tools based on
prior knowledge and initial experimental data.
Design of experiments or other experimental
approaches could then be used to evaluate the
impact of the higher ranked variables, to gain
greater understanding of the process, and to
develop a proper control strategy.

Ishikawa Diagram

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 Drying Analytical

Temp

RH

Air Flow Sampling

Shock Cycle Method

Water
Tablet
Drug
Content
Precompressing Water Substance
Temp/RH Main Compressing Binder Age
P.S.
Operator Feeder Speed Temp Process Conditions
LOD
Training Press Speed Spray Rate
Diluents
Punch Penetration
Depth Spray Pattern

Tooling P.S.
Plant Feed P.S.
Scrape Down
Factors Frame LOD
Chopper Speed Other
Compressing
Mixer Speed Lubricant
Disintegrant
Endpoint Raw
Binder Materials
Power
Granulation
Time

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 11. Risk Management Methods and
Tools
The purpose of this annex is to provide a
general overview of and references for some of
the primary tools that might be used in quality
risk management by industry and regulators.
The references are included as an aid to gain
more knowledge and detail about the particular
tool. This is not an exhaustive list. It is
important to note that no one tool or set of
tools is applicable to every situation in which a
quality risk management procedure is used.
1. Basic Risk Management Facilitation
Methods
Some of the simple techniques that are
commonly used to structure risk management
by organizing data and facilitating decision-
making are:
 Flowcharts;
 Check Sheets;
 Process Mapping;
 Cause and Effect Diagrams (also called
an Ishikawa diagram or fish bone
diagram).
2. Failure Mode Effects Analysis (FMEA)
FMEA (see IEC 60812) provides for an
evaluation of potential failure modes for
processes and their likely effect on outcomes
and/or product performance. Once failure
modes are established, risk reduction can be
used to eliminate, contain, reduce or control
the potential failures. FMEA relies on product
and process understanding. FMEA methodically
breaks down the analysis of complex processes
2

into manageable steps. It is a powerful tool for

summarizing the important modes of failure,

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 factors causing these failures and the likely
effects of these failures.
Potential Areas of Use(s)
FMEA can be used to prioritize risks and
monitor the effectiveness of risk control
activities.
FMEA can be applied to equipment and
facilities and might be used to analyze a
manufacturing operation and its effect on
product or process. It identifies
elements/operations within the system that
render it vulnerable. The output/ results of
FMEA can be used as a basis for design or
further analysis or to guide resource
deployment.
3. Failure Mode, Effects and Criticality
Analysis (FMECA)
FMEA might be extended to incorporate an
investigation of the degree of severity of the
consequences, their respective probabilities of
occurrence, and their detectability, thereby
becoming a Failure Mode Effect and Criticality
Analysis (FMECA; see IEC 60812). In order for
such an analysis to be performed, the product
or process specifications should be established.
FMECA can identify places where additional
preventive actions might be appropriate to
minimize risks.
Potential Areas of Use(s)
FMECA application in the pharmaceutical
industry should mostly be utilized for failures
and risks associated with manufacturing
processes; however, it is not limited to this
application. The output of an FMECA is a
relative risk “score” for each failure mode,
which is used to rank the modes on a relative
risk basis.

4. Fault Tree Analysis (FTA)

The FTA tool (see IEC 61025) is an approach
that assumes failure of the functionality of a
2 product or process. This tool evaluates system
(or sub-system) failures one at a time but can
combine multiple causes of failure by
identifying causal chains. The results are

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 represented pictorially in the form of a tree of
fault modes. At each level in the tree,
combinations of fault modes are described with
logical operators (AND, OR, etc.). FTA relies on
the experts’ process understanding to identify
causal factors.
Potential Areas of Use(s)
FTA can be used to establish the pathway to
the root cause of the failure. FTA can be used
to investigate complaints or deviations in order
to fully understand their root cause and to
ensure that intended improvements will fully
resolve the issue and not lead to other issues
(i.e. solve one problem yet cause a different
problem). Fault Tree Analysis is an effective tool
for evaluating how multiple factors affect a
given issue. The output of an FTA includes a
visual representation of failure modes. It is
useful both for risk assessment and in
developing monitoring programs.
5. Hazard Analysis and Critical Control
Points (HACCP)
HACCP is a systematic, proactive, and
preventive tool for assuring product quality,
reliability, and safety (see WHO Technical
Report Series No 908, 2003 Annex 7). It is a
structured approach that applies technical and
scientific principles to analyze, evaluate,
prevent, and control the risk or adverse
consequence(s) of hazard(s) due to the design,
development, production, and use of products.
HACCP consists of the following seven steps:
(1)conduct a hazard analysis and identify
preventive measures for each step of the
process;
(2)determine the critical control points;
(3)establish critical limits;
(4)establish a system to monitor the critical
control points;
(5)establish the corrective action to be
taken when monitoring indicates that the
2 critical control points are not in a state of
control;
(6)establish system to verify that the HACCP
system is working effectively;

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 (7)establish a record-keeping system.
Potential Areas of Use(s)
HACCP might be used to identify and manage
risks associated with physical, chemical and
biological hazards (including microbiological
contamination). HACCP is most useful when
product and process understanding is
sufficiently comprehensive to support
identification of critical control points. The
output of a HACCP analysis is risk management
information that facilitates monitoring of
critical points not only in the manufacturing
process but also in other life cycle phases.
6. Hazard Operability Analysis (HAZOP)
HAZOP (see IEC 61882) is based on a theory
that assumes that risk events are caused by
deviations from the design or operating
intentions. It is a systematic brainstorming
technique for identifying hazards using so-
called “guide-words”. “Guide-words” (e.g., No,
More, Other Than, Part of, etc.) are applied to
relevant parameters (e.g., contamination,
temperature) to help identify potential
deviations from normal use or design
intentions. It often uses a team of people with
expertise covering the design of the process or
product and its application.
Potential Areas of Use(s)
HAZOP can be applied to manufacturing
processes, including outsourced production and
formulation as well as the upstream suppliers,
equipment and facilities for drug substances
and drug (medicinal) products. It has also been
used primarily in the pharmaceutical industry
for evaluating process safety hazards. As is the
case with HACCP, the output of a HAZOP
analysis is a list of critical operations for risk
management. This facilitates regular
monitoring of critical points in the
manufacturing process.
7. Preliminary Hazard Analysis (PHA)
PHA is a tool of analysis based on applying
2 prior experience or knowledge of a hazard or
failure to identify future hazards, hazardous
situations and events that might cause harm,
as well as to estimate their probability of

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 occurrence for a given activity, facility, product
or system. The tool consists of: 1) the
identification of the possibilities that the risk
event happens, 2) the qualitative evaluation of
the extent of possible injury or damage to
health that could result and 3) a relative
ranking of the hazard using a combination of
severity and likelihood of occurrence, and 4)
the identification of possible remedial
measures.
Potential Areas of Use(s)
PHA might be useful when analyzing existing
systems or prioritizing hazards where
circumstances prevent a more extensive
technique from being used. It can be used for
product, process and facility design as well as
to evaluate the types of hazards for the general
product type, then the product class, and
finally the specific product. PHA is most
commonly used early in the development of a
project when there is little information on
design details or operating procedures; thus, it
will often be a precursor to further studies.
8. Risk Ranking and Filtering
Risk ranking and filtering is a tool for
comparing and ranking risks. Risk ranking of
complex systems typically requires evaluation
of multiple diverse quantitative and qualitative
factors for each risk. The tool involves breaking
down a basic risk question into as many
components as needed to capture factors
involved in the risk. These factors are
combined into a single relative risk score that
can then be used for ranking risks. “Filters,” in
the form of weighting factors or cut-offs for risk
scores, can be used to scale or fit the risk
ranking to management or policy objectives.
Potential Areas of Use(s)
Risk ranking and filtering can be used to
prioritize manufacturing sites for
inspection/audit by regulators or industry. Risk
ranking methods are particularly helpful in
situations in which the portfolio of risks and the
2
underlying consequences to be managed are
diverse and difficult to compare using a single
tool. Risk ranking is useful when management
needs to evaluate both quantitatively-assessed

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 and qualitatively-assessed risks within the
same organizational framework.
9. Supporting Statistical Tools
Statistical tools can support and facilitate
quality risk management. They can enable
effective data assessment, aid in determining
the significance of the data set(s), and
facilitate more reliable decision making. A
listing of some of the principal statistical tools
commonly used in the pharmaceutical industry
is provided:
 Control Charts, for example:
- Acceptance Control Charts (see ISO
7966);
- Control Charts with Arithmetic
Average and Warning Limits (see ISO
7873);
- Cumulative Sum Charts (see ISO
7871);
- Shewhart Control Charts (see ISO
8258);
- Weighted Moving Average.
 Design of Experiments (DOE);
 Histograms;
 Pareto Charts;
 Process Capability Analysis.

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