Quality Assurance and Quality Management M01 (BP 606T) D.Pharmacy 3rd Year 2023 (2022-2023) Previous Year's Question Papers/Notes Download - HK Technical PGIMS

Quality Assurance and Quality Management M01 (BP 606T)
Subject Name: Quality Assurance Module -1
Subject Code: BP 606T
 Understand the cGMP aspects in a pharmaceutical industry.
 Understand the responsibilities of QA & QC departments.
1) Students learnt about the quality assurance and quality control parameters which affects academics
as well as pharmaceutical industry.
2) Students learnt ICH guidelines which governs pharmaceutical quality management and process of
harmonization brief overview of QSEM
3) Students learnt about ISO guidelines, NABL accreditation and knowledge how to implement design
expert software to optimize the formulations.
Objectives of the course
Learning outcomes

1. Quality Assurance and Quality Management Concepts-Definition and concept of Quality control,
Quality assurance and GMP.
2. Total Quality Management (TQM)-Definition, elements, and philosophies.
3. ICH Guidelines- Purpose, participants, process of harmonization, Brief overview of QSEM, with
special emphasis on Q-series guidelines, ICH stability testing guidelines.
4. Quality By Design (QbD)-Definition, overview, elements of QbD program, tools.
5. ISO 9000 & ISO14000-Overview, Benefits, Elements, steps for registration.
6. NABL Accreditation-Principles and procedures.

Structure of Module -1 BP 606T Learning Material
Quality Assurance
According to WHO, quality assurance is a wide- ranging concept covering all
matters that individually or collectively influence the quality of a product. With
regard to pharmaceuticals, quality assurance can be divided into major areas:
development, quality control, production, distribution, and inspections.
ISO 9000 defines as "part of quality management focused on providing
confidence that quality requirements will be fulfilled"
 Quality Control
ISO 9000 defines quality control as "A part of quality management focused on
fulfilling quality requirements". It is that part of GMP concerned with sampling,
specification & testing, documentation & release procedures which ensure that the
necessary & relevant tests are performed & the product is released for use only
after ascertaining it’s quality.
Difference between QA and QC
Definition
QA is a set of activities for
ensuring quality in the processes
by which products are
developed.
QA is a managerial tool
QC is a set of activities for
ensuring quality in products.
The activities focus on
identifying defects in the actual
products produced.
QC is a corrective tool
What are its goals and on what
does it focus?
QA aims to prevent defects
with a focus on the process
used to make the product. It is
a proactive quality process.
The goal of QA is to improve
development and test processes
so that defects do not arise
when the product is being
developed.
QC aims to identify (and
correct) defects in the finished
product.
Quality control, therefore, is a
reactive process.
The goal of QC is to identify
defects after a product is
developed and before it's
released.
What and how does it work?
Prevention of quality problems
through planned and systematic
activities including
documentation.
Establish a good quality
management system and the
assessment of its adequacy.
Periodic conformance audits of
the operations of the system.
The activities or techniques
used to achieve and maintain
the product quality, process
and service.
Finding & eliminating sources
of quality problems through
tools & equipment so that
customer's requirements are
continually met.
Whose responsibility is it and
what is the example of it?
Everyone on the team involved
in developing the product is
responsible for quality
assurance.
Verification is an
example of QA.
Quality control is usually the
responsibility of a specific
team that tests the product for
defects.
Validation is an
example of QC.
Responsibilities of QA
The QA department is responsible for ensuring that the quality policies
adopted by a company are followed.
It helps to identify and prepare the necessary SOPs relative to the control
of quality.
It must determine that the product meets all the applicable specifications
and that it was manufactured according to the internal standards of GMP.
QA also holds responsible for quality monitoring or audit function. QA
functions to assess operations continually and to advise and guide them
towards full compliance with all applicable internal and external
regulations.
Responsibilities of QC
QC is responsible for the day-to-day control of quality within the
company.
This department is responsible for analytical testing of incoming raw
materials and inspection of packaging components, including labelling.
They conduct in-process testing when required, perform environmental
monitoring, and inspect operations for compliance.
They also conduct the required tests on finished dosage form.
QC plays a major role in the selection of qualified vendors from
whom raw materials are purchased. Testing of representative
samples is required, and in many cases, an audit of vendor’s
operations is necessary to determine their suitability and degree
of compliance with GMPs prior to their being approved.
The environmental areas for manufacturing of various dosage forms are
tested and inspected by QC department.
Sources of Quality Variation
Because of the increasing complexity of modern pharmaceutical manufacture
arising from a variety of unique drugs and dosage forms, complex ethical,
legal, and economic responsibilities have been placed on those concerned
with the manufacture of modern pharmaceuticals. An awareness of these
factors is the responsibility of all those involved in the development,
manufacture, control, and marketing of quality products.
Following variables may affect ultimate quality of product
Raw material
In process variations
Packaging material
Labeling
Finish product
Manual Error
Control of Quality Variation
Raw material control
Good raw material specifications must be written in precise
terminology, must be complete, must provide specific details of test
methods, type of instruments, and manner of sampling must be
properly identified.
Each raw material is sampled according to standard sampling procedures
and is sent to the quality control laboratory for testing according to
written procedures. If acceptable, it is moved to the release storage area,
after being properly stickered to indicate the item no., material name, lot
no., release date, reassay date and sign of QA inspector.
 QA personnel should keep preservation samples of active raw materials
that consists of atleast twice the necessary quantity to perform all tests
required, to determine whether the material meets the established
specifications. These preservation samples should be retained for atleast
7 years. Approved material should be rotated so that the oldest stock is
used first.
Raw materials may be classified into 2 groups:
 Active or therapeutic
 Inactive or inert

In-process Items Control
 Conformance to compendial standards as the sole basis for judging
the quality of a final dosage form can be grossly misleading. As the
final dosage forms are produced in millions of units, the no. Of units
assayed at the end is not likely to be representative of more than a
small fraction of the actual production.
 The FDA-CGMP regulations emphasize environmental factors to
minimize cross- contamination of products and errors, however, they do
little to minimize within-batch and batch-to- batch variation. Therefore,
it is important function of the IPQA program to ensure that the final
produts have uniform purity and quality.
There are some critical steps to be followed in this:
QA before start-up:
- Environmental and microbiologic control and sanitation
- Manufacturing Working Formula Procedures
- Raw Materials
- Manufacturing Euipment
QA at start-up:
- Raw Material Processing
- Compounding
- Packaging Materials Control
- Labels Control
- Finished Product Control

Manufacturing Variation Control
 Monitoring environmental conditions under which products are
manufactured/stored
 Monitoring of air and water systems to prevent contamination– Air
Handling Units
 Monitoring of personnel
 Feedback and follow-up
Quality Assurance Management Procedure
1. How to write Standard Operating Procedure?
 SOP describes standard SOP format that you can use immediately for
your quality procedure.
 SOP has instructions on how to write a formal operating procedure for
your systems which your people can follow everyday.
2. All Document-Classifications, Definitions and
Approval Matrix
 In this SOP you will find all type of quality and Technical/Master file
documents to build up a good quality management system for your
manufacturing sites, definition of documents, their classification,
approval requirements and retention requirements.
 This procedure has schematic diagrams for your understanding of how
different types of documents are prepared and stored in a typical
documentation.
3. Quality Documentation Management and Change Control
 This SOP describes how to generate new quality documents or change
control of existing documents, review of quality documents, satellite
file management, role of document author, approver, document control
officer and satellite file administrator.
 In this SOP you will also find numbering systems of different
quality documents like audit files, SOP’s, forms, manuals,
training files, QA agreements, project files etc and their effective
archiving system.
4. Documentation Rule for GMP Documents
This SOP describes the principles to be followed in GMP documents,
entry of data and information, signature requirements and correction
technique of incorrectly entered data or information.
5. Quality Documentation- Tracking, Control and
Distribution
 In this SOP you will find mainly the role of document control officer
during the initiation, creation, circulation and approval of new quality
related documents.
 It also describes the procedure of modification and review of existing
document using a documentation database.
 Management of existing and superseded documents is also a
art of this procedure.
 You will see all the forms referred during the instruction are
attached at the end of the procedure.
6. Preparation, Maintenance and Change Control
of Master Documents
 This SOP particularly focused on the management of master file
documents like specifications, control methods, raw materials, finished
goods and packaging specification and test reports, formulation,
stability files etc required to generate during the product registration in
the market.
 This SOP gives instruction on their creation, change control,
numbering system, approval requirements and maintenance in a
simple master file database.
 You will see all the forms referred during the instruction are
attached at the end of the procedure.
 7. Deviation Report System
 It is a regulatory requirement to capture all sorts of deviations evolves
in your systems in order to maintain the continuous improvement to
your processes and systems.
 This SOP describes how to categorize the deviations between
production, audit, quality improvements, technical deviations, customer
complaints and environmental, health and safety deviations.
 It describes the management responsibilities of initiating deviation,
capture data, analysis, investigation, determination of assignable
causes, generation of management report and initiatives to be taken on
corrective and preventative actions.
8. Example- Checklist for Batch Documentation
 This SOP describes the identification of all documentation relevant to a
production process in the form of “Batch Documentation Checklists”
and to ensure their collection by completion of the checklists by
Authorized Persons.
 This procedure is based on an example of tablet packaging process
described in the ‘Manufacturing’ category.
9. Evaluation of Batch Documentation and
Release of Sale
 This procedure describes the process of collection, evaluation
and record of batch related document generated during the
production of a batch before an authorized person can release
the batch for sale.
10. Raw Materials- Laboratory Testing and
Documentation
This SOP describes the procedure for sampling, location, pre-testing,
testing and documentation of all raw materials and components subject
to test, out of specification results, microbiological tests and release
procedure for passed raw materials and components.
11. Finished Goods- Laboratory Testing and
Documentation
This SOP describes the procedure for sampling, location, pre-testing,
testing and documentation of all finished products subject to test,
reagents and standards to be used for analysis, management of out of
specification results, microbiological tests and release procedure for
passed finished goods.
Relationship Between QA, QC and
GMP
Quality Assurance
Good Manufacturing
Practices
Quality Control
Total Quality Control (TQC)
The concept of total quality control refers to the process of striving to
produce a perfect product by a series of measures requiring an organised
effort at every stage in production.
Although the responsibility for assuring product quality belongs
principally to QA personnel, it involves many departments and disciplines
within a company.
To be effective, it must be supported by team effort.
Quality must be built into a drug product during product and process,
and it is influenced by the physical plant design, space, ventilation,
cleanliness and sanitation during routine production.
In products and process designing, it considers many parameters like:
 Materials
 In-process and product control
 Specification and tests for active ingredients, excipients
 Specific stability procedures of the product
 Freedom from microbial contamination and proper storage
 Containers, packaging and labelling
 Product protection from moisture, light, volatility, and drug/package
interaction
Total Quality Management(TQM)
According to ISO, TQM is definedas: "A management approach of
an organisation centred on quality, based on the participation of all
its members and aiming at long term success through customer
satisfaction and benefits to all members of the organisation and
society."
 The pharmaceutical industry is a vital segment of health care system
which is regulated heavily because; any mistake in product design or
production can severe, even fatal. The poor qualities of drug are not only a
health hazard but also a waste of money for both government and
individual consumers. So, the maintenance of the quality with continuous
improvement is very important for pharmaceutical industries. From this
concept Total Quality Management (TQM) was established. The aim of
TQM is prevention of defects rather than detection of defects. So TQM is
very important for pharmaceutical industries to produce the better product
and ensure the maximum safety of healthcare system and also protect
waste of money for both government & individual consumers.
 Total Quality Management consists of organization-wide efforts to install
and make permanent a climate in which an organization continuously
improves its ability to deliver high-quality products and services to
customers. While there is no widely agreed-upon approach, TQM efforts
typically draw heavily on the previously developed tools and techniques
of quality control.
 The production of quality pharmaceuticals products requires embracing
the principles of TQM.
 Additionally, TQM will serve to improve productivity and
customer satisfaction.
 The concept of TQM requires the total commitment of senior level
management and supervision of all departments, operators, suppliers, and
costumers.
 It continually strives for process improvement that begins with
product development and only concludes when feedback and
follow-up have been completed.
Activities in TQM
TQM is the foundation for activities, which include:
 Commitment by senior management and all employees
 Meeting customer requirements
 Reducing development cycle times
 Just in time/demand flow manufacturing
 Improvement teams
 Reducing product and service costs
 Systems to facilitate improvement
 Line management ownership
 Employee involvement and empowerment
 Recognition and celebration
 Challenging quantified goals and benchmarking
 Focus on processes / improvement plans
 Specific incorporation in strategic planning
Functions of TQM
Product quality criteria are established, and detailed specifications are
written. Meticulous, written procedures must be prepared for
production and control. Raw material must be characterised and then
purchased from reputable, approved suppliers.
Facilities must be designed, constructed, and controlled to provide the
proper stable environment for protecting the integrity of products.
Equipments must be selected that is efficient and can be cleaned
readily and sanitised.
 Personnel must be trained properly. The directions they use must be in
writing, approved by responsible individuals.
 Distribution departments are responsible for controlling the shipping
and handling of products, using inventory-control systems.
 The marketing department must be sensitive to the costumers’ needs and be
responsive to complaints.
 QA is ever present and gives approval only after assessing and being
assured that the entire production process has been completed
satisfactorily and that all the aspects of the GMPs have been satisfied.
Advantages of TQM
 Improves reputation- faults and problems are spotted and sorted quicker.
 Higher employee morale- workers motivated by extra responsibility, team
work and involvement indecisions of TQM
 Lower cost- decrease waste as fewer defective products and no need for
separate.
 Quality control inspector
Disadvantages of TQM
 Initial introduction cost.
 Benefits may not be seen for several years.
 Workers may be resistant to change
Major Keywords of Quality
Assurance
Calibration
Validation
Qualification
Calibration
Calibration is defined as operation that, under specified conditions, in a first
step, establishes a relation between the quantity values with measurement
uncertainties provided by measurement standards and corresponding indications
with associated measurement uncertainties (of the calibrated instrument or
secondary standard) and, in a second step, uses this information to establish a
relation for obtaining a measurement result from an indication.
Qualification
Qualification is defined as action of proving and documenting that equipment or
ancillary systems are properly installed, work correctly, and actually lead to the
expected results. Qualification is part of validation, but the individual
qualification steps alone do not constitute process validation.
Qualification includes the following steps:
 Design qualification (DQ)- Demonstrates that the proposed design (or the
existing design for an off- the-shelf item) will satisfy all the requirements
that are defined and detailed in the User Requirements Specification
(URS). Satisfactory execution of the DQ is a mandatory requirement
before construction (or procurement) of the new design can be
authorised.
 Installation qualification (IQ) – Demonstrates that the process or
equipment meets all specifications, is installed correctly, and all required
components and documentation needed for continued operation are
installed and in place.
 Operational qualification (OQ) – Demonstrates that all facets of the
process or equipment are operating correctly.
 Performance qualification (PQ) – Demonstrates that the process or
equipment performs as intended in a consistent manner over time.
Validation
Validation is a process of establishing documentary evidence demonstrating that
a procedure, process, or activity carried out in production or testing maintains
the desired level of compliance at all stages. In Pharma Industry it is very
important apart from final testing and compliance of product with standard that
the process adapted to produce itself must assure that process will consistently
produce the expected results. Since a wide variety of procedures, processes, and
activities need to be validated, the field of validation is divided into a number of
subsections including the following:
 Equipment validation
 Facilities validation
 HVAC system validation
 Cleaning validation
 Process Validation
 Analytical method validation
 Computer system validation
 Packaging validation
 Cold chain validation
Types of Validation
Prospective
Validation
Concurrent
Validation
Validation
Retrospective
Validation
Repeated
Validation
Prospective Validation
 Prospective validation is carried out during the development stage by
means of a risk analysis of the production process, which is broken
down into individual steps: these are then evaluated on the basis of past
experience to determine whether they might lead to critical situations.
 Where possible critical situations are identified, the risk is evaluated, the
potential causes are investigated and assessed for probability and extent,
the trial plans are drawn up, and the priorities set. The trials are then
performed and evaluated, and an overall assessment is made. If, at the
end, the results are acceptable, the process is satisfactory.
Unsatisfactory processes must be modified and improved until a
validation exercise proves them to be satisfactory. This form of
validation is essential in order to limit the risk of errors occurring on the
production scale, e.g. in the preparation of injectable products.
Concurrent Validation
 Concurrent validation is carried out during normal production. This
method is effective only if the development stage has resulted in a
proper understanding of the fundamentals of the process.
 Concurrent validation together with a trend analysis including stability
should be carried out to an appropriate extent throughout the life of the
product.
Retrospective Validation
 Retrospective validation involves the examination of past experience of
production on the assumption that composition, procedures, and
equipment remain unchanged; such experience and the results of inprocess and final control tests are then evaluated. Recorded difficulties
and failures in production are analysed to determine the limits of
process parameters. A trend analysis may be conducted to determine
the extent to which the process parameters are within the permissible
range.
 Retrospective validation is obviously not a quality assurance
measure in itself, and should never be applied to new processes or
products.
Revalidation or Repeated Validation
 Revalidation is needed to ensure that changes in the process and/or in
the process environment, whether intentional or unintentional, do not
adversely affect process characteristics and product quality.
Role of QA in Pharma Industries
1.To establish Quality Audit
 Establish the quality management system to describe how the firm
complies CGMPs and operates to maintain a state of control
 Keep current with good industry practices, and applicable to the
mission of your operation.
2. To audit compliance to the Quality System
 Audit for compliance to policies and procedures: on paper vs. practice
 Report on the performance of the quality system, including
trends, that help decision making for targeted actions.
3. To establish procedures and specifications
 Ensure that procedures and specifications are appropriate and
followed.
 Ensure that the procedures and specifications of firms under contract are
also appropriate and followed, i.e., maintain control and take
responsibility for third-party services providers (contract manufacturers,
contract laboratories, etc.)
4. To establish manufacturing controls
 Ensure that appropriate manufacturing in- process controls are
implemented.
 Ensure in-process controls are performed during manufacturing
operations and results are satisfactory
5. To perform laboratory tests
 Perform laboratory testing of components, containers, in-process
materials, packaging materials and drug product using validated methods
against scientifically-derived, fit-for-purpose specifications
 Approve or reject drug products manufactured, processed, packed,
or held undercontract by another company, i.e., final product release
is not delegated to a contractor
 Perform retests or reexamine approved components, drug product
containers and closures after long storage or exposure to adverse
conditions.
6. To review and approve or reject
 Review and approve/reject any document that gives work instructions
and set requirements such as procedures, protocols, test methods, and
specifications—including changes to these documents
 Review and approve/reject reprocessing and rework procedures
 Review and approve/reject production batch records and make the final
decision to release a product lot into commerce.

 7. To ensure investigation of nonconformance
 Ensure investigation is conducted and root cause is eliminated for
production and control record errors, discrepancies, and failure to meet
specification, including quality attributes
 Review complaints to determine if it relates to a failure to meet
specification, if so investigate and report to FDA if it is serious and
unexpected
8. To keep management informed
 Report on product, process and system risks
 Report on outcome of regulatory inspections and ensure responses
are complete and managed to verifiable closure
9. To describe responsibilities in writing
 Have a complete and compliant procedure that describes
responsibilities
 Follow the procedure
10. To remain independent
 Ensure there is no conflict of interest between regulatory
responsibilities and actual daily activities
 Be independent reviewer and approver with respect to manufacturing
and process/ product development units
Control and Assurance of Manufacturing
Practices
1. Personnel
Important parts for a successful personnel are:
 Proper selection
 Training
 Motivation of Production
 Packaging
 Control
 It is essential that the qualified personnel be employed to supervise the
formulation, Processing, Sampling, testing, packaging and labelling of the
drug product, and that competent staff be placed in charge of the
maintainance of machinery, equipment and sanitation.
2. Equipments and Buildings
 The building should provide adequate space for the orderly placement
of materials and equipment to minimize any risks of mix-ups or crosscontamination between the drugs, excipients, packaging and labelling
from the time the materials are received to the time the products are
released.
 The desired characteristics of equipments for producing quality
products are numerous, however, the equipment should be of suitable
size, accuracy and reproducibility.
 3. Control of records
The records, such as Master Formula and Batch production records,
should be prepared and maintained in accordance with established
procedures.
4. Control of Production Procedures
To ensure that products have the intended characteristics of identity,
strength, quality, and purity, production and the related in-process
quality control procedures should be rigidly followed as required by the
master formula record or batch production record.
5. Packaging Control
A packaging record bearing an identification number is issued to the
packaging section. This record specifies the packaging materials to be
used, operations to be performed, and the quantity to be packaged.
6. Validation
Validation of a process is the demonstration that controlling the
critical steps of a process results in products of repeatable attributes
or causes a reproducible event.
 7. Control and Assurance of Finished Products
 Unless the testing procedures by which the product quality is finally measured
are established on an equally sound basis,the entire system may be deficient.
 Product failures causing rejections or recalls after market introduction are serious
and can be easily detected and minimized by an effectively administered quality
testing program.
 Therefore, the testing of the finished products for compliance with the
established standards prior to release of the material for distribution is a critical
factor for quality control and assurance.
ICH International Conference onHarmonization
 ICH
 Mission
 Need to Harmonize
 Structure
 Observers
 Process of Harmonization
 Guidelines Q S E M
 Regulatory Requirements of Following countries:
 EU
 MHRA
 TGA
 ROW
ICH (April 1990)
International Conference on Harmonization
It is a joint initiative involving regulators & industry as equal partners in the
scientific & technical discussion of the testing procedure which are
recquired to ensure and assessthe Quality, Safety, &efficacyof medicinesT
Mission
To make recommendations towards achieving greater harmonization in the
interporetation and application of technical guidelines and requirements
for pharmaceutical product registration, there by reducing duplicating of
testing carries out during the research and development of new Human
Medicines.
Need to Harmonize
 Realisation was driven by tragedies, such as that with thalidomide in
Europe in the 1960s.
 The 1960s and 1970s saw a rapid increase in laws, regulations and
guidelines for reporting and evaluating the data on Quality, Safety
and Efficacy of new Medicinal products.
 Divergence in technical requirementsfrom country to country.
Observers
 WHO, EFTA (European Free Trade Association), Canada, Austrila – Non voting members
 IFPMA (International federations of Pharmaceutical
Manufactures Association)representative
u!!Structure
Regulatory Body Industry
US Food
& Drug
Associati
o n
(USFDA)
(JPMA)
Process of Harmonization
 ICH harmonization activities fall into 4 categories:
1. Formal ICH procedure: New topic for Harmonization
2. Q&A Procedure : Clarification on existing guideline
3. Revision Procedure
4. Maintenance Procedure
 The Guidelines – Q S E M
 Quality (Q1-Q11)
 Chemical & Pharmaceutical QA
 Safety (S1-S10,M3)
 Dealing with in-vitro & in-vivo preclinicaltesting
 Efficacy (E1-E16 ExceptE13)
 Clinical study in humanbeings
 Multidisciplinary (M1-M8)
 Terminology, electronic standards, common documents
Quality
 Q1- Stability
 Q2- Analytical Validation
 Q3- Impurities
 Q4- Pharmacopoeias
 Q5- Quality of Biotechnological Products
 Q6- Specification
 Q7- Good Manufacturing Practice
 Q8- Pharmaceutical Development
 Q9- Quality RiskManagement
 Q10- Pharmaceutical Quality System
Safety
 S1- Carcinogenicity Studies
 S2- Geno-toxicity Studies
 S3- Toxico-kinetics and Pharmacokinetics
 S4- ToxicityTesting
 S5- Reproductive toxicology
 S6- Biotechnological Product
 S7- pharmacology Studies
 S8- Imuno-toxicology Studies
 S9- Nonclinical evaluation for anticancer Pharmaceutical
 S10- Photosafety Evaluation
Efficacy
 E1&E2- Clinical Safety
 E3- Clinical Study Reports
 E4- Dose-response Studies
 E5- Ethnic Factors
 E6- Good Clinical Practice
 E7,E8,E9,E10,E11- Clinical Trials
 E12- Guidelines for Clinical Evaluation by therapeutic Category
 E14- Clinical Evaluation
 E15&E16- Pharmacogenomics
Multidisciplinary
 M1- MedDRA Terminology
 M2- Electronic Standards
 M3- Non-clinical Safety Studies
 M4- CTD
 M5- Data elements & Standardsfor Drug dictionaries
 M6- Gene Therapy
 M7- Genotoxic impurities
 M8- eCTD
Regulatory Requirements of Different Countries
European Union
 Intergovernmental political and economic union of 28 European
countries having internal single market through the standardized
system oflaws.
 Established under the name in 1992 by the treaty on European
Union.
 European Medicine Agency (EMA) is a decentralized agency of
the EuropeanUnion.
 EMA protects public and animal health by ensuring that all
medicines available on the EU market are safe, effective of high
quality.
 The agency isresponsible forthe scientific evaluation, supervision and
safety monitoring of the medicines developed by pharmaceutical
companiesforthe use in EU.
 EMA and the memberstate cooperate share expertise in the assessment
of new medicines and of newsafety information.
The Role of EMA
EMA plays an important role in the regulation of medicines in the EU. On the basis of scientific assessments carried out. It grants and refuses, changes and suspends marketing authorizations for medicine that have been submitted via the centralized procedure.
The European comission can also take action concerning other aspects of medicine regulations:
Right of Initiative- It can propose new legislation for
pharmaceutical sector;
Implementation- it can adopt implementing measures as
well as oversee the correct application of EU law on
pharmaceuticals;
Global outreach: it ensure appropriate collaboration with
relevant international partners and promotes the EU
regulatory systemglobally.
MHRA
 Medicine and Healthcare Products Regulatory Agency is an Executive
agency of the Department of the Health of United Kingdom.
 MHRA wasset up in April, 2003 bringing togetherthe function of
medicine Control agency (MCA) and the Medical Device
Agency(MDA).
 MHRAis responsible for ensuring that medicines and medical
devices work, and are acceptably safe.
 MHRA functions when the company wants to start clinical
trials in patients.
Role of MHRA
 Licencing
 Safety and efficacymonitoring
 Enforcement of laws
 Regulations of clinical trials
 Providing information to public and Health Professionals
 MHRAdoes notregulatedietary supplements, veterinary products
and cosmetics.
 TGA
 Therapeutic Goods Administration isthe regulatory body
for therapeutic good in Australia.
 TGA is responsible for conducting assessment and monitoring
activities to ensure that therapeutic goods available in Australia
are an acceptable standard.
 The objectives of Therapeutic Goods Act 1989, Which came into effect
on 15
th Feb 1991 is to provide a national framework for the regulation
of therapeutic goods in Australia to ensure quality, safety and efficacy
of the medicines and ensure quality, safety and performances of
medical devices.
 Essentially TG must be entered on Australian Register of Therapeutics
goods(ARTG)beforesuppliedinAustralia.
 ARTG is computer database of information of TG
 Australia Manufacture all medicines licensed under part 4 of the TG
act1989.
 Once approval for marketing in australia, ARTG can be identifiedby
AUST R (for registered Medicines) or AUST L (for listed medicine)
that appears on packaging of the medicines.
ROW
Rest of the world: divided the world in 5 regions (ASIA, Emerging Europe/Turkey/Israel,LatinAmerica,MiddleEast/Africa, Russia/CIS)
Key functions:
1. Product registration
2. Regulation of drug manufacturing, importation and
distribution
3. Adverse drug reactionmonitoring
4. Licensing of premises, person and practices.
5. Main goal of the agency is to guarantee the safety, efficacy, and
quality of the available drug product.
Quality-by-Design In Pharmaceutical Development
Quality by design (QbD) is a systematic approach to product
development that begins with predefined objectives and emphasizes
product and process understanding and controls based on sound
science and quality risk management (ICH Q8). Quality by Design is a
concept first outlined by Joseph M. Juran in various publication
Objective of QbD
 The main objective of QbD is to achieve the quality
products.
 To achieve positive performance testing
 Ensures combination of product and process knowledge
gained during development.
 From knowledge of data process desired attributes may be
constructed.
Benefits of QBD for Industry
 Eliminate batch failures.
 Minimize deviations and costly investigations.
 Empowerment of technical staff.
 Increase manufacturing efficiency, reduce costs and Project rejections and waste.
 Better understanding of the process.
 Continuous improvement.
 Ensure better design of product with less problem
Benefits FDA
Provide better consistency.
More flexibility in decision making.
Ensure scientific base of analysis.
Ensures decisions made on science and not on
empirical information.
Improves quality of review.
Approaches to pharmaceutical Development
Aspects Traditional QbD
Pharmaceutical
development
Empirical Systematic and
multivariate experiments.
Manufacturing process fixed Adjustable with
experiment design
space.
Process control Offline and has wide or
slow response
PAT (process analytical
technique) utilized for
feedback.
Product specification Based on batch data Based on the desired
product performance.
Control strategy By end product testing Risk based, controlled
shifted up stream, real
time release.
Life cycle management Post approval
changes
needed
Continual improvement
enable within design
space.
Flow of QbD
Life cycle management and continuous improvement.
Define Target product profile (TPP) and Quality Target Product profile (QTPP)
Carry out risk assessment, linking material attributes and process parameters CQA
Identify critical quality attributes (CQA)
Describe control strategy
Establish the design space.
Target Product Profile (TPP)
A prospective summary of the quality characteristics of drug product that
ideally will be achieved to ensure the desired quality, taking in to account
safety & efficacy of drug product.”(ICH Q8) Target product profile should
includes-
Dosage form
Route of administration
Dosage strength
Pharmacokinetics
Stability
The TPP is a patient & labeling centered concepts, because it identifies the desired performance characteristics of the product, related to the patient’s need & it is organized according to the key section in the drug labeling.
Quality Target Product Profile (QTPP)
QTPP is a quantitative substitute for aspects of scientific safety &
efficacy that can be used to design and optimize a formulation and
mfg. process.
QTPP should only include patient relevant product
performance.
The Quality Target product profile is a term that is an ordinary
addition of TPP for product quality
QTPP is related to identity, assay, dosage form, purity,
stability in the label.
Critical QualityAttributes (CQAs)
 A CQA has been defined as “a physical, chemical, biological or
microbiological property or characteristics that should be within an
appropriate limit, range, or distribution to ensure the desired product quality.
 Critical Quality Attributes are generally associated with the drug
substance, excipients, intermediates and drug product.
 The quality attributes of a drug product may include identity, assay,
content uniformity, degradation products, residual solvents, drug release,
moisture content, microbial limits.
 Physical attributes such as color, shape, size, odor, score
configuration, and friability. These attributes can be critical or
not critical
Critical Material Attributes (CMA)
 A CMA of a drug substance, excipient, and in-process materials is a
physical, chemical, biological, or microbiological characteristic of an input
material that should be consistently within an appropriate limit to ensure
the desired quality of that drug substance, excipient, or in-process material.
 The CMA is likely to have an impact on CQA of thedrug product.
 A material attributes can be an excipients raw material, drug
substances, reagents, solvents, packaging & labeling materials.
Critical Process Parameters (CPP)
A CPP of manufacturing process are the parameters which, when changed, can potentially impact product CQA and may result in failure to meet the limit of the CQA
Risk Assessment
12
Risk assessment is the linkages between material attributes & process parameters.
It is performed during the lifecycle of the product to identify the critical material
attributes (CMA) & critical process parameters (CPP).
Design Space
As per ICH Q8-
This is the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
A design space may be built for a single unit operation or for the ensure process.

TOOLS APPLIED IN QBD APPROACH
Design of Experiment (DoE):
This is a systematic approach applied to conduct experiments to obtain maximum
output. We have capability and expertize to perform DoE in product development
using software like Minitab and Statistica.
Design of experiments done by 2 methodScreening: Designs applied to screen large number of factors in minimal number
of experiments to identify the significant ones. Main purpose of these designs is to
identify main effects and not the interaction effects. For such studies common
designs used arePlacket-Burman and
Fractional factorial design.
Optimization: Experimental designs considered to carry out optimization are
mainly full factorial design, surface response methodology (e.g. Central composite,
Box-Behnken), and mixture designs. These designs include main effects and
interactions and may also have quadratic and cubic terms require to obtain
curvature. These designs are only applied once selected factors are identified,
which seem to be contributing in process or formulation.
Risk assessment methodology
1- Cause and Effect Diagrams (fish bone/Ishikawa): This is very basic
methodology to identify multiple possible factors for a single effect. Various cause
associated with single effect like man, machine, material, method, system, and
environment need to be considered to identify root cause
.
2- Failure Mode Effect Analysis (FMEA): This is an important tool to
evaluate potential failure modes in any process. Quantification of
risk by interaction of probability functions of severity, occurrence,
and detectability of any event can be done. FMEA can be
effectively performed with good understandingof process.
3- PAT (Process Analytical Technology) : Assurance of product quality
during intermittent steps using Process Analytical Technology (PAT)
is recommended by regulatory authorities, which is yet to be
extensively accepted by the pharmaceutical industry over
conservative methodologies. It involves advanced online
monitoring systems like NIR (Near IR), Handheld Raman
Spectrometer, Online Particle Size Analyzer etc. We are
experienced in application of NIR and Raman Spectrometer to
monitor processes viz. blending and wet granulation. These
technologies further make assurance of continuous improvement in
process and product quality through its life cycle.
Control strategy
Based on process and product understanding, during product
development sources of variability are identified.
Understanding the sources of variability and their impact on processes,
in-process materials, and drug product quality can enable appropriate
controls to ensure consistent quality of the drug product during the
product life cycle.
Elements of a Control Strategy
Procedural controls
In-process controls
batch release testing
Process monitoring
Characterization testing
Comparability testing
Consistency testing
 Application of Qb D
Application of QbD to Influenza Vaccines
Influenza vaccine: Influenza (flu) is caused by influenza viruses & is spread
mainly by coughing, sneezing, & close contact with infected person. Flu is
communicable disease that spreads around the US every winter in Oct.
Symptoms:
• Fever/chills
• Sore throat
• Muscle aches
• Fatigue
• Cough
• Headache
Vaccination : Vaccination is the phenomenon of protective immunization. In
modern concept vaccination involves the administration (injection or oral) of an
antigen to obtain an antibody response that will protect the organism against
future infections.
People should not take this vaccine-
If they have any severe, life-threatening allergies. E.g: Allergy to gelatin,
antibiotics or eggs, you may be not to get vaccinated.
If you are not feeling well, then also not to get vaccinated.
By using QbD the following parameters should be controlled during
vaccine production process
1) Cell propagation: In this step, limiting concentration of nutrients
may be helpful for optimal cell growth. If high nutrient
concentration then it inhibit cell growth. For that to do on line
monitoring of the nutrients concentration.
2) Virus prorogation: The following variable parameters controlled during
fermentation process.
pH: for maximum effectiveness of fermentation can be achieved
by continuous monitoring pH i.e. It required most favorable pH.
Temperature: Temperature control is important for good
fermentation process. If temperature is lower then it causes
reduced product formation & if it is higher then it affects the
growth of organisms. For avoiding this, bioreactors equipped with
heating & cooling system as per the requirement to maintain the
reaction vessel at optimal temperature.
Dissolved oxygen: Optimal supply of nutrients & oxygen, due to
this it prevents the growth of toxic metabolic byproducts.
Agitation: Good mixing also creates a favorable environment for
growth & good product formation. If agitation is excessive then it
damages the cells & increase temperature of medium.
Foam formation: Avoiding this parameter antifoam chemicals are
used such as mineral oils, vegetable oils which lowers the surface
tension of the medium & causes foam bubbles to collapse. Also
mechanical foam control devices fitted at top offermenter.
3)Purication: in this step check the purity by using ion exchange
chromatography & remove the impurity.
4)Inactivation: Optimum concentration of formaldehyde is used for
inactivation of viruses.
What is NABL ?
NABL specifies the general requirements for the competence to carry out
tests and calibrations, including sampling. It covers testing and calibration
performed using standard methods, non-standard methods, and laboratorydeveloped methods.
Benefits ofAccreditation:
Potential increase in business due to enhanced customer confidence and
satisfaction.
Savingsintermsoftimeandmoneyduetoreductionorelimination ofthe need for
re-testing .
Better control oflaboratory operations and feedback to laboratories as to whether
they have sound Quality Assurance System and are technically competent.
Increase of confidence in Testing / Calibration data and
personnel performing work.
Customers can search and identify the laboratories accredited by NABL for
their specific requirements from the directory of Accredited Laboratories.
 Users of accredited laboratories will enjoy greater access for their
products, in both domestic and international markets, when tested by
accredited laboratories.
TypesofLaboratorycanseek
Accreditation:
Laboratories undertaking anysortoftestingor calibration
in the specifiedfields.
Private or governmentlaboratories.
Smalloperationsto largemulti-field laboratories.
Site facilities, temporary field operations and
mobile laboratories.
TESTING LABORATORIES CALIBRATION
LABORATORIES
MEDICAL
LABORATORIES
 Biological
 Chemical
 Electrical
 Electronics
 Fluid-Flow
 Mechanical
 Non-Destructive Testing
 Photometry
 Radiological
 Thermal
 Forensic
 Electro-Technical
 Mechanical
 Fluid Flow
 Thermal & Optical
 Radiological
 Clinical Biochemistry
 Clinical Pathology
 Haematology &
Immunohaematol
ogy
 Microbiology & Serology
 Histopathology
 Cytopathology
 Genetics
 Nuclear Medicine (in-vitro tests
only)
PROFICIENCY TESTING
PROVIDERS
REFERENCE MATERIAL
PRODUCERS
 Testing
 Calibration
 Medical
 Inspection
 Chemical Composition
 Biological & Clinical Properties
 Physical Properties
 Engineering Properties
 Miscellaneous Properties
Approach to Accreditation
Awareness Training
Quality Policy& Objectives Finalization
Gap Analysis
Documentation / ProcessDesign
Documentation / ProcessImplementation
Internal Audit
Management ReviewMeeting
Shadow Audit
Corrective –PreventiveActions
Final CertificationAudit
Step 1:- AwarenessTraining:
Separate training sessions for top management, middle management and
junior level management.
Creates a motivating environment throughout the organization forISO 17025
implementation
Step2:-QualityPolicy&Objectives
Workshopwithtopmanagementondevelopment of qualitypolicy.
Work shop with top management and middle level functional management on
developmentofquality objectives.
Step 3:-GapAnalysis
Understandingofalltheoperationsofthe organization.
Developmentofprocessmapfortheactivitiesofthe organization.
 Comparing existing operations with requirements of ISO 17025:2005
standard
Step 4:-Documentation /Process Design
Quality Manual
 Functional Procedures
Work Instructions
System Procedures
Formats
 Step 5:-Documentation / Process Implementation
Work–shop on process / document implementation as per ISO 17025
requirements.
Departmental / Individual assistance in implementing the new processes /
documents.
Step 6:-InternalAudit
InternalAuditTraining&Examination(Optional).
Successfulemployees/wecarryoutinternalaudit oftheorganizationcovering
allthedepartments and operations.
Suggestcorrectiveandpreventiveactionsfor improvements in each of the
auditeddepartments
Step7:-ManagementReviewMeeting
 Quality Policy &Objectives
 Results of internalaudit
 Results of supplierevaluation
 Results of customercomplaints
 Results of customer feedback etc.
Step 8:-ShadowAudit
A replica of final certification audit.
FindsdegreeofcompliancewithISO17025 standard.
Gives an idea to the employees about the conduct of the final certification
audit.
Step9:-Corrective–PreventiveActions
On thebasis ofshadowaudit conducted in the last step,allthenon-conformities
willbeassigned correctiveandpreventiveactions.
AcheckwillensurethatalltheNCsareclosedand theorganizationisreadyforthe
finalcertification audit.
Step10:-FinalCertificationAudit
Upon completion of various stages of accreditation audit, the audit, your
organizationwillbeawarded accreditation.
Quality Standard-ISO 9000
Introduction to ISO 9000
The ISO 9000 family of standards is related to quality management systems and
designed to help organizations ensure that they meet the needs of customers and
other stakeholders while meeting statutory and regulatory requirements.
ISO 9000 deals with the fundamentals of quality management systems, including
the eight management principles on which the family of standards is based.
International standards promote international trade by providing one consistent set
of requirements recognized around the world.
ISO 9000 can help a company satisfy its customers, meet regulatory requirements
and achieve continual improvement. It provides the base level of a quality system,
not a complete guarantee of quality.
Originally published in 1987 by the International Organization for
Standardization (ISO), a specialized international agency for standardization
composed of the national standards bodies of 90 countries.
Eight Quality Management Principles
Custome
r focus Leadership Involvement
of people
Process
approach
System
approach to
manageme
nt
Continual
improvement
Factual
approach to
decisionmaking
Mutually
beneficial
supplier
relationship
s
Explains fundamental quality
concepts and provides guidelines for
the selection and application of each
standard
ISO 9000
Model for quality assurance in design,
development, production, installation
and servicing.
Model for quality assurance in the
production and installation of
manufacturing systems
ISO 9000 Series
Guidelines for the applications
of standards in quality
management and quality
systems.
ISO
9004
ISO 9000 and ISO 9004 are guidance standards. They describe what is
necessary to accomplish the requirements outlined in standards 9001,
9002 or 9003.
ISO
9003
Quality assurance in final
inspection and testing.
Advantages
Quality is maintained,
ISO registration also has a significant bearing on
market credibility as well.
Opportunity to compete with larger companies,
 More time spent on customer focus,
Confirmation that your company is committed to
quality
 May facilitate trade and increased market
opportunities,
Can increase customer confidence and
satisfaction.