SUBJECT: Quality Assurance

SUBJECT CODE:13PH0303
UNIT: I
DEPARTMENT: FOP MARWADI
UNIVERSITY
UNIT 1: Quality Assurance & Quality Management Concept
 Quality Assurance and Quality Management concepts

QUALITY
The totality of features and characteristics of a medicinal product and its ability to
satisfy stated and/or implied needs.
QUALITY MANAGEMENT SYSTEM
It is a management system to direct and control an organization with regard to quality
– ISO 9000:2000.
The basic elements of quality managements are quality system and systemic actions.
The quality system involves all phases from initial identification to final satisfaction of
requirements and customers expectation.
ISO:9000 state the following phases and activities:

Marketing and market research

 Design, specification engineering & product development
 Procurement
Process planning & development
Production
 Inspection, testing and examination
 Packaging & storage
 Sales & distribution

The first thing that a manufacturer will like to know is what product should be
manufactured? This may be found out by market research or survey.
Once the product is decided, the next thing is development of the product and its
specification. The next step follow as under:
QUALITY MANAGEMENT IN THE DRUG INDUSTRY

In the drug industry at large, quality management is usually defined as the
aspect of management function that determines and implements the “quality
policy”, i.e. the overall intention and direction of an organization regarding
quality, as formally expressed and authorized by top management.

The basic elements of quality management are:

an appropriate infrastructure or “quality system”, encompassing the
organizational structure, procedures, processes and resources;
 systematic actions necessary to ensure adequate confidence that a product
(or service) will satisfy given requirements for quality. The totality of these
actions is termed “quality assurance”.

Within an organization, quality assurance serves as a management tool. In

contractual situations, quality assurance also serves to generate confidence in
the supplier. The concepts of quality assurance, GMP and quality control are
interrelated aspects of quality management.
They are described here in order to emphasize their relationship and their
fundamental importance to the production and control of pharmaceutical products.

QUALITY ASSURANCE
“Quality assurance” is a wide-ranging concept covering all matters that individually
or collectively influence the quality of a product.

It is the totality of the arrangements made with the object of ensuring that
pharmaceutical products are of the quality required for their intended use.

Quality assurance therefore incorporates GMP and other factors, including those
outside the scope of this guide such as product design and development. QA is the
heart and soul of quality control

QA = QC + GMP+GLP+GCP
The system of quality assurance appropriate to the manufacture of pharmaceutical
products should ensure that:

a) pharmaceutical products are designed and developed in a way that takes account of
the requirements of GMP and other associated codes such as those of good
laboratory practice (GLP) and good clinical practice (GCP);

b) production and control operations are clearly specified in a written form and
GMP requirements are adopted;

c) managerial responsibilities are clearly specified in job descriptions;

d) arrangements are made for the manufacture, supply and use of the correct starting
and packaging materials;

e) all necessary controls on starting materials, intermediate products, and bulk

products and other in-process controls, calibrations, and validations are carried out;

f) the finished product is correctly processed and checked, according to the defined
procedures;
g) pharmaceutical products are not sold or supplied before the authorized persons
have certified that each production batch has been produced and controlled in
accordance with the requirements of the marketing authorization and any other
regulations relevant to the production, control and release of pharmaceutical products;

h) Satisfactory arrangements exist to ensure, as far as possible, that the

pharmaceutical products are stored by the manufacturer, distributed, and subsequently
handled so that quality is maintained throughout their shelf-life.

i) there is a procedure for self-inspection and/or quality audit that regularly

appraises the effectiveness and applicability of the quality assurance system;

j) deviations are reported, investigated and recorded;

k) there is a system for approving changes that may have an impact on product
quality;

l) regular evaluations of the quality of pharmaceutical products should be

conducted with the objective of verifying the consistency of the process and ensuring
its continuous improvement.
The purpose of quality assurance in pharmaceutical supply system is to help ensure
that each medicine reaching a patient is safe, effective and of appropriate quality.

To achieve the quality objective reliably there must be a comprehensively designed

and correctly implemented system of quality assurance incorporating GMP and
quality control.

The quality of pharmaceutical products is ensured by the technical managerial activities

of the quality system, which includes evaluating pharmaceutical product
documentation, performing or reviewing quality control laboratory tests, and
monitoring product performance.

All parts of quality assurance system should be adequately staffed with competent
personnel and should have sufficient premises, equipment and facilities.
GOOD MANUFACTURING PRACTICE (GMP)

Good manufacturing practice is that part of quality assurance which ensures that
products are consistently produced and controlled to the quality standards
appropriate to their intended use and as required by the marketing authorization.
GMP are aimed primarily at diminishing the risks inherent in any pharmaceutical
production.
Such risks are essentially of two types: cross contamination (in particular of
unexpected contaminants) and mix-ups (confusion) caused by,
for example, false labels being put on containers.
Under GMP:

 all manufacturing processes are clearly defined, systematically reviewed in the light of
experience, and shown to be capable of consistently manufacturing pharmaceutical
products of the required quality that comply with their specifications; qualification
and validation are performed;
all necessary resources are provided, including:
appropriately qualified and trained personnel;
adequate premises and space;
suitable equipment and services;
appropriate materials, containers and labels;
approved procedures and instructions;
suitable storage and transport;
adequate personnel, laboratories and equipment for in-process controls;
instructions and procedures are written in clear and unambiguous language,
Specifically applicable to the facilities provided; operators are trained to carry out
procedures correctly;
records are made (manually and/or by recording instruments) during
manufacture to show that all the steps required by the defined procedures and
instructions have in fact been taken and that the quantity and quality of the product
are as expected; any significant deviations are fully recorded and investigated;
records covering manufacture and distribution, which enable the complete history
of a batch to be traced, are retained in a comprehensible and accessible form;
the proper storage and distribution of the products minimizes any risk to their
quality;
a system is available to recall any batch of product from sale or supply;
complaints about marketed products are examined, the causes of quality defects
investigated, and appropriate measures taken in respect of the defective products to
prevent recurrence.
QUALITY CONTROL

That part of GMP which is concerned with sampling, specifications and testing.
Quality Control (QC) is part of quality management focused on fulfilling quality
requirements ISO 9000:2000.
QC is examining “control” materials of known substances along with patient samples to
monitor the accuracy and precision of the complete examination process.
The goal of QC is to detect errors and correct them before patients’ results are
reported.
The guidelines on quality control require that a manufacturer of
drugs/pharmaceutical products should have a quality control department and it
should be independent from production and other departments. It should be
headed by a person with appropriate qualifications and experience. Revised Schedule
M has this element under the title “Quality Control System”. These guidelines covers
following criteria:

 Facilities
Personnel
Equipment
Sampling
Testing
Documentation
Assessment of finished product and its release
Monitoring of procedures
Retention of reference samples
Total Quality Management (TQM):

Total Quality Management (TQM) is a management strategy aimed at embedding

awareness of quality in all organizational processes. TQM has been widely used in
manufacturing, education, government, and service industries.
Total Quality provides an umbrella under which everyone in the organization can
create customer satisfaction. TQ is a people focused management system that aims at
continual increase in customer satisfaction at continually lower real costs.
TQM = A process for managing quality; it must be a continuous way of life; a
philosophy of continuous improvement in everything we do.

Definition:
As defined by ISO:
"TQM is a management approach for an organization, centered 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 organization and to society.“

TQM (Total Quality Management) is the management of total quality. It’s a part of
Quality Management System, where Quality-by-design, Quality-by-time are the
different techniques to achieve it.
TQM requires that the company maintain this quality standard in all aspects of its
business. This requires ensuring that things are done right the first time and that defects
and waste are eliminated from operations. Traditionally, management includes the
following activities: planning, organizing, leading, and controlling.
Influences On The Total Quality Management Philosophy.

The Philosophy of TQM was born out of the concepts developed by namely four
great gurus of Quality management.
W. Edwards Deming
Joseph M Juran
Armand V Feigenbaum
Philip Crosby
Here is a short introduction to their concepts and how these contributed to Total
Quality Management Philosophy that we have today.
W. Edwards Deming

Deming’s argument was that quality that is achieved though a reduction in

statistical variation improves competitive position as well as productivity.

He defined Quality as being the direct result of quality of design, quality of
conformance and the quality of the sales and service function.

A great believer in measuring quality by direct statistical measurement against

specification, the goal of quality improvement is to reduce variation.

He developed a set of 14 points for management that express these issues. His
beliefs were that quality management and improvement were the responsibility
of all employees in a company.

Deming also believed that managers must change and to develop partnerships
with those at the operating level of the business, one of the key elements in the
Total Quality Management Philosophy.

1. Create consistancy
2. Cease dependance on inspection to achieve quality
3. Adopt new philosophy
4. end the practice of awarding the business on base of price tag only.
5. Improve constantly and forever every processes and planning ,
production And services.
6. training.
7.Leadership implement.
8.Drive out fear
9. Team work.
10 eliminate slogans, targets for the work force.
11. How process carried out not numerical target
12 encourage
13.Education and self improvement
14. Action for transformation.
Joseph Juran
Juran was probably the greatest contributor to the Total Quality Management
Philosophy.
He developed his ten-point plan which is the backbone of TQM implementation
nowadays.
The Juran Method:
Build awareness of the need and opportunity for improvement
Set goals for improvement
Organise to reach the goals
Provide training
Carry out projects to solve problems
Report progress
Give recognition
Communicate results
Keep the score
Maintain momentum by making annual improvement part of the regular system
and processes of the company.
Juran defined Quality as being “Fitness for Use” and really emphasized the cost of
quality.
He believed that it was important to take management structure as a starting point
and to build the quality improvement programme from that baseline.
Armand Feigenbaum

Feigenbaum was the originator of the term “Total Quality Control”. He believed that
significant quality improvement could only be achieved by the participation of
everyone in the organisation.
Fire-fighting quality management should be replaced with clear, customer-oriented
quality management which the employees understand and can commit themselves
to.
Feigenbaum believed that the goal of Quality improvement was to reduce the total
cost of quality to as low a percentage as possible.

Philip Crosby
Philip Crosby’s argument is that higher quality will ultimately reduce costs. He
defined Quality as being the “Conformance to Requirements”.
He developed a programme that has the focus of changing an organisation using action
plans for their implementation.
His absolute beliefs were that
•Quality means conformance and not elegance
•It is always cheaper to do a job right first time round
•The only performance indicator is the cost of quality
•The only performance standard is Zero Defects.
TQM IN PHARMACEUTICAL INDUSTRIES:

Total Quality Management is a managerial approach used by pharmaceutical

manufacturers in ensuring pharmaceutical products meets the required quality with
regard to their uses.
It is a potentially beneficial approach to manufacturing pharmaceutical products,
as it ensures they exceed customers' expectations in relation to quality standards,
efficiency and also effectiveness.
Pharmaceutical manufacturers play a key role in the system of health care and for
that case, they are heavily regulated by the relevant authorities since; any slight
mistakes in pharmaceuticals manufacturing can have fatal consequences.
In this case, pharmaceutical manufacturers need to maintain and improve
continuously on their products through Total Quality management system process
implementation.

Basic Approaches of TQM

A committed and involved management to provide long-term top - to - bottom
organizational support.
A focus on the customer, both internally and externally.
Effective involvement and utilization of the entire work force.
Continuous improvement of the business and production process.
Establish performance measures for the processes.
Major Elements of the TQM Approach

There are 8 elements of quality management for pharmaceutical companies.

1. Customer Focus:
“Striving to exceed customer expectations” should be the primary focus of a quality
management system, according to ISO.
Organizations achieve success when they earn customer confidence and use every
customer interaction to create value. Understanding the customers' needs in the present
and future is a necessity for success.

Pharmaceutical companies are facing extraordinary pressure to adapt to changing

market conditions, including the shifting role of the patient in healthcare.

Establishing a strong focus on the customer has clear benefits for quality driven
organizations in any industry, especially in pharma where customer expectations are
changing rapidly.

2. Total Involvement of Employees:

Every employee at a pharma organization has an impact on the company's ability to
deliver a quality product, from research scientists to janitorial staff.
All employees are involved in the quality production process, and so they should as
well take part in the innovation and improvement of quality.

Employees are ultimately responsible for quality, and continuous improvement

could not be achieved unless leadership provides workers with the resources needed--
including training, development, and recognition.

3. Process-Centered Approach:
A process-based approach is a core principle of ISO quality management systems
with increased impact on pharmaceutical QMS.

According to ISO, “consistent and predictable results are achieved more effectively
and efficiently when activities are understood and managed as interrelated
processes.

A process-centered approach involves the development of clear SOPs for every

role and responsibility in the organization, but it also requires pharma
organizations to shift their focus to the entire product lifecycle.
4. Integrated Systems:

Transparency throughout the product lifecycle is necessary to TQM. An organization

can only optimize products and performance by understanding how a system produces
results.
Transparency of information can be supported by a comprehensive QMS software
which complies with GMP and ICHQ10.
Based on ISO guidance and GMP, an integrated pharma system must support:
Quality policy
Personnel
Development and implementation
Production
Documents
Facilities and equipment
Self-inspection
Management responsibilities
Evaluation of suppliers and purchasing
Supplier production and analysis
Risk analysis
Monitoring and control
Complaints and recalls
Measurement, analysis, and improvement
5. Strategic and Systematic Approach:

Leadership is integral to a strategic and systemic approach to quality-driven

organizations. In a pharma company, the leadership team is tasked with creating a
culture of quality and inspiring excellent performance. A strategic approach to pharma
leadership allows a company to become more forward thinking.

Instead of focusing on immediate objectives, management review efforts are driven

by a clear roadmap for clinical development. Decisions are made based on accurate
documentation for risk management and clear quality objectives.

A QMS plays a core role in helping pharma companies take a systemic approach to
achieving both short-term and long-term quality objectives by providing transparency,
ease-of-access to information, and improving communication. An eQMS can support
strategic leadership with:
Coordination of processes across the organization
Support for real-time collaboration and communication
Training and education to help every member of the organization improve quality
6. Constant Improvement:
The mission for quality is an endless process in which individuals are constantly
attempting to improve on the product's features.
The pharmaceutical industry is under intense pressure to meet strict regulatory
requirements and pricing pressures while evolving to meet changing customer
expectations.
A formalized approach to improvement can allow organizations to meet standards
while capturing new opportunities consistently.
Efforts to improve in pharma should focus on developing greater internal efficiencies,
meeting current and emerging customer requirements, and adapting to meet changing
market conditions.

7. Fact-based Decision Making:

“Evidence-based decision making” is among the core principles of ISO, who writes
“decisions based on the analysis and evaluation of data and information are more likely
to produce desired results.”
Pharmaceutical executives are now required to make decisions based on data
throughout the product lifecycle.
Data can help leadership decide where change makes sense and when immediate
changes are necessary to protect product quality.
8. Communications

Effective relationships and communication are important to achieving the alignment of

people, processes and technology.
Systems for communication should support real-time, productive dialogue between
leadership, quality, employees, and third-party organizations in the supply chain.
TQM Implementation in Pharmaceuticals

TQM can be difficult to accomplish and maintain whether an organization is trying

hard to retain its quality of products or be in line with regulations from the
respective authorities. It can't be effectively accomplished without the significant and
relevant resources like funds and workforce.
TQM is a strategy through which managers, as well as employees, can be engaged
in the constant process of quality improvement of products. It is a blend of value and
managerial techniques focused on business expansion and reduction of losses because
of inefficient practices.
Benefits of Total Quality Management
TQM is the coordination of management efforts with the intention of improving on
quality at all levels within the organization. Thus, the TQM approach has various
benefits.
It comes with monetary benefits which incorporate lowered costs of production,
increased investment and sales profits, and also the power to increase product
prices to the quality involved.
Additional benefits may incorporate facilitated entry to worldwide markets,
higher client maintenance levels, development of new innovations within a short
period, and good company reputation.
Cause of Failure in TQM Implementation
TQM has yielded tremendous monetary benefits in various pharmaceutical
manufacturers, while struggles for quality fizzled and yielded peripheral outcomes in
some different manufactures.
Following are reasons which can be behind a failed TQM implementation process:
 Concentrating solely on momentary financial related outcomes while turning a
blind eye on the improvement of systems (Improvement on quality calls for a change
of thought in the management of the basic systems).
Managers' interference in teamwork,
 Unclear strategies and procedures,
 Failure to understand the TQM approach, and inadequate training as well as
insufficient education resources
ICH
ICH is the “International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use”.
The International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory
authorities and pharmaceutical industry to discuss scientific and technical
aspects of drug registration.
ICH is a joint initiative involving both regulators and research-based industry
representatives of the EU, Japan and the US in scientific and technical discussions of the
testing procedures required to assess and ensure the safety, quality and efficacy
of medicines.
Purpose or Mission of ICH
To make recommendations towards achieving greater harmonisation in the
interpretation and application of technical guidelines and requirements for
pharmaceutical product registration and the maintenance of such registrations;
 To maintain a forum for a constructive dialogue on scientific issues between
regulatory authorities and the pharmaceutical industry on the harmonisation of the
technical requirements for pharmaceutical products;
 To contribute to the protection of public health in the interest of patients from an
international perspective;
To monitor and update harmonised technical requirements leading to a greater
mutual acceptance of research and development data;

To avoid divergent future requirements through harmonisation of selected topics

needed as a result of therapeutic advances and the development of new
technologies for the production of medicinal products;

To facilitate the adoption of new or improved technical research and

development approaches which update or replace current practices;

 To encourage the implementation and integration of common standards

through the dissemination of, the communication of information about and
coordination of training on, harmonised guidelines and their use;

And to develop policy for the ICH Medical Dictionary for Regulatory Activities
Terminology (MedDRA) whilst ensuring the scientific and technical maintenance,
development and dissemination of MedDRA as a standardised dictionary which
facilitates the sharing of regulatory information internationally for medicinal
products used by humans.
History

The International Council for Harmonisation (ICH), formerly the International

Conference on Harmonisation (ICH) held the inaugural Assembly meetings on 23
October 2015 establishing ICH as an international association.
The Need to Harmonise
The realisation that it was important to have an independent evaluation of
medicinal products before they are allowed on the market was reached at
different times in different regions. For most countries, whether or not they had
initiated product registration controls earlier, the 1960s and 1970s saw a rapid
increase in laws, regulations and guidelines for reporting and evaluating the data on
safety, quality and efficacy of new medicinal products.

The industry, at the time, was becoming more international and seeking new global
markets; however the divergence in technical requirements from country to country
was such that industry found it necessary to duplicate many time-consuming and
expensive test procedures, in order to market new products, internationally.

The urgent need to rationalize and harmonize regulation was forced by concerns over
rising costs of health care, a rapid increase of the cost of R & D and need to meet
the public expectations that there should be a minimum of delay in making safe and
efficacious new treatments available to patients in need.
Initiation of ICH

Harmonisation of regulatory requirements was pioneered by the Europe, in the 1980s, as

the Europe moved towards the development of a single market for pharmaceuticals. The
success achieved in Europe demonstrated that harmonisation was feasible.

At the same time there were discussions between Europe, Japan and the US on
possibilities for harmonisation. It was, however, at the WHO Conference of Drug
Regulatory Authorities (ICDRA), in Paris, in 1989, that specific plans for action began
to materialise.

Soon afterwards, the authorities approached International Federation of

Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint
regulatory-industry initiative on international harmonisation, and ICH was conceived.
The Evolution of ICH
ICH's first decade saw significant progress in the development of ICH Guidelines on
Safety, Quality and Efficacy and other multidisciplinary topics.
Second decade started towards facilitating the implementation of ICH Guidelines in ICH's
own regions.
Now in its third decade of activity, ICH's attention is directed towards extending the
benefits of harmonisation beyond the founding ICH regions. A significant step was taken
in 2015 to facilitate this which saw ICH undergoing a series of organisational changes.
Organization of ICH:

ASSEMBLY
The ICH Assembly brings together all Members and Observers of the ICH. It adopts
decisions in particular on matters such as on the Articles of Association, admission of new
Members & Observers and adoption of ICH Guidelines.
The ICH Assembly meets biannually and its agendas as well as reports are made available
on the ICH website summarising the main decisions taken at each meeting.
AUDITORS
The Auditors are appointed for a period of two years and may be re-appointed. The
responsibility of the Auditors is to audit the financial statements of the Association upon
conclusion of each Year. They should ensure that the accounting of the Association
complies with Swiss law and generally accepted Swiss accounting principles.
MANAGEMENT COMMITTEE

The ICH Management Committee (MC) is the body that oversees operational aspects of
ICH on behalf of all Members, including administrative and financial matters and
oversight of the Working Groups (WGs). The MC is responsible for submitting
Recommendations on the selection of new topics for harmonisation as well as on the
adoption, withdrawal or amendments of ICH Guidelines.
To date, the ICH MC is composed of 16 Regulatory and Industry Members and 2 Standing
Observers. The ICH MC has permanent representatives from the six Founding Members (
Europe, United States, Japan), Standing Regulatory Members (Health Canada, Canada;
Swiss medic, Switzerland) as well as Standing Observers (IFPMA; WHO).

In addition, since June 2018 and as per the ICH Articles of Association, the following MC
Elected Representatives have been nominated to join the MC and will serve until the next
election in June 2021: ANVISA, Brazil; HSA, Singapore; MFDS, Republic of Korea; NMPA,
China; SFDA, Saudi Arabia; TFDA, Chinese Taipei; TITCK, Turkey & BIO; Global Self-Care
Federation; IGBA.

MedDRA MANAGEMENT COMMITTEE

The MedDRA Management Committee (MC) has responsibility for direction of MedDRA,
an ICH standardised dictionary of medical terminology. The MedDRA MC is composed of
the EC, Europe; EFPIA; MHLW/PMDA, Japan; JPMA; FDA, United States; PhRMA; MHRA
UK; Health Canada, Canada; and WHO (as Observer).
SECRETARIAT
The ICH Secretariat is responsible for day-to-day management of ICH, coordinating
ICH activities as well as providing support to the Assembly, the ICH Management
Committee and its Working Groups.
The ICH Secretariat also provides support for the ICH MedDRA Management
Committee. The Secretariat is located in Geneva, Switzerland.

COORDINATORS
Fundamental to the smooth running of ICH has been the designation of an ICH
Coordinator per ICH Member to act as the main contact point with the ICH Secretariat.
Coordinators ensure proper distribution of ICH documents to the appropriate
persons from their organisation and are responsible for the follow up on actions
within their respective organisation within assigned deadlines.
They also assist communication between the ICH Management Committee and/or
Assembly and the ICH Working Groups as needed.
WORKING GROUPS

An ICH Working Group (WG) is established for each technical topic selected for
harmonisation.
There are several different types of ICH working group:
 EWG: Expert Working Group is charged with developing a harmonised guideline
that meets the objectives in the Concept Paper and Business Plan.
 IWG: Implementation Working Group is tasked with developing Q&As to facilitate
implementation of existing guidelines.
 Informal Working Group: Is formed prior to any official ICH harmonisation
activity with the objectives of developing/finalising a Concept Paper, as well as
developing a Business Plan.
Discussion Group: Is a group established to discuss specific scientific
considerations or views i.e. Gene Therapy Discussion Group (GTDG), and ICH &
Women Discussion Group.
ICH Members and Observers appoint experts to participate in the WGs in line with
the applicable procedures in the Assembly Rules of Procedure and EWG/IWG Standard
Operating Procedures. A Rapporteur from one of the Members is designated by the
Assembly to lead the scientific discussions of the WG.
The Management Committee oversees the work of the WGs on an ongoing basis,
while the Assembly receives reports on each WG’s progress at the time of its biannual
face-to-face meetings.
ICH Guidelines:
The ICH topics are divided into the four categories as below.
1. Quality Guidelines
2. Safety Guidelines
3. Efficacy Guidelines
4. Multidisciplinary Guidelines

1) Quality Guidelines:
Harmonisation achievements in the Quality area include pivotal milestones such as
the conduct of stability studies, defining relevant thresholds for impurities testing
and a more flexible approach to pharmaceutical quality based on Good
Manufacturing Practice (GMP) risk management.
Q1A – Q1F

Q1 A: Stability Guidelines

Objectives: The following guideline is a revised version of the ICH Q1A guideline
and defines the stability data package for a new drug substance or drug product that
is sufficient for a registration application within the three regions of the EC, Japan, and
the United States.

General Principles:
The purpose of stability testing is to provide evidence on how the quality of a drug
substance or drug product varies with time under the influence of a variety of
environmental factors such as temperature, humidity, and light.

The choice of test conditions defined in this guideline is based on an analysis of the
effects of climatic conditions in the three regions of the EC, Japan and the United
States.
GUIDELINES

1. Drug Substance
Stress Testing:
Stress testing of the drug substance can help identify the likely degradation products,
which can in turn help establish the degradation pathways and the intrinsic
stability of the molecule and validate the stability indicating power of the analytical
procedures used.

Stress testing is likely to be carried out on a single batch of the drug substance.

It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C,
etc.) above that for accelerated testing, humidity (e.g., 75% RH or greater) where
appropriate, oxidation, and photolysis on the drug substance.

In case of solution or suspension, the testing should also evaluate the susceptibility
of the drug substance to hydrolysis across a wide range of pH values.
Examining degradation products under stress conditions is useful in establishing
degradation pathways and developing and validating suitable analytical procedures.
Selection of Batches:
Data from formal stability studies should be provided on at least three primary batches
of the drug substance.

Container Closure System:

The stability studies should be conducted on the drug substance packaged in a
container closure system that is the same as or simulates the packaging proposed for
storage and distribution.

Specification
Stability studies should include testing of those attributes of the drug substance that
are susceptible to change during storage and are likely to influence quality, safety,
and/or efficacy.
The testing should cover, as appropriate, the physical, chemical, biological, and
microbiological attributes. Validated stability-indicating analytical procedures
should be applied.
Testing Frequency
For long term studies, frequency of testing should be sufficient to establish the stability
profile of the drug substance.
For drug substances with a proposed re-test period of at least 12 months, the
frequency of testing at the long term storage condition should normally be every 3
months over the first year, every 6 months over the second year, and annually
thereafter through the proposed re-test period.
At the accelerated storage condition, a minimum of three time points, including the
initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is
recommended.
When testing at the intermediate storage condition is called for as a result of significant
change at the accelerated storage condition, a minimum of four time points, including
the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is
recommended.
Stability Commitment

When available long term stability data on primary batches do not cover the
proposed retest period granted at the time of approval, a commitment should be made
to continue the stability studies post approval in order to firmly establish the re-test
period.
The stability protocol used for studies on commitment batches should be the same as
that or the primary batches, unless otherwise scientifically justified.
Evaluation
The purpose of the stability study is to establish, based on testing a minimum of
three batches of the drug substance and evaluating the stability information
(including, as appropriate, results of the physical, chemical, biological, and
microbiological tests), a retest period applicable to all future batches of the drug
substance manufactured under similar circumstances.
The degree of variability of individual batches affects the confidence that a future
production batch will remain within specification throughout the assigned re-test
period.
Statements/Labeling
A storage statement should be established for the labeling in accordance with
relevant national/regional requirements. The statement should be based on the
stability evaluation of the drug substance.
 Drug Product
General
The design of the formal stability studies for the drug product should be based on
knowledge of the behaviour and properties of the drug substance and from stability
studies on the drug substance and on experience gained from clinical formulation
studies.
Photo stability Testing
Photo stability testing should be conducted on at least one primary batch of the drug
product if appropriate.
Selection of Batches
Data from stability studies should be provided on at least three primary batches of
the drug product. The primary batches should be of the same formulation and
packaged in the same container closure system as proposed for marketing.
Two of the three batches should be at least pilot scale batches and the third one can be
smaller, if justified.
Container Closure System
Stability testing should be conducted on the dosage form packaged in the container
closure system proposed for marketing (including, as appropriate, any secondary
packaging and container label).

Specification
Stability studies should include testing of those attributes of the drug product that are
susceptible to change during storage and are likely to influence quality, safety,
and/or efficacy.

The testing should cover, as appropriate, the physical, chemical, biological, and
microbiological attributes, preservative content (e.g., antioxidant, antimicrobial
preservative), and functionality tests (e.g., for a dose delivery system).

Testing Frequency
For long term studies, frequency of testing should be sufficient to establish the stability
profile of the drug product.
For products with a proposed shelf life of at least 12 months, the frequency of testing
at the long term storage condition should normally be every 3 months over the first
year, every 6 months over the second year, and annually thereafter through the
proposed shelf life.

At the accelerated storage condition, a minimum of three time points, including the
initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is
recommended.

When testing at the intermediate storage condition is called for as a result of

significant change at the accelerated storage condition, a minimum of four time points,
including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month
study is recommended.
Storage Conditions

In general, a drug product should be evaluated under storage conditions (with

appropriate tolerances) that test its thermal stability and, if applicable, its
sensitivity to moisture or potential for solvent loss.

Stability testing of the drug product after constitution or dilution, if applicable,

should be conducted to provide information for the labeling on the preparation,
storage condition, and in-use period of the constituted or diluted product.

Drug products packaged in impermeable containers

Sensitivity to moisture or potential for solvent loss is not a concern for drug
products packaged in impermeable containers that provide a permanent barrier to
passage of moisture or solvent.

Thus, stability studies for products stored in impermeable containers can be

conducted under any controlled or ambient humidity condition.
Drug products packaged in semi-permeable containers
Aqueous-based products packaged in semi-permeable containers should be evaluated
for potential water loss in addition to physical, chemical, biological, and
microbiological stability.

Ultimately, it should be demonstrated that aqueous-based drug products stored in

semipermeable containers can withstand low relative humidity environments.

Stability Commitment

When available long term stability data on primary batches do not cover the
proposed shelf life granted at the time of approval, a commitment should be made to
continue the stability studies post approval in order to firmly establish the shelf life.

The stability protocol used for studies on commitment batches should be the same
as that for the primary batches.
 Evaluation
A systematic approach should be adopted in the presentation and evaluation of the
stability information, which should include, as appropriate, results from the physical,
chemical, biological, and microbiological tests.

Statements/Labeling
A storage statement should be established for the labeling in accordance with relevant
national/regional requirements. The statement should be based on the stability
evaluation of the drug product.
Where applicable, specific instruction should be provided, particularly for drug
products that cannot tolerate freezing. There should be a direct link between the
label storage statement and the demonstrated stability of the drug product. An
expiration date should be displayed on the container label.
2) Q1B Stability Testing:
Photostability Testing of New Drug Substances and Products

Photostability testing is carried out on a single batch of material.

Under some circumstances these studies should be repeated if certain variations and
changes are made to the product (e.g., formulation, packaging).
A systematic approach to photostability testing is recommended covering, as appropriate,
studies such as:

1) Tests on the drug substance;

2) Tests on the exposed drug product
3) Tests on the drug product in the immediate pack; and if necessary ;
4) Tests on the drug product in the marketing pack.

The extent of drug product testing should be established by assessing whether or not
acceptable change has occurred at the end of the light exposure.
Light Sources
The light sources described below may be used for photostability testing. The
applicant should either maintain an appropriate control of temperature to minimize
the effect of localized temperature changes or include a dark control in the same
environment.
Option 1
Any light source that is designed to produce an output similar to the D/ID emission
standard such as an artificial daylight fluorescent lamp combining visible and
ultraviolet (UV) outputs, xenon, or metal halide lamp.
D65 is the internationally recognized standard for outdoor daylight. ID65 is the
equivalent indoor indirect daylight standard.
Option 2
For option 2 the same sample should be exposed to both the cool white fluorescent
and near ultraviolet lamp.
DRUG SUBSTANCE
For drug substances, photostability testing should consist of two parts:
1) forced degradation testing and
2) confirmatory testing.
The purpose of forced degradation testing studies is to evaluate the overall
photosensitivity of the material for method development purposes and/or
degradation pathway elucidation.

In these forced degradation studies, a variety of exposure conditions may be used,

depending on the photosensitivity of the drug substance involved and the intensity of
the light sources used.
For photostable materials, studies may be terminated after an appropriate exposure
level has been used.
Confirmatory studies should then be undertaken to provide the information necessary
for handling, packaging, and labeling.
Normally, only one batch of drug substance is tested during the development phase,
and then the photostability characteristics should be confirmed on a single batch
selected .
If the drug is clearly photostable or photolabile. If the results of the confirmatory study
are equivocal, testing of up to two additional batches should be conducted.
Presentation of Samples

Care should be taken to ensure that the effects of the changes in physical states of
sample such as sublimation, evaporation or melting are minimized.
Possible interactions between the samples and any material used for containers or
for general protection of the sample, should also be considered and eliminated.
As a direct challenge for samples of solid drug substances, an appropriate amount of
sample should be taken and placed in a suitable glass or plastic dish and protected
with a suitable transparent cover if considered necessary.
Solid drug substances should be spread across the container to give a thickness of
typically not more than 3 millimeters. Drug substances that are liquids should be
exposed in chemically inert and transparent containers.
Analysis of Samples

At the end of the exposure period, the samples should be examined for any changes in
physical properties (e.g., appearance, clarity, or color of solution) and for assay and
degradants by a method suitably validated for products.

 Judgement of Results
The forced degradation studies should be designed to provide suitable information to
develop and validate test methods for the confirmatory studies.
The confirmatory studies should identify precautionary measures needed in
manufacturing or in formulation of the drug product, and if light resistant packaging is
needed.
When evaluating the results of confirmatory studies to determine whether change due
to exposure to light is acceptable, it is important to consider the results from other
formal stability studies in order to assure that the drug will be within justified limits
at time of use.

DRUG PRODUCT
Normally, the studies on drug products should be carried out in a sequential manner
starting with testing the fully exposed product then progressing as necessary to the
product in the immediate pack and then in the marketing pack.
For some products where it has been demonstrated that the immediate pack is
completely impenetrable to light, such as aluminium tubes or cans, testing should
normally only be conducted on directly exposed drug product.
Presentation of Samples

when testing samples of the drug product outside of the primary pack, these should
be presented in a way similar to the conditions mentioned for the drug substance.
The samples should be positioned to provide maximum area of exposure to the light
source.
For example, tablets, capsules, etc., should be spread in a single layer. If testing of the
drug product in the immediate container or as marketed is needed, the samples should
be placed horizontally or transversely with respect to the light source, whichever
provides for the most uniform exposure of the samples.

Analysis of Samples
At the end of the exposure period, the samples should be examined for any changes in
physical properties (e.g., appearance, clarity or color of solution,
dissolution/disintegration for dosage forms such as capsules, etc.) and for assay.

 Judgement of Results
When evaluating the results of photostability studies to determine whether change
due to exposure to light is acceptable, it is important to consider the results obtained
from other formal stability studies in order to assure that the product will be within
proposed specifications during the shelf life.
3) Q1C Stability Testing for New Dosage Forms

A new dosage form is defined as a drug product which is a different pharmaceutical

product type, but contains the same active substance as included in the existing drug
product approved by the pertinent regulatory authority.

Such pharmaceutical product types include products of different administration

route (e.g., oral to parenteral), new specific functionality/delivery systems (e.g.,
immediate release tablet to modified release tablet) and different dosage forms of
the same administration route (e.g., capsule to tablet, solution to suspension).

Stability protocols for new dosage forms should follow the guidance in the parent
stability guideline in principle. However, a reduced stability database at submission
time (e.g., 6 months accelerated and 6 months long term data from ongoing studies)
may be acceptable in certain justified cases.
4) Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products

This document provides guidance on bracketing and matrixing study designs. Specific
principles are defined in this guideline for situations in which bracketing or matrixing
can be applied.

GUIDELINES
A full study design is one in which samples for every combination of all design factors
are tested at all time points.
A reduced design is one in which samples for every factor combination are not all
tested at all time points. A reduced design can be a suitable alternative to a full design
when multiple design factors are involved.
Before a reduced design is considered, certain assumptions should be assessed and
justified.
The potential risk should be considered of establishing a shorter retest period or shelf
life than could be derived from a full design due to the reduced amount of data
collected.
Applicability of Reduced Designs

Reduced designs can be applied to the formal stability study of most types of drug
products, although additional justification should be provided for certain complex drug
delivery systems where there are a large number of potential drug interactions.
The use of any reduced design should be justified.

Bracketing
Bracketing is the design of a stability schedule such that only samples on the extremes
of certain design factors (e.g., strength, container size and/or fill) are tested at all
time points as in a full design. Removal of some batches from testing.

Design Factors: Design factors are variables (e.g., strength, container size and/or fill)
to be evaluated in a study design for their effect on product stability.

I. Strength: Bracketing can be applied to studies with multiple strengths of

identical or closely related formulations. Examples include but are not limited to
(1) Capsules of different strengths made with different fill plug sizes from the same
powder blend,
(2) tablets of different strengths manufactured by compressing varying amounts of the
same granulation, and
(3) oral solutions of different strengths with formulations that differ only in minor
excipients. With justification, bracketing can be applied to studies with multiple
strengths where the relative amounts of drug substance and excipients change in a
formulation.
II. Container Closure Sizes and/or Fills:
Bracketing can be applied to studies of the same container closure system where
either container size or fill varies while the other remains constant.
Various characteristics of the container closure system that may affect product stability
include container wall thickness, closure geometry, surface area to volume ratio,
headspace to volume ratio, water vapour permeation rate or oxygen permeation
rate per dosage unit or unit fill volume.
Example: An example of a bracketing design is based on a product available in three
strengths and three container sizes.
Matrixing
Matrixing is the design of a stability schedule such that a selected subset of the total
number of possible samples for all factor combinations would be tested at a specified
time point. Removal of some testes from batches.
The design assumes that the stability of each subset of samples tested represents the
stability of all samples at a given time point.
Design Factors: Matrixing designs can be applied to strengths with identical or closely
related formulations.
Examples
1) capsules of different strengths made with different fill plug sizes from the same
powder blend,
2) tablets of different strengths manufactured by compressing varying amounts of
the same granulation, and
3) oral solutions of different strengths with formulations that differ only in minor
excipients.
Design Considerations
In a design where time points are matrixed, all selected factor combinations
should be tested at the initial and final time points, while only certain fractions of
the designated combinations should be tested at each intermediate time point.
All selected combinations of batch, strength, container size, and fill, among other
things, should also be tested at 12 months or at the last time point prior to
submission.

Example:
Examples of matrixing designs on time points for a product in two strengths (S1 and
S2).
The terms “one-half reduction” and “one-third reduction” refer to the reduction
strategy initially applied to the full study design. For example, a “one-half reduction”
initially eliminates one in every two time points from the full study design and a
“one-third reduction” initially removes one in every three.
5) Q1E Evaluation of Stability Data

This guideline addresses the evaluation of stability data that should be submitted in
registration applications for new molecular entities and associated drug products.

The guideline provides recommendations on establishing retest periods and shelf

lives for drug substances and drug products intended for storage at or below “room
temperature”*. It covers stability studies using single- or multi-factor designs and full
or reduced designs.

Data presentation

Data for all attributes should be presented in an appropriate format (e.g., tabular,
graphical) and an evaluation of such data should be included in the application. The
values of quantitative attributes at all time points should be reported as measured (e.g.,
assay as percent of label claim).
Extrapolation
Extrapolation is the practice of using a known data set to infer information about
future data. Extrapolation to extend the retest period or shelf life beyond the period
covered by long-term data can be proposed in the application, particularly if no
significant change is observed at the accelerated condition.
An extrapolation of stability data assumes that the same change pattern will continue
to apply beyond the period covered by long-term data.

Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or
Products Intended for Room Temperature Storage:
For drug substances or products intended for storage at room temperature, the
assessment should begin with any significant change at the accelerated condition and,
if appropriate, at the intermediate condition, and then through the long-term data.
6) Q1F Stability Data Package for Registration Applications in Climetic Zones III &
IV
ICH Q1 F Stability Data Package for Registration Applications in Climatic Zones III and
IV defined storage conditions for stability testing in countries located in Climatic
Zones III (hot and dry) and IV (hot and humid), i.e. countries not located in the ICH
regions and not covered by ICH Q1 A (R2) Stability Testing for New Drug Substances
and Drug Products. 30°C/65% RH was defined as the long-term storage condition for
Climatic Zone III/IV countries in ICH Q1F.
However, based on new calculations and discussions, some countries in Climatic Zone IV
have expressed their wish to include a larger safety margin for medicinal products to
be marketed in their region.
As a consequence, several countries and regions have revised their own stability
testing guidelines, defining up to 30°C/75 % RH as the long-term storage conditions for
hot and humid regions.
In assessing the impact of the withdrawal of ICH Q1F on intermediate testing conditions
defined in ICH Q1A (R2), the decision was reached to retain 30°C/65%RH.
However, regulatory authorities in the ICH regions have agreed that the use of more
stringent humidity conditions such as 30°C/75% RH will be acceptable should the
applicant decide to use them.
Q2 Analytical Validation

Introduction
The objective of validation of an analytical procedure is to demonstrate that it is suitable
for its intended purpose. A tabular summation of the characteristics applicable to
identification, control of impurities and assay procedures is included.

Types of Analytical Procedures to be Validated

The discussion of the validation of analytical procedures is directed to the four most
common types of analytical procedures:
 Identification tests;
 Quantitative tests for impurities' content;
 Limit tests for the control of impurities;
 Quantitative tests of the active moiety in samples of drug substance or drug product
or other selected component(s) in the drug product.

Although there are many other analytical procedures, such as dissolution testing for
drug products or particle size determination for drug substance and they are equally
important to those listed above.
Typical validation characteristics which should be considered are listed below:
1. Accuracy
2. Precision
Repeatability
Intermediate Precision
Reproducibility
3. Specificity
4. Detection Limit
5. Quantitation Limit
6. Linearity
7. Range
Furthermore revalidation may be necessary in the following circumstances:
– changes in the synthesis of the drug substance;
– changes in the composition of the finished product;
– changes in the analytical procedure.
Q3A-Q3D Impurities
This guidelines are intended to provide guidance for registration applications on the
content and qualification of impurities in new drug substances and products.

1. IMPURITIES IN NEW DRUG SUBSTANCES

Impurities can be classified into the following categories:
o Organic impurities
o Inorganic impurities
o Residual solvents

 RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES

The applicant should summarise the actual and potential impurities most likely to
arise during the synthesis, purification, and storage of the new drug substance.
The studies conducted to characterise the structure of actual impurities present in
the new drug substance.

 ANALYTICAL PROCEDURES
procedures are validated and suitable for the detection and quantification of impurities.
 REPORTING IMPURITY CONTENT OF BATCHES
• Analytical results should be provided in the application for all
batches of the new drug substance used for clinical, safety, and
stability testing, as well as for batches representative of the
proposed commercial process.
• For each batch of the new drug substance, the report should
include:
 Batch identity and size
 Date of manufacture
 Site of manufacture
 Manufacturing process
 Impurity content, individual and total
 Use of batches
 analytical procedure used
LISTING OF IMPURITIES IN SPECIFICATIONS

The specification for a new drug substance should include a list of impurities. Those
individual impurities with specific acceptance criteria included in the specification for
the new drug substance are referred to as "specified impurities" in this guideline.
Acceptance criteria should be set no higher than the level that can be justified by safety
data, and should be consistent with the level achievable by the manufacturing process
and the analytical capability.

QUALIFICATION OF IMPURITIES
Qualification is the process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity profile at the level(s)
specified.

The applicant should provide a rationale for establishing impurity acceptance criteria
that includes safety considerations. The level of any impurity present in a new drug
substance that has been adequately tested in safety and/or clinical studies would be
considered qualified.
2. IMPURITIES IN NEW DRUG PRODUCTS

This guideline addresses only those impurities in new drug products classified as
degradation products of the drug substance or reaction products of the drug
substance with an excipient and/or immediate container closure system.
The specification for a new drug product should include a list of degradation products
expected to occur during manufacture of the commercial product and under
recommended storage conditions.

The applicant should provide a rationale for establishing degradation product

acceptance criteria that includes safety considerations. The level of any degradation
product present in a new drug product that has been adequately tested in safety and/or
clinical studies would be considered qualified.
In summary, the new drug substance specification should include, where applicable, the
following list of impurities:
 Organic Impurities
 Each specified identified / unidentified impurity
 Total impurities
 Residual Solvents
 Inorganic Impurities
Q4A-Q4B Pharmacopoeias

The pharmacopoeial authorities, working together through the Pharmacopoeial

Discussion Group (PDG), have been closely involved with the work of ICH since the
outset and harmonisation between the major pharmacopoeias.
This document describes a process for the evaluation and recommendation by the
Expert Working Group (EWG) of selected pharmacopoeial texts to facilitate their
recognition by regulatory authorities for use.
There are many annex are given under this section which are listed below.

Annex 1: Residue on Ignition/Sulphated Ash General Chapter.

Annex 2: Test for Extractable Volume of Parenteral Preparations General

Chapter

Annex 3: Test for Particulate Contamination General Chapters

Annex 4A: Microbiological Examination of Non-sterile Products: Microbial

Enumeration Tests General Chapter.

Annex 4B: Microbiological Examination of Non-sterile Products: Tests for

specified Micro-Organisms General Chapter.
Annex 4C: Microbiological Examination of Non-sterile Products: Acceptance Criteria for
Pharmaceutical Preparations and Substances for Pharmaceutical Use General Chapter.

Annex 5: Disintegration Test General Chapter

Annex 6: Uniformity of Dosage units General Chapter

Annex 7: Dissolution Test General Chapter

Annex 8: Sterility Test General Chapter

Annex 9: Tablet Friability General Chapter

Annex 10: polyacrylamide Gel Electrophoresis General Chapter

Annex 11: Capillary Electrophoresis General Chapter

Annex 12: Analytical Sieving General Chapter

Annex 13: Bulk Density and Tapped Density of powders General Chapter

Annex 14: Bacterial Endotoxins Test General Chapter

Q5A-Q5E Quality of Biotechnological Products

Q5A(R1): Viral Saftey Evaluation of Biotechnology Products Derived from Cell

Lines of Human or Animal Origin
This document is concerned with testing and evaluation of the viral safety of
biotechnology products derived from characterised cell lines of human or animal
origin and outlines data that should be submitted in the marketing
application/registration package.

2. Q5A(R2): Viral Saftey Evaluation of Biotechnology Products Derived from Cell

Lines of Human or Animal Origin
The Q5A(R2) EWG is working on the revision of the of the Q5A(R1) Guideline with a
view to reflecting new biotechnology product types, advances in manufacturing
technology, analytical methods for virus testing, and scientific knowledge that have
occurred since publication of the original document in 1999.

3. Q5B: Analysis of the Expression Construct in Cells Used for Production of r-

DNA Derived Protein Products
This document is intended to describe the types of information that are considered
valuable in assessing the structure of the expression construct used to produce
recombinant DNA derived proteins.
Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/
Biological Products
This document augments the stability Guideline (Q1A) and deals with the particular
aspects of stability test procedures needed to take account of the special
characteristics of products in which the active components are typically proteins
and/or polypeptides.

Q5D: Derivation and Characterization of Cell Substrates Used for Production of

Biotechnological/Biological Products
This document provides broad guidance on appropriate standards for the derivation
of human and animal cell lines and microbial cells used to prepare biotechnological/
biological products, and for the preparation and characterisation of cell banks to be
used for production.

Q5E: Comparability of Biotechnological/Biological Products Subject to Changes

in their Manufacturing Process
The objective of this document is to provide principles for assessing the comparability
of biotechnological/biological products before and after changes are made in the
manufacturing process for the drug substance or drug product.
Q6A-Q6B Specifications

Q6A: Specification: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances.
This document provides guidance on the setting and justification of acceptance
criteria and the selection of test procedures for new drug substances of synthetic
chemical origin, and new drug products produced from them, which have not been
registered previously in the ICH regions.

Q6B: Specifications: Test Procedures and Acceptance Criteria for

Biotechnological/ Biological Products.
This document provides general principles on the setting and justification of a
uniform set of international specifications for proteins and polypeptides which are
produced from recombinant expression systems.
Q7 Good Manufacturing Practice

This document is intended to provide guidance regarding Good Manufacturing

Practice (GMP) for the manufacturing of Active Pharmaceutical Ingredients (APIs)
under an appropriate system for managing quality. It is also intended to help ensure
that APIs meet the requirements for quality and purity that they purport or are
represented to possess. This Guideline applies to the manufacture of APIs for use in
human drug (medicinal) products.

Q8 Pharmaceutical Development
This Guideline is intended to provide guidance on the contents of Section 3.2.P.2
(Pharmaceutical Development) for drug products as defined in the scope of Module
3 of the Common Technical Document .
The guideline does not apply to contents of submissions for drug products during
the clinical research stages of drug development.
To determine the applicability of this guideline for a particular type of product,
applicants should consult with the appropriate regulatory authorities.
Q9 Quality Risk Management

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.

Q10 Pharmaceutical Quality System

This Guideline applies to the systems supporting the development and manufacture
of pharmaceutical drug substances and drug products, including biotechnology and
biological products, throughout the product lifecycle.

The elements of Q10 should be applied in a manner that is appropriate to each of the
product lifecycle stages, recognising the differences among, and the different goals of
each stage.
Q11 Development and Manufacture of Drug Substances

This Guideline describes approaches to developing and understanding the

manufacturing process of the drug substance, and also provides guidance on what
information should be provided in Module.

It addresses aspects of development and manufacture that pertain to drug substance,

including the presence of steps designed to reduce impurities.

Q12 Lifecycle Management

Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle
Management This new Guideline is proposed to provide a framework to facilitate the
management of postapproval Chemistry, Manufacturing and Controls (CMC) changes in a
more predictable and efficient manner across the product lifecycle.
Q13 Continuous Manufacturing of Drug Substances and Drug Products

This Guideline is proposed to:

Capture key technical and regulatory considerations that promote harmonisation,
including certain Current Good Manufacturing Practices (CGMP) elements specific to
Continuous Manufacturing (CM),

Allow drug manufacturers to employ flexible approaches to develop, implement, or

integrate CM for the manufacture – drug substances and drug products – of small
molecules and therapeutic proteins for new and existing products,

 Provide guidance to industry and regulatory agencies regarding regulatory

expectations on the development, implementation, and assessment of CM
technologies used in the manufacture of drug substances and drug products.
Q13 Continuous Manufacturing of Drug Substances and Drug Products
It is revised guidelines of ICH Q2(R1) Guideline on Validation of Analytical
Procedures.

The scope of the revision of ICH Q2(R1) will include validation principles that cover
analytical use of spectroscopic or spectrometry data (e.g., NIR, Raman, NMR or MS)
some of which often require multivariate statistical analyses. The guideline will
continue to provide a general framework for the principles of analytical procedure
validation.

The new guideline is proposed to harmonise the scientific approaches of Analytical

Procedure Development, and to provide the principles relating to the description of
Analytical Procedure Development process.

This new guideline is intended to improve regulatory communication between

industry and regulators and facilitate more efficient, sound scientific and risk-based
approval as well as post-approval change management of analytical procedures.
2) Safety Guidelines
ICH has produced a comprehensive set of safety Guidelines to uncover potential risks
like carcinogenicity.
3) Efficacy Guidelines
The work carried out by ICH under the Efficacy heading is concerned with the design,
conduct, safety and reporting of clinical trials. It also covers novel types of medicines
derived from biotechnological processes to produce better targeted medicines.
4) Multidisciplinary Guidelines
Those are the cross-cutting topics which do not fit uniquely into one of the Quality,
Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA), the
Common Technical Document (CTD) and the development of Electronic Standards for
the Transfer of Regulatory Information (ESTRI).
Quality by design (QbD)

Definition & Concept:

‘systematic approach to development that begins with predefined objectives and
emphasizes product and process understanding and process control, based on sound
science and quality risk management’

 Qualıty by desıgn means designing and developing formulations and manufacturing

processes to ensure a predefined quality.

 Qualıty by desıgn requires understanding how formulation and manufacturing

process variables influence product quality.

 Qualıty by desıgn ensures Product quality with effective control strategy.

Objectives of QbD:
 The main objectives of QbD is to ensure the quality products, for that product &
process characteristics important to desired performance must be resulting from a
combination of prior knowledge & new estimation during development.
From this knowledge & data process measurement, desired attributes may be
constructed.

 Ensures combination of product & process knowledge gained during development.

 Provide a protective approach to product development, potential to reduce queries

and review time to quickly get to the root cause and resolution of any deviation.

 Allows for continuous improvements in products and manufacturing process.

 Allows for better understanding of how APIs and excipients affect manufacturing.

 Increase manufacturig efficiency, reduce costs and waste.

ICH guidelines Q8, Q9, Q10 & Q11 give the concept of QbD as those guidelines are
linked in a series of documents exploring pharmaceutical products lifecycle.

ICH Q8: Pharmaceutical Development

 ICH Q9: Quality Risk Management
 ICH Q10: Pharmaceutical Quality System
 ICH Q11: Development and Manufacture of Drug Substances
Elements of QbD Program
1. The Target Product Quality Profile (TPQP)
TPQP has been defined as a “prospective and dynamic summary of the quality
characteristics of a drug product that ideally will be achieved to ensure that the
desired quality, and thus the safety and efficacy, of a drug product is realized”.
TPP forms the basis for product design in the following way
 Dosage form
 Route of administration
 Strength
 Release
 Pharmacological characteristic
 Drug product quality criteria
 Pharmaceutical elegance

2. Critical Quality Attribute (CQA)

Once TPQP has been identified, the next step is to identify the relevant CQAs.
A CQA has been defined as “a physical, chemical, biological, or microbiological
property characteristic that should be within an appropriate limit, range, or
distributed to ensure the desired product quality” Prior product knowledge, such
as the accumulated laboratory, nonclinical and clinical experience with a specific
product-quality attribute, is the key in making these risk assessments.
3. Critical Process Parameter (CPPs)
Critical process parameters (CPPs) are defined as “parameters whose variability have
an impact on a CQA and therefore should be monitored or controlled to ensure the
process produces the desired quality”
Process robustness is defined as the ability of a process to demonstrate acceptable
quality and performance and tolerate variability in inputs at the same time.

4. Risk Assessment
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.
The initial list of potential parameters which can affect CQAs can be quite extensive but
can be reduced by quality risk assessment (QRA).

5. Design Space
The ICH Q8(R2) States that the design space is multi dimensional combination and
interaction of input variables (e.g., material attributes) and process parameters that
have been demonstrated to provide assurance of quality.
Working within the design space is not considered as a change. Movement out of the
design space is considered to be a change and would normally initiate a regulatory post
approval change process .
6. Control Strategy
Control strategy is defined as “a planned set of controls, derived from current product
and process understanding that assures process performance and product quality”.
The ability to evaluate and ensure the quality of inprocess and/or final product based
on process data which typically include a valid combination of measured material
attributes and process controls, ICH Q8(R2).
The control strategy can include the following elements:

Procedural Controls,
In Process Controls,
 Lot Release Testing,
Process Monitoring,
Characterization Testing,
Comparability Testing And
Stability Testing .

7. Life Cycle Management

In the QBD paradigm, process changes within the design space will not require review
or approval.
Therefore, process improvements during the product life cycle with regard to process
consistency and throughput could take place with fewer post approval submissions.
ISO 9000 & ISO14000
ISO (International Organization for Standardization) is an independent, non-
governmental organization and the world's largest developer of voluntary
International Standards.
ISO 9000:
ISO 9000 is a family of standards for quality management systems.
ISO 9000 is maintained by ISO, the International Organization for Standardization and
is administered by accreditation and certification bodies.
ISO 9000 is defined as a set of international standards on quality management and
quality assurance developed to help companies effectively document the quality system
elements needed to maintain an efficient quality system. They are not specific to any
one industry and can be applied to organizations of any size.
ISO 9000 can help a company satisfy its customers, meet regulatory requirements, and
achieve continuous improvement. It should be considered to be a first step or the base
level of a quality system.
Who created ISO 9000:
 International Organization for Standardization – Geneva
 ISO tech committee - TC 176 started in 1979
 Standards created in 1987
 To eliminate country to country differences
 To eliminate terminology confusion
 To increase quality awareness
The standards in the ISO 9000 family include:
1) ISO 9000:2015 – Quality Management System: Fundamentals & Vocabulary
2) ISO 9001:2015 – Quality Management System: Requirements
3) ISO 9004:2018 - Quality management — Quality of an organization —
Guidance to achieve sustained success
7 Quality Management Principles
ADVANTAGES OF ISO 9000 SYSTEM
The advantages associated with the ISO 9000 certification system are numerous, as
both business analysts and business owners will attest. These benefits, which can
impact nearly all corners of a company, range from increased stature to bottom-line
operational savings.

They include:
 Create a more efficient, effective operation
 Enhanced product quality at a reasonable price
 Increase customer satisfaction and retention
 Simplification for improved usability
 Reduce audits
 Enhance marketing
 Improve employee motivation, awareness and moral
 Promote international trade
 Increased distribution efficiency, and ease of maintenance
 Increase profit
 Improved health, safety and environmental protection, and reduction of waste.
ELEMENTS OF ISO 9000 SYSTEM

This standard is based on a number of quality management principles including a

strong customer focus, the motivation and implication of top management, the
process approach and continual improvement.
ISO 9000 consists of fundamental elements of basic quality system that includes:

1) Management responsibility
2) Quality system
3) Contract review
4) Design control
5) Document and data control
6) Purchasing
7) Customer supplied product
8) Product identification and traceability
9) Process control
10) Inspection and testing
11) Inspection, measuring and test equipment
12) Inspection and test status
13) Control of nonconforming product
14) Corrective and preventive action
15) Handling storage, packaging, preservation and delivery
16) Quality records
17) Internal quality audits
18) Training
19) Servicing
20) Statistical techniques

1) Management responsibility:
To comply with this requirement there must be a written Quality Policy for the
organization. This Quality Policy document must be signed by the current
management for the location or site in question.
The following criteria must be fulfilled:
The company has a brief but comprehensive Quality Policy.
This Quality Policy should be included in the Quality Manual as well as being on
public display.
Quality Objectives have been established by management and there is a statement
outlining the intent to deliver against these objectives.
2) Quality system:

It covers the quality system of the organization and it's documentation.

Initially the system organization is dealt with and recognized to be part of TQM (Total
Quality Management). Output from each function or part must meet agreed customers'
requirements.
The quality system is understood to be interrelated aspects of:
 Suppliers' needs and interests.
 Customers' needs and expectations.

3) Contract review
The 1994 version of ISO 9002 places a much greater emphasis on Contract Review
Where the sales of product and services are covered by contracts there must be
clear evidence of a review of terms and conditions attention should be paid to the
following:
 Ensuring requirements are agreed and clearly understood by all involved parties.
 Checking that all parties have the necessary resources, organization and facilities.
4) Design Control
5) Document and data control
It deals with how documentation should be treated. All documents in must be
checked before issue or re-issue after revision. Documents must be positioned so
that all persons concerned have easy access to them. A master record file has to be
kept. People responsible for revision and issuing of documentation must be identified.
6) Purchasing
It deals with purchasing. In the procurement of materials or external services,
quality need to be assessed in respect to agreed specifications.
Assessment of subcontractors (i.e. vendors or suppliers), ensures that all have the
capability of supplying materials or services of the required quality. A formal
assessment of capability is needed, possibly through an audit of a subcontractor's
quality or by way of other evidence. Documented evidence on formal assessments is
required.

7) Customer supplied product

deals with purchaser supplies. Here, purchaser means our external customers. In
manufacturing the external customer may make "Free Issue", which is where they
provide materials for incorporation in products they ultimately buy back.

8) Product identification and traceability

A manufactured product must be traced through the various stages of its production
and delivery.
This is crucial to help identify the stage and hence the cause of any product failure.
Where different products are similar or identical they must be identified using a
method of labeling or coding.
9) Process control
The process must be carried out in a controlled way, so that plans / procedures /
instructions are to hand, equipment and personnel used are adequate and that the
general conditions are amenable to achieving the plans.
To ensure that a process is carried out in a controlled manner the process must be well
documented and the staff well trained.

10) Inspection and testing

Inspection of incoming materials must be directed by a sampling plan which
details the selection of materials for inspection / testing from each received batch.
Results must be documented, describing material inspected, number of rejects,
reasons for rejection and corrective action.
In-process inspection and final inspection upon completion of all products must be
carried out.

11) Inspection, measuring and test equipment

It deals with the equipment used in inspection and testing, ensuring that it is
suitable for its purpose. Frequency of calibration of equipment used in manufacturing
should be based on stability, purpose and degree of utilization. Records of
maintenance work must be retained. Recalibration must carried out.
12) Inspection and test status
There needs to be an indicator that states what tests a product has been through and
whether it passed or failed.
In order to satisfy this part of the requirement, the company must:

Have a system or method for identifying the inspection and test status of the
product at all relevant stages in the process.
 Ensure that the system used is defined as part of the process specification or is
written documented work instructions.
 Ensure that the personnel who operate processes related to this segregation system
are trained in the discipline required to maintain it.
 Ensure that only products that have passed the required inspection and tests are
shipped, put into use, or installed.
13) Control of nonconforming product
The aim here is to ensure that non-conforming product is not used by mistake. Non-
conforming material must be isolated and clearly identified.
Every non-conforming lot should be accompanied by paperwork detailing the reasons
for failure. Defects and claims should be sent to vendors without delay.

14) Corrective and preventive action

It is necessary that avoidance of mistakes to be achieved following analysis of quality
records, service reports and customer complaints. In all cases corrective action must be
monitored.
To satisfy ISO requirement the Company must:
 Establish and document a system for investigating the cause of defective products
or processes.
 establish a system for ensuring that appropriate corrective action is decided upon
and implemented.
 Ensure that responsibility for corrective action is clearly defined.
 Establish and document procedures for analyzing the business.
 Keep records of all complaints and follow-up actions.
 Correct any deficiencies before they can cause defects in products or processes.
 Establish and document a process to ensure that corrective actions are implemented
in an effective manner.
 Keep records of defects, the investigation of their cause and the corrective actions.
 Establish and document a process that ensures procedure amendments, resulting from
corrective actions, are recorded and that work methods are changed to reflect the
changes in amended procedures.
15) Handling storage, packaging, preservation and delivery
A policy must be set for handling, storage and packaging. Handling of products, i.e. When
loading and unloading, must be done with due care for the product.
Storage areas must be clean and the environment properly controlled (for example,
heat, humidity, light.)
16) Quality records
Quality records are the routine control and reporting documents that show the
progress of the quality management system. Quality records should be kept over a
reasonable length of time and stored in a safe secure area.
The following are key records to be kept:
 Audits of the quality system.
 Calibration of test and measuring equipment.
 Analyses of process control data.
 Records of corrective actions.
 Customer complaints.
 Records of concessions (deviations).
 Training records.
17) Internal quality audits
Planned and documented checks on the implementation and operation of the Quality
Management System help to confirm that it is being operated correctly and effectively.
Internal Quality Audits must be conducted on a regular basis.

Records must be kept, such as the following:

 Deficiencies found.
 Corrective action required.
 Time agreed for corrective action to be carried out.
 Personnel responsible for corrective action.

18) Training
Training of personnel is concerned with the competence of personnel to do their
assigned task.
Where a lack of skills of qualifications is found, staff need to attend internal or
external training courses.
If a member of staff is new to the task then efforts must be made to train them. Staff
performance needs to be regularly appraised and recorded.
What is ISO 14000
Essentially, ISO 14000 is a series of international, voluntary environmental
management standards as well as guides and technical reports.

It specifies the requirements for establishing an Environmental policy

determining the environmental impacts of products or services, planning
environmental objectives, implementing programs to meet the various objectives,
and conducting corrective action and management review.

The objective of the ISO 14000 series of standards is to promote

effective environmental management systems in organizations. Besides, the
standards seek to provide cost-effective tools that make use of best practices for
organizing and applying information about environmental management.

Actually, the ISO 14000 family was developed in response to a recognized

industry need for standardization.
History of ISO 14000
According to history, the first environmental management system, BS 7750 was
published in 1992 by the BSI British standard institution group.

The International Organisation for Standardization (ISO) created the ISO 14000
family of standards in 1996.

Series of ISO 14000

In 2004, ISO 14001 underwent to revision and the current revision of ISO 14001
was published in September 2015.

Following are the aspects of environmental management addressed by the ISO

series:
Environmental Management Systems (EMS)
Environmental Auditing & Related Investigations (EA&RI)
Environmental Labels and Declarations (EL)
Environmental Performance Evaluation (EPE)
Life Cycle Assessment (LCA)
Terms and Definitions (T&D)
What are the basic Principles behind the ISO 14000 series?

Following are the key principles of the ISO 14000 standards

Result in better environmental management:
To Encompass environmental management system and the aspects of
environmental products
Applicable in all countries.
 Promote the broader interests of the public as well as users of these standards.
Cost-effective and flexible so they are able to meet the differing needs of
organizations of any type or size, worldwide
Flexibility to be suitable for internal and external verification
Scientifically based
 Practical, useful and usable.
What are the benefits of getting ISO 14000 Certified?
Following are the benefits of getting the ISO 14000 certification:
It identifies and controls the environmental impact of its activities, product or
services.
Continuously improve its environmental performance
Helps in implementing a systematic approach to setting environmental objectives
to achieving these and to demonstrating that they have been achieved.
 Ensuring legal compliance.

Internal Benefits:
Assurance to the management: It is in the control of the organizational procedures
and activities having an impact on the environment.
Assure employees: It assures the employees that they are working for an
environmentally responsible organization.
External Benefits:
It provides assurance on environmental issues to the external stakeholders
such as customers, community and regulatory agencies.
Comply with the regulations of the environment.

Claims and communication: It supports the organization’s claims and

communication about its own environmental policies, plans, and actions by
gaining its EMS certificate.

Demonstrate conformity: It provides a framework for the demonstration

conformity via suppliers’ declarations of conformity, assessment of conformity
by an external stakeholder such as business client and for certification of
conformity by an independent certification body.
Here are the six core elements of an EMS, according to the ISO 14001 standard:
Environmental policy
Planning
Implementation
Study & correct
Management review
Continuous improvement

1. Environmental policy
Clearly outline the environmental policy.
This is a clearly written statement outlining a business’s objectives and targets, in
the context of their environmental policy. It includes principles on environmental
sustainability as well as performance indicators relating to the EMS.
Policy should always be clearly communicated both internally and externally, as
well as fully implemented.
2. Planning
Make complete, thorough plans for implementing the EMS.
With clear, thorough planning, organizations stand to assess the environmental
impact of all operations. The purpose of planning is to develop a process for
identifying compliance requirements, documenting targets and objectives, and
creating a plan for deployment.
 3.Implementation
After planning, this step involves the execution of those plans.
This step will also incorporate adjustments and even building of new processes to
adapt to changing requirements.

It’s important that organizations clearly define, document, and communicate their
implementation procedures for purposes of training and compliance.
Well-documented processes also make it easier to improve upon those processes.
Scope of this section also includes emergency response planning and preparedness.

4.Study&correct
After implementing the most basic EMS, observe how it functions, and make
corrections or optimizations as needed.

This step involves the management of new and existing procedures to make sure
plans are hit and that the EMS is functioning as it should be.

Organizations will benefit from establishing a system for documentation as well as

conducting audits of the EMS.
5. Management review
This could really tie in with the previous section, but it’s important to have a
distinguished review of the EMS conducted by management, to make sure that
everything is functioning within the scope of successful performance. Management
will be best positioned to assess this kind of effectiveness.

6. Continuous improvement
Every EMS will utilize principles of continuous improvement to enable organizations
to optimize all aspects of the system.
STEPS FOR REGİSTRATİON
It must be noted that ISO itself does not provide certification to the companies.
Certification is done by the external bodies. It is very important that you choose
recognized and credible certification body.
1. Finding an ISO 9001 Registrar
You’ll need to begin searching for an ISO registrar during the 2 to 3 months your
company is still building its quality system. You can search the National Accreditation
Board (NAB) to select the registrar right for you.
Registrars must meet the requirements of the ISO Accreditation Bodies.

2. Selecting an ISO Registrar

Select a registrar that has experience within the scope category of your specific
industry, which you can also find on the NAB site.
Registrar qualifications are a key consideration. Registrars must be accredited in a
particular industrial sector in order for them to be able to certify a company in that
sector.
After qualifications, price is always a concern. Be sure to evaluate the total cost
including expenses, fees and the cost of surveillance.

3. Creating an ISO Application

A company and a registrar will agree on the application contract. This is an important
step of the ISO Registration Process because it defines the rights and obligations of
both parties, and includes liability issues, confidentiality and access rights.
4. Conducting a Quality Document Review
The registrar will require a copy of your quality manual and procedures to verify
that all the requirements of the standard are addressed. The ISO Registration Process
is not a quick process, be sure to allow 2-4 weeks in advance for the registrar to
fully review all of the necessary documents.

5. Determining Preassessment Need

It saves time and allows the registrar to assess any issues and resolve logistics
before the actual assessment audit.
The Preassessment is an initial review of your Quality Management System to
identify any significant omissions or weaknesses in the system and provide your
organization an opportunity to correct any deficiencies before the regular
registration assessment is conducted.

6. Issuing an ISO Assessment

During the audit, or physical onsite inspection of procedures in action, the
auditors will issue findings if they assess anything that doesn’t meet requirements,
or nonconformities.
The length of this step of the ISO Registration Process will depend on the scope of
the audit and the size your organization.
In general, the flow of activities during the audit is as follows:

1. Opening Meeting.
An introduction of the audit team and key personnel in your company. The scope
and general approach to the audit is discussed. This is also the time to question
anything that is unclear in the audit schedule and communicate any last minute
changes to the system or schedule.
2. Brief tour of the facility. Keep it brief, the auditors just want to get a general
feel for the layout and processes involved. This may also be done at the
preassessment.
3. Additional review of documents.
Audit team members review documentation for areas they will audit.
4. Examination. The audit is conducted, personnel are interviewed, and
objective evidence is collected to show the system has been effectively implemented.
5. Daily review. At the end of each day or the beginning of the next, the audit
team reviews any issues identified during the assessment. Potential findings or
nonconformities may be clarified at this time.
6. Closing Meeting. The audit team states their conclusions regarding the audit
and presents any findings or nonconformities that were identified along with any
observations they may have.
7. Audit Report issued. Within a few weeks of the audit, the Registrar issues the
audit report. The report generally restates what was discussed in the closing meeting.
During the audit, if the auditors find anything that does not meet with the
requirements of the ISO standard or that does not meet the requirements of your
procedures, they determine the severity and issue a finding. Audit findings are usually
called nonconformities and fall into one of two categories depending on severity.

8. Completing ISO 9001 Registration

After all of the findings are put into the ISO audit report and nonconformities are
addressed, your company has the option to register as ISO 9001 conformant. You will
receive a certificate and can also be listed in a register, which the company can use to
publicize its registration and use in advertising.

9. Checking with Surveillance Audits

To ensure that the system is maintained and that changes don’t result in deficiencies in
the system, registrars perform regular surveillances of the system. Over the three-year
period of your certificate, auditors will perform one full and two partial checks of your
system.
NATIONAL ACCREDITATION BOARD FOR TESTING
AND CALIBRATION LABORATORIES (NABL)

NABL stands for National Accreditation Board for Testing and Calibration
Laboratories. This institution is an autonomous body which is a part of the Quality
Council of India and registered under the Societies Act in 1992.
The main aim of this institution is to provide an impartial assessment of the quality
standards for institutions, government bodies, and primary institutions.

The type of testing conducted for NABL approval will include proficiency testing, lab
testing, medical testing, and testing for referenced medical producers. This would
also include testing for various food industries on the quality standards.

Why is NABL Approval Required?

NABL approval is a form of accreditation that provides an impartial report on the

quality standards on a particular product.

NABL approval is required for a Conformity Assessment Body (CAB) to prove that the
products developed come with the quality that meets consumers' needs. All CABs have
to ensure to take NABL approval to meet the requirements of quality standards.
Hence NABL approval would provide formal recognition related to a product that is
produced in a CAB. This would not only be important for domestic products but also
required when products and devices are exported outside India.

In the accreditation process, a third-party assessment is conducted on quality

standards. These quality standards should confirm with the international
requirements.
NABL approval is thus a quality assessment that provides technical standard approval
when it comes to products that are produced by the CABs.

What are the objectives of NABL Approval?

This form of approval would provide a license to the individual CABs to operate in
the domestic markets.
CABs complying with the requirements of the NABL will ensure that compliance is
followed regularly.
NABL approval would increase the standards of quality of CAB products,
especially in medical testing, food tasting, and forensic testing. This will improve the
quality of products developed and manufactured in India.
NABL has entered into MOUs (Memorandum of Understandings) with different
international institutions on enhancing training and access to technical R & D. Any
CAB with NABL approval would get the benefits of international training.
NABL approval will promote confidence and increase the production in medical
and calibration labs.
 Quality Assurance standards would be provided through NABL.
This approval will improve the long term performance of the CAB.
increase management system.
Confidence in customer

Eligibility Criteria for NABL Approval

To satisfy the requirement of the NABL, the institution (CAB) has to satisfy the
following eligibility criteria:
First and foremost, the institution must be a CAB carrying out relevant activities such
as laboratory testing, calibration, food processing, research, and development.
A CAB institution must either appoint a representative to start the formalities for
the NABL approval process.
The appointed representative must be aware of the existing quality processes
followed by the CAB.
The institution (CAB) must have developed a manual that indicates the quality
standards. Such quality standards must satisfy the requirements of :
a) ISO/ IEC 17025: 2005; or (International Electrotechnical Commission)
b) ISO 15189: 2012; or
c) ISO/IEC 17043/2010.

The CAB must have an appointed manager who has relevant training up to 4
days on internal audit and management policies, which are followed.

The quality document which is prepared by the CAB must be implemented

immediately. The CAB must also satisfy the criteria as required, according to
NABL 130 which provides the criteria for Site testing and Site Calibration
Laboratories.

Any applicant must participate in the Proficiency Training Program, which is

conducted by the NABL or an international institution. If there is no form of
training available, the institution can carry out an inter-lab comparison when it
comes to quality assessment.
The CAB must carry out at least one internal audit and management review before
applying for the NABL approval.
Procedure for NABL Approval

Step 1- Make an Application

In this step, the institution must make an application to the NABL. Along with the
application, respective documents must be submitted to the NABL. An application
must be made in triplicate (3 copies). Two copies must describe the quality manual of
the management system. This must be in accordance with the requirement of the
ISO/ IEC 17025: 2005 or ISO 15189: 2012 or ISO/IEC 17043:2010 or ISO
17034:2016.

Step 2- Payment of Fees

The applicant has to pay the respective fee, which is present under NABL 100. If an
applicant does not want to make any form of information disclosures, then the same
reasons must be provided to the authority.

Step 3- Receipt of Application

When the application is received by the NABL Secretariat (along with the requisite
fee), a unique identification number (UIN) will be issued. The applicant must quote
this number in all correspondences with the NABL.
Step 4- Pre-Assessment Visit
If there are no discrepancies in the application, then a lead assessor will be
appointed to carry out a pre-assessment visit to the CAB. The assessment is carried
out to understand if there are no discrepancies in the quality control adopted by the
CAB. Along with this, the assessor will find out if there is any other assessment
required to be carried out by the NABL.

Step 5- Submission of Report

After the evaluation is carried out by the lead assessor; a report is submitted to the
Secretariat of the NABL. A copy is submitted to the Secretariat, and all the records are
stored in the document management system of the Secretariat.

Step 6- Assessment Team

When the CAB has taken all the measures to correct the issues, the NABL will form a
team constituted by the lead assessor, technical experts, and other individuals
who are experienced in relevant fields and disciplines. The team analyses and
finds out if compliance is met in accordance with the required standards. If there are
any forms of discrepancies found in the CAB, then a report will be made and
submitted to the Secretariat. In the report, remedies would also be included to
address the discrepancies. A copy of this will be submitted to the respective CAB.
Step 7- Follow-up Action
When the NABL secretariat reviews the report, the CAB must take follow-up
action. This action must be taken within 60 days of the Report of the
Assessment Team. In action, the CAB must mention the corrective action it has
taken to mitigate difficulties.

Step 8- Recommendations
After the follow-up action is taken by the CAB; the Accreditation Committee
will make recommendations to the NABL Chairman. The Chairman's
decision is not binding, and it can be appealed to the director of the NABL.

Step 9- Grant of Certificate

When the accreditation is allowed, the NABL will send the following to the
applicant:
a) Unique Identification Number;
b) Certificate of NABL Approval;
c) Hologram having the NABL signs;
d) Date of Validity of the Certificate; and
e) Discipline.
Step 10- Outstanding Amount
If the applicant has any outstanding amount to pay the NABL; the same must be
made before the certificate is granted to the NABL.

Step 11- Compliance

The Applicant must ensure that compliance has to be maintained. The following
compliances have to be maintained by the applicant.
a) ISO/ IEC 17025: 2005; or
b) ISO 15189: 2012; or
c) ISO/IEC 17043:2010 or ISO 17034:2016.
d) Apart from this, the applicant also has to comply with the terms and conditions of
the NABL 131.