Disclaimer

This document is provided for general information only. Although the statements of fact in this report are obtained from sources that I consider reliable. I
don’t guarantee their accuracy and any such information may be incomplete or condensed. Views are subject to change on the basis of additional or new
research, new facts, developments or updates.
 COMPARISON GUIDELINES OF DRUG REGULATORY AUTHORITIES

 DRAP (Drug Regulatory Authority of Pakistan)

 USFDA (United States Food and Drug Administration)
 MHRA (Medicines and Healthcare products Regulatory Agency)
 MFDS (Ministry of Food and Drug Safety)
 TITCK/TMMDA (Turkish Medicines and Medical Devices Agency)
Report is covering below mentioned Pharmaceutical areas:
1. GMP
2. Registration dossier
3. Renewal dossier
4. Licensing
5. API source
6. Product recall
7. Bioequivalence
8. Pricing
9. Barcoding
10. Pharmacovigilance
11. Regulatory testing laboratory
 GOOD MANUFACTURING PRACTICE (GMP) COMPARISON REPORT OF
REGULATORY AUTHORITIES
DRAP MFDS MHRA USFDA TITCK/TMMDA
Although many aspects of In MFDS GMP guidelines, PHARMACEUTICAL cGMP AND THE CONCEPTS PHARMACEUTICAL
quality are discussed in there is a concept of quality QUALITY SYTEM OF MODERN QUALITY QUALITY SYTEM
DRAP Guidelines but there management which is same as The basic concepts of Quality SYSTEMS The basic concepts of Quality
is no concept of Pharmaceutical Quality Management, Good QUALITY: Management, Good
Pharmaceutical Quality system. Manufacturing Practice (GMP) Every pharmaceutical product Manufacturing Practice (GMP)
System. QUALITY and Quality Risk Management are has established identity, strength, and Quality Risk Management
MANAGEMENT inter-related. purity, and other quality are inter-related.
A. The manufacturer shall PHARMACEUTICAL characteristics designed to ensure PHARMACEUTICAL
ensure that the medicinal QUALITY SYSTEM the required levels of safety and QUALITY SYSTEM
product is suitable for the GMP applies to the lifecycle effectiveness. For the purposes GMP applies to the lifecycle
intended use and conforms to stages from the manufacture of of this guidance document, the stages from the manufacture of
the requirements of product investigational medicinal phrase achieving quality means investigational medicinal
approval (notification) so as to products, technology transfer, achieving these characteristics products, technology transfer,
be manufactured in a manner commercial manufacturing for a product. commercial manufacturing
that there would not be a risk through to product QUALITY UNIT: through to product
of safety, quality or discontinuation. However the Job responsibilities of QA AND discontinuation. However the
effectiveness to the patient. Pharmaceutical Quality System Q.C are separated. Pharmaceutical Quality System
B. Achieving the quality can extend to the pharmaceutical SIX SYSTEM INSPECTION can extend to the pharmaceutical
objective is the responsibility development lifecycle stage as MODEL: development lifecycle stage as
of manufacturer’s described in ICH Q10, which Quality system is related to 5 described in ICH Q10, which
management team and while optional, should facilitate other systems: while optional, should facilitate
requires the involvement and innovation and continual i. Production system innovation and continual
contribution of all employees improvement and strengthen the ii. Facilities and equipment improvement and strengthen the
of relevant departments within link between pharmaceutical system link between pharmaceutical
the company, suppliers and development and manufacturing iii. Packing and labelling development and manufacturing
distributors. activities. system activities.
C. To achieve a reliable While some aspects of the system iv. Lab control system While some aspects of the system
quality objective, it shall be can be company-wide and others v. Material system can be company-wide and others
necessary to design and site-specific, the effectiveness of QUALITY SYSTEM MODEL site-specific, the effectiveness of
implement the quality control the system is normally 4 Factors the system is normally
system including good demonstrated at the site level. 1- Management responsibilities demonstrated at the site level.
manufacturing practices A Pharmaceutical Quality System 2- Resources A Pharmaceutical Quality
(GMP) for medicinal products appropriate for the manufacture of 3- Manufacturing operations System appropriate for the
and quality risk management medicinal products should ensure 4- Evaluation activities manufacture of medicinal
in a comprehensive manner. that: Management Responsibilities: products should ensure that:
D. The quality control system (i) Product realisation is achieved (i) Product realisation is achieved
shall be sufficiently by designing, planning, by designing, planning,
documented, and its implementing, maintaining and
effectiveness shall be continuously improving a system
evaluated. that allows the consistent delivery
E. In all areas of the quality of products with appropriate
control system, competent quality attributes;
workers and adequate and (ii) Product and process
adequate facilities, equipment knowledge is managed throughout
and machines (devices) shall all lifecycle stages; quality
be provided. assurance system.
F. Manufacturer and (iii) Medicinal products are
authorized officers are legally designed and developed in a way
responsible for complying that takes account of the
with the provisions of relevant requirements of Good
laws and regulations. Manufacturing Practice;
G. The basic concepts of (iv) Production and control
quality assurance, good operations are clearly specified
manufacturing practices and Good Manufacturing Practice
(GMP) for medicinal adopted;
products, quality risk (v) Managerial responsibilities are
management shall be clearly specified;
interrelated. Their relationship (vi) Arrangements are made for
is important in manufacture the manufacture, supply and use of
and quality control of the correct starting and packaging
medicinal products. materials, the selection and
monitoring of suppliers and for
verifying that each delivery is
from the approved supply chain;
(vii) Processes are in place to
assure the management of
outsourced activities;
(viii) A state of control is
established and maintained by
developing and using effective
monitoring and control systems
for process performance and
product quality;
(ix) The results of product and
processes monitoring are taken
into account in batch release, in
the investigation of deviations,
and, with a view to taking
preventive action to avoid
 Provide leadership in which
senior management develop
the action plans.
 Organizational structure.
 Building the quality system
(procedures, control steps,
Q.A, review, investigate and
record control)
 Establishing the policies,
objectives and plans
 Review the system
(procedures, audits, customer
complaints, follow up
actions, improve the quality
system)
Resources:
 Personnel development
 Facilities and equipment
(calibrated, validated,
cleaned and maintained)
 Controlled outsource
manufacturing operations.
Manufacturing operations:
 Design, develop,
documentation of product
and processes.
 Examine inputs.
 Perform and monitor the
operations
 Address the non-
conformities.
Evaluation activities:
 Analyze data for trends
(ANNUAL REVIEW)
 Conduct internal audits
 Quality risk management
 Corrective and preventive
action
 Promote improvement
CHANGE CONTROL
implementing, maintaining and
continuously improving a system
that allows the consistent
delivery of products with
appropriate quality attributes;
(ii) Product and process
knowledge is managed
throughout all lifecycle stages;
quality assurance system.
(iii) Medicinal products are
designed and developed in a way
that takes account of the
requirements of Good
Manufacturing Practice;
(iv) Production and control
operations are clearly specified
and Good Manufacturing
Practice adopted;
(v) Managerial responsibilities
are clearly specified;
(vi) Arrangements are made for
the manufacture, supply and use
of the correct starting and
packaging materials, the
selection and monitoring of
suppliers and for verifying that
each delivery is from the
approved supply chain;
(vii) Processes are in place to
assure the management of
outsourced activities;
(viii) A state of control is
established and maintained by
developing and using effective
monitoring and control systems
for process performance and
product quality;
(ix) The results of product and
processes monitoring are taken
into account in batch release, in
the investigation of deviations,
and, with a view to taking
potential deviations occurring in
the future;
(x) All necessary controls on
intermediate products, and any
other in-process controls and
validations are carried out;
(xi) Continual improvement is
facilitated through the
implementation of quality
improvements appropriate to the
current level of process and
product knowledge;
(xii) Arrangements are in place for
the prospective evaluation of
planned changes and their
approval prior to implementation
taking into account regulatory
notification and approval where
required;
(xiii) After implementation of any
change, an evaluation is
undertaken to confirm the quality
objectives were achieved and that
there was no unintended
deleterious impact on product
quality;
(xiv) An appropriate level of root
cause analysis should be applied
during the investigation of
deviations, suspected product
defects and other problems.
This can be determined using
Quality Risk Management
principles
(xv) Medicinal products are not
sold or supplied before the
Responsible person has certified
that each production batch has
been produced and controlled in
accordance with the requirements
of the Marketing Authorisation
and any other regulations relevant
Change control is another well-
known CGMP concept that
focuses on managing change to
prevent unintended
consequences. The CGMP
regulations provide for change
control primarily through the
assigned responsibilities of the
quality control unit. Certain
major manufacturing changes
(e.g., changes that alter
specifications, a critical product
attribute or bioavailability)
require regulatory filings and
prior regulatory approval (21
CFR 314.70, 514.8, and 601.12).
Effective change control
activities (e.g., quality planning
and control of revisions to
specifications, process
parameters, procedures) are key
components of any quality
system. In this guidance, change
is discussed in terms of creating a
regulatory environment that
encourages change towards
continual improvement. This
means a manufacturer is
empowered to make changes
subject to the regulations based
on the variability of materials
used in manufacturing and
process improvements resulting
from knowledge gained during a
product’s lifecycle.
preventive action to avoid
potential deviations occurring in
the future;
(x) All necessary controls on
intermediate products, and any
other in-process controls and
validations are carried out;
(xi) Continual improvement is
facilitated through the
implementation of quality
improvements appropriate to the
current level of process and
product knowledge;
(xii) Arrangements are in place
for the prospective evaluation of
planned changes and their
approval prior to implementation
taking into account regulatory
notification and approval where
required;
(xiii) After implementation of
any change, an evaluation is
undertaken to confirm the quality
objectives were achieved and that
there was no unintended
deleterious impact on product
quality;
(xiv) An appropriate level of root
cause analysis should be applied
during the investigation of
deviations, suspected product
defects and other problems.
This can be determined using
Quality Risk Management
principles
(xv) Medicinal products are not
sold or supplied before the
Responsible person has certified
that each production batch has
been produced and controlled in
accordance with the requirements
of the Marketing Authorisation

QUALITY ASSURANCE
(a) Drugs are designed and
developed as per
requirements of good
manufacturing practices;
(b) Production and control
operations are clearly
specified in a written form
and good manufacturing
practices requirements are
adopted and followed;
(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 products are
correctly processed and
checked, according to the
defined procedures;
(g) Finished drugs are not
sold or supplied before the
authorized person(s) has
certified that each
QUALITY ASSURANCE:
The quality assurance system
that is appropriate for the
manufacture of medicinal
products shall ensure the
following:
1) Medicinal products shall be
designed and developed
considering the requirements
of the good manufacturing
practices (GMP) for medicinal
products.
2) Work regarding the
manufacture and management
shall be clearly prescribed,
and the good manufacturing
practices (GMP) for medicinal
products shall be applied.
3) Management responsibility
shall be prescribed clearly.
4) Measures to manufacture,
supply and use suitable
starting materials and
packaging materials shall be
prepared.
5) All management needed for
intermediate products and
management and validation
during other processes shall be
carried out.
6) The finished product shall
be suitably produced and
inspected according to the
prescribed procedures.
to the production, control and and any other regulations
release of medicinal products; relevant to the production,
(xvi) Proper Storage control and release of medicinal
(xvii) Self-inspection and/or products;
quality audit. (xvi) Proper Storage
(xvii) Self-inspection and/or
quality audit.
QUALITY ASSURANCE QUALITY ASSURANCE QUALITY ASSURANCE
(i) The authorisation of written QA primarily involves (i) The authorisation of written
procedures and other documents, (1) Review and approval of all procedures and other documents,
including amendments; procedures related to production including amendments;
(ii) The monitoring and control of and maintenance, (2) review of (ii) The monitoring and control of
the manufacturing environment; associated records, and the manufacturing environment;
(iii) Plant hygiene; (3) Auditing and (iii) Plant hygiene;
(iv) Process validation; performing/evaluating trend (iv) Process validation;
(v) Training; analyses. (v) Training;
(vi) The approval and monitoring (vi) The approval and monitoring
of suppliers of materials; of suppliers of materials;
(vii) The approval and monitoring (vii) The approval and
of contract manufacturers and monitoring of contract
providers of other GMP related manufacturers and providers of
outsourced activities; other GMP related outsourced
(viii) The designation and activities;
monitoring of storage conditions (viii) The designation and
for materials and products; monitoring of storage conditions
(ix) The retention of records; for materials and products;
(x) The monitoring of compliance (ix) The retention of records;
with the requirements of Good (x) The monitoring of
Manufacturing Practice; compliance with the
(xi) The inspection, investigation, requirements of Good
and taking of samples, in order to Manufacturing Practice;
monitor factors which may affect (xi) The inspection,
product quality; investigation, and taking of
(xii) Participation in management samples, in order to monitor
reviews of process performance, factors which may affect product
product quality and of the quality;
Pharmaceutical Quality System (xii) Participation in management
and advocating continual reviews of process performance,
improvement; product quality and of the
(xiii) Ensuring that a timely and Pharmaceutical Quality System
effective communication and and advocating continual
escalation process exists to raise improvement;
production batch has been
produced and controlled in
accordance with the
requirements of the good
manufacturing practices and
the relevant rules made
under the Act relevant to the
production, control and
release of drugs as well as of
conditions of registration;
(h) Satisfactory
arrangements exist to store
in appropriate storage
conditions;
(i) Procedure for self-
inspection and or quality
audit exists and
documented;
(j) Written Standard
Operating Procedure
available according to
which complaints about
marketed products are
examined, the causes of
quality defects investigated,
and appropriate measures
taken in respect of the
defective products and to
prevent recurrence and that
system
QUALITY CONTROL
Quality control department
exists which is independent
of other departments and
under the authority of a
person with the required
qualifications and
experience and with
adequate facilities.
Basic requirements.--
(a) During the period of
validity of license, adequate
7) Medicinal products shall quality issues to the appropriate (xiii) Ensuring that a timely and
not be sold or supplied prior to levels of management. effective communication and
approval by the competent escalation process exists to raise
authority in terms of product quality issues to the appropriate
approval (notification) levels of management.
according to the regulations
related to the manufacture,
management, and lot lease.
8) Proper measures shall be
taken to ensure that the
medicinal products are stored
and distributed so that the
quality is maintained during
the use-by (expiration) date.
9) Self-inspection shall be
carried out to periodically
evaluate the effectiveness and
applicability of the quality
assurance system.
QUALITY CONTROL: QUALITY CONTROL QUALITY CONTROL QUALITY CONTROL
Quality control is part of the It is concerned with sampling, QC usually involves It is concerned with sampling,
good manufacturing practices specifications and testing, and (1) assessing the suitability of specifications and testing, and
(GMP) for medicinal products with the organisation, incoming components, with the organisation,
related to the sampling, documentation and release containers, closures, labeling, in- documentation and release
specifications and testing, procedures. process materials, and the procedures.
organization, documentation The basic requirements of Quality finished products The basic requirements of
and shipping procedures. The Control are that: (2) Evaluating the performance Quality Control are that:
shipment procedure ensures (i) Adequate facilities, trained of the manufacturing process to (i) Adequate facilities, trained
that the product is not used personnel and approved ensure adherence to proper personnel and approved
until the necessary relevant procedures are available for specifications and limits; and (3) procedures are available for
tests are actually carried out sampling and testing starting sampling and testing starting
facilities, trained personnel
and approved procedures
are available for sampling,
inspecting, testing starting
materials, packaging
materials, intermediate,
bulk, and finished products,
and where appropriate for
monitoring environmental
conditions for good
manufacturing practices
purposes;
(b) Samples of starting
materials, packaging
materials, intermediate
products, bulk products and
finished products are taken
by methods, and personnel
approved of by the quality
control department.
(c) Testing methods are
validated;
(d) Records are made that all
the required sampling,
inspecting and testing
procedures have actually
been carried out and that any
deviation has been fully
recorded and investigated;
(e) The finished products
contain ingredients
complying with the
qualitative and quantitative
composition of the product
described in the marketing
authorization.
(f) Records are made of the
results of inspecting and
testing materials and
intermediate, bulk and
finished products against
and the quality is determined
to be appropriate and that the
medicinal products are not
shipped to be commercially
available. The basic
requirements of quality
control shall be as follows:
1) There shall be proper
facilities, trained workers and
approved sampling
procedures, inspection, and
testing of starting materials,
intermediate products, bulk
products before packaging,
and finished products and for
monitoring of environmental
conditions in compliance with
the good manufacturing
practices (GMP) for medicinal
products.
2) Samples of starting
materials, packaging
materials, intermediate
products, bulk products and
finished products shall be
collected by the workers
approved by the quality
control department according
to the approved methods.
3) The test methods shall be
validated.
4) Records verifying that all
required sample collections,
tests and test procedures are
actually carried out shall be
completed by hand, using a
recording device or both. All
deviations shall be recorded
and investigated.
5) The drug products shall
include an active ingredient
based on the composition in
materials, packaging materials, Determining the acceptability of materials, packaging materials,
intermediate, bulk, and finished each batch for release. intermediate, bulk, and finished
products, and where appropriate products, and where appropriate
for monitoring environmental for monitoring environmental
conditions for GMP purposes; conditions for GMP purposes;
(ii) Samples of starting materials, (ii) Samples of starting materials,
packaging materials, intermediate packaging materials,
products, bulk products and intermediate products, bulk
finished products are taken by products and finished products
approved personnel and methods; are taken by approved personnel
(iii) Test methods are validated; and methods;
(iv) Records are made (iii) Test methods are validated;
(v) The finished products contain (iv) Records are made
active ingredients complying with (v) The finished products contain
the qualitative and quantitative active ingredients complying
composition of the Marketing with the qualitative and
Authorisation or Clinical Trial quantitative composition of the
Authorisation, are of the purity Marketing Authorisation or
required, and are enclosed within Clinical Trial Authorisation, are
their proper containers and of the purity required, and are
correctly labelled; enclosed within their proper
(vi) Records are made of the containers and correctly labelled;
results of inspection and that (vi) Records are made of the
testing of materials, intermediate, results of inspection and that
bulk, and finished products is testing of materials, intermediate,
formally assessed against bulk, and finished products is
specification. Product assessment formally assessed against
includes a review and evaluation specification. Product assessment
of relevant production includes a review and evaluation
documentation and an assessment of relevant production
of deviations from specified documentation and an
procedures; assessment of deviations from
(vii) No batch of product is specified procedures;
released for sale or supply prior to (vii) No batch of product is
certification by the Responsible released for sale or supply prior
person that it is in accordance with to certification by the
the requirements of the relevant Responsible person that it is in
authorisations; accordance with the requirements
(viii) Sufficient reference samples of the relevant authorisations;
of starting materials and products (viii) Sufficient reference
are retained samples of starting materials and
products are retained
specifications and product
the items of product approval Good Quality Control Good Quality Control
assessment. (notification); shall conform Laboratory Practice should be Laboratory Practice should be
(g) No batch of product is
to the purity requirement; and developed developed
released for sale prior to
shall be labeled accurately Documentation Documentation
certification by the
after being put into an Sampling Sampling
authorized person(s) that it
appropriate container. Testing Testing
is in accordance with the
6) Records shall consist of test
requirement of the rules;
results, and tests on raw
(h) Sufficient samples of
materials, intermediate Stability Programme Stability Programme
starting materials and
products, bulk products before 1) Number of batch(es) per 1) Number of batch(es) per
products are retained topackaging, and finished strength and different batch strength and different batch
permit future examination
products shall be evaluated by sizes, if applicable; sizes, if applicable;
of the product. comparing with the standards. 2) Relevant physical, chemical, 2) Relevant physical, chemical,
(i) All quality control The evaluation of the product microbiological and microbiological and
procedures are established,
includes the review and biological test methods; biological test methods;
validated and implemented;
evaluation of documents 3) Acceptance criteria;
3) Acceptance criteria;
the reference standards for
related to the manufacture and 4) Reference to test methods;
4) Reference to test methods;
substances are evaluatedthe evaluation of deviations 5) Description of the container
maintained, and stored; from the prescribed closure system(s); 5) Description of the container
correct labeling of
procedures. 6) Testing intervals (time closure system(s);
containers of materials and
7) Medicinal products of all points); 6) Testing intervals (time
products is ensured; thebatches that are shipped shall 7) Description of the conditions points);
stability of the active not be shipped to the market of storage (standardised ICH 7) Description of the conditions
pharmaceutical ingredients
before they are approved by conditions for long term of storage (standardised ICH
and products is monitored.
the competent authority that testing, consistent with the conditions for long term
Complaints related to the
they are in conformity with the product labelling, should be testing, consistent with the
quality of the product are
relevant approval used); product labelling, should be
investigated. All these requirements. 8) Other applicable parameters used);
operations shall be carried
8) Sufficient reference specific to the medicinal 8) Other applicable parameters
out in accordance with samples of starting materials product. specific to the medicinal
written procedures. and finished products shall be product.
stored so that tests can be
carried out for medicinal
products if necessary. And the
storage samples of finished
products shall be kept in the
final packaging form unless
produced in large packages.
There is no concept of QUALITY RISK QUALITY RISK QUALITY RISK QUALITY RISK
Quality Risk Management MANAGEMENT. MANAGEMENT MANAGEMENT: MANAGEMENT
in DRAP GMP guidelines. Quality risk management is a Quality Risk Management is a Quality risk management is a Quality Risk Management is a
system for evaluating, systematic process for the valuable component of an systematic process for the
 managing, sharing, and
reviewing the risks of the
medicinal products quality.
Quality risk management can
be carried out preliminarily or
retrospectively.
The quality risk management
system shall ensure the
following:
1) Risk analysis about quality
shall be based on scientific
knowledge and an experience
in the process. This shall
ultimately lead to the
protection of patients.
2) The level of effort,
formalization and
documentation of the quality
risk management process shall
be determined in proportion to
the level of risk.
There is no concept of PRODUCT QUALITY
Product Quality Review ASSESSMENT.
in DRAP Guidelines so it A quality assessment shall be
should be included in the conducted on a regular basis
Guidelines to Comply with over a certain period, or if
International GMP necessary, on all licensed
Guidelines.
assessment, control,
communication and review of
risks to the quality of the
medicinal product. It can be
applied both proactively and
retrospectively.
The principles of Quality Risk
Management are that:
(i) The evaluation of the risk to
quality is based on scientific
knowledge, experience with the
process and ultimately links to the
protection of the patient;
(ii) The level of effort, formality
and documentation of the Quality
Risk Management process is
commensurate with the level of
risk.
PRODUCT QUALITY
REVIEW
(i) A review of starting materials
including packaging materials
used in the product, especially
those from new sources and in
particular the review of supply
effective quality systems assessment, control,
framework. Quality risk communication and review of
management can, for example, risks to the quality of the
help guide the setting of medicinal product. It can be
specifications and process applied both proactively and
parameters for drug retrospectively.
manufacturing, assess and The principles of Quality Risk
mitigate the risk of changing a Management are that:
process or specification, and (i) The evaluation of the risk to
determine the extent of quality is based on scientific
discrepancy investigations and knowledge, experience with the
corrective actions. process and ultimately links to
Effective decision-making the protection of the patient;
Elements of risk should be (ii) The level of effort, formality
considered relative to intended and documentation of the Quality
use of a product, and in the case Risk Management process is
of pharmaceuticals, patient safety commensurate with the level of
and ensuring availability of risk.
medically necessary drug
products. Assessment of the risk
including both the probability of
occurrence of harm and of the
severity of that harm. It is
important to engage appropriate
parties in assessing the risk.
Implementation of quality risk
management includes assessing
the risks, selecting and
implementing risk management
controls commensurate with the
level of risk, and evaluating the
results of the risk management
efforts
Quality risk management helps
manage and control change.
Analyze data for trend PRODUCT QUALITY
ANNUAL REVIEW REVIEW
Quality systems call for (i) A review of starting materials
continually monitoring trends including packaging materials
and improving systems. This can used in the product, especially
be achieved by monitoring data those from new sources and in
and information, identifying and particular the review of supply
medicinal products including
exported products.
In general, it shall be
conducted and documented
annually,
1) Review of packaging
materials and starting
materials used in the product
(especially when delivered by
a new supplier); Review of the
results of management and
testing of finished products
among critical processes;
2) Review of all batches not
complying with the
established standards and the
investigation thereof;
3) Review of all significant
deviations & investigations
4) Review all changes related
to the process or test methods;
5) Review of applications,
approvals, and rejections
related to changes in the
product approval
6) Review of the results and
all abnormal trends of a
stability monitoring program;
7) Review of returns,
complaints, and recalls related
to the quality and
investigations conducted at
that time;
8) Review of all corrective
measures
9) Review of the compliance
10) Status of relevant
machines and supporting
equipment such as an air
handling unit, water for
pharmaceutical use,
compressed gas, etc.
chain traceability of active
substances;
(ii) A review of critical in-process
controls and finished product
results;
(iii) A review of all batches that
failed to meet established
specification(s) and their
investigation;
(iv) A review of all significant
deviations or non-conformances,
their related investigations, and
the effectiveness of resultant
corrective and preventive actions
taken;
(v) A review of all changes carried
out to the processes or analytical
methods;
(vi) A review of Marketing
Authorisation variations
submitted, granted or refused,
including those for third country
(export only) dossiers;
(vii) A review of the results of the
stability monitoring programme
and any adverse trends;
(viii) A review of all quality-
related returns, complaints and
recalls and the investigations
performed at the time;
(ix) A review of adequacy of any
other previous product process or
equipment corrective actions;
(x) For new Marketing
Authorisations and variations to
Marketing Authorisations, a
review of post-marketing
commitments;
(xi) The qualification status of
relevant equipment and utilities,
e.g. HVAC, water, compressed
gases, etc;
resolving problems, and
anticipating and preventing
problems.
Quality systems procedures
involve collecting data from
monitoring, measurement,
complaint handling, or other
activities, and tracking this data
over time, as appropriate.
Analysis of data can provide
indications that controls are
losing effectiveness. The
information generated will be
essential to achieving problem
resolution or problem prevention.
Although the CGMP regulations
require product review on at least
an annual basis, a quality systems
approach calls for trending on a
more frequent basis as
determined by risk. Trending
enables the detection of potential
problems as early as possible to
plan corrective and preventive
actions. Another important
concept of modern quality
systems is the use of trending to
examine processes as a whole;
this is consistent with the annual
review approach. Trending
analyses can help focus internal
audits
chain traceability of active
substances;
(ii) A review of critical in-process
controls and finished product
results;
(iii) A review of all batches that
failed to meet established
specification(s) and their
investigation;
(iv) A review of all significant
deviations or non-conformances,
their related investigations, and
the effectiveness of resultant
corrective and preventive actions
taken;
(v) A review of all changes
carried out to the processes or
analytical methods;
(vi) A review of Marketing
Authorisation variations
submitted, granted or refused,
including those for third country
(export only) dossiers;
(vii) A review of the results of the
stability monitoring programme
and any adverse trends;
(viii) A review of all quality-
related returns, complaints and
recalls and the investigations
performed at the time;
(ix) A review of adequacy of any
other previous product process or
equipment corrective actions;
(x) For new Marketing
Authorisations and variations to
Marketing Authorisations, a
review of post-marketing
commitments;
(xi) The qualification status of
relevant equipment and utilities,
e.g. HVAC, water, compressed
gases, etc;
 11) Review of the terms of
contract. Manufacturer and
marketing authorization
holder shall evaluate the
results of the above quality
review and determine whether
corrective and preventive
measures or revalidation is
necessary. The cause of such
corrective measures shall be
documented. The corrective
and preventive measures that
have been determined shall be
completed in a timely and
effective manner. There shall
be procedures for ongoing
management and evaluation
of corrective and preventive
measures, and the
effectiveness of these
procedures shall be confirmed
during the self-inspection
process.
D. If it is scientifically
reasonable, the quality
assessment may be carried out
by grouping into product types
such as solid, liquid, aseptic
preparations, etc.
NO concept of quality by NO concept of quality by
design & development design & development
(xii) A review of any contractual
arrangements as defined in
Chapter 7 to ensure that they are
up to date.
The manufacturer and, where
different, Marketing Authorisation
holder should evaluate the results
of the review and an assessment
made as to whether corrective and
preventive action or any
revalidation should be undertaken,
under the Pharmaceutical Quality
System. There should be
management procedures for the
ongoing management and review
of these actions and the
effectiveness of these procedures
verified during self-inspection.
Quality reviews may be grouped
by product type, e.g. solid dosage
forms, liquid dosage forms, sterile
products, etc. where scientifically
justified.
NO concept of quality by design
& development
(xii) A review of any contractual
arrangements as defined in
Chapter 7 to ensure that they are
up to date.
The manufacturer and, where
different, Marketing
Authorisation holder should
evaluate the results of the review
and an assessment made as to
whether corrective and
preventive action or any
revalidation should be
undertaken, under the
Pharmaceutical Quality System.
There should be management
procedures for the ongoing
management and review of these
actions and the effectiveness of
these procedures verified during
self-inspection. Quality reviews
may be grouped by product type,
e.g. solid dosage forms, liquid
dosage forms, sterile products,
etc. where scientifically justified.
QUALITY BY DESIGN AND NO concept of quality by
DEVELOPMENT: design & development
Quality by design means
designing and developing a
product and associated
manufacturing processes that will
be used during product
development to ensure that the
product consistently attains a
predefined quality at the end of
the manufacturing process.
Quality by design, in conjunction
with a quality system, provides a
 sound framework for the transfer
of product knowledge and
process understanding from drug
development to the commercial
manufacturing processes and for
post-development changes and
optimization. The CGMP
regulations, when viewed in their
entirety, incorporate the concept
of quality by design. This
guidance describes how these
elements fit together.
SELF-INSPECTION SELF-INSPECTION SELF INSPECTION INTERNAL AUDITS SELF INSPECTION
The management shall Compliance with the Self-inspections are done to A quality systems approach calls Self-inspections are done to
appoint a self-inspection principles of the good comply with GMP and to propose for audits to be conducted at comply with GMP and to propose
team. The team responsible manufacturing practices CAPA. planned intervals to evaluate CAPA.
for self-inspection shall (GMP) Personnel matters, premises, effective implementation and Personnel matters, premises,
consist of personnel who A review shall be performed equipment, documentation, maintenance of the quality equipment, documentation,
can evaluate the with a cycle in accordance production, quality control, system. As with other production, quality control,
implementation of good with a program planed in distribution of the medicinal procedures, audit procedures distribution of the medicinal
manufacturing practices advance so as to verify that products, arrangements for should be developed and products, arrangements for
objectively; allmatters related to the workers dealing with complaints and documented to ensure that the dealing with complaints and
recommendations for involved in medicinal recalls, and self-inspection, should planned audit schedule takes into recalls, and self-inspection,
corrective action shall be products, facilities, equipment be examined at intervals following account the relative risks of the should be examined at intervals
implemented; and machines (devices), a pre-arranged programme in various quality system activities, following a pre-arranged
Frequency of self- documentation, order to verify their conformity the results of previous audits and programme in order to verify
inspection.- it shall be at manufacturing, quality with the principles of Quality corrective actions, and the need their conformity with the
least once every year. control, sales, complaints and Assurance. to audit the complete system. principles of Quality Assurance.
Quality audit: recall procedures, and self- By designated competent By designated competent
Audit of a quality system. inspections comply with the person(s) from the company. person(s) from the company.
Supplier’s audits quality assurance principles Independent audits by external Independent audits by external
It should be done by experts may also be useful. experts may also be useful.
designated personnel All self-inspections should be All self-inspections should be
All self-inspections shall be recorded. recorded.
recorded
COMPLAINTS: COMPLAINTS COMPLAINTS AND CAPA (Corrective and COMPLAINTS AND
Review of complaints Designated person PRODUCT RECALL Preventive Action) PRODUCT RECALL
Person authorized Documented procedures Appropriate procedures CAPA is a well-known CGMP Appropriate procedures
Written procedures Recorded and thoroughly All concerned Competent regulatory concept that focuses All concerned Competent
Recording defects and investigated. The quality Authorities should be informed in on investigating, understanding, Authorities should be informed in
investigation. control officer shall be a timely manner in case of a and correcting discrepancies a timely manner in case of a
Follow-up action. confirmed quality defect (faulty while attempting to prevent their confirmed quality defect (faulty
Recording measures. involved in the investigation
Review for recurring
of such problems
problems. If a product defect is
PRODUCT RECALLS: discovered or suspected in one
There shall be a system to
batch, consideration shall be
promptly and effectively given to determining whether
recall from the market the
other batches are also affected.
products known or
Complaint records shall be
suspected to be defective.
reviewed regularly
Authorized person Special caution should be
Written procedure taken to identify whether
Recall with promptness complaints have resulted due
Distribution records to counterfeit products.
Recording of progress Manufacturer shall notify the
Evaluation Regional Office of Ministry of
Storage of recalled drugsFood and Drug Safety within
the jurisdiction
RECALLS
Designated Person
Documented procedures
Commenced immediately
Notified in a proper manner to
the competent authorities of
all countries in which it is
distributed.
The sales record shall be
readily available
The recalled products shall be
identifiable and kept
separately in a controlled area
until the disposal is
determined.
Regular Evaluation
PERSONNEL PRINCIPAL WORKERS
Organizational chart The principal workers include
Qualified personnel the head of the production
Written duties department and the head of the
GMP awareness quality control department
Duties of heads of Q.C & The head of Production & Q.C
Production are defined. have defined responsibilities
Training Education & Training
Personal hygiene Personnel Hygiene
manufacture, product
deterioration, detection of
falsification, non-compliance with
the marketing authorization or
product specification file, or any
other serious quality problems)
In case of outsourced activities, a
contract should describe the role
and responsibilities of the
manufacturer, the marketing
authorization holder and/or
sponsor and any other relevant
third parties in relation to
assessment, decision-making, and
dissemination of information and
implementation of risk reducing
actions relating to a defective
product.
Written procedures are defined for
complaints and product recalls.
PERSONNEL
Adequate number of personnel
with the necessary qualifications
and practical experience.
Organizational chart
Written job descriptions and
adequate authority
Training & personal hygiene
recurrence. Quality system
models discuss CAPA as three
separate concepts, all of which
are used in this guidance.
 Remedial corrections of an
identified problem
 Root cause analysis with
corrective action to help
understand the cause of the
deviation and potentially
prevent recurrence of a
similar problem
 Preventive action to avert
recurrence of a similar
potential problem
PERSONNEL
DEVELOPMENT
Under a quality system, senior
management should support a
problem-solving and
communicative organizational
culture.
Designated responsibilities to
Qualified personnel
manufacture, product
deterioration, detection of
falsification, non-compliance
with the marketing authorization
or product specification file, or
any other serious quality
problems)
In case of outsourced activities, a
contract should describe the role
and responsibilities of the
manufacturer, the marketing
authorization holder and/or
sponsor and any other relevant
third parties in relation to
assessment, decision-making,
and dissemination of information
and implementation of risk
reducing actions relating to a
defective product.
Written procedures are defined
for complaints and product
recalls.
PERSONNEL
Adequate number of personnel
with the necessary qualifications
and practical experience.
Organizational chart
Written job descriptions and
adequate authority
Training & personal hygiene
 Training
PREMISES FACILITIES, PREMISES AND FACILITIES AND PREMISES AND
Material storage areas EQUIPMENT AND EQUIPMENT EQUIPMENT EQUIPMENT
should be clean and free of MACHINES Minimal risk of causing Under a quality system, the Minimal risk of causing
microbes. These areas Facilities, equipment and contamination of materials or technical experts (e.g., engineers, contamination of materials or
should be thoroughly machines (devices) shall be products. development scientists), who products.
inspected. arranged, designed, Premises should be carefully have an understanding of Premises should be carefully
Storage of Intermediate constructed, adjusted and maintained pharmaceutical science, risk maintained
and bulk products maintained in accordance with Lighting, temperature, humidity factors, and manufacturing Lighting, temperature, humidity
Storage of Finished the work being performed. and ventilation should be processes related to the product, and ventilation should be
pharmaceutical products The arrangement and design appropriate are responsible for defining appropriate
Placed in Quarantine area of facilities, equipment and Premises should be designed and specific facility and equipment Premises should be designed and
Release label machines shall be done in such equipped so as to afford maximum requirements. equipped so as to afford
Rejected and recovered a way so as to minimize the protection against the entry of Under the cGMP regulations, the maximum protection against the
materials are placed risk of errors and to allow insects or other animals. quality unit (QU) has the entry of insects or other animals.
separately and clearly effective cleaning and Steps should be taken in order to responsibility of reviewing and Steps should be taken in order to
marked maintenance so that cross- prevent the entry of unauthorised approving all initial design prevent the entry of unauthorised
Processing operations contamination, accumulation people criteria and procedures pertaining people
Material handling. of dusts or contaminants, and Production Areas to facilities and equipment and Production Areas
Avoiding deviation adverse effects on the overall Storage Areas any subsequent changes Storage Areas
Yield checks product quality can be Storage areas should be of Under the cGMP regulations, Storage areas should be of
Avoiding mix-ups prevented. sufficient equipment must be qualified, sufficient capacity
Labelling Production Area Quality Control Areas calibrated, cleaned, and Quality Control Areas
No cross contamination To minimize the risk of Ancillary Areas maintained to prevent Ancillary Areas
should be there serious medical hazards EQUIPMENT contamination and mix-ups. Note EQUIPMENT
Microbiological monitoring resulting from the cross- Repair and maintenance that the cGMP regulations Repair and maintenance
Processing operations, contamination, dedicated operations should not present any require a higher standard for operations should not present any
intermediate and bulk enclosed facilities shall be hazard to the quality of the calibration and maintenance than hazard to the quality of the
products used for the manufacture of products. most non-pharmaceutical quality products.
Sanitation and hygiene certain medicinal products Washing and cleaning equipment system models. The cGMP Washing and cleaning equipment
A high level of sanitation such as highly sensitive Calibration regulations place as much Calibration
and hygiene substances (e.g.: penicillin, PRODUCTION emphasis on process equipment PRODUCTION
Validation cephalosporin, etc.) or Production operations must follow as on testing equipment while Production operations must
Pre-defined protocols. biologicals (e.g.: formulations clearly defined procedures; they most quality systems focus only follow clearly defined
Process Validation to be derived from live must comply with the principles of on testing equipment procedures; they must comply
performed as per written microorganisms). Good Manufacturing with the principles of Good
procedures Toxic products such as PREVENTION OF CROSS- Manufacturing
Validation of critical insecticides and herbicides CONTAMINATION IN PREVENTION OF CROSS-
processes shall not be manufactured in PRODUCTION CONTAMINATION IN
Validation of new master facilities where medicinal A Quality Risk Management PRODUCTION
formula products are manufactured. process, which includes a potency A Quality Risk Management
and toxicological evaluation, process, which includes a
Validation of equipment and Sufficient work space & should be used to assess and potency and toxicological
materials proper lighting and control the cross-contamination evaluation, should be used to
ventilators. risks presented by the products assess and control the cross-
Separate weighing room manufactured. contamination risks presented by
Storage areas These could include, but are not the products manufactured.
Sufficient space for storage limited to, the following: These could include, but are not
Labelled areas for 1) Technical Measures limited to, the following:
identification 2) Organizational Measures 4) Technical Measures
Controlled temperature & 3) Validation Studies 5) Organizational Measures
humidity 6) Validation Studies
Q.C area should be separate
from production and
laboratory should be properly
designed to prevent cross-
contamination.
Auxiliary areas should be
separate & common
Machines
The machines (devices) for
production use shall be
designed, installed and
maintained adequately for the
intended use. The repair and
maintenance work shall not
cause any harm to the product
quality.
Clearly marked Fixed piping
Measuring, weighing,
recording and management
machines (devices) shall be
calibrated and checked
Cleaning should be done
according to documented
procedure
 DISCUSSION:
Good manufacturing practices (GMP) for medicinal products are part of a quality assurance system that ensures that medicinal
products are manufactured and managed consistently according to the quality standards that are adequate for the purpose of medicinal
products and the requirements of product approval (notification) and product specifications. GMP guidelines of various Regulatory
Authorities like DRAP (PAKISTAN), MHRA (UK), USFDA (USA), TICTK/TMMDA (TURKEY) and MFDS/NIFDS
(KOREA) have been discussed earlier. The sole purpose of this study is to highlight the differences between DRAP and other
Approved/Authentic Regulatory Agencies of the World. The basic difference is that MHRA, USFDA, MFDS and TICTK are
the members of PIC/S (Pharmaceutical Inspection Cooperative Scheme) and follow the GMP Guidelines of PIC/S while DRAP
has its own local GMP guidelines. Moreover, UK (MHRA), U.S (USFDA) AND TURKEY (TICTK) are the members of ICH
(International council for harmonization of technical requirements for pharmaceuticals for human use) while KOREA is observer of
ICH. So, the members of ICH follow the ICH Quality Guidelines (Q7, Q8, Q9, and Q10). U.K and Turkey are the members of
European Union so they follow the European Union GMP Guidelines which are identical to PIC/S and ICH Guidelines. The basic
concepts of Quality management, GMP and Quality Risk Management are inter related in every Guideline except DRAP.
 Quality Assurance is same in every Guideline and the responsibilities of Q.A are to evaluate the quality, safety and effectiveness
of the product by validating the S.O.P’s of each department and controlling the documentation. Procedures for Self-inspections are
prepared by the Q.A Department which are periodically done by every Regulatory Authority. Managerial responsibilities are clearly
specified in job descriptions. The specifications of each batch are checked from dispensing to final packaging. Quality Assurance
in DRAP and MFDS is separately defined but in MHRA, TICTK and USFDA, it comes under Pharmaceutical Quality
System. Personnel are trained for respective responsibilities. Validations are done by the Quality Assurance Department. MHRA &
TITCK follow PQS under PIC/S.

 Quality Control section is placed in Pharmaceutical quality system in MHRA and TICTK as well as separately as a chapter. USFDA
places it in quality system as well. DRAP and MFDS define it separately as different sections but the responsibilities are same.
Quality control is responsible for testing of the product as well as validation of procedures. Stability studies are performed by Quality
Control department. Product is released by the Q.C Department if product complies with the required specifications otherwise it is
rejected and investigation is done. Records of the tests are maintained.

 4 Factors have been discussed in every Guideline

1) Management responsibilities
2) Resources
3) Manufacturing operations
4) Evaluation activities
CONCLUSION:
1. SEMINARS should be arranged by DRAP on specific topics specified in GMP guidelines like Management of risk through-out
product life cycle, good laboratory practices and inspectorates of the future.

2. The goal of USFDA SIX SYSTEM INSPECTION MODEL is to describe a model for use in pharmaceutical manufacturing
that can help manufacturers comply with the CGMP regulations. So, DRAP should adopt this model to comply with International
GMP Guidelines. It involves the following systems:
i. Production system
ii. Facilities and equipment system
iii. Packing and labelling system
iv. Lab control system
v. Material system

3. Trainings should be given to inspectors by DRAP on GMP inspection as PIC/S provide training to inspectors for GMP
inspections so that there is proper implementation of GMP Guidelines in every Pharmaceutical Industry.

4. Quality risk management is a system for evaluating, managing, sharing, and reviewing the risks of the medicinal products
quality. It guides the setting of specifications and process parameters for drug manufacturing, assess and mitigate the risk of
changing a process or specification, and determine the extent of discrepancy investigations and corrective actions. Quality risk
management can be carried out preliminarily or retrospectively. The quality risk management system shall ensure the following:

1) Risk analysis about quality shall be based on scientific knowledge and an experience in the process. This shall
ultimately lead to the protection of patients.
2) The level of effort, formalization and documentation of the quality risk management process shall be determined
in proportion to the level of risk.

5. Product Quality Review is a very important parameter for GMP Inspections. It is defined extensively in all other guidelines
except DRAP. Regular periodic or rolling quality reviews of all authorized medicinal products, including export only products,
should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current
specifications for both starting materials and finished product, to highlight any trends and to identify product and process
improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews.

6. Good Laboratory Practices should be developed in order to comply with International GMP Guidelines
7. Change control is another well-known cGMP concept that focuses on managing change to prevent unintended consequences.
The cGMP regulations provide for change control primarily through the assigned responsibilities of the quality control unit.
Certain major manufacturing changes (e.g., changes that alter specifications, a critical product attribute or bioavailability) require
regulatory filings and prior regulatory approval. Effective change control activities (e.g., quality planning and control of
revisions to specifications, process parameters, procedures) are key components of any quality system. In this guidance, change
is discussed in terms of creating a regulatory environment that encourages change towards continual improvement. This means
a manufacturer is empowered to make changes subject to the regulations based on the variability of materials used in
manufacturing and process improvements resulting from knowledge gained during a product’s lifecycle. So, effective change
control activities must be included in the cGMP audit Performa of DRAP.

DRAP
The Drugs Act, 1976
regulates the import, export,
manufacture, storage,
distribution and sale of drugs.
The grant of licenses to
manufacture drugs is
regulated by Central
Licensing Board (CLB)
setup under section 5 of the
Drugs Act, 1976
CLB consists of 14 members
TYPES OF LICENSES
1) By way of Formulation
2) By way of Basic
Manufacture
3) By way of Semi Basic
Manufacture
4) By way of Repacking
5) By way of Experimental
purpose.
PROCEDURE:
1. Application is submitted
to CLB for establishment
of pharmaceutical unit
2. Inspection of proposed
site by Area FID
3. Approval of site
4. Layout plan according to
cGMP requirements is
submitted
5. Approval of layout plan
6. Unit is constructed
7. Application for grant of
Drug Manufacturing
License (DML) on the
LICENSING COMPARISON OF REGULATORY AUTHORITIES
MFDS TITCK/TMMDA USFDA MHRA
Article 31 (Permission for No specific data found. TYPES OF LICENSES TYPES OF LICENSES
Manufacturing Business, etc.) 1) Internal Commercial Use 1) Manufacturer/importer
Each person who intends to Licenses license
manufacture drugs for business 2) Biological Materials License 2) Manufacturer ‘specials’
purposes, shall obtain (BML) license
permission from the Minister of 3) Commercial Evaluation 3) Manufacturer license for
Food and Drug Safety, as Licenses investigational medicinal
prescribed by Ordinance of the 4) Nonexclusive Patent Licenses products
Prime Minister, after obtaining 5) Exclusive Patent Licenses 4) Manufacturer license exempt
necessary facilities meeting THE LICENSING PROCESS advanced therapy products
standards for facilities AT FDA (Hospital exemption license)
prescribed by Presidential 1. Review the FDA listing of PROCEDURE FOR
Decree. technology abstracts online MANUFACTURER LICENSE
and select the technology you 1. Your application will be
are interested in licensing assessed by MHRA and
2. Discuss the technology with should take 90 working days
the contact listed on the to process.
abstract to confirm the next 2. Variations to licenses should
steps take 30 working days to
3. Submit any necessary process. This will be extended
Confidential Disclosure to 90 working days if the
agreement for unpublished variation requires an
Patent Application to the inspection.
Agency-level FDA 3. MHRA may:
Technology Transfer Program  check the identities of
E-mail the ‘responsible person’
to: FDAInventionLicensing@ and named staff
fda.hhs.gov  check a named company
4. Review the technology with with Companies House
the scientist and the 4. For manufacturing sites you
Technology Transfer will have to provide a site
Specialist Master plan
5. Review the various types of 5. Shortly after the inspection
licenses available for use you will receive a report
online 6. When the inspector is satisfied
6. Submit a License Application that these issues have been
to the Agency-level FDA
 prescribed Form-I along Technology Transfer addressed, MHRA will grant
with the necessary Program your registration and you will
documents / information. E-mail receive:
8. The panel of experts / to: FDAInventionLicensing@  a license document
inspectors including a fda.hhs.gov  a manufacturer’s
member of C.L.B. 7. Include any necessary certificate of good
inspects the premises to business development plan manufacturing practice
evaluate the facilities with the License Application (GMP) for each inspected
provided for production 8. Negotiate site
and Quality Control of 9. Licensing
drugs to be manufactured 10. Reporting
9. The inspection report is Internal Commercial Use
placed before the CLB in Licenses
its meeting for Grants a licensee the nonexclusive
consideration right to make and use the invention
10. If a case for grant of DML for internal use only. These
is approved by the CLB a licenses do not grant the right to
license is issued on sell or otherwise distribute the
prescribed Form-2 for a invention, but allow the licensee to
period of five years use the invention in their
11. Renewal of DML is made commercial development
on FORM 1-A after 5 activities.
years (Inspection is done
by panel)

DISCUSSION:
In every country, before marketing of a registered product, the first very important step is to get a LICENSE TO MANUFACTURE product from
concerned Regulatory Authority. Any company cannot manufacture a Medicinal product without getting the license. DRAP (PAKISTAN), USFDA
(USA), TITCK/TMMDA (TURKEY), MHRA (UK) & MFDS (KOREA) have their own guidelines regarding license to manufacture of a product.
Moreover, there are different types of licenses which are mentioned in the above report. In Pakistan, The Drugs Act, 1976 regulates the import,
export, manufacture, storage, distribution and sale of drugs. The grant of licenses to manufacture drugs is regulated by Central Licensing Board
(CLB) setup under section 5 of the Drugs Act, 1976. Application is submitted to CLB, then site inspection is done, site gets approved, layout plan
gets submitted and approved, application for DML (Drug Manufacturing License) is given on FORM-I with prescribed fee and required documents,
inspection of the premises is done by panel of experts and if the report is ok the DML is issued on FORM-2 which is renewed after every 5 years.
In Korea, Article 31 (Permission for Manufacturing Business, etc.) of Pharmaceutical Affairs Act states that each person who intends to
manufacture drugs for business purposes, shall obtain permission from the Minister of Food and Drug Safety, as prescribed by Ordinance of the
Prime Minister, after obtaining necessary facilities meeting standards for facilities prescribed by Presidential Decree. In USA, online applications
are submitted to FDA to get a license according to a defined procedure. Similarly in U.K, MHRA has a defined procedure to get a license according
to which application is submitted, master plan is provided, inspection of premises is done and after inspection the license document/cGMP certificate
is issued. TMMDA/TITCK (Turkey) has its own defined Guidelines to get a license.
 REGISTRATION GUIDELINES COMPARISON REPORT OF
REGULATORY AUTHORITIES

DRAP (CTD) USFDA (eCTD) MHRA (eCTD) MFDS (eCTD) TITCK (eCTD)
MODULE 1: Administrative MODULE 1: MODULE 1: Module 1 MODULE 1: Administrative
Part Administrative Part Administrative Part 1.1 Table of contents of Part
1.1 Covering Letter and Fee Module 1
Deposit Slip 1.1 Forms 1.0 Cover letter 1.1. Table of contents
1.2 Table of Contents (From 1.2 Application form or A comprehensive table of
Module 1 to Module 5) 1.2 Cover letters 1.1 Comprehensive table of approval contents of Modules 1 to 5
1.3 Applicant Information contents application(Copy)
1.3.1 Name, address and contact 1.3.1.1 Change of address or 1.2. Application form
details of Applicant / Marketing corporate name 1.2 Application form 1.3 Signature of the
Authorization Holder: 1.3.1.2 Change in contact person in charge of 1.3. Summary of product
1.3.2 Name, address and contact agent 1.3 Product information preparation of CTD, characteristics, Labelling and
details of manufacturing site. 1.3.1.3 Change in sponsor documents His/Her Package Leaflet
1.3.3 Specify whether the 1.3.1.4 Transfer of obligation information(career) 1.3.1. Summary of Product
Applicant is: 1.3.1.5 Change in ownership 1.3.1 SmPC, Labelling and Characteristics
of an application or Package Leaflet 1.4 Certificate of 1.3.2. Packaging and package
reissuance of license 1.3.2 Mock-up translator leaflet
1.3.2 Field copy certification 1.3.3 Specimen 1.3.3. Mock-ups and specimens
above (contract giver) 1.3.3 Debarment 1.3.4 Consultation with Target 1.5 Information on the
1.3.4 Valid Drug Manufacturing certification Patient Groups use of the applied drug in 1.4. Information Regarding the
License (DML) of manufacturer 1.3.4 Financial certification 1.3.5 Product Information foreign countries Experts
/ Applicant or Drug Sale and disclosure already approved in the
License, whichever is 1.3.5.1 Patent information Member States 1.6 Information on 1.5. Specific Requirements for
applicable. 1.3.5.2 Patent certification 1.3.6 Braille comparison with other Different Types of Applications
1.3.5 Evidence of approval of 1.3.5.3 Exclusivity claim similar products
manufacturing facility / 1.4 Information on the experts available in the Korean 1.6. Environmental Risk
Approved Section from 1.4.1 Letter of authorization 1.4.1 Quality market and properties of Assessment
Licensing Authority 1.4.2 Statement of right of 1.4.2 Non-Clinical the applied drug
1.3.6 List of already approved reference 1.4.3 Clinical
registered drugs in this section 1.4.3 List of authorized 1.7 Various documents MODULE 2-5 are as per ICH
1.3.7 Identification of persons to incorporate by 1.5 Specific requirements for related to Regulations on Guidelines
Signature(s) of authorized reference different types of applications Safety of
persons, in charge Production, 1.4.4 Cross reference to (if required) Pharmaceuticals Article
Quality Control and in charge previously submitted 1.5.1 Information for 4 (1)
Quality Assurance information Bibliographical Applications 1.7.1 Bioequivalence test
1.3.8 Manufacturer’s Site 1.5.2 Information for Generic, data/ Dissolution test
Master File and Credential (for 1.5.1 Withdrawal of an IND ‘Hybrid’ or Bio-similar data 1.7.2 CPP 1.7.3
importer) 1.5.2 Inactivation request Applications
1.4 Type of Application 1.5.3 Reactivation request 1.5.3 (Extended) Data/Market GMP data 1.7.4 DMF
1.4.1 Application is for the 1.5.4 Reinstatement request Exclusivity data
registration of: 1.5.5 Withdrawal of an 1.5.4 Exceptional 1.8 A contract(In case
unapproved BLA, NDA, Circumstances any process during
ANDA or supplement 1.5.5 Conditional Marketing manufacturing, QC test
1.4.1 Pharmaceutical product is 1.5.6 Withdrawal of listed Authorisation would be outsourced)
intended for: drug
1.5.7 Withdrawal of 1.6 Environmental Risk 1.9 LTOC
approval of an application or Assessment
revocation of license 1.10 Package
1.4.2 For imported products, 1.6.1 Non-GMO insert(draft)
please specify one of following: 1.6.1 Meeting request 1.6.2 GMO
1.6.2 Meeting background 1.11 Other data
Product Import materials 1.7 Information relating to
1.6.3 Correspondence orphan market exclusivity (if MODULE 2-5 are as
repacking (specify status of regarding meetings required) per ICH Guidelines
bulk)
1.7.1 Fast track designation 1.7.1 Similarity
for Export purpose only request 1.7.2 Market Exclusivity
1.4.3 Contract Manufacturing as 1.7.2 Fast track designation
per Rule 20-A of Drugs withdrawal request 1.8 Information relating to
(Licensing, Registering and 1.7.3 Rolling review request pharmacovigilance
Advertising) Rules, 1976. 1.8.1 Clinical study
1.8.2 Carcinogenicity study 1.8.1 Pharmacovigilance
1.8.3 Stability study System
1.5 Detailed Information of 1.9.1 Request for waiver of 1.8.2 Risk-management
Drug, Dosage From & pediatric studies System
Labelling Claims 1.9.2 Request for deferral of
1.5.1 Generic name with pediatric studies 1.9 Information relating to
chemical name & synonyms of 1.9.3 Request for pediatric clinical trials (if required)
the applied drug. exclusivity determination 1.10 Information relating to
1.5.2 Strength / concentration of 1.9.4 Proposed pediatric pediatrics.
drug of Active Pharmaceutical study request and
ingredient (API) per unit amendments MODULE 2 - 5
1.5.3 The proposed proprietary 1.9.6 Other correspondence No additional file formats are
name / brand name under which regarding pediatric defined for Modules 2 to 5
the drug is intended to be sold exclusivity or study plans other than those mentioned in
with trade mark certification / 1.10.1 Request for dispute the ICH eCTD Specification
clearance. resolution Document. In line with the
1.5.4 Proposed Pack size and 1.10.2 Correspondence statement on regional use of
Proposed unit price of drug e.g., related to dispute resolution other formats in the ICH
per tablet / capsule. Maximum eCTD Specification
Retail Price (MRP) per pack 1.11.1 Quality information Document, individual
shall also be mentioned. amendment Member States and
1.5.5 Pharmacotherapeutic 1.11.2 Non-clinical pharmaceutical companies
Group of Active Pharmaceutical information amendment could agree on a case-by-case
Ingredient (API) 1.11.3 Clinical information basis to use formats other than
1.5.6 Pharmacopoeial reference / amendment the common formats.
Status of applied formulation 1.11.4 Multiple module However, the use of formats
1.5.7 Route of administration information amendment other than those specified by
1.5.8 For Generic Drug 1.12.1 Pre IND the ICH eCTD Specification
Product, reference of other correspondence Document is discouraged.
similar approved medicines with 1.12.2 Request to charge for
information pertaining to clinical trial
Manufacturer name, brand 1.12.3 Request to charge for
name, strength, composition, expanded access
registration number & dosage 1.12.4 Request for comments
form, Pack size and Price. and advice
1.5.9 The registration status of 1.12.5 Request for a waiver
applied drug in same molecule 1.12.6 Exception from
and salt, strength, dosage form, informed consent for
container closure system, emergency research
indications and route of 1.12.7 Public disclosure
administration etc. in other statement for exception from
countries. The status in reference informed consent for
regulatory authorities is emergency research
mandatory to mention. 1.12.8 Correspondence
1.5.10 Dosage form of applied regarding exception from
drug informed consent for
1.5.11 Proposed label (outer emergency research
(secondary) & inner (primary)) 1.12.9 Notification of
& colour scheme in accordance discontinuation of clinical
with Drug (Labelling & trial
Packing) Rules, 1986 along with 1.12.10 Generic drug
specimens enforcement act statement
1.5.12 Description of Batch 1.12.11 ANDA basis for
numbering system submission statement
1.5.13 Training evidence of 1.12.12 Comparison of
technical staff with respect of generic drug and reference
manufacturing of applied drug listed drug
(mandatory in case of specially 1.12.13 Request for waiver
designed pharmaceutical for in vivo studies
product / Novel Dosage Form). 1.12.14 Environmental
analysis
1.5.14 Summary of Product 1.12.15 Request for waiver
Characteristics (SmPC) of in vivo bioavailability
including Prescribing studies
Information (PI) along with 1.12.16 Field alert reports
Patient information Leaflet 1.12.17 Orphan drug
(PIL) of the Finished designation
Pharmaceuticals Product (FPP). 1.13.1 Summary for
1.5.15 Commitment / nonclinical studies
Undertaking that after 1.13.2 Summary of clinical
registration of applied drug, the pharmacology information
Pharmacovigilance department 1.13.3 Summary of safety
of the applicant / manufactureis information
liable to impose similar 1.13.4 Summary of labeling
restrictions, addition of any changes
clinical information (like in 1.13.5 Summary of
Indications, Contra-indications, manufacturing changes
Side effects, Precautions, 1.13.6 Summary of
Dosage & Adverse Drug microbiological changes
Reactions etc. in Summary of 1.13.7 Summary of other
Product Characteristics (SmPC), significant new information
Labelling & Promotional 1.13.8 Individual study
material) or withdraw the drug information
from market in Pakistan within 1.13.9 General
fourteen days after knowing that investigational plan
such information (which was not 1.13.10 Foreign marketing
available or approved by the 1.13.11 Distribution data
DRAP at the time of 1.13.12 Status of post
registration) / actions taken (for marketing study
safety reasons) by any reference commitments and
/ stringent drug regulatory requirements
agency / authority & also inform 1.13.13 Status of other post
the DRAP (Drug Regulatory marketing studies and
Authority of Pakistan) for requirements
further action in this regard. 1.13.14 Log of outstanding
1.5.16 Commitment / regulatory business
Undertaking that the applicant 1.13.15 Development safety
shall recall the defective update report
Finished Pharmaceutical 1.14.1.1 Draft carton and
Products (FPP) and notify the container labels
compliance to the authority 1.14.1.2 Annotated draft
along with detail of actions taken labeling text
by him as soon as possible but 1.14.1.3 Draft labeling text
not more than ten days. The level
of recall shall also be defined.
1.5.17 Commitment
Undertaking that in case of any
false claim / concealing of
information, the DRAP has the
right to reject the application at
any time, before and even after
approval or registration of the
product in case if proved so.
1.5.18 Commitment
Undertaking that the firm shall
follow the official
pharmacopoeia specifications
for product / substance as
published in the latest edition &
shall update its specification as
per latest editions of the same. In
case, the specifications of
product / substance not present
in any official pharmacopoeia
the firm shall establish the
specifications. In both cases, the
validation of specifications shall
be done by the applicant.
1.5.19 Commitment
Undertaking that in case of any
post approval change, the
applicant shall ensure that the
product with both approvals
shall not be available in the
market at the same time. And the
product with new approvals
shall be marketed only after
consumption / withdrawal of
stock with previous approvals.
The company shall be liable to
inform the same regarding
marketing status of product to
the DRAP after getting such
post-registration approvals.
1.14.1.4 Label
comprehension studies
/ 1.14.1.5 Labeling history
m1.14.2.1 Final carton or
container labels
1.14.2.2 Final package insert
package inserts patient
information medication
guides
1.14.2.3 Final labeling text
/ 1.14.3.1 Annotated
comparison with listed drug
1.14.3.2 Approved labeling
text for listed drug
1.14.3.3 Labeling text for
reference listed drug
1.14.4.1 Investigational
brochure
1.14.4.2 Investigational drug
label
1.14.5 Foreign labeling
1.14.6 product labeling for
2253 submissions
1.15.1.1 Request for
advisory comments on
/ launch materials
1.15.1.2 Request for
advisory comments on non
launch materials
1.15.1.3 Pre submission of
launch promotional materials
for accelerated approval
products
1.15.1.4 Pre submission of
non launch promotional
materials for accelerated
approval products
1.15.1.5 Pre dissemination
review of televions ads
1.15.1.6 Response to untitled
letter or warning letter
1.5.20 other commitment e.g., 1.15.1.7 Response to
regarding stability studies etc. information request
1.5.21 Protocols along with the 1.15.1.8 Correspondence
commitment to follow Good accompanying materials
Laboratory Practices (GLP) by previously missing or
the Manufacturer. 1.5.22 rejected
Protocols to implement Good 1.15.1.9 Withdrawal request
Pharmacovigilance Practice by 1.15.1.10 Submission of
the Pharmacovigilance annotated references
department/section of the 1.15.1.11 General
Manufacturer / Company. correspondence
1.6 Miscellaneous Information 1.15.2.1.1 Clean version
1.6.1 Information on Prior- 1.15.2.1.2 Annotated version
related Applications 1.15.2.1.3 Annotated
1.6.2 Appendix 1.6.3 Electronic labeling version
Review Package 1.15.2.1.4 Annotated
1.6.4 QIS (Quality Information references
Summary) 1.16.1 Risk management non
1.6.5 Drug Substance related rems
Document including following: 1.16.2.1 Final rems
a. Name and address of API 1.16.2.2 Draft rems
manufacturer. 1.16.2.3 REMS (Risk
b. Approval of manufacturing Evaluation and Mitigation
facility of API by regulatory Strategies) assessment
body of country and validity. 1.16.2.4 REMS (Risk
c. Vendor qualification / audit is Evaluation and Mitigation
Strategies) assessment
methodology
d. Reason for point c. 1.16.2.5 Rems
correspondence
MODULE 2-5 are as per ICH 1.16.2.6 Rems modification
M4 guidelines history
1.17.1 Correspondence
regarding post marketing
commitments
1.17.2 Correspondence
regarding post marketing
requirements
1.18 Proprietary names
1.19 Pre eua and eua
1.20 General investigational
plan for initial ind
 MODULE 2 - 5
No additional file formats are
defined for Modules 2 to 5
other than those mentioned
in the ICH eCTD
Specification Document. In
line with the statement on
regional use of other formats
in the ICH eCTD
Specification Document,
individual Member States
and pharmaceutical
companies could agree on a
case-by-case basis to use
formats other than the
common formats. However,
the use of formats other than
those specified by the ICH
eCTD Specification
Document is discouraged

Discussion:
United States, UK & KOREA are the members of ICH while Turkey is observer of ICH so they follow the ICH M4 Guidelines for CTD but now
they accept the eCTD (ICH M8) format which is electronic format of the CTD. The Common Technical Document (CTD) is organized into five
modules. Module 1 is region specific. Modules 2, 3, 4, and 5 are intended to be common for all regions. Conformance with this guideline should
ensure that these four modules are provided in a format acceptable to the regulatory authorities. The only difference is in MODULE 1 which is
administrative part and it is region specific. DRAP recently announced to receive applications of dossiers on FORM 5-F (CTD) which is as per ICH
Guidelines but it is yet to be implemented.

Module 1: Administrative Information and Prescribing Information

1.1 Table of Contents of the Submission Including Module 1
1.2 Documents Specific to Each Region (for example, application forms, prescribing information)

Module 2: Common Technical Document Summaries

2.1 Common Technical Document Table of Contents (Modules 2-5)
2.2 CTD Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries
  Pharmacology
 Pharmacokinetics
 Toxicology
2.7 Clinical Summary
 Biopharmaceutics Studies and Associated Analytical Methods
 Clinical Pharmacology Studies
 Clinical Efficacy
 Clinical Safety
 Literature References
 Synopses of Individual Studies

Module 3: Quality
3.1 Table of Contents of Module 3
3.2 Body of Data
3.2 S Active substance
3.2 P Finished Medicinal Product
3.3 Literature References

Module 4: Nonclinical Study Reports

4.1 Table of Contents of Module 4
4.2 Study Reports
4.3 Literature References

Module 5: Clinical Study Reports

5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies
5.3 Clinical Study Reports
5.4 Literature References

CONCLUSION:
It’s a good achievement that DRAP has taken initiative to move on CTD guidelines but currently there is a gap in practices of following CTD as
other mentioned regulatory authorities Although MODULE 1 is region specific and every country has its own requirements for the registration of
the product. DRAP needs to include Environmental Risk Assessment in its Module 1.
 RENEWAL REGISTRATION GUIDELINES COMPARISON REPORT OF
REGULATORY AUTHORITIES

DRAP USFDA MHRA MFDS TITCK/TMMDA

Applied on form 5-B issued by Renewal applications should be Documents should be Renewal applications should be
DRAP. submitted in eCTD format and submitted : submitted in eCTD format and
ENCLOSURES OF THE have to contain the documents 1) Summary reports on Safety have to contain the documents
APPLICATION FOR listed below. and Efficacy of the drug product listed below.
RENEWAL OF Documents to submit including the last 5-year Documents to submit
REGISTRATION OF A DRUG MODULE 1: 2) Usage in foreign countries, MODULE 1:
Dosage Form: 1.0 Cover letter Any action related to safety in 1.0 Cover letter
1- Brand (Proprietary) name of the 1.2 Renewal Application form foreign countries 1.2 Renewal Application form
drug. 1.3.1 Summary of Product 3) Data on Product Quality 1.3.1 Summary of Product
2- Strength of active ingredient(s) Characteristics, Labelling and 4) Safety update report Characteristics, Labelling and
per unit, e.g., each tablet or 5ml, etc. Package Leaflet: 5) In case anything would be Package Leaflet
contains. 1.3.3 Specimens: changed from approval, its 1.3.3 Specimens
3- Name and address of the 1.4 Information about the evidential data 1.4 Information about the
manufacturer. Expert 6) Document on Drug Display Expert
4- Name and address of the agent or 1.4.1 Information about the (Label in carton, PI and so on) 1.4.1 Information about the
indentor in case of imported drug. Expert: Quality (incl. Signature 7) Manufacturing or Importing Expert Quality (incl. Signature
5-Whether the drug is registered for + CV) records during the last five-year + CV)
local manufacture or import. 1.4.2 Information about the 8) Product Permission letter 1.4.2 Information about the
6- Patent number in Pakistan & its Expert: Non-clinical (incl. issued by MFDS Expert Non-clinical (incl.
expiry date. Signature + CV) – if applicable Signature + CV) – if applicable
7- Name of the registered drug with 1.4.3 Information about the 1.4.3 Information about the
its registration number and date of Expert: Clinical (incl. Signature Expert: Clinical (incl. Signature
initial registration and last renewal. + CV) + CV)
8- Changes, if any, in information 1.8.1 Summary of 1.8.1 Summary of
furnished at the time of initial pharmacovigilance system pharmacovigilance system
registration or last renewal. 1.8.2 Risk Management Plan: 1.8.2 Risk Management Plan:
9- If withdrawn from the market
anywhere: (i) the name of the MODULE 2: MODULE 2:
country; and (ii) the reasons
thereof. 2.3 Addendum to Quality 2.3 Addendum to Quality
UNDERTAKING Overall Summary: Overall Summary:
2.4 Addendum to Non-clinical 2.4 Addendum to Non-clinical
Overview: Overview:
2.5 Addendum to Clinical 2.5 Addendum to Clinical
Overview: Overview
DISCUSSION:
Renewal of dossier of all the products is compulsory after 5 years of its registration, so every Drug Regulatory Authority has its own Guidelines for
the renewal of dossier. DRAP has its own application form FORM-5 B for the renewal of registration of the product which is filled and required
documents are submitted with it for the renewal. MHRA, TITCK/TMMDA, USFDA & MFDS accept the renewal of dossier in eCTD format. As
MFDS has own requirements listed above. While, MHRA & TITCK/TMMDA follow EMA (European Medicine Agency). So, they follow the EMA
guidelines for renewal of registration of dossier and submit the some required documents from MODULE 1 & MODULE 2 in eCTD format.
Similarly, required documents are submitted in eCTD format to USFDA for the renewal of registration of the dossier. DRAP should update its
renewal requirement as others.
 API SOURCE (DMF/ASMF) COMPARISON REPORT OF
REGULATORY AUTHORITIES
DRAP USFDA MHRA TITCK/TMMDA MFDS
 DMF (Open Part)  DMF (Open & Closed Part)  ASMF (Open & Closed  ASMF (Open & Closed  DMF (Open & Closed Part)
 ICH Guidelines "Guidance  Letter of access (LOA) Part) Part)  ICH Guidelines "Guidance
for Industry M4Q: The  ICH Guidelines "Guidance  Letter of access (LOA)  Letter of access (LOA) for Industry M4Q: The
CTD - Quality" for Industry M4Q: The  ICH Guidelines "Guidance  ICH Guidelines "Guidance CTD - Quality"
CTD - Quality" for Industry M4Q: The for Industry M4Q: The
CTD - Quality" CTD - Quality"
DMF CONTENTS Type II DMFs for drug  EMA accepts both ASMF as  EMA accepts both ASMF as As a minimum, the APIs need to
(DRUG SUBSTANCE) substances should be submitted well as a Certificate of well as a Certificate of comply with the local
3.2.S.1 General information in the format for "Drug Suitability (CEP). Suitability (CEP) monograph when existing or
3.2.S.1.1 Nomenclature substance" in the "Guidance A Certificate of Suitability A Certificate of Suitability with EP or USP one and need to
3.2.S.1.2 Structure for Industry M4Q: The CTD - (CEP) certifies the compliance (CEP) certifies the compliance be manufactured under GMP.
3.2.S.1.3 General properties Quality" of a material with the of a material with the DMF CONTENTS
3.2.S.2 Manufacture (RP) Type II API DMFs must requirements laid down in the requirements laid down in the 3.2.S.1 General information
3.2.S.2.1 Manufacturer(s) undergo an FDA completeness relevant monograph of the relevant monograph of the 3.2.S.1.1 Nomenclature
3.2.S.2.2 Description of assessment (CA). European Pharmacopoeia. European Pharmacopoeia. 3.2.S.1.2 Structure
Manufacturing Process and The manufacturer could submit After submission by the API After submission by the API 3.2.S.1.3 General properties
Process a DMF (Drug Master File) manufacturer, the European manufacturer, the European 3.2.S.2 Manufacture (RP)
controls type II - this one is dedicated to Directorate for the Quality of Directorate for the Quality of 3.2.S.2.1 Manufacturer(s)
3.2.S.2.3 Control of Materials API; it is divided in two parts Medicines (EDQM) assesses Medicines (EDQM) assesses 3.2.S.2.2 Description of
3.2.S.2.4 Control of critical steps (open and closed). the CEP dossier and grants a the CEP dossier and grants a Manufacturing Process and
and intermediates In the same way, the API’s certificate. certificate. Process
3.2.S.2.5 Process validation manufacturer provides to his A declaration of access to the A declaration of access to the controls
and/or Evaluation customer an LOA (letter of CEP is signed by the API CEP is signed by the API 3.2.S.2.3 Control of Materials
3.2.S.2.6 Manufacturing Process access) to his DMF to protect manufacturer and is added to the manufacturer and is added to the 3.2.S.2.4 Control of critical steps
Development confidential information, this MAA of the Drug product MAA of the Drug product and intermediates
3.2.S.3 Characterization dossier and GMP will be also the manufacturer. manufacturer. 3.2.S.2.5 Process validation
3.2.S.3.1 Elucidation of basis in case of FDA Inspection. The Active substance Master The Active substance Master and/or Evaluation
Structure and other DMF CONTENTS File is composed of two parts: File is composed of two parts: 3.2.S.2.6 Manufacturing Process
Characteristics 3.2.S.1 General information the open part and the closed the open part and the closed Development
3.2.S.3.2 Impurities 3.2.S.1.1 Nomenclature part. The open part is included part. The open part is included 3.2.S.3 Characterization
3.2.S.4 Control of Drug 3.2.S.1.2 Structure in the Marketing authorization in the Marketing authorization 3.2.S.3.1 Elucidation of
Substance 3.2.S.1.3 General properties of the drug product of the drug product Structure and other
3.2.S.4.1 Specification 3.2.S.2 Manufacture (RP) manufacturer while the closed manufacturer while the closed Characteristics
3.2.S.4.2 Analytical procedures 3.2.S.2.1 Manufacturer(s) part (confidential information) part (confidential information) 3.2.S.3.2 Impurities
3.2.S.4.3 Validation of 3.2.S.2.2 Description of is submitted by the API is submitted by the API 3.2.S.4 Control of Drug
analytical procedures Manufacturing Process and manufacturer to the Health manufacturer to the Health Substance
3.2.S.4.4 Batch analysis Process Authorities. Authorities. 3.2.S.4.1 Specification
3.2.S.4.5 Justification of controls ASMF CONTENTS ASMF CONTENTS 3.2.S.4.2 Analytical procedures
specification 3.2.S.2.3 Control of Materials 3.2.S.1 General information 3.2.S.1 General information 3.2.S.4.3 Validation of
3.2.S.5 Reference standards or 3.2.S.2.4 Control of critical steps 3.2.S.1.1 Nomenclature 3.2.S.1.1 Nomenclature analytical procedures
materials and intermediates 3.2.S.1.2 Structure 3.2.S.1.2 Structure 3.2.S.4.4 Batch analysis
3.2.S.6 Container Closure 3.2.S.2.5 Process validation 3.2.S.1.3 General properties 3.2.S.1.3 General properties 3.2.S.4.5 Justification of
System and/or Evaluation 3.2.S.2 Manufacture (RP) 3.2.S.2 Manufacture (RP) specification
3.2.S.7 Stability 3.2.S.2.6 Manufacturing Process 3.2.S.2.1 Manufacturer(s) 3.2.S.2.1 Manufacturer(s) 3.2.S.5 Reference standards or
3.2.S.7.1 Stability summary and Development 3.2.S.2.2 Description of 3.2.S.2.2 Description of materials
conclusion 3.2.S.3 Characterization Manufacturing Process and Manufacturing Process and 3.2.S.6 Container Closure
3.2.S.7.2 Post-approval Stability 3.2.S.3.1 Elucidation of Process Process System
Protocol and Stability Structure and other controls controls 3.2.S.7 Stability
Commitment Characteristics 3.2.S.2.3 Control of Materials 3.2.S.2.3 Control of Materials 3.2.S.7.1 Stability summary and
3.2.S.7.3 Stability data 3.2.S.3.2 Impurities 3.2.S.2.4 Control of critical steps 3.2.S.2.4 Control of critical steps conclusion
3.2.S.4 Control of Drug and intermediates and intermediates 3.2.S.7.2 Post-approval Stability
Substance 3.2.S.2.5 Process validation 3.2.S.2.5 Process validation Protocol and Stability
3.2.S.4.1 Specification and/or Evaluation and/or Evaluation Commitment
3.2.S.4.2 Analytical procedures 3.2.S.2.6 Manufacturing Process 3.2.S.2.6 Manufacturing Process 3.2.S.7.3 Stability data
3.2.S.4.3 Validation of Development Development
analytical procedures 3.2.S.3 Characterization 3.2.S.3 Characterization
3.2.S.4.4 Batch analysis 3.2.S.3.1 Elucidation of 3.2.S.3.1 Elucidation of
3.2.S.4.5 Justification of Structure and other Structure and other
specification Characteristics Characteristics
3.2.S.5 Reference standards or 3.2.S.3.2 Impurities 3.2.S.3.2 Impurities
materials 3.2.S.4 Control of Drug 3.2.S.4 Control of Drug
3.2.S.6 Container Closure Substance Substance
System 3.2.S.4.1 Specification 3.2.S.4.1 Specification
3.2.S.7 Stability 3.2.S.4.2 Analytical procedures 3.2.S.4.2 Analytical procedures
3.2.S.7.1 Stability summary and 3.2.S.4.3 Validation of 3.2.S.4.3 Validation of
conclusion analytical procedures analytical procedures
3.2.S.7.2 Post-approval Stability 3.2.S.4.4 Batch analysis 3.2.S.4.4 Batch analysis
Protocol and Stability 3.2.S.4.5 Justification of 3.2.S.4.5 Justification of
Commitment specification specification
3.2.S.7.3 Stability data 3.2.S.5 Reference standards or 3.2.S.5 Reference standards or
materials materials
3.2.S.6 Container Closure 3.2.S.6 Container Closure
System System
3.2.S.7 Stability 3.2.S.7 Stability
3.2.S.7.1 Stability summary and 3.2.S.7.1 Stability summary and
conclusion conclusion
 3.2.S.7.2 Post-approval Stability 3.2.S.7.2 Post-approval Stability
Protocol and Stability Protocol and Stability
Commitment Commitment
3.2.S.7.3 Stability data 3.2.S.7.3 Stability data

DISCUSSION:
Active Pharmaceutical Ingredient (API) is any substance or mixture of substances intended to be used in the manufacture of a medicine and that,
when used in the production of a drug product, becomes an active ingredient of the drug product. Such substances are intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the odds structure or
function. Linked to their uses, APIs should be manufactured according to the current regulation in order to reach a high level of safety, efficiency
and quality. EMA (MHRA & TITICK/TMMDA) accepts both ASMF (Active Substance Master File) as well as a Certificate of Suitability (CEP)
along with letter of access (LOA). While FDA uses the term Type II DMF dedicated to API and it is divided into 2 parts (open & closed). Letter
of access (LOA) is also provided. Type II DMFs/ASMF for drug substances should be submitted in the format for "Drug substance" in the
"Guidance for Industry M4Q: The CTD - Quality" of ICH Guidelines. In MFDS, as a minimum, the APIs need to comply with the local
monograph when existing or with EP or USP one and need to be manufactured under GMP. DMF Contents are same for active substance. DRAP
requires the Open part of DMF of active substance. It is highly encouraged that it should be submitted in eCTD format to FDA while in other
Regulatory authorities it should be submitted in CTD Format.
 PRODUCT RECALL COMPARISON REPORT OF
REGULATORY AUTHORITIES
DRAP USFDA MHRA MFDS TITCK/TMMDA
Recall definition Recall definition Recall definition Recall definition Recall definition
Recall mean any measure aimed Recall is a firm's removal or Recall mean any measure aimed Recall mean any measure aimed Recall mean any measure aimed
at achieving the return of a correction of a marketed product at achieving the return of a at achieving the return of a at achieving the return of a
dangerous product that has that FDA considers to be in dangerous product that has dangerous product that has dangerous product that has
already been supplied or made violation of the laws it already been supplied or made already been supplied or made already been supplied or made
available to consumers by the administers, and against which available to consumers by the available to consumers by the available to consumers by the
producer or distributor the Agency would initiate legal producer or distributor producer or distributor producer or distributor
action.
Regulatory body Regulatory body Regulatory body Regulatory body Regulatory body
(Drug Regulatory Authority of United States Food and Drugs European Medicines Agency MFDS (Ministry of food & Drug European Medicines Agency
Pakistan) DRAP Administration (USFDA) with (EMA) safety) (EMA)
CRU (Central Recall Unit) or Defective Medicines Report
OEIO/DE. Centre (DMRC) under MHRA
Electronic System Electronic System Electronic System Electronic System Electronic System
N/A The Recall Enterprise System Yes N/A Yes
(RES) is an electronic data
system used by FDA recall
personnel to submit, update,
classify, and terminate recalls
Legal Requirement Legal requirement Legal requirement Legal requirement Legal requirement
WHO Guidelines 21CFR Part 7, Subparts A and C; Article 40 of Directive Annex 17 (MFDS GMP Article 40 of Directive
DRAP GMP Guidelines 21CFR Part 107, Subpart E; 21 2001/83/EC and Article 44 of Guidelines) 2001/83/EC and Article 44 of
CFR Part 1270 - Human Tissue Directive 2001/82/EC is Directive 2001/82/EC is
PHS Act - 42 U.S.C. 262 required under Article 13(1) of required under Article 13(1) of
Directive 2003/94 and Article 13 Directive 2003/94 and Article 13
of Directive 91/412/EC of Directive 91/412/EC
EMA GMP Guidelines EMA GMP Guidelines
Initiation of Recall Initiation of Recall Initiation of Recall Initiation of Recall Initiation of Recall
Statutory Recalls (by NRA) Voluntary, FDA requested or Voluntary or at the request of the The recalls shall be able to be Voluntary or at the request of the
Voluntary Recall (by FDA mandated recall competent authorities in commenced immediately and at competent authorities in
Manufacturer) accordance with Article 8(1)(f) any time. accordance with Article 8(1)(f)
(Directive 2001/83/EC) (Directive 2001/83/EC)
Recall Classification Recall Classification Recall Classification Recall Classification Recall Classification
Class I, II and III Class I, II and III Class I, II and III Class I, II and III Class I, II and III
Class I: defects are potentially Class I: defects are potentially Class I: defects are potentially Class I: defects are potentially Class I: defects are potentially
life threatening. life threatening. life threatening. life threatening. life threatening.
Class II: defects could cause
illnesses or mistreatment, but are
not Class I.
Class III: defects may not pose
a significant hazard to health,
but withdrawal may be initiated
for other reasons.
Health hazard evaluation
(HHE)
By DRAP
Termination of a Recall
N/A
Recall Strategy
There shall be established
written procedures, regularly
checked and updated for the
organization of any recall
activity. A person responsible
for the execution and
coordination of recalls shall be
designated.
Notification and Public
Warning
Communicate/warn Public
related professionals about the
health hazard of recalled
product. In cases of Class I
recall, public announcements
shall be made to stop the usage
of the drug immediately, using
fastest mode of communication
such as Newspapers, Television,
Radio, Website etc.
Recall Communication
All competent authorities to
whom a given product may have
been distributed shall be
promptly informed of any
intention to recall the product.
Class II: defects could cause Class II: defects could cause Class II: defects could cause Class II: defects could cause
illnesses or mistreatment, but are illnesses or mistreatment, but are illnesses or mistreatment, but are illnesses or mistreatment, but are
not Class I. not Class I. not Class I. not Class I.
Class III: defects may not pose Class III: defects may not pose Class III: defects may not pose Class III: defects may not pose
a significant hazard to health, a significant hazard to health, a significant hazard to health, a significant hazard to health,
but withdrawal may be initiated but withdrawal may be initiated but withdrawal may be initiated but withdrawal may be initiated
for other reasons. for other reasons. for other reasons. for other reasons.
Health hazard Health hazard Health hazard Health hazard
evaluation(HHE) evaluation(HHE) evaluation(HHE) evaluation(HHE)
By the Health Hazard Relative health hazard By MFDS Relative health hazard
Evaluation Committee associated with the use or associated with the use or
exposure to the recalled product exposure to the recalled product
Termination of a Recall Termination of a Recall Termination of a Recall Termination of a Recall
Written notification of N/A N/A N/A
termination to the recalling firm
Recall strategy Recall strategy Recall strategy Recall strategy
A recalling firm should conduct In order to protect public health, There shall be a person who is In order to protect public health,
the recall in accordance with an a system and appropriate responsible for the a system and appropriate
approved recall strategy procedures should be in place to implementation and procedures should be in place to
record, assess, investigate and coordination of recalls. record, assess, investigate and
review complaints including There shall be documented review complaints including
potential quality defects. Quality procedures that have been potential quality defects. Quality
Risk Management principles established to systemize all Risk Management principles
should be applied. recall activities should be applied.
Notification and Public Notification and Public Notification and Public Notification and Public
Warning Warning Warning Warning
Public warning is issued to alert Notification by the European If products are to be recalled Notification by the European
the public about the serious Commission because they are defective or Commission
hazard to health presented by the Information available to the suspected of having defects, it Information available to the
product being recalled. It is authorities of the Member States shall be notified in a proper authorities of the Member States
reserved for urgent situations or the Commission relating to manner to the competent or the Commission relating to
where other means for risks to consumer health and authorities of all countries in risks to consumer health and
preventing use of the recalled safety posed by products shall in which it is distributed. safety posed by products shall in
product appear inadequate. The general be available to the All Class I recalls shall be general be available to the
FDA in consultation with the public, in accordance with the executed up to the levels of public, in accordance with the
recalling firm ordinarily issues requirements of transparency. hospital/ distributor/wholesaler / requirements of transparency.
such publicity. Public warning is Member States and the retailer/ consumer/user. Member States and the
issued as, general public Commission take steps All Class II and Class III recalls Commission take steps
warning in the national or local necessary to ensure not to shall be executed up to the levels necessary to ensure not to
media news or through disclose information covered by of hospital / distributor / disclose information covered by
specialized media news, e.g., professional secrecy in duly wholesaler/ retailer. professional secrecy in duly
professional or trade press, or to justified cases, except for justified cases, except for
All Class I recalls shall be
executed up to the levels of
hospital/ distributor/wholesaler /
retailer/ consumer/user.
All Class II and Class III recalls
shall be executed up to the levels
of hospital / distributor /
wholesaler/ retailer.
Recall Timeline
Class I: 7 days
Class II: 15 days
Class III: 30 days
Evaluation
The effectiveness of the
arrangements for recalls shall be
evaluated from time to time.
Recording Of Progress
The progress of the recall
process shall be recorded and a
final report issued, including a
reconciliation between the
delivered and recovered
quantities of the products.
specific segments of the
population such as physicians,
hospitals, etc.
All Class I recalls shall be
executed up to the levels of
hospital/ distributor/wholesaler /
retailer/ consumer/user.
All Class II and Class III recalls
shall be executed up to the levels
of hospital / distributor /
wholesaler/ retailer.
Recall timeline
Timeline given by CRU (Central
Recall Unit) based on product to
be recalled.
Effectiveness Checks
The recalling firm is responsible
for conducting effectiveness
checks and FDA also assist
where necessary and
appropriate. The recall strategy
specify the level of effectiveness
checks to be followed as
Level A: 100 percent of
consignees to be contacted;
Level B: depends on a case-by-
case basis, < 10 percent to > 100
percent of consignees
Level C: 10 percent of
consignees to be contacted;
Level D: 2 percent of consignees
to be contacted; or
Level E: No effectiveness
checks.
Monitoring and Auditing the
Recall
Implements a recall audit
program
information relating to product
safety.
All Class I recalls shall be
executed up to the levels of
hospital/ distributor/wholesaler /
retailer/ consumer/user.
All Class II and Class III recalls
shall be executed up to the levels
of hospital / distributor /
wholesaler/ retailer.
Recall timeline
Class I: immediate
Class II: within 48 hours
Class III: within 5 days
Investigation And Decision-
Making
The validity and extent of all
reported quality defects are
documented and assessed in
accordance with Quality Risk
Management principles.
Following quality defect
investigations decisions are
made reflecting the level of risk
presented by the quality defect
and any noncompliance with
respect to the requirements of
marketing authorization. The
decision making processes
should ensure that appropriate
risk-reducing actions are
documented. CAPA is prepared.
Monitoring and Auditing the
Recall
The effectiveness of recalls is
periodically evaluated and
documented
Recall timeline
Not Defined
Effectiveness Checks
The effectiveness of the recall
methods shall be evaluated
regularly.
Monitoring and Auditing the
Recall
The progress of a recall process
shall be recorded, and a final
report shall be written including
a comparison of quantities of
products that have been shipped
and recalled.
information relating to product
safety.
All Class I recalls shall be
executed up to the levels of
hospital/ distributor/wholesaler /
retailer/ consumer/user.
All Class II and Class III recalls
shall be executed up to the levels
of hospital / distributor /
wholesaler/ retailer.
Recall timeline
Not defined
Investigation And Decision-
Making
The validity and extent of all
reported quality defects are
documented and assessed in
accordance with Quality Risk
Management principles.
Following quality defect
investigations decisions are
made reflecting the level of risk
presented by the quality defect
and any noncompliance with
respect to the requirements of
marketing authorization. The
decision making processes
should ensure that appropriate
risk-reducing actions are
documented. CAPA is prepared.
Monitoring and Auditing the
Recall
The effectiveness of recalls is
periodically evaluated and
documented
Root cause identification, CAPA
& documentation
Storage of Recalled Products
An instruction shall be included
to store recalled products in a
secure segregated area while
their fate is decided.
Storage of Recalled Products
The recalled products shall be
identifiable and kept separately
in a controlled area until the
disposal is determined.
Storage of Recalled Products
The recalled products shall be
identifiable and kept separately
in a controlled area until the
disposal is determined.
Storage of Recalled Products
The recalled products shall be
identifiable and kept separately
in a controlled area until the
disposal is determined.
Storage of Recalled Products
The recalled products shall be
identifiable and kept separately
in a controlled area until the
disposal is determined.

DISCUSSION:
The regulatory bodies controlling drug regulation are USFDA (for USA), EMA (For United Kingdom & Turkey), MFDS (For Korea)
and DRAP (for Pakistan). The legal provisions are 21 CFR for USA, European Commission (EC) directive for UK & Turkey and
WHO guidelines for DRAP (Pakistan). In all the countries recall is classified as Class I, II and III with slight difference in
terminologies. Recall strategy in USFDA is well defined with detailed procedure although in EMA the process is not clear but Quality
Risk Management principles should be applied. In USA recall must be conducted in accordance with the approved recall strategy. Recall
notification and public warning are provided in newspapers, television, radio, press release and in FDA’s web site mostly for Class I
recall. All Class I recalls shall be executed up to the levels of hospital/ distributor/wholesaler / retailer/ consumer/user. All Class II and
Class III recalls shall be executed up to the levels of hospital / distributor / wholesaler/ retailer. .In USA & U.K, the recall timeline is
defined and in Turkey & Korea, the recall timeline is not defined. As DRAP follows the WHO Guidelines so it has defined timeline.
Recall investigation report is required to be submitted and assessment of effectiveness of recalls are done and documented. USFDA
issues written notification of termination to the recalling firm ensuring proper implementation of corrective and preventive action. The
recall termination process is not defined in any Authority except USFDA. The effectiveness of recalls is periodically evaluated and
documented. The recalled products shall be identifiable and kept separately in a controlled area until the disposal/fate is determined.
CONCLUSION:
Drug product recall is not a desirable event for any pharmaceutical company also recalling a product is not an easy task once released
into the market as recovery from different levels are difficult and tedious job. Recall of any product adversely affects the financial status
and commercial goodwill of the manufacturing company. The regulatory bodies ensure proper fulfilment of recalling by implementing
strict guideline defining procedure from notification to termination. Recalling can be done smoothly when company management
follows guideline, and do all the recalling activities as defined
 BIOEQUIVALENCE STUDY REPORT COMPARISON OF
REGULATORY AUTHORITIES
DRAP USFDA MHRA TITCK/TMMDA MFDS
BIOEQUIVALENCE (BE) GUIDELINES
 WHO, ICH and other  USFDA Guidance for  Guideline on the  Guideline on the  Standard on Pharmaceutical
international standards industry Guidelines Investigation of Investigation of Equivalence Test (2018)
 Bio-Study Rules 2017  21 CFR part 320 Bioequivalence (EMA Bioequivalence (EMA  Guidance Document for
 ICH guidelines GUIDELINES) (January GUIDELINES) (January Bioequivalence Study
2010) 2010) (December 2008)
 ICH guidelines  ICH guidelines  ICH guidelines
 Directive 2001/83/EC  Directive 2001/83/EC
BIOEQUIVALENCE
“BE” means bio-equivalence The absence of a significant The absence of a significant The absence of a significant The absence of a significant
phenomenon, according to difference in the rate and extent difference in the rate and extent difference in the rate and extent difference in the rate and extent
which two medicinal products to which the active ingredient or to which the active ingredient or to which the active ingredient or to which the active ingredient or
containing same pharmaceutical active moiety in pharmaceutical active moiety in pharmaceutical active moiety in pharmaceutical active moiety in pharmaceutical
formulation and quantity of the equivalents or pharmaceutical equivalents or pharmaceutical equivalents or pharmaceutical equivalents or pharmaceutical
same active ingredient, are alternatives becomes available at alternatives becomes available at alternatives becomes available at alternatives becomes available at
considered bioequivalent if they the site of drug action when the site of drug action when the site of drug action when the site of drug action when
are pharmaceutically equivalent administered at the same molar administered at the same molar administered at the same molar administered at the same molar
and their bio-availabilities, in dose under similar conditions in dose under similar conditions in dose under similar conditions in dose under similar conditions in
terms of rate and extent, after an appropriately designed study. an appropriately designed study. an appropriately designed study. an appropriately designed study.
administration in the same molar (FDA Guidelines) (ICH Guidelines) (ICH Guidelines) (ICH Guidelines)
dose, lie within acceptable
predefined limits (Bio-study
Rules 2017)
DEFINITIONS OF A GENERIC DRUG PRODUCT AND REFERENCE DRUG PRODUCT
Generic drug product Generic drug product Generic drug product Generic drug product Generic drug product
A pharmaceutical product that is A pharmaceutical product that is A generic medicinal product is a A generic medicinal product is a A drug product whose active
interchangeable with the interchangeable with the product which has the same product which has the same ingredients (including salts and
innovator product, which is innovator product, which is qualitative and quantitative qualitative and quantitative isomers), strength and route of
usually marketed without a usually marketed without a composition in active substances composition in active substances administration is the same as
license from the innovator license from the innovator and the same pharmaceutical and the same pharmaceutical those of the reference product.
company and marketed after company and marketed after form as the reference medicinal form as the reference medicinal Reference/Innovator drug
expiry of the patent or other expiry of the patent or other product, and whose product, and whose product
exclusivity rights. (ICH exclusivity rights. (ICH bioequivalence with the bioequivalence with the A pharmaceutical to be
Guidelines) Guidelines) reference medicinal product has reference medicinal product has compared with test product
Reference/Innovator drug Reference/Innovator drug been demonstrated by been demonstrated by whose safety and efficacy were
product product appropriate bioavailability appropriate bioavailability previously established as its
The innovator pharmaceutical
product is that which was
authorized for marketing on the
basis of documentation of
efficacy, safety and quality.
(ICH Guidelines)
A minimum of 10% of the
commercial batch size or
100,000 units, whichever is
greater
A randomized, two-period, two-
sequence single dose crossover
design is recommended as
standard
Non-replicate study designs are
recommended for most orally
administered, immediate-release
dosage forms.
Replicated crossover designs
may also be used; and
Parallel designs may be used for
long half-life drugs
Healthy normal subjects
18–55 years of age
Weight within an acceptable
range
Subjects can belong to either sex
Minimum of 12 subjects
Subjects are not allowed to drink
1 hr before dosing and 1 hr after
dosing except 240ml of water at
A reference listed drug means studies. (Directive 2001/83/EC, studies. (Directive 2001/83/EC, manufacturing (importing) had
the listed drug identified by the Article 10(2)(b) Article 10(2)(b) been approved, or that the
FDA as the drug product upon Reference/Innovator drug Reference/Innovator drug Ministry of Food and Drug
which an applicant relies in product product Safety (MFDS) recognized its
seeking approval of its ANDA. A drug product whose marketing A drug product whose marketing validity as a reference product.
authorization in the EU has been authorization in the EU has been (Standard on Pharmaceutical
granted on the basis of a granted on the basis of a Equivalence Test (2018)
complete dossier. complete dossier
GENERAL BE STUDY DESIGN
Number of units of test product to be manufactured for the bioequivalence study
A minimum of 10% of the A minimum of 10% of the A minimum of 10% of the At least 100,000 units
commercial batch size or commercial batch size or commercial batch size or
100,000 units, whichever is 100,000 units, whichever is 100,000 units, whichever is
greater greater greater
BASIC STUDY DESIGN
A randomized, two-period, two- A randomized, two-period, two- A randomized, two-period, two- A randomized, two-period, two-
sequence single dose crossover sequence single dose crossover sequence single dose crossover sequence single dose crossover
design is recommended as design is recommended as design is recommended as design is recommended as
standard standard standard standard
Non-replicate study designs are Non-replicate study designs are Non-replicate study designs are Non-replicate study designs are
recommended for most orally recommended for most orally recommended for most orally recommended for most orally
administered, immediate-release administered, immediate-release administered, immediate-release administered, immediate-release
dosage forms. dosage forms. dosage forms. dosage forms.
Replicated crossover designs Replicated crossover designs Replicated crossover designs Replicated crossover designs
may also be used; and may also be used; and may also be used; and may also be used; and
Parallel designs may be used for Parallel designs may be used for Parallel designs may be used for Parallel designs may be used for
long half-life drugs long half-life drugs long half-life drugs long half-life drugs
SUBJECTS
Healthy normal subjects Healthy normal subjects Healthy normal subjects Healthy normal subjects
At least 18 years of age At least 18 years of age At least 18 years of age Age of 19–55
Individuals representative of the Body Mass Index (BMI) within Body Mass Index (BMI) within Any females used in the
general population 18.5 and 30 kg/m2 18.5 and 30 kg/m2 bioequivalence studies should
Any females used in the Any females used in the Any females used in the not be pregnant
bioequivalence studies should bioequivalence studies should bioequivalence studies should Subjects can belong to either sex
not be pregnant not be pregnant not be pregnant Minimum of 12 subjects
Subjects can belong to either sex Subjects can belong to either sex Subjects can belong to either sex
Minimum of 12 subjects Minimum of 12 subjects Minimum of 12 subjects
FLUID REQUIREMENT
Subjects are not allowed to drink Subjects are not allowed to Subjects are not allowed to Subjects are not allowed to
1 hr before dosing and 1 hr after drink 1 hr before dosing and 1 drink 1 hr before dosing and 1 drink 1 hr before dosing and 1
dosing except 240ml of water at hr after dosing except 150ml of hr after dosing except 150ml of hr after dosing except 240ml of
dosing, thereafter water is dosing, thereafter water
provided ad-libitum.
All subjects are required to fast
for at least 10 hours pre dose
and 4 hours post-dose
Generally the marketed strength
with the greatest sensitivity to
BE assessment should be
administered as a single unit
“Add-on” or “additional” studies
are recommended when the first
(preceding) study fails to meet
BE limits
Actual sampling times and
deviations from the prespecified
sampling times should be
recorded. Deviations should be
reported in the study report and
should be taken into
consideration when calculating
the pharmacokinetic parameters.
The storage conditions of
samples depend on the
investigational drug.
Records for the storage and
retrieval of samples should be
maintained.
is water at dosing, thereafter water water at dosing, thereafter water water at dosing, thereafter water
provided ad-libitum. is provided ad-libitum. is provided ad-libitum. is provided ad-libitum.
FASTING REQUIREMENT
All subjects are required to fast At least 8 hours prior to At least 8 hours prior to All subjects are required to fast
for at least 10 hours pre dose administration of the products administration of the products for at least 10 hours pre dose
and 4 hours post-dose and no food is allowed for at and no food is allowed for at and 4 hours post-dose
least 4 hours post-dose. least 4 hours post-dose.
DOSE STRENGTH
Generally in vivo studies should Generally in vivo studies should Generally in vivo studies should Generally in vivo studies should
be performed on the highest be performed on the highest be performed on the highest be performed on the highest
strength, unless reasons of safety strength, unless reasons of safety strength, unless reasons of safety strength, unless reasons of safety
justify use of a lower strength justify use of a lower strength justify use of a lower strength justify use of a lower strength
ADD-ON / ADAPTIVE DESIGNS
“Add-on” or “additional” studies “Add-on” or “additional” studies “Add-on” or “additional” studies “Add-on” or “additional” studies
are recommended when the first are recommended when the first are recommended when the first are recommended when the first
(preceding) study fails to meet (preceding) study fails to meet (preceding) study fails to meet (preceding) study fails to meet
BE limits BE limits BE limits BE limits
Will accept a two-stage adaptive Will accept two-stage group- Will accept two-stage group- The additional trial uses at least
design BE study, provided that sequential design BE studies, sequential design BE studies, 12 subjects per group
the intent to use the approach is provided that the plan to use a provided that the plan to use a The protocol should clearly state
predefined in the protocol two-stage approach and adjusted two-stage approach and adjusted that additional trials were
significance levels is predefined significance levels is predefined conducted
in the protocol in the protocol
SAMPLE COLLECTION AND SAMPLING TIMES
Under normal circumstances, A sufficient number of samples A sufficient number of samples From blood or urine shall be
blood, rather than urine or tissue, to adequately describe the to adequately describe the collected with appropriate time
should be used. plasma concentration-time plasma concentration-time point and sufficient frequency.
In most cases, drug, or profile should be collected. The profile should be collected. The In addition, the time points and
metabolites are measured in sampling schedule should sampling schedule should frequency of sampling of test
serum or plasma. include frequent sampling include frequent sampling and reference products shall be
For most drugs, 12 to 18 around predicted tmax to around predicted tmax to the same.
samples, including a predose provide a reliable estimate of provide a reliable estimate of Blood collection shall be
sample, should be collected per peak exposure. peak exposure. conducted with sufficient time
subject per dose. This sampling If urine is used as the biological If urine is used as the biological period of more than 3 times the
should continue for at least three sampling fluid, urine should sampling fluid, urine should elimination half-life or AUC0-t
or more terminal half-lives of the normally be collected over no normally be collected over no to reach at least 80% of AUC∞.
drug. The exact timing for less than three times the less than three times the For products that demonstrate
sample collection depends on terminal elimination half-life. terminal elimination half-life. long half-life and low within-
the nature of the drug and the However, in line with the However, in line with the subject variability in distribution
input from the administered recommendations on plasma recommendations on plasma and clearance, blood samples
dosage form.

Single-dose bioequivalence
study under fasting conditions
A fed bioequivalence study
should always be conducted for
IR formulations.
Single-dose BE studies under
fasting and fed conditions
Meal should be based on local
custom and diet, administered 30
min prior to dosing
For Extended-release (ER)
dosage forms
BE for a suspension should
generally be established as for
immediate-release solid oral
dosage forms, and both in vivo
and in vitro studies are
recommended.
In vivo studies should always be
performed for systemically
active formulations
sampling, urine does not need to sampling, urine does not need to shall be collected for at least 72
be collected for more than 72 h. be collected for more than 72 h. hrs.
BE STUDY TYPE FOR VARIOUS DOSAGE FORMS
Immediate-release (IR) solid oral dosage forms
2 studies: fasting plus fed-state, 1 study: fasting, 2-way, single- 1 study: fasting, 2-way, single- Single-dose bioequivalence
2-way, single-dose, crossover in dose, crossover in >12 healthy dose, crossover in >12 healthy study under fasting conditions
healthy subjects, analyzing adults, analyzing parent in adults, analyzing parent in
parent (and metabolite, if plasma, AUC0-t and Cmax plasma, AUC0-t and Cmax
applicable) in plasma
Modified-release (MR) solid oral dosage forms
2 studies: fasting plus fed-state, Delayed-release formulations: Delayed-release formulations: Single-dose BE studies under
similar to IR formulations, Similar to IR formulations Similar to IR formulations fasting and fed conditions
multiple-dose studies Prolonged-release Prolonged-release
discouraged formulations: formulations:
3 studies: fasting single-dose 3 studies: fasting single-dose
plus fasting steady-state plus plus fasting steady-state plus
fed-state single-dose, waiver fed-state single-dose, waiver
possible for additional strengths possible for additional strengths
at steady-state, not for single- at steady-state, not for single-
dose studies dose studies
Meal used in fed BE studies
800–1,000 kcal of which 50% is 800–1,000 kcal of which 50% is 800–1,000 kcal of which 50% is High-fat meal, administered 30
fat, administered 30 min prior to fat, administered 30 min prior to fat, administered 30 min prior to min prior to dosing
dosing dosing dosing
Multiple-dose studies
For Extended-release (ER) For MR dosage forms For MR dosage forms For MR dosage forms
dosage forms
Suspensions
BE for a suspension should BE for a suspension should BE for a suspension should BE for a suspension should
generally be established as for generally be established as for generally be established as for generally be established as for
immediate-release solid oral immediate-release solid oral immediate-release solid oral immediate-release solid oral
dosage forms, and both in vivo dosage forms, and both in vivo dosage forms, and both in vivo dosage forms, and both in vivo
and in vitro studies are and in vitro studies are and in vitro studies are and in vitro studies are
recommended. recommended. recommended. recommended.
Non-oral formulations (transdermal products)
For transdermal products: For transdermal products: For transdermal products: In vivo studies should always be
Single-dose BE studies Single- and multiple-dose BE Single- and multiple-dose BE performed for systemically
Compare test and reference studies studies active formulations
adhesion, local irritation, The site of application should be The site of application should be
sensitization in the same body area for the test in the same body area for the test
and reference product and reference product

Use non compartmental analysis
to determine AUC0−t,
AUC∞, C max, and T max, T 1/2,
and k el for single-dose studies
Perform log-transformation on
AUC and C max
Calculate test/reference GMRs
for AUC and C max
Use analysis of variance
(ANOVA) and the two one-
sided tests procedure, performed
at the 5% level of significance,
to determine if the 90% cis of the
test/reference GMRs meet BE
limits
Require AUC0-t to meet 80–
125% limits
80–125% limits for C max
Truncation of AUC, to replace
AUC0−t
Truncation to 72 h
Determine
aucτ, C maxss, T maxss, C minss, C avg
ss, % fluctuation
noncompartmental methods
Perform log-transformation on
aucτ and C maxss
Calculate test/reference GMRs
Use a replicate study design if Use a replicate study design if
the test and reference use the test and reference use
different release mechanisms different release mechanisms
(for example, a reservoir versus (for example, a reservoir versus
a matrix) a matrix)
Compare test and reference Compare test and reference
adhesion, local irritation, adhesion, local irritation,
sensitization, and photo-toxicity sensitization, and photo-toxicity
PK PARAMETER DETERMINATION AND BE STATISTICS
Single-dose fasting and fed BE studies
Use non compartmental analysis Use non compartmental analysis Use non compartmental analysis Use non compartmental analysis
to determine AUC0−t, to determine AUC0−t, to determine AUC0−t, to determine AUC0−t,
AUC∞, C max, and T max, T 1/2, AUC∞, C max, and T max, T 1/2, AUC∞, C max, and T max, T 1/2, AUC∞, C max, and T max, T 1/2,
and k el for single-dose studies and k el for single-dose studies and k el for single-dose studies and k el for single-dose studies
Perform log-transformation on Perform log-transformation on Perform log-transformation on Perform log-transformation on
AUC and C max AUC and C max AUC and C max AUC and C max
Calculate test/reference GMRs Calculate test/reference GMRs Calculate test/reference GMRs Calculate test/reference GMRs
for AUC and C max for AUC and C max for AUC and C max for AUC and C max
Use analysis of variance Use analysis of variance Use analysis of variance Use analysis of variance
(ANOVA) and the two one- (ANOVA) and the two one- (ANOVA) and the two one- (ANOVA) and the two one-
sided tests procedure, performed sided tests procedure, performed sided tests procedure, performed sided tests procedure, performed
at the 5% level of significance, at the 5% level of significance, at the 5% level of significance, at the 5% level of significance,
to determine if the 90% cis of the to determine if the 90% cis of the to determine if the 90% cis of the to determine if the 90% cis of the
test/reference GMRs meet BE test/reference GMRs meet BE test/reference GMRs meet BE test/reference GMRs meet BE
limits limits limits limits
Require AUC0-t to meet 80– Require AUC0-t to meet 80– Require AUC0-t to meet 80– Require AUC0-t to meet 80–
125% limits 125% limits 125% limits 125% limits
80–125% limits for AUC∞ 80–125% limits for C max 80–125% limits for C max 80–125% limits for AUC∞
80–125% limits for C max 80–125% limits for C max
Long half-life drugs
Truncation of AUC, to replace Truncation of AUC, to replace Truncation of AUC, to replace Truncation of AUC, to replace
AUC0−t AUC0−t AUC0−t AUC0−t
Truncation to 72 h Truncation to 72 h Truncation to 72 h
Steady-state BE studies
Determine Determine Determine Determine
aucτ, C maxss, T maxss, C minss, C avg aucτ, C maxss, T maxss, C minss, C avg aucτ, C maxss, T maxss, C minss, C avg aucτ, C maxss, T maxss, C minss, C avg
via ss, % fluctuation via ss, % fluctuation via ss, % fluctuation via ss, % fluctuation via
noncompartmental methods noncompartmental methods noncompartmental methods noncompartmental methods
Perform log-transformation on Perform log-transformation on Perform log-transformation on Perform log-transformation on
aucτ and C maxss aucτ and C maxss aucτ and C maxss aucτ and C maxss
Calculate test/reference GMRs Calculate test/reference GMRs Calculate test/reference GMRs Calculate test/reference GMRs
Use analysis of variance
(ANOVA)
Require aucτ, C maxss to meet 80–
125% BE limits
Nonparametric analysis applied
to non-transformed data, only if
T max is judged to be clinically
relevant.
Limits should be a clinically
determined range
Crossover or parallel study
designs
Non-compartmental analysis to
determine PK parameters
ANOVA, performed at the 5%
level of significance, on the
GMRs
A steady-state BE study can be
conducted to reduce variability
In the case of an especially
narrow therapeutic range, the BE
limits may need to be tightened
based on clinical justification.
Use analysis of variance Use analysis of variance Use analysis of variance Use analysis of variance
(ANOVA) (ANOVA) (ANOVA) (ANOVA)
Require aucτ, C maxss to meet 80– Require aucτ, C maxss to meet 80– Require aucτ, C maxss to meet 80– Require aucτ, C maxss to meet 80–
125% BE limits 125% BE limits 125% BE limits 125% BE limits
C minss should meet C minss should meet
bioequivalence limits of 80– bioequivalence limits of 80–
125% 125%
Evaluation of T max
If differences in T max are judged If rapid release is claimed to be If rapid release is claimed to be Limits should be 80–125%
to be clinically relevant, this clinically relevant and of clinically relevant and of
may provide evidence that the importance for onset of action or importance for onset of action or
test and reference products are related to adverse events, there related to adverse events, there
not therapeutically equivalent should be no apparent difference should be no apparent difference
in T max and its variability in T max and its variability
between test and reference between test and reference
products products
BE Studies of Highly variable Drugs
Crossover or parallel study Crossover or parallel study Crossover or parallel study Crossover or parallel study
designs designs designs designs
Non-compartmental analysis to Non-compartmental analysis to Non-compartmental analysis to Non-compartmental analysis to
determine PK parameters determine PK parameters determine PK parameters determine PK parameters
ANOVA, performed at the 5% ANOVA, performed at the 5% ANOVA, performed at the 5% ANOVA, performed at the 5%
level of significance, on the level of significance, on the level of significance, on the level of significance, on the
GMR GMR GMR GMR
A RSABE approach may be A reference-scaled average BE A reference-scaled average BE Do not specify/mention
applied to AUC and C max (RSABE) approach may be (RSABE) approach may be Within subject CV (%)
The AUC and C max GMR in applied to C max only applied to C max only 30= 80.00-125.00
the study should fall within 0.80 The C max GMR in the study The C max GMR in the study 35= 77.23-129.48
to 1.25 should fall within 0.80–1.25 should fall within 0.80–1.25 40= 74.62-134.02
Within subject CV (%) Within subject CV (%) 45= 72.15-138.59
30= 80.00-125.00 30= 80.00-125.00 ≥50= 69.84-143.19
35= 77.23-129.48 35= 77.23-129.48
40= 74.62-134.02 40= 74.62-134.02
45= 72.15-138.59 45= 72.15-138.59
≥50= 69.84-143.19 ≥50= 69.84-143.19
BE Study Designs and Acceptance Limits for Narrow Therapeutic Index Drugs
BE limits of 80–125% be In specific cases of NTI drugs, In specific cases of NTI drugs, BCS bio waivers cannot be
applied to AUC and Cmax for the acceptance interval for AUC the acceptance interval for AUC applied to NTI drugs
NTI drugs should be tightened to 90.00– should be tightened to 90.00– Imposes more stringent types of
BCS bio waivers cannot be 111.11%. 111.11%. BE requirements for certain
applied to NTI drugs; and types of post approval

Solution formulations intended
for parenteral use should have
the same active and inactive
ingredients in the same amounts
(i.e., be qualitatively and
quantitatively, Q1/Q2, the same)
If the solution is to be
administered orally or topically,
the test product should not be
formulated in such a manner that
would cause drug absorption to
differ between the test and
reference products
BE is demonstrated in vivo for at
least one strength
In vitro dissolution testing is
acceptable; and
Strengths considered for the
biowaiver are proportionally
similar to the strength that
underwent acceptable in vitro
testing.
Will consider granting Will
biowaivers for BCS Class I and biowaivers for BCS class I biowaivers for BCS Class I and biowaivers for BCS Class I and biowaivers for BCS class I drugs
BCS class III drugs drugs
More stringent types of BE manufacturing process/site, or
requirements are imposed on formulation changes
certain types of post approval
manufacturing process/site, or
formulation changes
Require assayed potency
specifications of 95–105%
If within-subject variability
≥20%, then use BE limits of 80–
125%
BIOWAIVERS
Solution formulations intended Solution formulations intended Solution formulations intended Solution formulations intended
for parenteral use should have for parenteral use should have for parenteral use should have for parenteral use should have
the same active and inactive the same active and inactive the same active and inactive the same active and inactive
ingredients in the same amounts ingredients in the same amounts ingredients in the same amounts ingredients in the same amounts
(i.e., be qualitatively and (i.e., be qualitatively and (i.e., be qualitatively and (i.e., be qualitatively and
quantitatively, Q1/Q2, the same) quantitatively, Q1/Q2, the same) quantitatively, Q1/Q2, the same) quantitatively, Q1/Q2, the same)
If the solution is to be If the solution is to be If the solution is to be If the solution is to be
administered orally or topically, administered orally or topically, administered orally or topically, administered orally or topically,
the test product should not be the test product should not be the test product should not be the test product should not be
formulated in such a manner that formulated in such a manner that formulated in such a manner that formulated in such a manner that
would cause drug absorption to would cause drug absorption to would cause drug absorption to would cause drug absorption to
differ between the test and differ between the test and differ between the test and differ between the test and
reference products reference products reference products reference products
NON-BIOSTUDY STRENGTHS OF A SOLID DOSAGE FORM PRODUCT LINE
BE is demonstrated in vivo for at BE is demonstrated in vivo for at BE is demonstrated in vivo for at BE is demonstrated in vivo for at
least one strength least one strength least one strength least one strength
In vitro dissolution testing is In vitro dissolution testing is In vitro dissolution testing is In vitro dissolution testing is
acceptable; and acceptable; and acceptable; and acceptable; and
Strengths considered for the Strengths considered for the Strengths considered for the Strengths considered for the
biowaiver are proportionally biowaiver are proportionally biowaiver are proportionally biowaiver are proportionally
similar to the strength that similar to the strength that similar to the strength that similar to the strength that
underwent acceptable in vitro underwent acceptable in vitro underwent acceptable in vitro underwent acceptable in vitro
testing testing testing testing
Linear elimination kinetics
should be established over those
approved therapeutic dose
ranges
BCS-BASED BIOWAIVERS
consider granting Will consider granting Will consider granting Will consider granting
BCS class III drugs BCS class III drugs
According to the BCS, drug
substances are classified as
follows:
Class 1: high solubility–high
permeability
Class 2: low solubility–high
permeability
Class 3: high solubility–low
permeability
Class 4: low solubility–low
permeability.
Establish high solubility of:
Highest dose
pH:
1.2–6.8
Number of pH values to test:
At least 3
Volume = 250 ml
Temperature = 37 ± 1°C
Use shake flask or similar
method
In vivo intestinal permeation
studies can use humans or
animals
In vitro intestinal permeation
studies can use human or animal
tissue
In vitro permeability studies use
epithelial cell monolayers
Are in vivo permeability
studies acceptable:
Yes
Are in vitro permeability
studies acceptable
No; perhaps as supportive
Are in vivo or in vitro
intestinal permeation studies
acceptable
Yes
According to the BCS, drug According to the BCS, drug According to the BCS, drug According to the BCS, drug
substances are classified as substances are classified as substances are classified as substances are classified as
follows: follows: follows: follows:
Class 1: high solubility–high Class 1: high solubility–high Class 1: high solubility–high Class 1: high solubility–high
permeability permeability permeability permeability
Class 2: low solubility–high Class 2: low solubility–high Class 2: low solubility–high Class 2: low solubility–high
permeability permeability permeability permeability
Class 3: high solubility–low Class 3: high solubility–low Class 3: high solubility–low Class 3: high solubility–low
permeability permeability permeability permeability
Class 4: low solubility–low Class 4: low solubility–low Class 4: low solubility–low Class 4: low solubility–low
permeability. permeability. permeability. permeability.
BCS BIOWAIVER CRITERIA
Basic criteria for establishing that drug substance is highly soluble
Establish high solubility of: Establish high solubility of: Establish high solubility of: Establish high solubility of:
Highest dose Highest dose Highest dose Highest dose
pH: pH: pH: pH:
1–7.5 1.2–6.8 1.2–6.8 1–7.5
Number of pH values to test: Number of pH values to test: Number of pH values to test: Number of pH values to test:
Depends on ionization profile At least 3 At least 3 Depends on ionization profile
Volume = 250 ml Volume = 250 ml Volume = 250 ml Volume = 250 ml
Temperature = 37 ± 1°C Temperature = 37 ± 1°C Temperature = 37 ± 1°C Temperature = 37 ± 1°C
Use shake flask or similar Use shake flask or similar Use shake flask or similar Use shake flask or similar
method method method method
Basic criteria for establishing that drug substance shows high intestinal permeability
In vivo intestinal permeation In vivo intestinal permeation In vivo intestinal permeation In vivo intestinal permeation
studies can use humans or studies can use humans or studies can use humans or studies can use humans or
animals animals animals animals
In vitro intestinal permeation In vitro intestinal permeation In vitro intestinal permeation In vitro intestinal permeation
studies can use human or animal studies can use human or animal studies can use human or animal studies can use human or animal
tissue tissue tissue tissue
In vitro permeability studies use In vitro permeability studies use In vitro permeability studies use In vitro permeability studies use
epithelial cell monolayers epithelial cell monolayers epithelial cell monolayers epithelial cell monolayers
Are in vivo permeability Are in vivo permeability Are in vivo permeability Are in vivo permeability
studies acceptable: studies acceptable: studies acceptable: studies acceptable:
Yes Yes Yes Yes
Are in vitro permeability Are in vitro permeability Are in vitro permeability Are in vitro permeability
studies acceptable studies acceptable studies acceptable studies acceptable
Yes No; perhaps as supportive No; perhaps as supportive Yes
Are in vivo or in vitro Are in vivo or in vitro Are in vivo or in vitro Are in vivo or in vitro
intestinal permeation studies intestinal permeation studies intestinal permeation studies intestinal permeation studies
acceptable acceptable acceptable acceptable
Yes No No Yes
Highly permeable in vivo
≥85%
Optimal paddle speed
Should be 75
Optimal basket speed
Should be 100
Criteria for rapid dissolution
≥85% in 30 min
Criteria for very rapid
dissolution
>85% in 15 min
Volume = at least 900 ml
Temperature 37 ± 0.5°C
At least 3 ph values, ph 1.2, 4.5,
6.8
Surfactants are not permissible
At least 12 units each of test and
reference product
Class I
Use well-established excipients
in usual amounts
Class III
Should be Q1 same, Q2 very
similar
Differences between test and
reference excipients are only
acceptable for class I
Highly permeable in vivo Highly permeable in vivo Highly permeable in vivo Highly permeable in vivo
≥90% ≥85% ≥85% ≥90%
Basic criteria for establishing that product is rapidly dissolving or very rapidly dissolving
Class I should be at least rapidly dissolving
Class III should be very rapidly dissolving
Optimal paddle speed Optimal paddle speed Optimal paddle speed Optimal paddle speed
Should be 50 Usually 50 Usually 50 Should be 50
Optimal basket speed Optimal basket speed Optimal basket speed Optimal basket speed
Should be 50 Usually 100 Usually 100 Should be 100
Criteria for rapid dissolution Criteria for rapid dissolution Criteria for rapid dissolution Criteria for rapid dissolution
≥85% in 30 min ≥85% in 30 min ≥85% in 30 min ≥85% in 30 min
Criteria for very rapid Criteria for very rapid Criteria for very rapid Criteria for very rapid
dissolution dissolution dissolution dissolution
Not defined >85% in 15 min >85% in 15 min >85% in 15 min
Volume = at least 900 ml Volume = at least 900 ml Volume = at least 900 ml Volume = at least 900 ml
Temperature 37 ± 1°C Temperature 37 ± 1°C Temperature 37 ± 1°C Temperature 37 ± 0.5°C
At least 3 ph values, ph 1.2, 4.5, At least 3 ph values, ph 1.2, 4.5, At least 3 ph values, ph 1.2, 4.5, At least 3 ph values, ph 1.2, 4.0,
6.8 6.8 6.8 6.8
Surfactants are not permissible Surfactants are not permissible Surfactants are not permissible Surfactants are not permissible
At least 12 units each of test and At least 12 units each of test and At least 12 units each of test and At least 12 units each of test and
reference product reference product reference product reference product
Restrictions on how excipients can vary from test to reference product
Class I Class I Class I Class I
Use well-established excipients Recommend Q1 same, Q2 very Recommend Q1 same, Q2 very Use well-established excipients
in usual amounts similar, but test and reference similar, but test and reference in usual amounts
Class III excipients may differ excipients may differ Class III
Does not grant biowaivers for Class III Class III Does not grant biowaivers for
class III Should be Q1 same, Q2 very Should be Q1 same, Q2 very class III
Differences between test and similar similar Differences between test and
reference excipients are only Differences between test and Differences between test and reference excipients are only
acceptable for class I reference excipients are only reference excipients are only acceptable for class I
acceptable for class I acceptable for class I
DISCUSSION:
BE studies are an important part of the generic drug approval process throughout the world. This report focused on the BE study
requirements and regulatory specifications among a number of worldwide jurisdictions and organizations. Although there are important
differences in BE approaches throughout the various regulatory agencies but there are many more similarities. This is particularly the
case with respect to general BE study design, methods of calculating key PK parameters, statistical analysis methods used to verify BE,
and criteria necessary for the granting of bio waivers. Identifying the existence of commonalities underlying regulatory evaluation of
BE throughout the world is an important first step in working toward global harmonization and convergence of generic drug
development. “CRO” is used throughout WHO document to refer not only to a contract research organization (CRO), but also to any
organization involved in the conduct or analysis of in vivo bioequivalence studies. As defined in the International Conference on
Harmonization (ICH) Tripartite Harmonized Guidelines, Guidelines for Good Clinical Practice, a “CRO” is a person or an organization
(commercial, academic or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions.
 PRICING COMPARISON REPORT OF REGULATORY AUTHORITIES
DRAP
Drug Pricing Policy 2018
DRAP sets the maximum
prices and determines the
pricing measures.
Basis of Pricing
 Drugs for human use will
be divided into 2
categories in terms of
pricing in the country:
 National essential
medicine list
(NEML)
 All the other drugs
List of drugs & biologicals in
NEML may be revised after 3
years or earlier as per WHO
List.
MRP of generic shall not
exceed MRP of originator
brand.
Product shall not be sold
exceeding its MRP printed on
it by anyone.
MRP’s of NCE’s & NBE’s
MRP fixation of originator
brand of NCE’s & NBE’s in a
particular dosage form,
strength & delivery system
shall be based on average
price of the same dosage form
& strength of the same brand
available in India & top. Typically, research,
Bangladesh. If product is not
available in these countries
USFDA MHRA TITCK/TMMDA MFDS
National Health Service Act "Tariff Communiqué" Article External Price Referencing
2006 2/h SINGLE PRICE SYSTEM
Part VIIIA of the Drugs Tariff (Korean Pharmaceutical
Affairs Law; provision 78).
The US system of pharma UK PRICING CONTROLS The Ministry of Health sets Agency that Sets Price
reimbursement is multi- Within the UK, two pricing the maximum prices and Ministry of Health and
faceted and somewhat arrangements for branded invokes pricing measures. Welfare (MOHW)
opaque, and often results in medicines exist: Turkey adopts a Pharmaceutical manufacturers
different prices for different 1) The Voluntary REFERENCE PRICING are free to set prices of those
buyers. Scheme for Branded SYSTEM whereby drugs which are not
The US doesn’t directly Medicines Pricing and pharmaceutical prices are reimbursed. Since 1999, retail
regulate drug prices, meaning Access. determined based on the pharmacists have also set their
that drug companies can set 2) The Statutory reference prices from five own prices for the medicines
whatever sticker price they Scheme. reference countries (among which are not reimbursed.
deem fit. VOLUNTARY SCHEME European Union countries) EXTERNAL PRICE
Medicaid, the federal Took effect from 1 January determined by the Ministry of REFERENCING
programme to cover the 2019. Health. As per Article 4 of the The practice of using the
medical costs of low-income Pharmaceutical Price Communiqué, reference EU price(s) of a pharmaceutical
individuals, receives a Regulation Scheme (PPRS) countries are France, Spain, product in one or several
mandated discount, but The 2019 Voluntary Scheme İtaly, Portugal and Greece. countries in order to derive a
Medicare – which provides is a voluntary agreement made The Reference Price refers to benchmark (or reference
insurance for Americans over between the DHSC, on behalf the lowest warehouse sales price) for the purposes of
65 and is the pharma of the UK health departments, price for original and licensed setting or negotiating the price
industry’s biggest single and the branded products (exclusive of of the product in a given
customer, spending $137bn on pharmaceutical industry, discount) in the reference country but with important
prescription drugs in 2015 – is represented by the lead countries. However, if a methodology variations
not allowed to negotiate at the industry body, the Association country where the product is (number of reference
federal level. of the British Pharmaceutical produced or imported from is countries, calculation of the
COST-BASED PRICING Industry (ABPI) (section 261, not one of the reference reference price, etc.)
Simply put, cost-based pricing National Health Service Act countries, but the warehouse PRICING AND
consists of adding up the cost 2006). sales price of the relevant REIMBURSEMENT
of all expenses incurred to The UK price is often used for product is lower than the For pharmaceuticals in the
bring a product to market and setting reimbursement prices reference prices in the Positive List
adding an acceptable profit on in other countries. This reference countries, the lower Prices of reimbursed drugs
explains why there is the price will be considered as the have been regulated since the
development, manufacturing, option of Patient Access reference price. beginning of the National
packaging, distribution and Schemes (PAS). Health Insurance (NHI)
then Indonesia, Philippines,
Lebanon, Srilanka & Malaysia
will be taken as reference. If
product is not available in
these countries then price is
fixed at average retail price of
the country in which Original
Brand is available.
Prices of new chemical
entities will be verified from
independent sources which
are authentic.
MRP of generics of NCE’s &
NBE’s
MRP of generics shall be fixed
at 30% less than MRP of the
originator Brand, however it
can be reduced to 20% in
cases wherein compliance in
case of regulatory requirement
is established.
After expiry of 6 years or till
the time of entry of at least 3
generics/biosimilar products
in the market, whichever is
later, maximum MRP of
originator brand of NCE /
NBE shall be reduced by 10%
per annum for 3 consecutive
years. MRP of any generic
shall be at least 15% less than
the MRP of the originator
Brand so reduced. However, if
the average of the originator
brand price in INDIA &
Bangladesh is lower by 0% to
30% the price will be revised
by that difference.
MRP’s of new strengths
Calculation of MRP of lower
strength is calculated by
sales & marketing costs are
used for the calculation of the
price. The added profit margin
is generally based on the
company’s own objectives or
target, or what is usually
acceptable for the type of
product and market. Research
and development costs cannot
justify prices for most
products especially specialty
products. $2.6 billion in fully
loaded R&D costs per product
is often quoted but the real
cost for each single product is
usually much lower. For all
these reasons, this pricing
structure is never used for
pharmaceutical products.
VALUE-BASED PRICING
The objective of value-based
pricing is to uncover the right
blend of product attributes,
costs, company profit targets
and pricing that satisfies the
needs and desire of customers.
In the pharmaceutical
industry, there are two ways of
looking at value-based
pricing:
The first technique consists
of understanding the
perceived value of the product
by key stakeholders and to
what extent a price premium
can be applied. Well-designed
market research with payers,
physicians and patients is
critical to understand the
perceived value of a product
and the roadblocks that may
have to be overcome.
• Financially-based
• Outcome-based
In creating the 2019 Voluntary
Scheme and its predecessors,
the DHSC has put in place a
mechanism with the
overarching aim of achieving
a balance between access to
good quality, branded
medicines by the National
Health Service (NHS) at
reasonable prices and a fair
return for the industry to
enable it to research, develop
and market new and improved
medicines.
The 2019 Voluntary Scheme
applies to "Branded Health
Service Medicines", which
includes but is not limited to,
branded products supplied
through tendering processes
and on central or local
contracts; branded generics;
biological medicinal products.
However, the Voluntary
Scheme does not apply to
sales of medicines for supply
on private prescription or
other use outside the NHS.
Any company that is not a
member of the 2019
Voluntary Scheme is
automatically subject to the
reserve statutory powers, that
is, the Statutory Scheme
Each scheme continues for 5
years.
For the first year, the payment
percentage (rebate to be paid
back to DHSC) is 9.6%, and it
The Ministry of Health has
discretion to change reference
countries, provided it makes
an announcement at least two
months before. In this pricing
method, equivalent of 1 (one)
Euro in Turkish Liras is
used, upon multiplying with
the adaptation co-efficient
designated as 70 percent of the
average annual Euro value to
be calculated upon taking into
basis the daily indicative Euro
foreign exchange sales rate
realizations of the Central
Bank of the Republic of
Turkey declared in the
Turkish Official Gazette of the
previous year.
AMENDMENT
However, with the
amendment which was
published in the Official
Gazette on 14.02.2019, the
rate of "70%" given in the
Decision was changed to
"60%". Thereafter, Minister of
Health Fahrettin Koca made
an explanation and stated that
the rate was determined as
TRY 3.40 with an increase of
26.4% compared to the last
year.
PRICING PROCEDURE
TIMELINE
 The Price Evaluation
Commission (consisting
of representatives of the
Ministry of Finance,
Ministry of Development,
under secretariat of
Treasury and Directorate
system. The market prices for
POMs that have a 70–80 %
market share are governed by
the Maximum Allowable
Price (MAP) system (KHIDI
2013).
How Are the Maximum
Allowable Prices
Determined?
The MAP, which has been in
force since the beginning of
the NHI, is a form of price cap
that sets an upper limit of
remuneration for each
pharmaceutical product. It is
decided at the ministerial level
through a process involving
several government bodies.
Generally, different rules
apply to on- and off-patent
original drugs, and generics.
During the last decade, there
were two substantial changes
in pricing policy: the PERP in
2006 and the Single Price
System in 2012.
Process of pricing
HIRA assesses whether a
candidate product is more
cost-effective than the most
frequently used comparator.
If the candidate drug is a
generic, the maximum
allowable reimbursement
price will be calculated
according to a statutory
pricing guideline.
If a candidate product is newly
developed, with no
comparators for pricing, the
MOHW refers this to the
NHIS to begin a negotiation
MRP=MRP of higher strength
– 40%
 Calculation of MRP of
higher strength is
calculated by
MRP=(MRP of lower strength
x 100)/60
MRP’s of new pack sizes
If the new pack size is 2 times
of the existing pack size, MRP
will be reduced to 2% & if
pack size is 4 times or more of
the existing pack size then 4%
price will be reduced.
Costing and pricing division
of DRAP will confirm the
submission submitted by the
applicant within 60 days.
MRP of drugs containing
combination of already
registered drugs will be sum of
MRP of individual drugs and
sum total reduced by 5%.
Annual Adjustments
Linked with CPI of the
immediately preceding
financial year.
Effective 1st July 2018,
manufacturers and importers
may, without prior approval
increase their existing MRP’s
of essential drugs/biologicals
(excluding lower priced)
equal to 70% increase in CPI
(with a cap of 7%) & MRP’s
of all the other drugs & lower
priced drugs up to increase in
CPI (with a cap of 10%)
subject to the following
conditions:
The other technique, only
applicable in the
pharmaceutical industry,
consists of using
Pharmacoeconomic Data.
Pharmacoeconomic benefits
are often hard to calculate.
Costs of care vary from one
payer or even one hospital to
another and a unified pricing
strategy based on such
calculations is hard to come
by.
COMPETITOR-BASED
PRICING
Rarely used alone,
competitor-based pricing is
usually a component of value-
based pricing. When testing
the perceived value of a new
product, its potential benefits
are benchmarked against its
current competitors. That
perceived value becomes a
key element of the new
pricing. One of the challenges
is that the perceived value may
not be acceptable in the real
world regardless of the
strength of the data. If your
main competitors are branded
products, their price can be
used as a starting point to set
up your own pricing.
Whether you product is priced
higher or lower than the
competition will then depend
on its perceived competitive
value by key stakeholders.
SKIMMING PRICING
is expected to increase to
14.2% in year two.
STATUTORY SCHEME
Sections 262, 263 and 264 of
the National Health Service
Act 2006 provide that the
Secretary of State may set up
a regime whereby, after
consulting the industry body,
he may limit prices and profits
of health service medicines
and require information in
relation to such medicines.
The Statutory Scheme is set
out in the Branded Health
Service Medicines (Costs)
Regulations 2018 (SI
2018/345), which came into
force on 1 April 2018.
Manufacturers are required to
pay a rebate to the DHSC
reflecting a percentage of their
sales of branded medicines to
the NHS. Percentage was set
at 7.8% but the amending
regulations that then came into
force on 1 January 2019
removed that rate of 7.8% and
instead imposed rebates on
manufacturers of 9.9%,
14.7% and 20.5% for 2019,
2020 and 2021 respectively.
The Statutory Scheme can
establish a maximum price
that can be charged for the
supply of a specific drug.
Advantage of PPRS
A conceivable advantage of
the voluntary PPRS is a five-
year period of predictability in
the market as it is renegotiated
every five years, whereas the
of Social Security
Organization) sets a
meeting within the first
six months of each year to
evaluate drug prices.
 A license holder applies to
the Ministry of Health,
including the price
declaration form and
supporting documents
indicating the
determination process of
the price.
 Applications for receiving
an initial price are
concluded within 60 days,
although this can be
extended by up to 30 days
depending on work load.
 Price-related applications
other than the initial
pricing must be finalized
within ten days.
The license holder must
inform the Ministry of Health
about price fluctuations.
The Ministry of Health has
discretion to check the
accuracy of information and
documentation through
national or international data
bases, as well as via official
inquiries.
with applicants to determine
an appropriate price.
SINGLE PRICE SYSTEM
(SPS)
Prices for off-patent originals
were again reduced to 70 %
on the price when the patent
was valid and other generics
were priced at 85 % of the off-
patent counterparts
(equivalent to 59.5 % of the
patent price) regardless of
their market entry ranking.
One year after patent expiry,
all pharmaceuticals including
off-patent originals and
generics are priced at 53.55 %
of the price of the original
patent products.
How Are the Maximum
Allowable Prices Managed?
Once the MAP is determined
for each pharmaceutical
product, it is revised regularly
via a price survey to reflect
market dynamics. Three major
revisions of this process have
taken place: Investigating
price system; Reporting
price system; and Actual
Transaction Price (ATP)
system.
Revised Calculation Signed
by CEO/managing partner at
least 30 days prior to increase.
Hard copy is submitted
No overlapping, masking of
prices
Label is printed according to
labeling & packing rules 1986.
MRP of new entrants
If not fixed then it will be
fixed at the time of
registration.
If strength is same in a specific
dosage form then same MRP
will be fixed for its all forms.
Hardship cases
It is filed if the manufacturer
or importer is unable to
recover its cost & the profit
margin as per the S.O.P given
by DRAP.
It can be applied once in 3
years.
For locally manufactured
drugs
Price is calculated by the
following formula:
MRP = (cost of active
material + cost of excipients
+ cost of packaging
materials) x factor as per
drug pricing policy 2018.
For Imported Drugs
Trade price = landed cost +
mark-up @ 45% but in case of
anti-cancer, biologicals,
immune suppressants & anti-
retroviral drugs, the mark up
shall be 40%
All hardship applications shall
be decide within 180 days of
Skimming pricing consist of
maximizing margins in an
attempt to extract as much
profit as possible. This
strategy requires a lack of
strong competition or no
competition at all. It’s also
easier to apply in a smaller
market where volumes will be
limited.
statutory regulations may
change at any time, subject to
approval by Parliament.
GENERIC PRICING
Generic (unbranded, out of
patent medicines) are covered
by the Drug Tariff, which is
produced each month by the
Pharmaceutical Directorate of
the NHS Business Services
Authority and is provided to
pharmacists and health care
practices. Part VIIIA of the
Drugs Tariff lists basic prices
for generic drugs. This Part is
divided into:
 Category A items, which
include generics that are
widely used and are
widely available. The
price of these is based on
a weighted average of list
prices from wholesalers
and generic
manufacturers.
 Category C items, which
are based on a particular
brand or manufacturer's
price.
 Category M items, which
includes readily available
drugs. For these, the
DHSC calculates the price
based on information
submitted by
manufacturers.
Part VIIIB lists basic prices
for some unlicensed
medicines. It provides that, in
that case, the pack size listed
for the product will be used as
the minimum amount for
the case submission
(maximum 270 days).
Lower priced drugs
If the price of the drug is lower
than the following threshold
then it will be considered as
lower priced
 Rs 3.11/- per tablet /
capsule / caplet
 Rs 3.11/- 5ml of syrup /
suspension / elixir
 Rs 3.11/- per patch
 Rs 6.21/- per sachet
 Rs 15.53/- per injection
 Rs 3.11/- per 1gm of
cream / ointment (non-
sterile)
 Rs 4.14/- per 1gm of
cream / ointment (sterile)
 Rs. 4.14/- per ml of eye /
ear / nasal drops / nasal
spray / inhalational
solution (sterile) subject
to maximum pack size of
10 ml.
Threshold price limit shall
increase by equal to CPI every
year.
Encouragement for exports
to USA & EUROPE
Exempted from price control
in local market.
Miscellaneous
Authority & provincial health
authorities shall monitor
MRP’s of all the drugs.
DPC (Drug pricing
Committee) will decide all
cases related to pricing of
products as per drug pricing
policy 2018.
reimbursement. Where a
prescription orders any more
than the minimum amount, the
price will be based on the
listed pack size plus the 1ml or
1g list price for every
additional 1ml or 1g
prescribed.
HEALTH TECHNOLOGY
ASSESSMENT (HTA)
Health Technology
Assessment (HTA)
(commonly described as
"value-based assessment" or
"value-based pricing").
It involves the use of
economic techniques to assess
the value of new and existing
medicines whereby a drug's
cost-effectiveness as against
its comparator will determine
the price premium over its
existing product and therefore,
the pharmaceutical's price.
The resulting of cost
effectiveness and cost utility
analysis is often represented
as an incremental cost-
effectiveness ratio (ICER) in
Euros or Pounds per Quality
Adjusted Life Year (QALY).
QALY is a combined measure
of quality of life and length of
life as a result of an
intervention and then enables
a determination as to its level
of therapeutic benefit and cost,
in relation to its comparators.
The UK combines rate-of-
return controls with HTA
appraisals.
NICE and HTA in the UK
Other measures for price The reimbursement process
increase differs for each of the
Different SRO’s issued by devolved nations within the
DRAP UK, unlike the pricing scheme
which applies to the whole of
the UK. HTAs are conducted
by the relevant body for each
nation (the National Institute
for Health and Care
Excellence (NICE) for
England, the Scottish
Medicines Consortium
(SMC) for Scotland, the All
Wales Medicines Strategy
Group (AWMSG) for Wales
and the Department of
Health (DH) for Northern
Ireland). NICE and the SMC
conduct their own HTAs,
whereas the AWMSG
generally adopts the
recommendations of NICE, as
does the DH for Northern
Ireland, which also takes into
account the SMC's decision.
NICE
The National Institute for
Health and Care Excellence is
the body which advises the
NHS (National Health
Services) on whether a new
medicine is cost effective; It
does this by comparing how
much it costs to give a patient
an extra year of ‘quality life’
compared with the treatment
already being used. NICE is
accountable to the DH, but
operationally independent of
government.
DISCUSSION:
Pricing of medicines is regulated throughout the world and almost by every Regulatory Authority, as provision of medicine is necessary to all the
patients for their treatment which should be cost-effective. In Pakistan, DRAP sets the maximum prices and determines the pricing measures as per
Drug pricing policy 2018. The US doesn’t directly regulate drug prices, meaning that drug companies can set whatever price they deem fit.
Medicaid, the federal programme to cover the medical costs of low-income individuals, receives a mandated discount, but Medicare – which
provides insurance for Americans over 65. Pharma companies in U.S set their prices by Cost-Based Pricing, Skimming Pricing, Value based
pricing & Competitor-Based Pricing. Within the UK, two pricing arrangements for branded medicines exist which are Voluntary scheme (PPRS)
& statutory scheme. The Pharmaceutical Price Regulation Scheme (PPRS) is the mechanism used by the UK Department of Health to ensure
that the NHS has access to good quality branded medicines at reasonable prices. PPRS uses value based pricing system. Under statutory scheme,
Manufacturers are required to pay a rebate to the DHSC reflecting a percentage of their sales of branded medicines to the NHS. Percentage was set
at 7.8% but the amending regulations that then came into force on 1 January 2019 removed that rate of 7.8% and instead imposed rebates on
manufacturers of 9.9%, 14.7% and 20.5% for 2019, 2020 and 2021 respectively. The National Institute for Health and Care Excellence (NICE) is
the body which advises the NHS (National Health Services) on whether a new medicine is cost effective; It does this by comparing how much it
costs to give a patient an extra year of ‘quality life’ compared with the treatment already being used. The UK price is often used for setting
reimbursement prices in other countries. This explains why there is the option of Patient Access Schemes (PAS) which is Financially-based &
Outcome-based. The reimbursement process differs for each of the devolved nations within the UK, unlike the pricing scheme which applies to the
whole of the UK. HTAs are conducted by the relevant body for each nation. Generics (unbranded, out of patent medicines) are covered by the Drug
Tariff, which is produced each month by the Pharmaceutical Directorate of the NHS Business Services Authority and is provided to pharmacists
and health care practices. Part VIIIA of the Drugs Tariff lists basic prices for generic drugs. In Turkey, The Ministry of Health sets the maximum
prices and invokes pricing measures. Turkey adopts a Reference Pricing System whereby pharmaceutical prices are determined based on the
reference prices from five reference countries (among European Union countries) determined by the Ministry of Health. As per Article 4 of the
Communiqué, reference EU countries are France, Spain, İtaly, Portugal and Greece. The Price Evaluation Commission (consisting of
representatives of the Ministry of Finance, Ministry of Development, under secretariat of Treasury and Directorate of Social Security Organization)
sets a meeting within the first six months of each year to evaluate drug prices. In Korea, Ministry of Health and Welfare (MOHW) sets Price. If a
candidate product is newly developed, with no comparators for pricing, the MOHW refers this to the NHIS to begin a negotiation with applicants
to determine an appropriate price. External Price Referencing & Single Price System is used. Once the MAP is determined for each pharmaceutical
product, it is revised regularly via a price survey to reflect market dynamics. Three major revisions of this process have taken place: Investigating
price system; Reporting price system; and Actual Transaction Price (ATP) system.
As DRAP has its clear Drug Pricing Policy therefore Authority & provincial health authorities shall monitor MRP’s of all the drugs.
 BARCODING COMPARISON REPORT OF REGULATORY AUTHORITIES
DRAP USFDA MHRA TITCK/TMMDA KOREA
 S. R. O. 470 (I)/2017  Guidance for Industry  Article 62 of Council  Guidance On  “Drug bar Code Labels
regarding 2D Data Matrix.  Bar Code Label Directive 2001/83/EC Implementation Of and Management”.
 GS1 Standard Requirements  EMA Guidelines Identification And KOREA Ministry of Health
 21 CFR 201.25  Best practice guidance on Barcoding Of Medicinal & Welfare Notice No.
 GS1 Standard the labelling and packaging Products For Human Use 2011-58, 31 May 2011
of medicines (MHRA)  GS1 Standard  GS1 Standard
 GS1 Standard  Pharmaceutical Affairs Act
APPLICABLITY Final rule was published in 2004 QR codes should not be Ministry: Republic of Turkey Ministry of Health and
Applicable to Biological, The rule applies to drug confused with 2D barcodes (2D Ministry of Health Welfare
human, veterinary manufacturers, repackers, Matrix) which are added to IDENTIFICATION OF  Division of Pharmaceutical
Not applicable to alternative relabelers, and private label labelling at the time of PRODUCTS Policy
medicines, Health & OTC, distributors who are subject to packaging. ARTICLE 4- (1) General Health Care Policy
Nutraceuticals, medical devices, the establishment registration Data/attributes required to be The following identifiers will be Administration, especially
Radio pharmaceuticals requirements under the Act embedded in 2D Data Matrix: used in the identification of responsible for Drug and
BARCODE LABEL Through support of a  GTIN - AI(01) Medicinal Products for Human Medical Device Distribution &
REQUIREMENTS government mandate on drug  Batch No - AI(10) Use: Management Policy
Data/attributes required to be packaging in the U.S.,  Manufacturing Date AI(11) a) GTIN-Global Trade Item It established KPIS (Korea
embedded in 2D Data Matrix: approximately 60% of hospitals  Expiry date - AI(17) Number: Pharmaceutical Information
 GTIN - AI(01) have implemented medication  Product Identification This is a number composed of at Service), and is mandated for
 Batch No - AI(10) bar coding (2012) (dispensing Information - AI(240) most 14 digits used to uniquely managing Drug Bar Codes and
 Manufacturing Date AI(11) and administration)  Serial No - AI (21) identify products on a global distribution history, providing
 Expiry date - AI(17) APPLICABLITY Marketing authorization holders scale. In circumstances when corporate and business with
 Product Identification Applies to most prescription in UK are required to place the commercial product is used information about the supply.
Information - AI(240) drugs and certain OTC drugs safety features on the packaging at the retail sales point, the All drugs distributed in Korean
 Serial No - AI (21) (OTC drug products must bear a of all medicines which fall number placed on the product market are required to have
GTIN-Global Trade Item bar code if commonly used in within the remit of this consists of the EAN-13 barcode Global Standard barcodes or
Number: hospitals and dispensed regulation by 9 February 2019. symbology and has 13 digits. In RFID tags which encode the KD
This is a number composed of at pursuant to an order) regulated A unique identifier must be such circumstances, the number Code.
most 14 digits used to uniquely under FD&C and PHS Acts. placed on medical products that “0” shall be placed before the Drug standard code (KD code
identify products on a global Not applicable to medical can be scanned at fixed points 13- digit number and a 14-digit or Korea Drug Code) is a
scale. In circumstances when devices, Radio pharmaceuticals along the supply chain GTIN number will be number uniquely assigned for
the commercial product is used GS1 Data Matrix was widely The Unique Identifier: composed. identification of an individual
at the retail sales point, the used on secondary packaging in  Must be applied to every GTIN consists of four parts. drug product. The code is
number placed on the product successful drug traceability pack of medicine at point of These are GS1 Country prefix, composed of a 13 digit number
consists of the EAN-13 barcode pilots in the United States (U.S.) manufacture by the Company prefix, product including the country
symbology and has 13 digits. In Data/attributes required to be marketing authorization reference number and check identification code, the
such circumstances, the number embedded in 2D Data Matrix: holder
digit. The GTIN is determined company identification code,
“0” shall be placed before the  GTIN - AI(01) by authorized/brand owners the item code, and the
according to GS1 GTIN verification number (check
13- digit number and a 14-digit
GTIN number will be
composed.
GTIN consists of four parts.
These are GS1 Country prefix,
Company prefix, product
reference number and check
digit. The GTIN is determined
by authorized/brand owners
according to GS1 GTIN
Allocation Rules. Use of
pharmaceutical code in GTIN is
optional. If it is desired to use a
pharmaceutical code, characters
N9 and N10 may be used for
pharmaceutical code. The GS1
Application Identifier
identifying the GTIN
information is “01”.
Serial Number: (optional)
This is a number used in
identifying each unit of a
product identified by GTIN. A
serial number used for a product
may not be used again for the
same type of product. The serial
number is of variable length and
may contain 20 alphanumeric
characters at most. The
marketing authorization holder
designates a unique serial
number. The GS1 Application
Identifier identifying the serial
number is “21”.
Expiration Date:
It refers to the final date on
which the product may be used
safely. It is a numeric data
composed of 6 characters. The
format of the data shall be
YYMMDD.
Batch/Lot Number:
 Batch No - AI(10)
 Manufacturing Date AI(11)
 Expiry date - AI(17)
 Product Identification
Information - AI(240)
 Serial No - AI (21)
BARCODE LABEL
REQUIREMENTS
21 CFR 201.25 21
Meets European Article
Number/Uniform Code Council
(now GS1) or Health Industry
Business Communications
Council (HIBCC) standards or
another standard or format that
has been approved by FDA.
The expiration date of a product
has no bearing on the bar code
requirements.
QUALITY, APPEARANCE,
AND PLACEMENT OF THE
BAR CODE
Under 21 CFR 207.35(b) (2),
the Agency uses the National
Drug Code (NDC) numbering
system in assigning an NDC
number. The number is a 10-
character code that uses only
numerals.
The NDC number is divided
into three segment.
The first segment, the labeler
code, identifies the
manufacturer or distributor and
is four or five characters long.
The second segment, the
product code, identifies the drug
product and is three or four
characters long.
The third segment, the package
code, identifies the trade
 Must be coded into a 2D
data matrix – sometimes
known as a 2D barcode –
and also as human readable
information
 Must relate to the product
type and other specific
information such as batch
number and expiry date.
 Must be uploaded to a data
repository by the marketing
authorization holder (this
includes distributors who
repackage goods)
 This unique number – the
product type, batch number
and expiry date – can be
verified and authenticated at
any point in the supply
chain, for example, by
scanning it using a barcode
reader
 Before the medicine is
dispensed, the pharmacy or
hospital must verify the
authenticity of a medicine
by checking it against the
data repository
Quick Response (QR) codes
QR codes may be included on
packaging provided they are
subordinate in prominence and
Placement to the statutory
information (in line with all
information included under
article 62). In addition such a
code must link to information
which is compliant with the
provisions of article 62.
It must therefore be:
 Compatible with the SmPC
 Useful for the patient
Allocation Rules. Use of
pharmaceutical code in GTIN is
optional. If it is desired to use a
pharmaceutical code, characters
N9 and N10 may be used for
pharmaceutical code. The GS1
Application Identifier
identifying the GTIN
information is “01”.
b) Serial Number:
This is a number used in
identifying each unit of a
product identified by GTIN. A
serial number used for a product
may not be used again for the
same type of product. The serial
number is of variable length and
may contain 20 alphanumeric
characters at most. The
marketing authorization holder
designates a unique serial
number. The GS1 Application
Identifier identifying the serial
number is “21”.
c) Expiration Date:
It refers to the final date on
which the product may be used
safely. It is a numeric data
composed of 6 characters. The
format of the data shall be
YYMMDD.
d) Batch/Lot Number:
This is a number used to
differentiate one batch/lot from
others during production.
e) Group seperator (FNC1):
This character, which is used as
a character corresponding to
FNC1 (function1) in the
barcode symbology for GS1-
compatible systems, shows
barcode type when it is placed at
digit). A GTIN-13 is identical
to the Korea Drug Code. By
adding an indicator digit to
specify the level of packaging, a
GTIN-13 can be converted to a
GTIN-14. This may also
impact the check digit.
In South Korea, there are two
options for labeling at the
saleable package level. Either a
GS1 Data Matrix or GS1-128
linear bar code can be used to
comply with regulations.
To meet January 1, 2013
requirements, GTIN, lot, and
expiration must be embedded in
the data carrier. Human
readable elements may be
excluded if there is a limited
amount of packaging space.
When the data carrier is a GS1
Data Matrix (or GS1-128 linear
bar code), the Korean Drug
Code should be converted to a
GTIN-14 (by addition of an
indicator digit) to satisfy AI (01)
requirements. This is necessary
as AI (01) requires a data field
length of 14 digits.
This GS1 2D Data Matrix will
comply with January 1, 2015
regulations.
In regards to January 1, 2015
regulations, if a saleable unit
contains an outer box and a
primary package, the serial
number should accompany the
outer box in addition to GTIN,
lot, and expiration date. The
primary package may contain
only a GTIN. Although, it is
preferred both the outer box and
This is a number used to
differentiate one batch/lot from
others during production.
DRAP SOFTWARE FOR
SCANNING
Drug Barcode Verifier
developed by DRAP is used for
scanning of barcodes which
verifies the data encoded in
respective scanned barcode by
linking it to DRIS (Drug
Regulatory Information
System).
The same information of the
respective batch is added to
DRIS and once submitted then it
cannot be modified.
package size and type and is one
or two characters long.
The 10-character NDC
number can be in the following
three configurations of labeler
code–product code–package
code:
4–4–2, 5–4–1, or 5–3–2.
When the bar code is not easily
machine-readable through the
overwrap, the overwrap should
contain the bar code.
 Non-promotional.
An applicant intending to
include a QR code on the
labelling or in the patient
information leaflet for a
particular product must make an
application to the Patient
Information Quality Unit in
the usual manner.
Inclusion of a QR code on the
label or in the PIL cannot be
achieved by means of a
notification since the
application must include as part
of the dossier, a detailed account
of the information to which this
code links.
the first or second position in the primary package contain
barcode symbology. In other identical serial number,
positions, it is used as a GTIN, lot, and expiry date.
character corresponding to field The drug bar code must not be
separator. susceptible to damage or
PLACEMENT removal.
ARTICLE 7- OTC DRUGS
The barcode should be on a flat KDC(GTIN)
(even) surface. - The barcode GS1-DataMatrix
should not be placed on parts or
where the package is EAN-13
folded/joined. - The barcode and ETC drugs (Prescription
the data matrix should not be drugs)
positioned in a point of the KDC (GTIN)
package where they may get +Expiration date/Batch number
creased, the section where the /Serial number
barcode and the data matrix are GS1-DataMatix
printed should not get creased or
and folded. - The barcode and GS1-128
the data matrix should not be Safety check service (Under
covered with any object or plan)
shape. Drug information lookup
Composition of Barcodes through Mobile application
ARTICLE 8- (1) The company software
owning the product shall be Benefits of Pharmaceutical
responsible for the smooth industry
reading by the automatic data Prove a Product Authentication
collectors (barcode readers) for Protect company brand and
the composition of the barcodes reputation
to be placed on Medical Efficient recall process
Products for Human Use. Position of the Drug Bar Code
Human Readable Information At the Saleable Unit
ARTICLE 9- (1) The content of Easily visible position
the barcodes to be placed on
Medicinal Products for Human
Use shall be printed in a human
readable or legible manner
below the barcode in linear
barcodes and adjacent to the
data matrix in data matrices.
Application ARTICLE 10- (1)
There are no restrictions relating
 to the printing of the barcode
and data matrix on the package.
Registration/permit holders
shall be free in performing the
application with the most
suitable method for them.
For all barcode applications, the
degree of the printing quality
shall be by minimum at “D”
grade. In serial production
lines, it shall suffice to conduct
product testing through
sampling to ensure the same
grade.

DISCUSSION:
Barcodes are symbols that can be scanned electronically using laser or camera-based systems. They are used to encode information such as product
numbers, serial numbers and batch numbers. Barcodes play a key role in supply chains, enabling parties like retailers, manufacturers, transport
providers and hospitals to automatically identify and track products as they move through the supply chain. Bar codes will allow health care
professionals to use bar code scanning equipment to verify that the right drug (in the right dose and right route of administration) is being given to
the right patient at the right time. This new system is intended to help reduce the number of medication errors that occur in hospitals and health care
settings. Use of Identifiers embedded in Data Matrix are based on country legislation that may incorporate GS1 and other than GS1 identifiers as
applicable under the labeling rules. GS1 identifiers usage is based on global practices and country specific requirements. DRAP has its own
guidelines for barcode entry as per GS1 Standard (GTIN 14) while USFDA, MHRA, TITCK/TMMDA & MFDS have their own guidelines
following GS1 Standard. A GTIN® (pronounced Gee-Tin) is the acronym for Global Trade Item Number® it’s a number that uniquely identifies
a product and can be found below a U.P.C. barcode symbol. GTINs are used as the global standard to identify products. USFDA uses the National
Drug Code (NDC) numbering system in assigning an NDC number. The number is a 10-character code that uses only numerals. NDC is divided
into 3 segments.1st segment represents Manufacturer, 2nd segment represents the product and 3rd segment represents trade package size and type.
Korea Food and Drug Administration (KFDA) and Ministry of Health & Welfare (MOHW) have enacted the regulations as per GS1 standards.
Clear timelines have been established for drug manufacturers to adhere to regarding label requirements on the saleable unit and the case level. The
Korean Pharmaceutical Information Service (KPIS) also influences serialization requirements. MHRA & TITCK/TMMDA follow EMA
Guidelines & GS1 guidelines regarding Barcode/QR code. The 2D Barcode represents Batch number, Expiry date and other product specific details
to be recorded on the labelling. Data/attributes required to be embedded in 2D Data Matrix according to DRAP as per GS1 are GTIN - AI (01),
Batch No – AI (10), Manufacturing Date AI (11), Expiry date – AI (17), Product Identification Information – AI (240), and Serial No - AI
(21).
 REGULATORY TESTING LABS COMPARISON REPORT OF REGULATORY AUTHORITIES

DRAP USFDA MHRA TITCK/TMMDA MFDS

National institute of health, FDA is responsible for the Under contract to the Medicines Baygen Laboratory and Health MFDS is responsible of testing
Islamabad (NIH) (National testing of drugs. and Healthcare products Services of Drugs
level) Regulatory Agency (MHRA), Duzen Laboratories Group
Drug testing laboratories (DTL) LGC hosts and operates the
(District level) UK’s combined Official
Provincial quality control board Medicines Control
(PQCB) Laboratory (OMCL) for
(provincial level) chemical testing and the British
Pharmacopoeia (BP)
Commission Laboratory.
ROLE
The MHRA laboratories
function as the Official
Medicines Control Laboratory
(OMCL) was first established at
LGC in 2001 to carry out
routine surveillance testing on
licensed medicines to ensure the
integrity of the market, as well
as testing on unlicensed, illegal
and counterfeit medicines.
The work of The MHRA
Laboratories at LGC helps to
protect public health by
ensuring that medicines and
healthcare products are safe for
those who use them. The
laboratory is operated under a
Government Owned,
Contractor Operated (GOCO)
model in Teddington.
PRIMARY ROLE
One of The MHRA
Laboratory's primary roles is to
procure, establish and maintain
 reference standards (British
Pharmacopoeia Chemical
Reference Substances -
BPCRS). The laboratory also
supports the work of the British
Pharmacopoeia Commission in
establishing methods (known as
monographs) for generic
medicinal products (including
herbals) available in the UK.
The monographs established by
laboratory staff are
subsequently published in the
British Pharmacopoeia.

Discussion:
Testing of drugs released into the market by the National Drug Regulatory testing labs is very important to ensure the quality of medicine and to
ensure patient safety. In Pakistan, DTL is established in many cities like Lahore, Faisalabad, Bahawalpur & Multan etc. Similarly, on Provincial
level, Quality Control Labs are established by Quality Control Boards for the testing of medicines. On National Level, National Institute of
Health (NIH) is responsible for the retesting of medicines if requested by the Manufacturing Firm. In USA, FDA is responsible for testing of
medicines. In UK, under contract to the Medicines and Healthcare products Regulatory Agency (MHRA), LGC hosts and operates the UK’s
combined Official Medicines Control Laboratory (OMCL) for chemical testing and the British Pharmacopoeia (BP) Commission
Laboratory. One of The MHRA Laboratory's primary roles is to procure, establish and maintain reference standards (British Pharmacopoeia
Chemical Reference Substances - BPCRS). The laboratory also supports the work of the British Pharmacopoeia Commission in establishing
methods (known as monographs) for generic medicinal products (including herbals) available in the UK. The monographs established by laboratory
staff are subsequently published in the British Pharmacopoeia. In Turkey, Baygen Laboratory & Health Services and Duzen Laboratories Group
are responsible for testing of medicines which are regulated by TMMDA/TITCK. In Korea, MFDS is responsible for the testing of medicines.
 PHARMACOVIGILENCE COMPARISON REPORT OF REGULATORY AUTHORITIES
DRAP USFDA MHRA TITCK/TMMDA MFDS
 Guidelines undertaken for  Guidance for Industry Good  Regulation (EC) No  Regulation on the safety of  Pharmaceutical Affairs
the performance of Pharmacovigilance Practices 726/2004, Directive medicinal products Law
pharmacovigilance and Pharmacoepidemiologic 2001/83/EC and  Directive 2010/84/EC  Korean institute of drug
activities Assessment  Commission Implementing governing medicinal safety and risk
ICH Guidelines Regulation (EU) No products in the European management (KIDS)
520/2012. Union.
EMA Guidelines
Introduction Introduction Introduction Introduction Introduction
Pharmacovigilance is improved This document provides guidance Pharmacovigilance is the Chapter eight Systems
risk minimizing mechanism in to industry on good science and activities relating to General principles for Quality  The re-examination of
connection with use of medicinal pharmacovigilance practices and the detection, assessment, System for PV the new drugs
products/therapeutic goods pharmacoepidemiologic understanding and prevention Article 25 (mandatory)
(Drugs, Medicines, Biologicals assessment of observational data of adverse effects or any other The quality system will cover  The re-evaluation of
and Medical Devices) including regarding drugs, including medicine-related problem.  Organization structure, drugs(mandatory)
detection, assessment, biological drug products (WHO) responsibilities, and  Spontaneous ADR
minimization and (excluding blood and blood Module 1 procedures. Monitoring(spontaneous)
communication of risk of components). Specifically, this Structures and processes  Quality adherence
adverse reactions and document provides guidance on Quality  Quality control and
management of data thereof. 1-safety signal identification A pharmacovigilance system assurance
2-pharmacoepidemiologic like any system is characterized  Quality improvements
assessment ad safety signal by its structures, processes and Management of human
interpretation outcomes. resources
3-pharmacovigilance plan Quality cycle Article 26
development. The quality system shall be
 The marketing authorization
based on all of the following
activities: holder will assemble a
 Quality planning competent and appropriately
 Quality adherence qualified and trained
 Quality control and personnel for the
assurance performance of
 Quality improvements pharmacovigilance
Quality Objectives activities.
Complying with legal  The duties of staff will be
requirements for defined in job descriptions
pharmacovigilance tasks and  All personnel involved in
responsibilities/ contributing to pharmacovigilance
 the protection of patients and activities will receive initial
public health. and continued training.
Principles for GVP  The marketing authorization
 The needs of patients, holder will provide
healthcare professionals appropriate instructions.
and the public Assessment by the agency
 Resources and tasks should Article 23
be organized 1-The agency may require the
 Quality improvement. marketing authorization holder
Monitoring to fulfill the following
 Reviews of the systems by obligations.
those responsible for  Conducting a post
management authorization safety study
 Audits  Conducting a post
 Compliance monitoring authorization efficacy
 Inspections studies
Specific quality system 2-The agency performs a
processes scientific assessment of all data
 The submission of adverse using the pharmacovigilance
reaction data to Eudra system and considers risk
Vigilance within the legal minimization and prevention
timelines. options.
The retention of Post assessment actions
pharmacovigilance data and Article 24
documents for at least further After the assessment , the
10 years after the marketing agency initiates the following
authorization has ceased to actions
exist.  Conducting a post
authorization studies
 Implementing risk
minimization measures
 Prohibiting
procurement of the
medicinal product.
 Changing product
information.
Purpose 2-Background Objectives of Purpose/Aim Current PV system in
Information about safety, A-PDUFA III Risks Pharmacovigilance This Regulation sets forth the Korea
efficacy and quality of Management Guidance Goal  Preventing harm from principles and procedures for Goals (PV systems)
therapeutic goods/agents In the context of the Prescription adverse reactions in taking appropriate measures to  To build up the
Drug User Fee Act III, FDA humans arising from the facilitate systematic monitoring infrastructure for the
including drugs, medicines, agreed to satisfy certain use of authorized medicinal of adverse reactions and of the rational and safe use of
biological etc. performance goals which are as products within or outside risk-benefit balance to ensure drugs.
Aim follows: the terms of marketing safe use of medicinal products,  To activate the ADR
1- To get unbiased information 1-Premarketing authorization or from including gathering, capturing, Reports
on medicine’s product’s safety Risk Assessment occupational exposure assessment, archiving, and  To induce and settle the
and minimizing its risk for 2-Development and Use of Risk  Promoting the safe and exchange of information careful use of drugs for
increasing benefits to the Minimization Action Plans effective use of medicinal between relevant parties, and healthcare professionals.
patients. 3-Good Pharmacovigilance products, in particular minimization of potential harms
2- To promote rationale use of Practices and through providing timely from medicinal products.
therapeutic goods through Pharmacoepidemiologic information about the
evaluation /assessment of Assessment safety of medicinal
benefits, harms, effectiveness products to patients,
and affordability. healthcare professionals
3-To promote understanding and and the public.
education through effective
communication to healthcare
professionals and general public,
in a minimum time frame.
Scope Legal Basis Legal basis, scope and process Chapter One Legal Basis/Regulations
1-Management of spontaneous During all risk assessment and for GVP Purpose, Scope, Basis Pharmaceutical Affairs Law
reporting program risk minimization activities, The pharmacovigilance legal Scope The Regulation on the
2-Management of manufacturer sponsors must comply with requirements and GVP apply to Article 2 Management of Safety
/importers derived applicable regulatory all medicinal products This Regulation applies to information of the drugs, etc.
pharmacovigilance data about requirements involving human authorized in the EU, whether monitoring, research, recording,
the therapeutic goods subjects research and patient centrally or nationally archiving and assessment
3-Management of privacy. authorized. activities, and natural or juristic
Pharmacovigilance data 45 CFR part 46 and 21 CFR parts GVP is being developed within persons undertaking such
4-Devise mechanism for 50 and 56. See also the Health a governance structure set up by activities, for securing the safety
communication and interaction Insurance Portability and the Agency and national of authorized or unauthorized
and evaluation of Accountability Act of 1996 competent authorities medicinal products in Turkey.
pharmacovigilance related (HIPAA) (Public Law 104-191) specifically for the Basis
issues raised within Pakistan. and the Standards for Privacy of implementation of the new Article 3
5-International coordination and Individually Identifiable Health pharmacovigilance legislation. A) Law#1262 dated 14.05.1928
sharing of data with other Information (the Privacy Rule) This structure allows for the on Pharmaceutical and
regulatory authorities including (45 CFR part 160 and subparts A close collaboration of Member Medicinal Products;
WHO. and E of part 164). The Privacy States, the Agency and Fundamental Law#3359 dated
6-Conducting advance drug Rule specifically permits covered European Commission 07.05.1987 on HealthCare
monitoring studies based on entities to report adverse events services, with regular Services, Article 3,
ADR s and ADEs of new and other information related to stakeholder meetings an Subparagraph (k); and Decree
therapeutic goods including the quality, effectiveness, and integral part of the Law#663 dated 11.10.2011 on
drugs, medicines, biologicals safety of FDA-regulated products implementation process. the Organization and Mandate of
and medical devices, in both to manufacturers and
connection with irrational use of directly to FDA (45 CFR Prepared Draft chapters are the Ministry of Health and Its
medicines, medication errors. 164.512(b)(1)(i) and (iii), and 45 agreed by the Heads of Subordinate Agencies;
CFR 164.512(a)(1)). Medicines Agencies EU B) Directive 2010/84/EC
21 CFR parts 50 and 56 network Pharmacovigilance governing medicinal products in
Oversight Group. the European Union.
Responsibility FDA Recommendations: Pharmacovigilance in the EU: Chapter Two Partners of
Division of Pharmacy Services , FDA recommends that a sponsor Roles of different actors Responsibilities of the Pharmacovigilance
Drug Regulatory Authority of re-evaluate the safety risk and the In the EU, a regulatory network, marketing authorization  WHO, UMC
Pakistan , along with other effectiveness of its consisting of the competent holder  Health Professionals
functions , as specified under pharmacovigilance plan. Such authorities in Member states, Article 5 (Doctors/Pharmacists
rules, is mandated to provide re-evaluation may result in the European Commission and Assure the safety of its /Nurses, etc.
comprehensive guideline on revisions to the the European Medicines medicinal products by  Pharmaceutical
regulatory requirement of pharmacovigilance plan for a Agency is responsible for Establishing a Industry
Pharmacovigilance , for product. In some circumstances, granting marketing pharmacovigilance system (Distributors/
stakeholder who are required to FDA may decide to bring authorizations and supervising Use MedDRA terminology for Manufacturers/
submit information about safety questions on potential safety risks medicinal products, including the classification of adverse Importers)
, efficacy and quality of and pharmacovigilance plans the conduct of reactions occurring in relation to  National Health
therapeutic goods .agents before its Drug Safety and Risk pharmacovigilance. The its medicinal products. Authorities
including drugs , medicines , Management Advisory Agency has a core role in Regular audits of (PV centers of foreign
biologicals etc which are Committee or the FDA Advisory coordinating these activities for pharmacovigilance system countries
licensed under DRAP Act,2012 Committee dealing with the the network. Implement the following as a  Academia
and regulated therein. specific product in question. An EU legal framework for part of the pharmacovigilance (Clinical
International Sharing of For most products, routine patient reporting in all Member system: Pharmacology and
Information pharmacovigilance (i.e., States has now been introduced A- Employing qualified person. pharmacy)
If permitted by the Authority, the compliance with applicable through the new B- Common QP for several  Patients and Others
information will be shared with postmarket requirements under pharmacovigilance legislation. marketing authorization holders Media, Consumer
the International agencies the FDCA and FDA The new legislation further functioning under a partnership advocacy groups,
including WHO, as it is a implementing regulations) is increases public participation framework lawyers, etc.
requirement for an associate sufficient for postmarketing risk by including patient and C-Notifying the details of QP or
member like Pakistan to share. assessment. However, in certain healthcare professional his/her deputy within seven
This process takes 07 working limited instances, unusual safety representatives in the new days of their appointment.
days to complete. risks may become evident before Pharmacovigilance And Risk D-Ensuring that QP has attended
Local sharing of information approval or after a product is Assessment Committee basic training program on
with other departments of marketed that could suggest that (PRAC) and through public pharmacovigilance provided by
DRAP for necessary remedial consideration by the sponsor of a hearings on pharmacovigilance the Agency.
measures pharmacovigilance plan may be and benefit -risk matters at the E-Preparing, maintaining and
This process takes 07 working appropriate. Agency, involving all upon request presenting the
days to complete. stakeholders. Agency with a
Use MedDRA terminology for pharmacovigilance system
the classification of adverse master file.
reactions occurring in relation to F- Preparing and updating where
its medicinal products. necessary, the risk management

Reporting format and Details
Information can be reported on
ADR reporting form.
Manufacturer has to report drug
related information on Council
for International Organizations
of Medical Sciences specified
CIOMS form.
Submission of Report as per
requirement
1-Spontaneous serious and non-
serious reports shall be
Process of reporting
Through medwatch form and
online through FAERS (FDA
Adverse reaction reporting event)
Serious ADR Reporting time
period
Within 15 days
Process of reporting
Through yellow card form or
via online reporting to yellow
card portal or via email
Module VI – Collection,
management and submission
of reports of suspected
adverse reactions to
medicinal products
The guidance provided in this
Module does not address the
collection, management and
system with specified and
potential risks of the medicinal
product.
G- Monitoring the outcome of
actions implemented as part of
the risk management plan.
Appends a standard wording to
the package leaflet, asking
consumers to report any
suspected adverse reactions to
healthcare professional or
directly to TUFAM.
For medicinal products included
in the additional monitoring list,
appends an inverted black
equilateral triangle in the
summary of product
characteristics.
Immediately notifies the agency
in the event the market supply of
the product has been suspended
or marketing authorization has
been withdrawn.
Responds fully and without
delay to any requests
communicated by the Agency
according to this regulation.
Assures the accuracy and
currency of any
pharmacovigilance information.
Chapter seven Process of reporting
Reports Submitted to the KAERS is a system
Agency and Assessment of developed by KIDS to
Reports facilitate reporting and
Reports by healthcare management of adverse event
professionals (AE) reports. All reports
Article 21 of AEs have been
Healthcare professionals will accumulated in KAERS since
report any adverse reactions 2012.
which result from, or may be - Suspected drug and AE
associated with the use of a information are reported to
medicinal product to TUFAM KIDS in a form named
submitted within 15 days by
Health Care Professionals.
2- Serious ADR Reports should
be submitted within 15 working
days by the manufacturers /
importers.
3-Life threatening Adverse drug
reactions shall be reported
within 7 days follow- Up report
shall be submitted within next 7
days.
4-AEFI Reports should be
submitted within 15 working
days by the vaccine
manufacturers / importers.
5-All importers are also required
to submit ADR reports as
submitted in their country of
origin, on monthly basis.
6- Non-serious reports shall be
reported on Monthly basis
Minimum Requirement of
ADR Reporting
1-An identifiable patient
2-An identifiable reporter
3-At least one suspected
substance /pharmaceutical
product/therapeutic good
4-At least one suspected
reaction.
submission of individual within fifteen days, directly or ‘Individual Case Safety
reports of events or patterns of through the pharmacovigilance Reports (ICSRs)’.
use, which do not result in contact point established at their - AEs can also be reported
suspected adverse reactions health care institution. via ADR call center and other
(e.g. asymptomatic overdose, Reports by marketing routes such as fax and e-mail.
abuse, misuse or medication authorization However, all
error) and which are not Article 22 information received are
required to be submitted as  Maintains and archives a stored within KAERS as an
individual case safety reports detailed record of all ICSR. KIDS detects and
(ICSRs). This information may suspected adverse reactions evaluates signals from
however need to be collected  Reports all suspected cumulated data
and presented in periodic safety serious adverse reactions to generate and provide
update reports for the occurring in Turkey to drug safety information.
interpretation of safety data or TUFAM within fifteen KAERS database is
for the benefit risk evaluation of days after becoming aware compatible with the
medicinal products. of such information. international
 If reports received from standards, and the WHO-
other countries where the UMC (Uppsala Monitoring
product is marketed alters Centre) international drug
the medicinal products monitoring program.
known risk-benefit balance, - The minimum criteria for
informs the TUFAM an adverse event report to be
immediately after receiving valid are AE information,
such information. drug information, and patient
 Submits a risk management and reporter information.
plan - KIDS periodically
 Prepares the periodic risk provides Ministry of Food
benefit assessment reports and Drug Safety (MFDS)
every six months during the with AE report statistics and
first two years of safety information
authorization in Turkey. generated.
 Submits periodic risk Administrative Process on
benefit assessment reports to ADR
the agency 18 months after AE / ADR Should be reported
the product is placed on the by Hospitals /clinics,
market Pharmacies, Manufacturers /
Importers /Patients/
Consumers and then should
be reviewed and should be
taken administrative
measures for that.
Periodic Safety Update Identifying and describing Module VII – Periodic safety Literature Report Report of Safety
Reports safety signals: From case update report Article 17 Information
Periodic Safety Update Report is reports to case series Each marketing authorization The marketing authorization  Fax
intended to be provide Good pharmacovigilance holder shall be responsible for holder will submit to TUFAM a  Mail
periodically an update of practice submitting PSURs for its own copy of any national and  E-Mail
worldwide safety experience of A-Good Reporting Practice: products [DIR Art 107b] [REG international article involving an  KFDA Homepage
therapeutic goods. All the Spontaneous case reports of Art 28 (2)] and should submit adverse reaction that occurred in  Phone etc.
manufacturers/importers are adverse events submitted to the PSURs to the Agency according Turkey. Report of Safety
required Sponsor and FDA, and reports to the following timelines: Chapter Five Information to
from other sources such as the • within 70 calendar days of Periodic Risk-Benefit  Manufacturers
medical literature or clinical the data lock point (day 0) for Assessment Reports (Importers)/Clinical
studies, may generate signals of PSURs covering intervals up to Content Periodic risk –benefit Pharmacists
adverse effects of drugs. 12 months (including intervals assessment reports  Clinical MD, Dentist,
Characteristics of a good Case of exactly 12 months); and  The periodic risk-benefit traditional MD
Report • within 90 calendar days of assessment report will be
 Patients/ Consumers
Description of adverse events, the data lock point (day 0) for based on all available data
Time limit for Reports
Suspected and concomitant PSURs covering intervals in related to medicinal
 Following Information to
product therapy details, patient excess of 12 months; product’s risks and benefits
Manufacturers
characteristics, including • the timeline for the submission including information on
demographic information, of ad hoc PSURs requested by (Importers)/ Clinical
off-label use and data from
Documentation of the diagnosis competent authorities will Pharmacists should
clinical studies
report within 15 days:
of the events ,clinical course of normally be specified in the  The periodic risk-benefit
the event and patient outcomes, request, otherwise the ad hoc  Serious AE, ADR
assessment report will
relevant therapeutic measures PSURs should be submitted  Unexpected ADR
provide an accurate estimate
and laboratory data at baseline, within 90 calendar days of the of the population exposed to  Withdrawal or recall
information about response to data lock point. the medicinal product. taken by foreign
– government
dechallange and rechallange. Module VIII Post-  The periodic risk-benefit
For reports of medication authorisation safety studies assessment report will Kinds of Safety
errors, good case reports also Non-interventional PASS contain the results of Information
include full descriptions of the concerned can be: assessment of the  Serious AE/ADR
following: • imposed as an obligation in effectiveness of risk  Unexpected ADR
Product involved and established accordance with REG Art minimization activities  Drug Interactions
name, manufacturer, dosage 9(4)(cb) and Art 10a(1)(a) and relevant to the risk benefit  Other AE/ADR
form, strength, concentration with DIR Art 21a(b) and Art assessment  Information published in
/sequence of events leading up to 22a(1)(a) (category 1 of studies  Marketing authorization domestic /overseas,
the error /work environment in in GVP Module V); holders will not be required medical/pharmaceutical
which error occurred /and type of • imposed as a specific to include systematically journals
personnel involved with the error. obligation in the framework of detailed listings of  Information on the safety
C-Developing a Case Series a marketing authorisation individual cases, including measures taken by
FDA suggests that sponsors granted under exceptional case narratives, in the foreign regulatory
initially evaluate a signal circumstances (category 2 of periodic risk-benefit authorities
generated from post marketing studies in GVP Module V); assessment report.
spontaneous reports through a
careful review of the cases and a
search for additional cases. It
includes:
The clinical and laboratory
manifestations and course of the
event, demographic
characteristics of patients with
events, exposure duration, time
from initiation of product
exposure to the adverse event,
doses used in cases, including
labeled doses / overdoses, use of
concomitant medications,
changes in event reporting rate
over calendar time or product life
cycle.
E-Use of Data Mining to
Identify Product -Event
Combinations
At various stages of risk
identification and assessment,
systematic examination of the
reported events by using
statistical or mathematical tools,
or so-called data mining, can
provide additional information
about the existence of an excess
of adverse events reported for a
product.
By applying data mining
techniques to large adverse event
databases, such as FDA’s AERS
or VAERS, it may be possible to
identify unusual or unexpected
product-event combinations
warranting further investigation.
F-Safety Signals
G-Putting the Signal into
Context: Calculating
Reporting Rates Vs. Incidence
Rates
• required in the risk  Based on evaluation of the  Other safety -related
management plan (RMP) to cumulative safety data and information
investigate a safety concern or risk –benefit analysis , the
to evaluate the effectiveness of marketing authorization
risk minimisation activities holder will draw
(category 3 of studies in GVP conclusions in the periodic
Module V); or risk-benefit assessment
• conducted voluntarily by a report as to the need for
marketing authorisation holder. changes or actions
Module XV – Safety  Unless otherwise specified
communication by the Agency, a single
Communicating safety periodic risk-assessment
information to patients and report will be prepared for
healthcare professionals is a all medicinal products
public health responsibility and containing the same active
is essential for achieving the substance and authorized for
objectives of one marketing authorization
pharmacovigilance in terms of holder.
promoting the rational, safe and  If the substance that is the
effective use of medicines, subject of the periodic risk-
preventing harm from adverse benefit assessment report is
reactions, minimising risks and also authorized as a
contributing to the protection of component of a fixed dose
patients’ and public health combination medicinal
product, either a separate
periodic risk benefit
assessment report will be
submitted or the
combination data will be
submitted within one of the
single substance periodic
risk-benefit assessment
reports.
In pharmacoepidemiologic
studies, the numerator (number of
new cases) and denominator
(number of exposed patients and
time of exposure or if known time
at risk) maybe readily
ascertainable. In contrast, for
spontaneously reported events, it
is not possible to identify all cases
because of under reporting, and
the size of the population at risk
is at best an estimate.
2B-Overview of the Risks
Management Guidance
When reviewing the
recommendations provided in
this guidance, sponsors and
applicants should keep following
points in mind
 Many recommendations in
this guidance are not
intended to be generally
applicable to all products
 It is of critical importance to
protect patients and their
privacy
 To the extent possible this
guidance conforms the
FDA’s commitment to
harmonize international
definitions and standards as
appropriate .
 When planning risk
assessment and risk
minimization activities,
sponsors should consider
input from health care
participants likely to be
affected by these activities.
There are points of overlap
among three guidance.
Inspection by penal of experts, No inspection point is mentioned
if so desired by the Authority
Expert inspection may be carried
out if so directed by the
Authority for Verification of
incident reported to the
Pharmacovigilance center.
This process takes
approximately 30 working days
to complete.
N/A
Pharmacovigilance Inspection No inspection point is
in this guideline inspections (Rev 1) Article 32 mentioned in this guideline
This Module contains guidance Marketing authorization
on the planning, conduct, holders’ healthcare institutions
reporting and follow-up of and organizations, contract
pharmacovigilance inspections pharmacovigilance service
in the EU and outlines the role providers and other relevant
of the different parties involved. entities will be subject to
The objectives of inspection.
pharmacovigilance Regulatory penalties
inspections are: Article 33
• to determine that the In the event that any violation of
marketing authorisation holder this regulation is detected during
has personnel, systems and inspections by the agency, the
facilities in place to meet their marketing authorization will be
pharmacovigilance obligations; allowed fifteen days to three
• to identify, record and address months, if violation is not
non-compliance which may rectified, marketing
pose a risk to public health; authorization will be suspended
• to use the inspection results as until the situation is resolved.
a basis for enforcement action, Guideline
where considered necessary Article 34
For marketing authorisation The Agency will issue specific
holders of non-centrally guidelines to provide guidance
authorised products (i.e. and clarity for implementation
nationally authorised products, of regulation.
including those authorised Enforcement
through the mutual recognition Article 37
or the decentralised procedure), The regulation will be enforced
it is the responsibility of the by the President of Turkish
competent authority of the Medicines and Medical Devices
Member State concerned, in Agency.
cooperation with the Agency, to
ensure by means of inspection
that the legal requirements
governing medicinal products
are complied with.
Beyond Case Review: Module II – Chapter three N/A
Investigating a signal through Pharmacovigilance system Pharmacovigilance System
observational studies master file (Rev 2) Master file,
This document focuses on three The legal requirement for Pharmacovigilance
types of non-randomized marketing authorisation holders
observational studies (1) to maintain and make available Documents Required for
pharmacoepidemiologic studies upon request a Marketing Authorization
(2) registries (3) surveys. pharmacovigilance system Article 9
FDA recommends that sponsors master file (PSMF) was 1-The marketing authorization
choose the method best suited to introduced by Directive holder must submit an overview
the particular signal and research 2010/84/EU amending, as which comprise of following
question of interest. regards pharmacovigilance, information:
A-Pharmacoepidemiologic Directive 2001/83/EC (see A) A document showing that the
Studies Recitals (7) and (35), Article marketing authorization holder
Pharmacoepidemiologic studies 23(4), Article 104(3)(b) of has appointed the qualified
can be of various designs, Directive 2010/84/EU) and person responsible for
including cohort (prospective or Regulation (EU) No 1235/2010 pharmacovigilance.
retrospective), Case control, amending, as regards B) A signed statement issued by
nested case control, case - pharmacovigilance of marketing authorization holder,
crossover, or other models. The medicinal products for human that qualified person has
results of such studies may be use, Regulation (EC) No necessary qualification
used to characterize one or more 726/2004 (see Recitals (22) and C- A statement that the
safety signals associated with a (25), Article 16(3a) of medicinal product has a
product, or may examine the Regulation (EU) No pharmacovigilance system
natural history of a disease or 1235/2010), to harmonise and master file.
drug utilization patterns. strengthen the conduct of 2- A risk management must be
When performing a pharmacovigilance activities in submitted with application.
pharmacoepidemiologic study, the EU. Content of pharmacovigilance
FDA suggests that investigators system master file
seek to minimize bias and to Article 11
account for possible 1-The pharmacovigilance
confounding. Confounding by system master file will contain:
indication is one of example of an  A description of
important concern in performing responsibilities
a pharmacoepidemiologic studies  Professional background of
evaluating the same hypothesis the qualified person
may provide different or even  Contact details of qualified
conflicting results. It is always person
prudent to conduct more than one  Details of backup
study, in more than one arrangements
environment and even use 2-A Description of the
different designs. Agreement of organizational structure
the results from more than one 3- A Description off the location
study helps to provide of functionality and operational
reassurance that the observed responsibility for computerized
results are robust. systems used to report, record
information
A Protocol for a 4-A Description of data
pharmacoepidemiologic study
generally includes:
 Clearly specified study
objectives
 A critical review of the
literature
 A detailed description of the
research methods.
Depending on study objectives,
factors that may affect the choice
of data bases includes:
 Demographic characteristics
of patients enrolled in the
health plans
 Turnover rate of patients in
health plans
 Plan coverage of medications
of interest
 Size and characteristics of
exposed population available
for study
 Availability of outcomes of
interest
 Access to medical records
 Access to patients for data
not captured electronically.
B-Registries
In this guidance document, a
registry is “an organized system
for collection, storage, retrieval ,
analysis ,and dissemination of
information of information on
individual persons exposed to a
specific medical intervention
who have either a particular
disease, a condition that
predisposes to the occurrence of a
health -related event , or prior
exposure to substances known or
handling, continuous monitoring
of the risk benefit balance,
collection assessment and
reporting of individual safety
reports.
5- A description of the quality
system for the performance of
pharmacovigilance activities.
Content of the annex to the
pharmacovigilance system
master file
Article 12
The pharmacovigilance system
master file will have the annex
containing following
documents:
A list of medicinal products
covered by pharmacovigilance
system under master file, a list of
written policies and procedures,
a list of contract with contract
pharmacovigilance service
providers, a list of all scheduled
and and completed audits, an
electronic log book.
Ensuring the master file is
kept up to date Article 13
The marketing authorization
holder will keep the
pharmacovigilance system
master file up to date
Form of the documents
contained in the
pharmacovigilance master file
Article 14
Pharmacovigilance system
master file documents will be
complete and legible, the
particulars and documents of
master file maybe presented in
modules, the pharmacovigilance
suspected to cause adverse health master fie maybe stored stored in
effects. electronic form, the marketing
Registries can be particularly authorization holder will record
useful for: in the electronic logbook any
 Collecting outcome alteration of the content of the
information not available in pharmacovigilance system
large automated databases master file made within the last
 Collecting information from five years.
multiple sources Availability and location of the
A Sponsor can initiate a registry pharmacovigilance system
at any time. master file
 The types of additional risk The pharmacovigilance system
information desired master file will be located at the
 The attainability of that site where pharmacovigilance
information through other activities are performed.
methods Chapter four
 The feasibilty of establishing Suspected Adverse Reaction
the registry. Reports
C-Surveys Content of suspected adverse
Patient or health care provider reaction reports
surveys can gather information to Article 16
assess:  A TUFAM reporting form
 A safety signal will be used for submitting
 Knowledge about labeled suspected adverse reaction
adverse events reports to TUFAM.
 Use of product as labeled,  Marketing authorization
particularly when the holders will ensure that
indicated use is for a adverse reaction reports are
restricted population or complete
numerous contraindications  Marketing authorization
exist holders will record the
 Compliance with the details necessary for
elements of a Risk Map obtaining follow-up
Confusion in the practicing information on adverse
community over sound alike or reaction.
look alike trade names.  When reporting suspected
adverse reaction, marketing
authorization holders will
provide all available
information. i.e a report
type, date, reporter s
address, information

Case report storage should No audit plan is mentioned
ensure traceability (audit trail) of
all data entered or modified,
including dates and sources of
received data, dates and
destination of transmitted data.
No risk management plan is The Role of Pharmacovigilance
defined and Pharmacoepidemiology in
risk management
Risk assessment during product
development should be
conducted in a thorough and
rigorous manner however it is
impossible to identify all safety
concerns during clinical trials.
Once a product is marketed, there
is generally a large increase in the
number of patients exposed,
including those with co-morbid
identifying the patient,
relevant medical history etc.
Module IV – Audit No audit plan is mentioned
Pharmacovigilance audits Article 29
The entry into force of the new Risk based audits of the quality
legislation on system will be performed at
pharmacovigilance in July regular intervals
2012, established legal
requirements for competent
authorities in the Member
States and the European
Medicines agency (the Agency)
and marketing authorisation
holders to perform audits of
their pharmacovigilance
systems [DIR Art 101(2), Art
104(2), REG Art 28f], including
risk based audits of their quality
systems [IR Art 13 (1), Art 17
(1)]. For the purposes of this
Module reference to
pharmacovigilance audit(s) and
pharmacovigilance audit
activity(ies) are deemed to
include pharmacovigilance
system audits and audit(s) of the
quality system for
pharmacovigilance activities
Guideline on good
Module V – Risk management Chapter six N/A
systems Risk Management Plans
the RMP contains: 1. the Format and content of risk
identification or management Plans
characterisation of the safety Article 19-
profile of the medicinal The risk management plan
product, with emphasis on established by the marketing
important identified and authorization holder will contain
important potential risks and the following elements
missing information, and also  A characterization of the
on which safety concerns need safety profile of the
to be managed proactively or medicinal products
further studied (the ‘safety concerned
conditions and those being
treated with concomitant medical
products. Therefore, post-
marketing safety data and risk
assessment based on
observational data are critical for
evaluating and characterizing a
product’s risk profile and for
making informed decisions on
risk minimization.
This guidance document focuses
on pharmacovigilance activities
in the post-approval period.
This guidance uses the term
pharmacovigilance to mean all
scientific and data gathering
activities relating to the detection,
assessment and understanding of
adverse events. This includes the
use of pharmacoepidemiologic
studies. These activities are
undertaken with the goal of
identifying adverse events and
understanding, to the extent
possible, their nature, frequency,
and potential risk factors.
specification’); 2. The planning  An indication of how to
of pharmacovigilance activities characterize further
to characterise and quantify safety profile of the
clinically relevant risks, and to medicinal products
identify new adverse reactions concerned
(the ‘pharmacovigilance plan’); A documentation of measures to
3. the planning and prevent or minimize the risks
implementation of risk associated with the medicinal
minimisation measures, product including an assessment
including the evaluation of the of the effectiveness of those
effectiveness of these activities measures
(the ‘risk minimisation plan’)
Module XVI – RISK
MINIMISATION
MEASURES: selection of
tools and effectiveness
indicators
Safety concerns of a medicinal
product are normally
adequately addressed by routine
risk minimisation measures (see
GVP Module V). In exceptional
cases however, routine risk
minimisation measures will not
be sufficient for some risks and
additional risk minimisation
measures will be necessary to
manage the risk and/or improve
the risk-benefit balance of a
medicinal product. This module
provides particular guidance on
the use of additional risk
minimisation measures,
including the selection of tools
and the evaluation of their
effectiveness. In specific
circumstances, however, the
effectiveness evaluation may
also apply to routine risk
minimisation measures
associated with safety
concern(s) which are described
 in the summary of product
characteristics (SmPC) and
package leaflet (PL) (e.g. the
SmPC provides guidance for
clinical actions beyond routine
standards of clinical care for
either the risk itself or
management of the target
population). In these
circumstances, the guidance
provided in this Module on
effectiveness evaluation also
applies to routine risk
minimization measures

DISCUSSION:
While much progress has been made in PV practices, many deficiencies and issues still exist in the efforts to ensure safe medicine usage.
Harmonization of PV practices beyond regulation requires defining and implementing “best suitable practices” for the health-care
professionals, industry and the regulatory authorities. It requires formal training for PV professionals and better communication tools. Safety
information is communicated between different regulatory agencies, regulatory agencies and manufacturers, healthcare professionals and
manufacturers, agencies and healthcare professionals, healthcare professionals and consumers. All parties in communication utilize different
tools– from product labeling to adverse event reports. In today's technological environment these communications are occurring more
frequently over the internet, through social media and the cloud. For PV practices to become truly global, there is a further need to integrate
these PV best practices with these new modes of communication.
Identifying the discrepancies in existing practices is also only a first step. More work is required to establish the best practices, tools and
infrastructure that will be required to address the needs of PV in the future. International organizations must continue to advance their
understanding of PV and establish guidelines for shifting away from a focus on finding harm and more toward extending knowledge about
safety to all appropriate stakeholders. Wallace and Evans write, “Pharmacovigilance should operate in a culture of scientific development.
This requires the right balance of inputs from various disciplines, a stronger academic base, and greater availability of basic training
and resource which is dedicated to scientific strategy.” Of course, implementing such strategies will require legislative change; thus, the
process that begins with the legislation to identify where disharmony exists, must also end with the legislation to create a framework at a
national level that allows for an international harmonization of practice.
CONCLUSION:
Following are few suggestions for strengthening the Pharmacovigilance System in Pakistan and Measures which DRAP should take:

 Confronting falsified sub-Standard Products

 Developing Comprehensive PV Guidelines
 Strengthening Spontaneous reporting
 Reforming Organizational Structure to Achieve integrated Safety Surveillance
 Improve PV Funding within the Program
 Develop sustainable risk assessment and evaluation activities
 Risk assessment and evaluation
 Risk management and communication