2. Pharmaceutical regulatory affairs
Objectives of the session
At the end of this chapter, students should able to
mention the main goal of pharmaceutical regulatory affairs
explain the principles & concepts PRA for achieving goal
list basic pharmaceutical regulatory strategic areas to
safeguard public health
mention requirements for marketing authorization of
medicines
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3. Introduction
Drug discovery, development & commercialization process
continuous & complex process
assure effectiveness & safety of drug product
average time till product launch around 10 to 12 years
costs 1.5 billion dollars
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5. Objective of pharmaceutical R&D
converting
ideas into candidate drugs for development
candidate drugs into products for registration & sale
extremely challenging & difficult major hurdles
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6. Hurdles in pharmaceutical R&D (requirement)
novel compound & biological mechanism potent &
selective,
meets customer needs (unmet medical needs),
high margin of safety,
tolerable side effects profile,
efficacious,
bulk drug synthesizable/ scale up, manufacturable
quality of data/ documentation
passing preapproval inspection,
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7. Pharmaceutical regulatory affairs
specialized profession within pharmaceutical/biotechnology
sector to oversees organization’s compliance with
regulations & laws
applying to development, manufacturing & marketing
process for regulated products
drugs, medical devices, biologics, in vitro diagnostics,
nutritional products, cosmetics & complementary
medicines
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8. pharmaceutical industry is one of the most stringently
regulated industry
to protect public health
o ensures quality, safety & efficacy of healthcare
products
o requires development of extensive & complex
regulations
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9. Core functions of regulatory affairs
establishment of regulations and guidance document
review & approval of pre-marketing submissions
product dossier evaluation registration & market
authorization
inspection & audits: documentation, facility, …
product quality testing & verification
check labelling, packaging & promotional material
truthful, informative, not misleading
clinical trials regulation,
post-marketing surveillance
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10. Different pharmaceutical regulatory bodies in the world
EFDA,
FDA (USA),
Medicines and Healthcare Products Regulatory Agency
(MHRA) (UK),
European Medicines Agency (EMA),
medicine product in Europe Union member states
Health Canada,
Pharmaceuticals and medical devices agency (Japan), …
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11. Regulatory standards development
triggered by adverse incidents
1906 - Development of the Pure Food and Drug Act
unsanitary meat industry in Chicago
1938 - Federal Food, Drug and Cosmetic Act (Sulfanilamide
crisis)
demonstration of safety required for approval
expanded requirements for prescriptions
1941 - Initiation of GMP (Sulfathiazole contaminated with
phenobarbital ) 11
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12. 1963 - Establishment of GMPs for Drugs (Thalidomide
tragedy)
mandated efficacy testing, in addition to safety testing, for
premarket approval of drugs
stricter regulation of clinical trials & informed consent by
patients participating in clinical trials
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13. Core principles & concepts of regulation
cornerstone in achieving the goal of regulation
a. safety,
b. efficacy/ effectiveness,
c. quality,
d. purpose,
e. risk/benefit
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14. Basic elements in regulatory strategy to safeguard public health
A. product development,
B. product manufacture &
C. product market vigilance
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15. A. Product development
Product developers must
conduct safety, efficacy & quality study (clinical trials)
generate sufficient data
presented results & activities to regulatory authorities for
review
for all drugs & high-risk medical devices
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16. Ideally the product
should do no harm (safe),
must do some good (intended purpose),
indications for use (drugs) or intended use (medical
devices)
benefits outweigh risks enhances public health
e.g. chemotherapy drugs with significant side effects
reliable & consistent or conformance to agreed
specifications
content, purity & stability 16
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17. B. Product manufacture
all manufacturing sites must
be registered with authorities
expect regular visits from inspection bodies
once commercial production commences, regulatory body
ensures
manufacturing under hygienic conditions in suitable
facilities &
application of appropriate quality systems to control the
process
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18. Quality assurance systems
applied to ensure safety, effectiveness & acceptable quality
of products
used in good manufacturing practice (GMP), good laboratory
practice (GLP), good clinical practice, design, development,
production, installation & servicing
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19. Key element in quality systems
1. personnel
a) job descriptions : duties, responsibilities & authority level
b) job specifications: qualifications, skills & experience
2. facilities & equipment
3. corrective & preventive action: self-correcting & self-
improving
regular internal auditing by personnel independent of the
operational area
feedback from the market, data from day-to-day 19
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20. 4. Documentation
a) written procedures: performance of all tasks
Standard Operating Procedures (SOPs), General
Operating Procedures (GOPs) or protocols for non-
repetitive tasks (e.g. clinical trial protocol)
b) records: showing what has been done & results
batch records , experimental records, log book
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21. Inspections of pharmaceutical manufacturing facilities
Inspection involves review of documents, records, facilities &
other resources
assess their conformity to the requirements of GMP of
medicinal products
normally scheduled visits usually every 2 years
could be un-announced (if the circumstances so warrant)
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22. Objective of pharmaceutical inspections
to enforce cGMP compliance,
to provide authorization for manufacture of specific
pharmaceutical products,
to monitoring quality of pharmaceutical products in
distribution channels,
from the point of manufacture to delivery to the
recipient
• to eliminate hazard posed by infiltration of falsified
medicines
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23. During an inspection, the inspection team will
1. interview relevant personnel
o for additional documentation & samples for testing during
the inspection
2. review documents
3. conduct site visits
at the closing, meeting will provide feedback & discuss
any deficiencies with institution & agree timelines for
corrective actions
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24. Site visits may include any facility or process involved in
producing, purchasing & distributing medicines
such as
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o manufacturing areas,
o quality control (QC)
laboratories,
o stock & stock
management,
o storage areas,
o temperature monitoring,
o purchasing & sales
functions,
o transportation
arrangements, etc
25. Regulatory actions for noncompliance
based on national regulations
correction of unsatisfactory situations,
closing down of a factory,
withholding of authorizations,
product recall,
fines, compensations, decline in company reputation
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26. C. Product market vigilance
activities relating to detection, assessment, understanding &
prevention of adverse effects or any other drug-related
problem
to identify risks that did not surface during the premarketing
phase
over the lifetime of the product
reporting need system from manufacturer & regulatory
authority
allowing for appropriate remedial action
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27. Registration/ Marketing authorization of medicines
the final step in bringing a drug to the marketplace
Approval for safety, efficacy, and quality follows after
thorough evaluation of
Product Dossier
Premises GMP compliance (at least prior to MA)
Product testing
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28. Application dossier
contains quite large volume of information
can easily run up to 120, 000 pages of hard copy
containing extensive technical data on the quality, safety
and efficacy of drug collected during non-clinical & clinical
studies, together with
administrative & other documents such as application
forms, declarations, labels & leaflets
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29. The authorities subject the dossier to a thorough review
ensure there is satisfactory evidence as to the quality, safety
and efficacy of drug grant marketing authorization
the drug can contribute to public health, without undue
risk
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30. Contain assessments of
a) quality,
b) non-clinical study reports &
c) clinical study reports (clinical documentation)
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31. I. Quality module
must contain information on the identity/ composition
(chemistry), characteristics, manufacturing methods, control,
packaging and stability of both the drug substance & final
drug product
to satisfy quality concerns
by chemical, biological & pharmaceutical testing
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32. II. Non-clinical study reports
conducted to investigate the pharmacological & toxicological
properties of the drug substance/ product
mostly undertaken in the pre-clinical phase of drug
development
serve both to
o guide developer (i.e., drug product development) &
o satisfy regulatory authorities (i.e., safe & worthwhile to
proceed)
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33. 1) Pharmacological studies
must be conducted
o can be broken down into pharmacodynamic &
pharmacokinetic studies,
o using a combination of in-vitro and animal models
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34. a) Pharmacodynamic studies
focuses on how a drug brings about a particular response,
and the effective levels that are required
investigate drug/ target interactions & responses
o to establish detailed dose-response curves
illustrated drug potency & effectiveness
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35. b) Pharmacokinetic studies
concerns the fate of a drug in the body at the approximate
therapeutic dose range
the fate of a drug is dictated by the rates of:
absorption, distribution, metabolism & excretion from the
body
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36. 2) Toxicology Studies
required to establish the toxicological profile of the drug
substance
must assess its
o direct toxic effects &
o potential toxic effects
• a reproductive toxin, mutagen, or carcinogen
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37. III. Clinical study: clinical documentation
any investigation in human subjects intended to
o discover the clinical & pharmacological effects of
investigational medicinal product(s), and/or
o to identify any adverse reactions of investigational
medicinal product(s) and/or
o to study ADME of investigational medicinal product(s)
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38. The overall objective is
o to establish a drug therapy that is safe and effective in
humans, to the extent that the risk–benefit relationship is
acceptable
probably the most critical stage in the regulatory pathway
o ultimately determine whether or not a successful
marketing authorization application can be made
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39. The three consecutive phases for conducting clinical trials
for drug approval:
A. Phase I
B. Phase II
C. Phase III
additional safety studies (Phase IV trials) may be conducted
post-approval
each phase distinguished in terms of its specific purpose
and relative complexity
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40. a. Phase I Trials
primarily to assess the safety of the drug in humans
study subject:
o normally conducted in healthy male volunteers
o the number of subjects is normally between 10 and 100
o the study commence with the administration of low
doses
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41. specific categories of subject may be used in certain case
Example:
subjects with mild hypertension for the evaluation of
antihypertensive drugs
patients in the case of drugs expected to produce significant
toxic effects (e.g. anti-cancer cytotoxic drugs)
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42. subjects are closely monitored for changes in vital signs &
the emergence of any adverse side effects
based on the carefully analyzed and assessed findings,
appropriate Phase II trials can be planned
usually completed within a year
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43. b. Phase II Trials
primarily to explore therapeutic efficacy in patients
study subject:
o number: may range from 50 to 500
o patients may be selected based on specific restrictive
criteria;
e.g., those suffering only from the condition under
study, disease stage, age, …..
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44. may commence with short range-finding studies in a small
number of patients before more extensive studies are
conducted
may last from 1 to 2 years
determine the dosage level and regimen for Phase III trials
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45. c. Phase III Trials
to confirm the safety & therapeutic efficacy of a drug in a
broader range of subject 2000 people
involve studying groups that differ in terms of age, gender,
disease stage, additional medical or physiological
conditions (e.g. kidney or liver failure, pregnancy, breast-
feeding), existing drug therapy, or ethnic background
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46. may take from 3 to 5 years, or even longer, to complete
on completion the drug developer should have identified
and confirmed:
o indications for use;
o contraindications;
o the appropriate dosage regimen; and
o possible adverse side effects
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47. Parallel to the clinical trials, outstanding non-clinical studies
will be continued; may involve
o the optimization of a drug formulation as dictated by
clinical trial results, and
o conducting of stability studies on the final drug product
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48. Dossier Evaluation
o Currently most countries organize dossiers in the Common
Technical Document (CTD) format
o The documents are divided into five modules
1. Module 1: Regional information: Administrative information and
prescribing information
2. Module 2: Summaries such as quality, clinical, & non-clinical
summaries
3. Module 3: Quality information
4. Module 4: Non-clinical information
5. Module 5: Clinical information 48
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49. Benefits of the Common Technical Document (CTD)
more “reviewable” applications
complete, well-organized submissions
more predictable format
more consistent reviews
easier analysis across applications
easier exchange of information
suitable for electronic submission
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