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Fundamentals of Regulatory
Affairs eighth edition
Chapters 12 Postapproval Prescription
Drug Submissions and
Chapter focus
• cGMP manufacturing regulations,
• Postmarketing adverse drug experience reporting
• Postapproval maintenance of regulatory applications/files
(e.g., NDAs, ANDAs and Drug Master Files (DMFs)), including
postapproval changes and postapproval requirements of
commercial prescription drug manufacturing
• 21 CFR 210 and 211
• Non compliance = adulteration
• The CGMP regulations for drugs establish minimum requirements for
manufacturing, personnel, equipment, control of product,
containers/closures, facilities, packaging, holding and distribution
procedures and the associated process controls
• Ensure that drugs are safe and that requirements are met for quality,
identity, strength and purity
• Active pharmaceutical ingredients (APIs) are subject to the
adulteration provisions of Section 501(a)(2)(B) of the FD&C Act, which
requires all drugs to be manufactured in conformance with CGMPs
• Doesn’t distinguish between API and Drug Product
• No regulations specific to API or Drug Component cGMPs
• FDA applies concepts of 21CFR 210 and 211 to APIs
• Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients Q7A. ICH Q7 (as it now is commonly called) represents
FDA’s current thinking on CGMPs for APIs.
Quality Systems Approach to Pharmaceutical
Current Good Manufacturing Practice Regulations
• 2006 FDA guidance
• Build quality into product
• Four major sections of the quality systems model include
manufacturing operations
evaluation activities
• Facilitate the development of a quality system, harmonize CGMP
regulations, reduce the number of prior-approval type regulatory
submissions, implementing Quality by Design (QbD)
FDA’s Compliance Program Manual
• Instructions to FDA personnel for conducting inspections
• Six interrelated systems are the quality system and the five
manufacturing systems (facilities and equipment, materials,
production, packaging and labeling and laboratory controls
• Systems-based inspection compliance program ensures the applicant
must have the ability to assess whether each of the systems is in a
state of control
Guidance for Industry: Pharmaceutical Quality
System ICH Q10
• Describes one comprehensive model for an effective pharmaceutical
quality system that is based on International Organization for
Standardization (ISO) quality concepts
• Complements ICH Pharmaceutical Development Q8 and Quality Risk
Management Q9
• The content of the guidance that exceeds current regional GMP
requirements is optional
• Intent is to strengthen the link between pharmaceutical development
and manufacturing activities
Post Approval Changes
• Discussed in 21 CFR 314.71, including:
• Only the sponsor, or its designated agent, can supplement the application
• Only information related to the proposed change(s) is required to be submitted
• Requirements for archival, review and field copiesare the same as for original
• Require reporting CMC changes to the drug substance and drug product
that may affect the marketed product’s identity, strength, quality, purity or
• Typographical and spelling errors and changes in formatting to standard
operating procedures or batch records need not be submitted
Three types of changes
Type of Change
Reporting Category
Major Change
The change has
substantial potential to
cause an adverse effect
on a drug product’s
identity, strength, quality,
purity or potency
Prior Approval
Supplement (PAS)
Approval of the
supplement is required
prior to distribution of
product manufactured
using the proposed
Establishing a new regulatory
analytical procedure including
designation of an alternative
analytical procedure as a
regulatory procedure
• A change in qualitative or
quantitative formulation
Moderate Change
The change has moderate
potential to cause an
adverse effect on a drug
product’s identity,
quality, purity or potency.
Changes Being
Effected in 30 Days
Supplement (CBE-30)
Product manufactured
using the proposed
change(s) may be
distributed 30 days after
submission of the
supplement if the sponsor
is not informed otherwise
by FDA
Changes in the size or shape
of a container for a sterile
drug substance
• Relaxing an acceptance
criterion or deleting a test to
comply with an official
compendium that is
consistent with FDA statutory
and regulatory requirements
Three Types of Changes, Continued
Moderate Change
Changes Being
The change has moderate Effected Supplement
potential to cause an
(CBE or CBE-0)
adverse effect on a drug
product’s identity,
strength, quality, purity or
Manufacturer can
product manufactured
using the proposed
change(s) immediately
following submission of
the supplement
A change in or addition or
deletion of a desiccant
• Adding or strengthening
a contraindication,
warning, precaution
or adverse reaction on
the product Labeling
Minor Change
Annual Report
The change has minimal
potential to cause an
adverse effect on the
drug product’s identity,
strength, quality, purity or
Product manufactured
using the proposed
change(s) can be
distributed prior to
reporting the change; the
change is reported in the
next Annual Report
A move to a different
manufacturing site for
secondary packaging
• Extension of an
expiration date based on
full shelf-life data when
the data were obtained in
accordance with an
approved stability
Type of Change
Reporting Category
Post Approval Guidances
• Comparability protocols – may get approval to reduce reporting
category one level
• PAS becomes a CBE30, etc
• Check the guidance for good examples
Adverse Drug Experiences
The sponsor is required to review ADE information obtained
from all potential sources (foreign and domestic), including:
• marketing experience (e.g., ADE reports from
• healthcare providers, patients, competitors, etc.)
• scientific literature (peer-reviewed and
• non-peer-reviewed)
• unpublished reports
• postmarketing clinical investigations
• postmarketing epidemiological/surveillance studies
Reporting requirements
• Postmarketing 15-Day Alert Reports—A sponsor shall submit any
foreign or domestic ADE that is both serious and unexpected (defined
below), whether or not it is considered to be drug related, within 15
days following receipt of the information. If additional information is
received after an initial report is submitted, the new information also
shall be submitted within 15 days of receipt as follow-up reports or as
requested by FDA.
• Periodic Adverse Drug Experience Reports (PADER)—For the first
three years following a drug’s approval, a sponsor shall submit a
PADER on a quarterly basis. Unless otherwise requested by FDA, after
three years, the sponsor shall submit the PADER at annual intervals.
ADE reports
• a narrative summary and analysis of the report’s information,
including all ADE information obtained during the reporting period
• analysis of the 15-Day Alert Reports submitted during the reporting
• any Form FDA 3500A (MedWatch) for an ADE that was not submitted
as a 15-Day Alert Report
• any actions taken during the reporting period due to ADEs (e.g.,
labeling changes or additional studies initiated)
• Sponsors with a product that is approved in the US and at least one
other ICH region have successfully negotiated with the FDA to
manage some of the periodic ADE reporting requirements more
efficiently by use of the Periodic Safety Update Report (PSUR) or the
emerging Periodic Benefit-Risk Evaluation Report (PBRER)
ADE reporting
• Know each requirement:
• “unexpected” ADE is defined as an ADE not listed in the
drug product’s current labeling
• “serious” ADE is defined as an experience that results in:
a life-threatening event
in-patient hospitalization or prolongation of existing
a persistent or significant disability/incapacity
a congenital anomaly/birth defect
Medical Terminology
• MedWatch forms
• Council for International Organizations of Medical Sciences (CIOMS)
• FDA Adverse Event Reporting System (FAERS)
• FDA initiative to rapidly collect, analyze and disseminate drug safety
information. This initiative is highlighted by FDA’s Guidance: Drug
Safety Information—FDA’s Communication to the Public (March
• REMS Risk Evaluation and Mitigation Strategies
Other Reporting
• Field Reports
• Annual Reports content review
• Advertising and labeling
• Orange Book Submissions for patent exclusivity
• Complaints – could be an ADE
• Class I Recall—when there is a reasonable probability that the use of
or exposure to a suspected product will cause serious adverse health
consequences or death
• Class II Recall—when the use of or exposure to a suspected product
may cause temporary or medically reversible adverse health
consequences, or where the probability of serious adverse health
consequences is remote
• Class III Recall—when use of or exposure to a suspected product is
not likely to cause adverse health consequences, but the product
violates FDA labeling or manufacturing laws
• Type II—chemistry, manufacture and control information for drug
substances, intermediates and materials used in their preparation or
similar information for drug products
• Type III—component, composition, controls for release and intended
uses of packaging materials
• Type IV—excipients, colorants, flavors, essences or materials used in
their preparation
• Type V—FDA-accepted reference information