1. Fundamentals of Regulatory Affairs eighth edition
Chapters 12 Postapproval Prescription
Drug Submissions and
Compliance

2. Chapter focus cGMP manufacturing regulations,
Postmarketing adverse drug experience reporting requirements
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

3. cGMPS 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

4. API GMPs
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.

5. 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 management responsibilities resources
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)

6. 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

7. 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

8. 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 application
Require reporting CMC changes to the drug substance and drug product that may affect the marketed product’s identity, strength, quality, purity or potency
Typographical and spelling errors and changes in formatting to standard operating procedures or batch records need not be submitted

9. Three types of changes Type of Change Postapproval Reporting Category
Implementation
Examples
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 change(s)
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, strength,
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

10. Three Types of Changes, Continued
Type of Change
Postapproval
Reporting Category
Implementation
Examples
Moderate Change
The change has moderate
potential to cause an
adverse effect on a drug
product’s identity, strength, quality, purity or potency.
Changes Being
Effected Supplement
(CBE or CBE-0)
Manufacturer can distribute
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
The change has minimal
adverse effect on the drug product’s identity, strength, quality, purity or potency.
Annual Report
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 (manufacturing)
• Extension of an expiration date based on full shelf-life data when the data were obtained in accordance with an approved stability protocol

11. Post Approval Guidances
SUPAC IR, MR, SS
Comparability protocols – may get approval to reduce reporting category one level
PAS becomes a CBE30, etc
Check the guidance for good examples

12. 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

13. 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.

14. 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 interval
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)

15. PSUR vs PADER
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)

16. 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:
death
a life-threatening event
in-patient hospitalization or prolongation of existing
hospitalization
a persistent or significant disability/incapacity
a congenital anomaly/birth defect

17. Medical Terminology MedWatch forms
Council for International Organizations of Medical Sciences (CIOMS)
MEDRA
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 2007).
REMS Risk Evaluation and Mitigation Strategies

18. Other Reporting Field Reports Annual Reports content review
Advertising and labeling
Orange Book Submissions for patent exclusivity
Complaints – could be an ADE

19. Recalls
• 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

20. DMFs
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