CMC(Chemistry, Manufacturing & Control),Post Approval Regulatory Affairs

1. Presentation on
CMC(Chemistry, Manufacturing &
Control),Post Approval Regulatory
Affairs

2. INTRODUCTION ON CMC
 CMC stands for Chemistry , Manufacturing, and controls.
 It plays a pivotal role in the development, licensure ,
manufacturing and ongoing marketing of pharmaceutical
products.
 CMC team has a similar function to the product
development team , focused on the manufacturing process
development , registration , manufacturing facility & site
inspections.
 It ensures compliance to cGMP, GLP & Clinical practices.
 It also audit compliance & readiness for regulatory
inspections of the laboratory ,clinical & manufacturing
facilities & information technologies.
 The required content and format of the CMC section of
various application types are described in guidance
documents from both the “International Conference On
harmonisation” (ICH)

3.  CMC is relatively small section (approx. 15-20%) of a
typical new drug application(NDA), but it often becomes a
reason for delay in the approval of NDA/Biologics
licensing application(BLAs).
For ANDA CMC section is significant(around 80-90%).
It is important section in post approval life cycle
management of the products.
It should be noted that CMC section is made up of three
distinctly different but overlapping disciplines/sciences
which are:-
1.Synthetic/ Fermentation Chemistry
2.Analytical Chemistry
3.Formulation Chemistry

4. What is CMC Regulatory Affairs
 To conduct clinical investigations and market pharmaceutical products,
pharmaceutical companies are legally required to obtain and maintain
regulatory approvals.
 The government regulatory agencies typically involved in the approval
process are:-
o The Food and Drug Administration(FDA)
o European Medicines Agency(EMA)
o Japanese Pharmaceuticals and Medical Devices Agency (PMDA),etc.
 CMC(RA) is a specific area with in RA that has the ultimate responsibility
for providing CMC regulatory leadership and strategy required to achieve
regulatory approvals.
 As a strategic function ,CMC RA collaborates closely with multiple
scientific ,technical , quality, and commercial areas within a company or
with external contract manufacturing organisations (CMOs).
 Information regarding CMC for drugs is an important and detailed section
in a dossier to support clinical studies &marketing applications . This
information must be updated throughout drug’s lifecycle

5. REGULATION
21 CFR 312.23(a)(7)(i) –
As appropriate for the particular
investigations covered by the IND, a section
describing the composition, manufacture,
and control of the drug substance and the
drug product sufficient CMC information to
assure the proper identification, quality,
purity and strength of the investigational
drug

6. CMC INFORMATION
 Same for all INDS or diseases, however,
• Regulations emphasize the graded nature of CMC
information needed in an IND
• The amount of CMC information needed varies
according to type of trial – Phase, Size and Duration of
clinical trial, Dosage form, Prior Usage, History, etc.
• FDA recognizes that CMC development parallels
clinical investigations

7. CMC REVIEW AT IND STAGES
 Primary objective is to assure the safety of patients, during all
phases of the IND
 Phase 1 CMC evaluated mainly from the point of risk to
patient.
 Phase 2 and 3 CMC evaluates safety, and additionally the
linkage of the clinical test product to the to-be-marketed
product

8. POST PHASE 1 SUBMISSIONS
Continue to provide CMC data to support clinical studies
• Develop data for future NDA submission
- Demonstrate that the to-be-marketed drug has the same/similar
identity, quality, purity and strength as that of the investigational
drug proven to be effective and safe through clinical studies
– Demonstrate consistency and reliability of drug manufacturing
process over product life

9. DEVELOPMENT ELEMENTS-ICH
Q8
1. Quality Target Product Profile (QTPP)
 Intended use
 Route of administration
 Dosage form
 Delivery
 Bioavailability
 Strength
 Container closure
 Stability
 QTPP Example
 Pediatric Suspension for oral administration

10. CONTD.
 2. Identify Critical Quality Attributes (CQA) of the
drug product, drug substance and excipients
– For manufacture
• Particle Size, Polymorphic Form,
– For performance
• Dissolution/disintegration,
– For stability
• Water content, light protection, impurity control

11. CONTD.
3. Control Strategy
– Control of drug substance
– Control of excipients and intermediates
– Process controls
– In-process testing
– Container closure system
– Drug product specification

12. CONTD.
4. Manufacturing process
– Systematic and thoughtful design incorporating QTPP,
CQA, etc., elements
– Process improvement and control
– Process robustness

13. EOP 2 MEETINGS
 • EOP2 meetings can be multi-disciplinary, clinical
only or CMC only
 • If significant CMC issues are to be discussed, a CMC
only EOP2 meeting can be requested
 • CMC only EOP2 meeting should be held soon after
or before the clinical EOP2 meeting, prior to Phase 3
activities

14. CMC PERSPECTIVE AT EOP 2
MEETINGS
 • Purpose of EOP2 CMC discussion is to
 – Evaluate CMC development results to date
 – Discuss sponsor’s plans
 – Identify and resolve potential problems
 – Ensure that meaningful data will be generated during
3 studies to support a planned marketing application.
 • Focus on CMC issues related to the Phase 3 drug
(and registration stability drug)

16. CMC Regulatory Submissions
contains -:
 CMC regulatory submissions are not limited to information
associated with API and the finished dosage form , it contains:-
 Names and locations of manufacturing and testing sites.
 Characterization of the API and composition of the dosage
form.
 Description of the product & process development.
 Description of the manufacturing process.
 Analytical methods and specifications used for testing and
release of raw material , in-process controls , container and
closure systems , API and the dosage form.
 Release and stability testing data for both the API and the
dosage form.

17. CMC Regulatory Services
 Preparation and review of regulatory submissions including:-
 Investigational new drug (IND)
 Clinical trial authorization (CTA)
 Investigational medicinal product dossier (IMPD)
 New drug application (NDA)
 Marketing authorization application(MAA)
 Abbreviated new drug application(ANDA)
 Authority of annual reports ,drug master files, dossier
amendments and supplements
 Preparation ,publication and submission of eCTD applications
 Direct interactions & negotiations with U.S. FDA , EMA and
national agencies

18. CMC SPECIALITIES IN
PHARMACEUTICAL &
BIOPHARMACEUTICAL INDUSTRIES
 Interpretation & application of CMC regulatory regulations and guidance for IND , NDA and
DMF
 Strategic advice on the interpretation and application of CMC regulatory guidance , legal
requirements of CMC regulations and establishment of CMC case study precedence
 CMC regulatory strategy development and implementation inclusive of quality , safety and
efficacy
 CMC regulatory gap analysis for identification , assessment and provision of CMC regulatory
mitigation strategies for remediation
 Mitigation strategies for CMC regulatory conformance and compliance
 CMC regulatory planning , preparation and participation for FDA or EMA meetings
 CMC regulatory problem solving related to API, drug product , dosage form, contract
manufacturing organization(CMO) or technology transfer
 CMC regulatory sciences due diligence for assessment ,analysis, summary and
recommendations for potential startups , joint ventures, acquisitions or business
partnerships

19. STRATEGIC ELEMENTS OF REGULATORY
CONTRIBUTION
TPP/ product inception
Global CTA/IND fillings clinical trial conduct
Fast track ;orphan drug; opportunities for acceleration,
manufacturing strategies
TPP-Driven regulatory agency meeting /consultations and
scientific advice
Special protocol assessment/pivotal studies
Stakeholder engagements HTA/Experts
Competitive benchmarking Benefit/Risk assessment
Global filing of marketing applications eCTD

20. CMC AND ITS CORRELATION WITH
CLINICAL PHASES
PHASE-1
TRIALS
The CMC section is
quite small and
contains laboratory
scale
manufacturing ,
experience for the
drug substance
and the drug
products with quite
simple analytical
methodologies.
PHASE-2
TRIALS
The CMC section
evolves to pilot
scale
manufacturing of
the drug substance
and the drug
products ,and the
specifications and
analytical
methodologies
become more
sophisticated.
END OF PHASE
2 & PHASE 3
TRIAL
EOP 2 means major shift
in planning & execution
for CMC section . The
drug substance & the
drug product
manufacture typically
need to be moved to
commercial scale, and
the specifications & the
analytical
methodologies need to
be upgraded and
finalized . So, CMC is a
“Moving Target”. After
phase 3 NDA/BLA is
submitted to US FDA for
review & approval.

21. POST APPROVAL STUDIES
 Post-approval studies (PAS) are conditions of device approval
 The FDA may require a post-approval study (or studies) at the time of approval of a
Premarket Approval (PMA), Humanitarian Device Exemption (HDE), or product development
protocol (PDP) application to help assure continued safety and effectiveness (or continued
probable benefit, in the case of an HDE) of the approved device
 CDRH’s Post-Approval Studies Program ensures that methodologies are well-designed and
conducted effectively, efficiently and in the least burdensome manner.
 CDRH has established the Post-Approval Studies Database to share general information
regarding each PAS ordered since January 1, 2005, provides the overall study status (based on
protocol-driven timelines and the adequacy of the data) and the applicant’s current reporting
status for each submission due.

22. PROCEDURES FOR HANDLING PAS IMPOSED
BY PMA ORDER
 This guidance document is intended to assist you if you are subject to post-approval study
requirements imposed by the PMA order by providing:
 procedural information
 recommendations on the format, content, and review of post-approval submissions
 recommendations applicable to both clinical and non-clinical post-approval studies.
This guidance document also aims to increase the transparency of FDA’s approach to post-
approval study requirements to stakeholders.

23. CONTD.
 FDA also initiated an internal review to evaluate its ability to monitor post-approval studies. As
a result of that review, we have:
 expanded consultation between the Office of Device Evaluation (ODE), Office of In-Vitro
Diagnostic Device Evaluation and Safety (OIVD), and the Office of Surveillance and Biometrics
(OSB) on designing post-approval studies
 developed a new post-approval study electronic tracking system
 shifted the responsibility for monitoring the progress and results of post-approval studies
from the premarket staff (ODE and OIVD) to the postmarket staff (OSB)
 established an FDA work group staffed with premarket and postmarket reviewers to evaluate
and recommend methods to improve the quality and completion of post-approval studies
 determined appropriate public notification (via the website and advisory meetings) and
enforcement options concerning post-approval studies
 increased focus on inspections to assess compliance with the post-approval study agreement,
protocol adherence, human subject protection, and data integrity.

24. POST APPROVAL STUDY PROTOCOLS
 Prior to PMA approval, post-approval study protocols and subsequent changes to the approved
protocols are submitted and reviewed as amendments to the PMA. However, after PMA approval,
post-approval study protocols and subsequent changes are submitted and reviewed as post-
approval study supplements to the PMA.
ELEMENTS OF PROTOCOL INCLUDE:-
 background (e.g., regulatory history, brief description of device, indications for use)
 purpose of study
 study objectives and hypotheses
 study design
 study population (including subject inclusion and exclusion criteria and definition
and source of comparator group)
 sample size calculation (statistically justified and based on study hypothesis)

25. CONTD.
 primary and secondary endpoints (including definitions for study endpoints, success criteria, list
of adverse events/complications, standard operating procedures for a determination of
relatedness with device and/or the procedure)
 length of follow-up, follow-up schedule, description of baseline and follow-up assessments
 description of data collection procedures (including recruitment plans, enrollment targets, plans
to minimize losses to follow-up, follow-up rate targets, quality assurance, and control)
 statistical analysis
 data collection forms, informed consent forms, and IRB approval forms
 reporting requirements for interim and final reports

26. WHEN TO SUBMIT POST APPROVAL STUDY PROTOCOL
Ideally, the final protocol for a post-approval study and the schedule for study
completion are based on agreements reached between FDA and the sponsor
during the PMA review process prior to approval of the PMA.
Accordingly, It is recommended you submit a proposed post-approval study
protocol or, at minimum, post-approval study plans, in the original PMA
submission
HOW TO SUBMIT CHANGES
If you wish to propose a change to an approved post-approval study protocol,
It is recommended you submit a PMA supplement, clearly labeled as a Post-
Approval Study Protocol, for FDA review and approval. If multiple protocols are
to be revised, we recommend each be submitted as a separate PMA
supplement.