Cmc and post regulatory
- 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.