Preparing an IND Application: CMC


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Speaker: Peter Pekos, Dalton Pharma Services. Part of the MaRS Best Practices Series.This session, led by seasoned industry experts, will explore how to effectively set up your pre-clinical POC studies, address pre-clinical safety requirements and issues, and give you an overview of the manufacturing standards required for Phase I studies
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Preparing an IND Application: CMC

  1. 1. Preparing an IND Application: CMC Principles & Content Outline Peter Pekos, President Dalton Pharma Services May 13, 2008 May 2008 P Pekos
  2. 2. Company Profile • over 80 employees • 26 at Ph.D. / M.Sc. level • 42,000 sq ft facility in Greater Toronto Area • Adjacent to Toronto’s York University • Proximity to Toronto area pharma, biotech, medical research facilities • Integrated synthesis laboratories • Research library • cGMP manufacturing suites • Biopolymer synthesis laboratory • Secure, controlled environment • Analytical laboratory May 2008 P Pekos
  3. 3. Services Contract Research Custom Synthesis Contract Analysis API Manufacturing Sterile Filling May 2008 P Pekos
  4. 4. Drug Development Support SAR elucidation Batch Records Small Focused Libraries Analytical Bulk intermediates & impurity standards • Method Development • Method Validation Process Optimization & Scale Up • Stability Programs Lead Optimization • Impurity Identification Regulatory Support Prodrug synthesis • CMC API Manufacturing (GMP) • IND Sterile Filling (GMP) • NDA May 2008 P Pekos
  5. 5. Disclaimer  Views presented here are provided to illustrate the general process and issues of preparing for an IND  Each therapeutic development program may differ in the details particular to that drug  Be sure to consult all laws, regulations and guidances that apply to your situation May 2008 P Pekos
  6. 6. Business Of Medical Manufacturing  All the issues common to any manufacturing business, plus… • Your product acts DIRECTLY on your consumers • Most products are inherently dangerous • Simple to use and to misuse • Highly intrusive regulatory environment  Conversely, the regulatory environment provides for a process to manage business risk as well as risk to the public • Consider each Health Authority as a resource to consult with, not an adversary! May 2008 P Pekos
  7. 7. Investigational New Drug Application  IND regulations exempt the investigation of a new drug (or new drug use) from the regulations governing the production and marketing of a commercial drug product.  Seeks to balance protection of the public with the need to introduce new therapies.  Current regulations at 21 CFR 312.22 and 312.23 contain the general principles underlying the IND submission and the general requirements for an IND's content and format May 2008 P Pekos
  8. 8. IND regulation of CMC  Balancing protection with investigation leads to a graduated, “bootstrapping” approach • Early studies provide limited data to assess risk vs. benefit, consistency and control, etc., so minimize the initial human exposure • As the program develops, the accuracy, precision, and breadth of your data is expected to improve over time • By the time of a marketing application, the sponsor must demonstrate they are ready and able to meet the full requirements for a marketed drug May 2008 P Pekos
  9. 9. FDA View on Early CMC Data “It is recognized that modifications to the method of preparation of the new drug substance and dosage form, and even changes in the dosage form itself, are likely as the investigation progresses. The emphasis in an initial Phase 1 CMC submission should, therefore, generally be placed on providing information that will allow evaluation of the safety of subjects in the proposed study.” GUIDANCE FOR INDUSTRY. CONTENT AND FORMAT OF INVESTIGATIONAL NEW DRUG APPLICATIONS (INDs) FOR PHASE 1 STUDIES OF DRUGS, INCLUDING WELL CHARACTERIZED, THERAPEUTIC, BIOTECHNOLOGY- DERIVED PRODUCTS (Nov 1995) May 2008 P Pekos
  10. 10. Causes for “Clinical Hold” based on CMC section of your IND  Unknown or impure components  Chemical structures of known or highly likely toxicity  Product that cannot remain chemically stable throughout the testing program proposed  Product with an impurity profile indicative of a potential health hazard or an impurity profile insufficiently defined to assess a potential health hazard  Poorly characterized master or working cell bank  Refer to 21 CFR 312.23(a)(7) (see May 2008 P Pekos
  11. 11. Basic CMC Strategy for IND  Develop pre-clinical data or cite research to answer these two questions: • Does the chemistry of either the drug substance or the drug product present any signals of potential human risk? • Does the manufacturing of either the drug substance or the drug product present any signals of potential human risk?  Continue to address these questions throughout your development program! May 2008 P Pekos
  12. 12. INTRODUCTION TO cGMP  Legal basis for cGMP  What does that “c” mean?  General Principles May 2008 P Pekos
  13. 13. FD & C Act; 501 (a) (2) (B)  “A drug shall be deemed adulterated if: • … the methods used in, or the facilities or controls used for its manufacture, processing, packing or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.” May 2008 P Pekos
  14. 14. cGMP Legal Principles  Quality must be built into product • By “taking care” in making medicine • Can’t test quality into product  Missing or inadequate cGMP risk harm • Products(s) may be adulterated (defects need not be shown before action brought) • Firm is responsible May 2008 P Pekos
  15. 15. cGMP Legal Principles  Non-compliance may lead to your product failing to meet your label claims: • Super-potency or sub-potency • Contamination • Misbranding • Bioavailability (e.g., altered pharmacology) • Safety and efficacy  The mere risk of harmful consequences justifies legal action and remedy! May 2008 P Pekos
  16. 16. cGMP Legal Principles  “c” = “Current” = Dynamic • Standards evolve over time, e.g., ICH efforts of the past decade, and US process overhaul underway right now* *  “Good” Practices • Minimal acceptable standards • Not necessarily “best practices” • Unless “best” is, in fact, the current minimal May 2008 P Pekos
  17. 17. cGMP Legal Principles  Feasible and valuable • No “percentage” in practice threshold • Doesn’t have to be “predominant” • Enforceable even if no one else is currently practicing it • Although a stronger case is made if someone else has adopted that practice May 2008 P Pekos
  18. 18. cGMP Scope  Any ingredient (including excipients)  Finished dosage forms administered to humans and/or animals • OTC, Rx products • Biologics, veterinary drugs • Drugs undergoing study (IND)  Manufacturers, test laboratories, packagers (including pharmacies), and warehouses May 2008 P Pekos
  19. 19. Excluded from cGMP  Drug products compounded per Section 503 Pharmacy Compounding (FDAMA)  Position Emission Tomography (PET) agents, but draft rule published in 2007 suggests these will be covered too: • May be met by producing PET drugs in accordance with the United States Pharmacopeia (USP) general chapter on compounding PET radiopharmaceuticals May 2008 P Pekos
  20. 20. General cGMP Responsibilities  Prepare, review, approve and distribute SOP  Ensure adequate qualifications, training, and experience for personnel operating under cGMP  Follow SOP and MBR  Review MBR and executed BR  Evaluate all deviations, investigate and resolve critical deviations  Ensure sanitary facilities  Calibrate and maintain equipment and facilities, and document that maintenance  Review and approve validation protocols and reports  Establish a change control process May 2008 P Pekos
  21. 21. General Quality Principles  Quality is everyone’s job  Establish a Quality  Sponsors must establish a Control Unit (QCU) quality system • Independent of production management  Responsibilities must be • Responsible for QC and clearly stated QA (QA could be done  Real-time quality records separately)  Investigate all deviations • Notification process for defects, recalls,  Quarantine before release inspections, and serious GMP deficiencies May 2008 P Pekos
  22. 22. Quality Control Unit  Must be involved in all  Cannot delegate main quality issues responsibilities  Must review and • Lot release or rejection approve all quality- • Establishing raw related documents material, WIP, packaging and labeling acceptance  (See: Quality Systems system Regulation, 21 CFR • Batch record review prior part 820) to release • Deviation investigation resolution • Quality audits and validation reviews • Stability data May 2008 P Pekos
  23. 23. Content of IND Item 7: CMC [21 CFR 312.23 (a) (7)] May 2008 P Pekos
  24. 24. Item 7 of the IND: CMC  7.1 Introduction  7.2 Drug Substance  7.3 Drug Product  7.4 Diluent (if applicable)  7.5 Placebo (if applicable)  7.6 Test Procedures  7.7 Environmental Assessment May 2008 P Pekos
  25. 25. Introduction: Section 7.1  Drug Substance/Product  Container/closure description: description • chemical name, structure,  Diluent used to administer physical, chemical, and/or product, if applicable biological characteristics,  Name, address, and and generic name (if description of each location available) and internal ID used in the manufacture of code. the Product and  Names and amounts of Substance(s) Drug Substance(s) used in • Reference existing IND or DMF if available, if not, Product provide, floor plans,  Names and amounts of equipment lists, and excipients, including material flows for each location preservatives or delivery  Summary flow chart of enhancers manufacturing process May 2008 P Pekos
  26. 26. Drug Substance: Section 7.2  A brief process description:  Full name and street list reagents, solvents, and address of each catalysts used. A detailed manufacturing location flow diagram is  Information on the stability recommended. of the Drug Substance  Methods and specs for during the tox & clinical identity, strength, quality, programs and purity • A brief description of the • Reference Standard(s) stability program and test • Brief description of the test methods methods • Preliminary tabular data • Proposed acceptable limits based on representative material may be submitted • Recommend including CofA in lieu of final data • Validation data and • Neither detailed stability established specs may be data nor the stability requested for biotech or protocol should be human/animal source drugs submitted May 2008 P Pekos
  27. 27. Drug Product: Section 7.3  Citing USP-NF may be sufficient  Methods & specs used for identity, strength,  List components & quality level quality, and purity: • Active Pharmaceutical Ingredients • Reference Standard(s) • Excipients (including alternatives) • Brief description of methods used • Everything used in the • Proposed acceptable limits manufacturing process, not just • Recommend including CofA appearing in the final formulation • Assess bioactivity for biotech drugs • For novel excipients, additional info • Validation data and established specs may be may be necessary. requested for biotech or human/animal source • Summary table of composition drugs.  The full name and street address of  Information on the stability of the Drug each manufacturing location Product during the tox & clinical programs  Brief description of manufacturing and • A brief description of the stability study and the packaging procedures test methods in the container/closure system and clinical storage conditions • Include sterilization process for sterile • Preliminary tabular data based on products representative material may be submitted. • Flow diagrams are recommended • Neither detailed stability data nor the stability • Specify Container/Closure system protocol should be submitted proposed for clinical studies May 2008 P Pekos
  28. 28. Label information (7.3.9)  A copy of all labels and labelling to be provided to each investigator:  A mock-up or printed representation of the proposed labelling. • Investigational labels in USA must carry a caution statement as required by 21 CFR 312.6(a). • “Caution: New Drug - Limited by Federal (or United States) law to investigational use.”  NB: Label production and use regulated!  NB: Other nations have different rules for labels! May 2008 P Pekos
  29. 29. Dilulent/Placebo Sections 7.4 & 7.5  A brief general description of the composition, manufacture, and control of any • Diluent used to reconstitute the product, if needed • Placebo to be used in the proposed clinical trial(s)  Recommend using diagrammatic and/or tabular information where possible  NB: Placebo lots require the same care as active lots and consume similar time and resources! May 2008 P Pekos
  30. 30. Environmental Impact Section  Most investigational drugs able to claim categorical exclusion from an environmental assessment under 21 CFR 25.24  Possible exceptions: Cytotoxics or processes that create large volume of hazardous waste. • See Guidance for Industry for the Submission of Environmental Assessments for Human Drug Applications and Supplements, November, 1995. May 2008 P Pekos
  31. 31. Electronic IND Submissions: eCTD format  Differs substantially from paper outline described here, but same principles apply  Still optional for CDER submissions  May offer long term advantages for eventual marketing applications, but technology and process is still evolving  Consult current CDER guidance: htm May 2008 P Pekos
  32. 32. Other CMC Considerations  Investigator’s Brochure references CMC info  Integrate the Tox and Clinical protocols with CMC via the Pharmacy Manual • Storage, handling, and disposal of the drug • If required, preparing/compounding the drug for administration (e.g., reconstitution with Diluent) • Specifications and stability limits for any contact materials (e.g., IV bags, catheters, syringes, pumps, etc.)—often overlooked, risking clinical timeline  Combination products (e.g., with device) governed by additional rules, see: May 2008 P Pekos
  33. 33. cGMP Resources  Internet WWW site by DMPQ • • CGMP regulations and ongoing changes • Division subject contacts • Medical gases • Active pharmaceutical ingredients • Human Drug cGMP Notes • Etc. May 2008 P Pekos
  34. 34. Other Web Resources  ICH website (future of harmonized regulation?) • Quality guidelines: •  CDER handbook (useful background, but not current) • May 2008 P Pekos
  35. 35. Thank you Special Acknowledgement to Mark Winnett May 2008 P Pekos