Reg & Qa GMP

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An introduction for people new to GMP regulatory requirements in drug development.

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Reg & Qa GMP

  1. 1. Regulatory and QA Considerations for Drug Product Development Louise Johnson, M.S. Chinese American Biopharmaceutical Society Meeting June 5, 2010
  2. 2. Core Principles <ul><li>Patient safety guides FDA’s review of CMC information during development </li></ul><ul><li>CMC development proceeds simultaneously with clinical development </li></ul><ul><li>Data generated during development builds upon early work and should be planned to compose a complete NDA CMC section that supports product approval </li></ul>
  3. 3. Topics <ul><li>CMC goals in development </li></ul><ul><li>Standards for product quality </li></ul><ul><ul><li>Good Manufacturing Practice (GMP) </li></ul></ul><ul><ul><li>Quality Assurance (QA) </li></ul></ul><ul><li>Quality Assurance and Quality Control </li></ul><ul><li>CMC Information for Original INDs </li></ul><ul><li>CMC Information as Development Progresses </li></ul><ul><li>NDA Planning </li></ul>
  4. 4. CMC Development Goals <ul><li>Manufacture the drug product in a manner so that you can assure its identity, strength, quality, and purity* </li></ul><ul><li>Create documentation of your processes so that you can demonstrate to FDA that you understand the critical characteristics of the product and the process and can reliably manufacture a high quality product </li></ul><ul><li>* FD&C Act Section 505(d)(3) </li></ul>
  5. 5. Standards Used to Ensure Product Quality <ul><li>GMP – Good Manufacturing Practice (21 CFR 210 and 211) </li></ul><ul><ul><li>A standard for the production and testing of a pharmaceutical or device to ensure product quality </li></ul></ul><ul><ul><li>Required for human use </li></ul></ul><ul><ul><li>Not required for animal studies </li></ul></ul><ul><ul><ul><li>However, there are GLP requirements for study material </li></ul></ul></ul><ul><ul><li>Described in the Food, Drug & Cosmetic Act and FDA regulations </li></ul></ul><ul><li>Quality Assurance (QA) </li></ul><ul><ul><li>All those planned and systematic production processes that are established to ensure the investigational product is fit for the intended purpose </li></ul></ul><ul><li>Quality By Design (QbD) </li></ul><ul><ul><li>A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management </li></ul></ul><ul><ul><li>Provides a basis for risk management and increased regulatory flexibility after NDA approval </li></ul></ul>
  6. 6. Principles Underlying GMP <ul><li>Right the first time (can’t inspect quality in) </li></ul><ul><li>Documentation of all actions and decisions </li></ul><ul><li>Double checking work & calculations </li></ul><ul><li>Establish acceptance criteria – specifications </li></ul><ul><li>Analytical testing to confirm product characteristics </li></ul><ul><li>Define standard processes for manufacturing and analytical testing in writing </li></ul><ul><li>Final product release by personnel independent of manufacturing department </li></ul><ul><li>Personnel qualified by education and training </li></ul><ul><li>Label, segregate, and control components & equipment </li></ul>
  7. 7. Regulatory Affairs Function <ul><li>Act as liaison between the company and FDA </li></ul><ul><li>Make all regulatory submissions </li></ul><ul><li>Advise on current regulatory requirements, guidance, and agency activities </li></ul>
  8. 8. Quality Assurance Function <ul><li>Responsible for independent, objective assessment of manufacturing systems and operations </li></ul><ul><li>Responsible for lot release, Certificates of Analysis </li></ul><ul><li>Manages SOPs, revisions, distribution </li></ul><ul><li>Provides GMP training </li></ul><ul><li>Audits facilities, operations, documentation </li></ul><ul><li>Manages change control </li></ul>
  9. 9. Quality Control Function <ul><li>Sample, test, and report results for starting materials, excipients, API, final product </li></ul><ul><li>Perform line checks </li></ul><ul><li>Involved in the manufacturing process </li></ul>
  10. 10. Example Company Organizational Chart CEO Quality Compliance Manufacturing Quality Assurance Quality Control Clinical & Regulatory Affairs Regulatory Affairs
  11. 11. So What CMC Information Is Needed At Each Stage Of Development? <ul><li>Regulations allow great deal of flexibility in the amount and depth of data </li></ul><ul><li>The type of information needed will depend on </li></ul><ul><ul><li>Phase of investigation (Phase 1, 2, or 3) </li></ul></ul><ul><ul><li>Specifics of the human study proposed (dose regimen, duration of dosing) </li></ul></ul><ul><ul><li>Nature and source of the drug substance (synthetic, animal source) </li></ul></ul><ul><ul><li>Drug product dosage form (oral, IV) </li></ul></ul>
  12. 12. CMC Information for Original IND <ul><li>Sufficient information for evaluation of the safety of the proposed investigational product </li></ul><ul><li>Data relating the clinical supplies to the drug used in the animal toxicology studies that support the safety of the proposed human study </li></ul><ul><li>Statement of whether you believe there are signals of potential human risk in: </li></ul><ul><ul><li>the chemistry of either the drug substance or the drug product or </li></ul></ul><ul><ul><li>the manufacturing of either the drug substance or the drug product </li></ul></ul>
  13. 13. IND for Phase 1 Study <ul><li>Identification of a safety concern or insufficient data to evaluate safety are the only CMC reasons for a clinical hold </li></ul><ul><li>Special note: While FDA has exempted Phase 1 clinical supplies from GMP regulations, the Federal Food, Drug, and Cosmetic Act still requires clinical supplies to be manufactured under GMP </li></ul><ul><ul><li>Section 501(a)(1)(B) of the FD&C Act </li></ul></ul>
  14. 14. CMC Safety Concern Examples <ul><li>Unknown or impure components </li></ul><ul><li>Chemical structures of known or highly likely toxicity (structural alert) </li></ul><ul><li>Unstable throughout the proposed testing period </li></ul><ul><li>Impurity profile indicative of a potential health hazard or impurity profile insufficiently designed </li></ul>
  15. 15. IND – CMC Section <ul><li>Manufacturing </li></ul><ul><ul><li>Brief description of the composition, manufacture, and control of drug substance, drug product, and any placebo </li></ul></ul><ul><li>Controls </li></ul><ul><ul><li>Brief description of analytical methods and acceptable limits for drug substance, drug product, and any placebo </li></ul></ul><ul><li>Stability </li></ul><ul><ul><li>Brief description of stability data and analytical methods (can use a representative lot) </li></ul></ul><ul><li>Labels </li></ul><ul><ul><li>A mock-up of the investigational product labels for the clinical trial </li></ul></ul><ul><ul><li>Caution: New Drug - Limited by Federal (or United States) law to investigational use. </li></ul></ul>
  16. 16. As Development Proceeds <ul><li>Early discussion of unique CMC issues encouraged </li></ul><ul><ul><li>End of Phase 2 meeting </li></ul></ul><ul><ul><li>Pre-NDA meeting </li></ul></ul><ul><li>Update information previously submitted </li></ul><ul><ul><li>Annual reports </li></ul></ul><ul><ul><li>Information amendments </li></ul></ul><ul><ul><ul><li>Emphasis should be on reporting significant changes that can have a safety-related impact </li></ul></ul></ul>
  17. 17. Examples of CMC Modifications That Can Affect Safety <ul><li>Changes in drug substance synthesis </li></ul><ul><ul><li>material change in one of the bond forming steps </li></ul></ul><ul><ul><li>change in a solvent used for the last reaction and/or crystallization step </li></ul></ul><ul><ul><li>change resulting in a different impurity profile </li></ul></ul><ul><li>Change in method of sterilization </li></ul><ul><li>Change in the composition and/or dosage form of the drug product </li></ul><ul><li>Change in the drug product manufacturing process that could affect product quality </li></ul><ul><li>Change in specifications </li></ul><ul><li>Change in the drug product container closure system </li></ul>
  18. 18. Phase 2 – CMC Information <ul><li>Provide more detailed descriptions of the characteristics of the drug substance and drug product, e.g. </li></ul><ul><ul><li>Configuration and chemical structure for complex organic compounds </li></ul></ul><ul><ul><li>Any non-compendial excipients </li></ul></ul><ul><ul><li>Particle size distribution, polymorphic form </li></ul></ul><ul><ul><li>Stability of reconstituted products </li></ul></ul><ul><li>Provide more detailed descriptions of manufacturing processes and any changes to them </li></ul>
  19. 19. Phase 3 – CMC Information <ul><li>Augment the elucidation and characterization of drug substance structure </li></ul><ul><li>Identify, qualify, quantify, and report impurities and degradation products, along with suitable limits </li></ul><ul><li>Provide detailed step-by-step descriptions of manufacturing processes </li></ul><ul><ul><li>In-process controls </li></ul></ul><ul><ul><li>Acceptance criteria </li></ul></ul><ul><li>Detailed listing of all tests performed on starting materials, excipients, drug substance, drug product </li></ul><ul><ul><li>Validation information for unique tests </li></ul></ul>
  20. 20. Phase 3 – CMC Information continued <ul><li>Stress testing to demonstrate inherent stability, potential degradation pathways, capability and suitability of proposed analytical procedures </li></ul><ul><ul><li>Different pH levels </li></ul></ul><ul><ul><li>Presence of oxygen and light </li></ul></ul><ul><ul><li>Elevated temperatures and humidity levels </li></ul></ul><ul><ul><li>Thermal cycling </li></ul></ul><ul><li>Protocol for formal stability program to support NDA </li></ul>
  21. 21. Advice for CMC Development <ul><li>Focus on patient safety, re-evaluate as development proceeds </li></ul><ul><li>Plan experiments to maximize their ability to support clinical studies and subsequent development work </li></ul><ul><li>Seek feedback from FDA for unique situations </li></ul><ul><li>Consider implementing a Quality by Design program to increase product understanding </li></ul>
  22. 22. References for NDA Preparation <ul><li>21 CFR 314.50 (d)(1) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314 </li></ul><ul><li>Guideline for Submitting Documentation for the Manufacture and Controls of Drug Products http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070630.pdf </li></ul><ul><li>ICH Quality Guidelines http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm </li></ul><ul><li>ICH M4 Common Technical Document format </li></ul><ul><li>FDA’s Manufacturing Web Page </li></ul><ul><li>http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/default.htm </li></ul>
  23. 23. <ul><li>Louise C. Johnson, M.S. </li></ul><ul><li>[email_address] </li></ul><ul><li>http://www.bcg-usa.com </li></ul><ul><li>http://www.regref.com </li></ul><ul><li>Louise_Johnson </li></ul><ul><li>On Twitter </li></ul>Thank you!

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