Qa & Gmp 29 May2010
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Transcript of Qa & Gmp 29 May2010
Regulatory and QA Considerations for Drug Product Development
Louise Johnson, M.S.
Chinese American Biopharmaceutical Society MeetingJune 5, 2010
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Core Principles
Patient safety guides FDA’s review of CMC information during development
CMC development proceeds simultaneously with clinical development
Data generated during development builds upon early work and should be planned to compose a complete NDA CMC section that supports product approval
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Topics
CMC goals in development Standards for product quality
Good Manufacturing Practice (GMP) Quality Assurance (QA)
Quality Assurance and Quality Control CMC Information for Original INDs CMC Information as Development
Progresses NDA Planning
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CMC Development Goals
Manufacture the drug product in a manner so that you can assure its identity, strength, quality, and purity*
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
* FD&C Act Section 505(d)(3)
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Standards Used to Ensure Product Quality GMP – Good Manufacturing Practice
(21 CFR 210 and 211) A standard for the production and testing of a pharmaceutical or device to
ensure product quality Required for human use Not required for animal studies
However, there are GLP requirements for study material Described in the Food, Drug & Cosmetic Act and FDA regulations
Quality Assurance (QA) All those planned and systematic production processes that are established
to ensure the investigational product is fit for the intended purpose Quality By Design (QbD)
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
Provides a basis for risk management and increased regulatory flexibility after NDA approval
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Principles Underlying GMP
Right the first time (can’t inspect quality in) Documentation of all actions and decisions Double checking work & calculations Establish acceptance criteria – specifications Analytical testing to confirm product characteristics Define standard processes for manufacturing and
analytical testing in writing Final product release by personnel independent of
manufacturing department Personnel qualified by education and training Label, segregate, and control components &
equipment
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Regulatory Affairs Function
Act as liaison between the company and FDA Make all regulatory submissions Advise on current regulatory requirements,
guidance, and agency activities
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Quality Assurance Function
Responsible for independent, objective assessment of manufacturing systems and operations
Responsible for lot release, Certificates of Analysis
Manages SOPs, revisions, distribution Provides GMP training Audits facilities, operations, documentation Manages change control
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Quality Control Function
Sample, test, and report results for starting materials, excipients, API, final product
Perform line checks Involved in the manufacturing process
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Example Company Organizational Chart
CEO
Quality Compliance Manufacturing
Quality Assurance Quality Control
Clinical &Regulatory Affairs
Regulatory Affairs
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So What CMC Information Is Needed At Each Stage Of
Development? Regulations allow great deal of flexibility in the amount and depth of data
The type of information needed will depend on Phase of investigation (Phase 1, 2, or 3) Specifics of the human study proposed (dose
regimen, duration of dosing) Nature and source of the drug substance
(synthetic, animal source) Drug product dosage form (oral, IV)
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CMC Information for Original IND
Sufficient information for evaluation of the safety of the proposed investigational product
Data relating the clinical supplies to the drug used in the animal toxicology studies that support the safety of the proposed human study
Statement of whether you believe there are signals of potential human risk in: the chemistry of either the drug substance or the drug
product or the manufacturing of either the drug substance or the drug
product
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IND for Phase 1 Study
Identification of a safety concern or insufficient data to evaluate safety are the only CMC reasons for a clinical hold
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 Section 501(a)(1)(B) of the FD&C Act
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CMC Safety Concern Examples Unknown or impure components Chemical structures of known or highly likely
toxicity (structural alert) Unstable throughout the proposed testing
period Impurity profile indicative of a potential health
hazard or impurity profile insufficiently designed
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IND – CMC Section
Manufacturing Brief description of the composition, manufacture, and control of
drug substance, drug product, and any placebo Controls
Brief description of analytical methods and acceptable limits for drug substance, drug product, and any placebo
Stability Brief description of stability data and analytical methods (can
use a representative lot) Labels
A mock-up of the investigational product labels for the clinical trial
Caution: New Drug - Limited by Federal (or United States) law to investigational use.
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As Development Proceeds
Early discussion of unique CMC issues encouraged End of Phase 2 meeting Pre-NDA meeting
Update information previously submitted Annual reports Information amendments
Emphasis should be on reporting significant changes that can have a safety-related impact
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Examples of CMC Modifications That Can Affect Safety
Changes in drug substance synthesis material change in one of the bond forming steps change in a solvent used for the last reaction and/or
crystallization step change resulting in a different impurity profile
Change in method of sterilization Change in the composition and/or dosage form of the drug
product Change in the drug product manufacturing process that could
affect product quality Change in specifications Change in the drug product container closure system
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Phase 2 – CMC Information
Provide more detailed descriptions of the characteristics of the drug substance and drug product, e.g. Configuration and chemical structure for complex organic
compounds Any non-compendial excipients Particle size distribution, polymorphic form Stability of reconstituted products
Provide more detailed descriptions of manufacturing processes and any changes to them
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Phase 3 – CMC Information
Augment the elucidation and characterization of drug substance structure
Identify, qualify, quantify, and report impurities and degradation products, along with suitable limits
Provide detailed step-by-step descriptions of manufacturing processes In-process controls Acceptance criteria
Detailed listing of all tests performed on starting materials, excipients, drug substance, drug product Validation information for unique tests
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Phase 3 – CMC Information continued Stress testing to demonstrate inherent stability,
potential degradation pathways, capability and suitability of proposed analytical procedures Different pH levels Presence of oxygen and light Elevated temperatures and humidity levels Thermal cycling
Protocol for formal stability program to support NDA
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Advice for CMC Development
Focus on patient safety, re-evaluate as development proceeds
Plan experiments to maximize their ability to support clinical studies and subsequent development work
Seek feedback from FDA for unique situations
Consider implementing a Quality by Design program to increase product understanding
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References for NDA Preparation 21 CFR 314.50 (d)(1)
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314
Guideline for Submitting Documentation for the Manufacture and Controls of Drug Products http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070630.pdf
ICH Quality Guidelines http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005.htm
ICH M4 Common Technical Document format FDA’s Manufacturing Web Page
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/default.htm
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Louise C. Johnson, M.S.
http://www.bcg-usa.com
http://www.regref.com
Louise_Johnson
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Thank you!