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.

ljohnson@bcg-usa.com

http://www.bcg-usa.com

http://www.regref.com

Louise_Johnson

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Thank you!