# Presentation: 919832

## Draft Guidance for Industry: CGMPs for  Phase 1 INDs

- Joseph C. Famulare, Director
- Division of Manufacturing & Product Quality
- Office of Compliance, CDER, FDA
- Advisory Committee for Pharmaceutical Science
- Manufacturing Subcommittee
- 20-21 July 2004

## Background

- 501(a)(2)(B) requires _***all***_ drug products be manufactured in accordance with current good manufacturing practice (CGMP)
- CGMP Regulations, published in 1978 and codified in 21 CFR 210 and 211 primarily directed to commercial manufacturing of approved drugs and biologics

## Background (cont’d.)

- Preamble to 1978 CGMP regulations:
- states that CGMP regulations are applicable to preparation of _***any***_ drug product for administration to humans or animals
- indicated FDA’s intent to publish additional regulations specific to investigational clinical studies

## Background (cont’d.)

- The 1991 Guideline for preparation of investigational new drug products:
- does not adequately cover all manufacturing situations
- does not fully address Agency expectation that an incremental approach to CGMP compliance is acceptable for investigational products

## Background (cont’d.)

- Draft guidance for Phase 1 INDs and complementing regulation:
- articulates FDA’s intent to implement an incremental approach to CGMP compliance for clinical investigational products
- recognizes that some controls and the extent of controls differ between investigational and commercial manufacturing, as well as phases of clinical studies

## Guidance – Development Principles 

- Developed by Agency workgroup (CDER, CBER, ORA) composed of compliance staff, CMC reviewers, and inspectors
- Utilize risk-based approach
- available knowledge
- emphasis on safety
- General CGMP

## Scope

- Draft Guidance
- Applies to investigational new drug and biological drug products used during phase 1 clinical studies
- Specifically addresses phase 1 studies designed to assess tolerability or feasibility for further drug development work
- Some phase 1 studies are excluded (e.g., drug metabolism, structure-activity relationships, food interaction)

## Scope (cont’d.)

- Draft Guidance:
- provides direction for special production situations (i.e. microdose, multi-product, multi-lot) and specific product types
- intended to serve as a companion to other guidance describing chemistry, manufacturing and control info submitted in Phase 1 INDs, and CGMPs for the manufacture of APIs (ICH-Q7A)

## Recommendations for complying with CGMP Requirements

- Utilize appropriate quality control (QC) standards, i.e.:
- well defined procedures
- adequately controlled equipment
- accurate recording of all data
- Application of QC standards leads to implementation of CGMPs consistent with good scientific methodology

## Recommendations for complying with CGMP Requirements (cont’d.)

- Use available technology and resources to facilitate product development, CGMP compliance, and lessen CGMP burden, i.e.:
- disposable equipment and process aids
- prepackaged water for injection (WFI)  and sterilized containers
- contract manufacturing and testing facilities

## Recommendations for complying with CGMP Requirements (cont’d.)

- Prevent contamination and cross-contamination:
- evaluate production environment to identify potential hazards
- ensure that substances (i.e. chemicals, adventitious agents) from previous or concurrent research or production are removed

## General CGMP Requirements

- Personnel:
- education, experience and training, (or any combination of the three) to perform assigned functions, e.g. training to include GMPs outlined in guidance

## General CGMP Requirements (cont’d.)

- Quality Control Function:
- is established for every producer of IND products
- responsibilities are documented in writing and include:
- examination of components, containers, closures, in-process materials, packaging and labeling materials
- review and approval of production and testing procedures, acceptance criteria
- review of completed production records for release or rejection of each clinical batch
- is the responsibility of all staff involved in production
- in operations with limited staff* *– QC function may be carried out by the same person performing production (with periodic review by another qualified person)

## General CGMP Requirements (cont’d.)

- Facilities:
- adequate work areas for intended tasks
- water of appropriate source and quality
- adequate air handling to prevent contamination and cross-contamination

## General CGMP Requirements (cont’d.)

- Equipment:
- in proper working condition, maintained calibrated, cleaned and sanitized at appropriate intervals
- appropriate for intended function
- should not contaminate or be reactive, additive or absorptive with product
- identified and documented in production records

## General CGMP Requirements (cont’d.)

- Control of Components:
- written procedures describing handling and control of components
- written, specified attributes or acceptance criteria
- COA or other documentation for components to ensure conformance with specified attributes
- records of receipt, quantity, supplier’s name, lot number, expiration date

## General CGMP Requirements (cont’d.)

- Production and Documentation:
- records including laboratory and production data detailing components, equipment and procedures used
- records of changes in processes and procedures
- appropriate microbiological control for production of sterile processed products

## General CGMP Requirements (cont’d.)

- Laboratory Controls:
- tests conducted using established written procedures under controlled conditions
- scientifically sound analytical procedures
- properly calibrated and maintained analytical lab equipment
- initiate stability study to support use of product in clinical investigation

## General CGMP Requirements (cont’d.)

- Container Closure and Labeling:
- Package to protect product from alteration, contamination and damage during storage, handling and shipping
- Controlled labeling to preclude mix-ups
- Distribution:
- Describes the transport of the IND product from the point of production to the patient/subject for consumption

## General CGMP Requirements (cont’d.)

- Recordkeeping
- Retain records related to quality and operation of production processes including:
- Equipment maintenance and calibration
- Production records and related analytical test records
- Distribution records
- All quality control functions
- Component records
- Retain records for 2 years after approval of marketing application or until 2 years after shipment and delivery of the product is discontinued and FDA is notified

## Special Production Situations	

- Screening/Microdose INDs
- Multi-Product Facilities
- Biological and Biotechnological Products
- Sterile/Aseptically processed products

## Screening/Microdose INDs

- The application of CGMPs controls to Screening IND and Microdose studies should be proportional to the scale and scope of the operation.
- Special provisions for lab scale production are provided in the guidance with respect to QC, facility, equipment, and lab control.

## Multi-product Facilities

- An area or room can be used for multiple purposes and products, provided that:
- only one product is produced in an area at any given time
- appropriate cleaning and change over procedures are in place to ensure there is no carry-over of materials or products or mix-ups

## Biological and Biotechnological Products 	

- Additional safeguards
- Some production systems may warrant additional safeguards to protect personnel (e.g., pathogenic microorganisms, some products made from spore-forming microorganisms, live viral vaccines and gene therapy vectors)
- Equipment qualification and controls in production assure success of unit operations with safety-related functions (e.g., viral clearance, virus/ toxin attenuation, pasteurization)

## Biological and Biotechnological Products (cont’d.) 	

- Retained samples (e.g., drug substance, drug product, intermediates) can be subsequently analyzed and compared to provide assurance of product consistency throughout clinical development.
- In-process testing and detailed records ensure product consistency for Phase 1 products which are produced in multiple lots

## Sterile/Aseptically Processed Products

- Investigational products intended to be sterile require specific precautions, for example:
- personnel should be properly trained in aseptic techniques
- aseptic manipulation should be conducted in a Class 100 environment e.g. laminar flow hood
- controls should be in place to assure appropriate air quality of the aseptic environment