Draft Guidance for Industry: CGMPs for Phase 1 INDs

Joseph C. Famulare, DirectorDivision of Manufacturing & Product QualityOffice of Compliance, CDER, FDA

Advisory Committee for Pharmaceutical ScienceManufacturing Subcommittee20-21 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Draft guidance for Phase 1 INDs and complementing regulation: articulates FDA’s intent to implement an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Draft Guidance Applies to investigational new drug and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Draft Guidance: provides direction for special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