Thursday, June 4, 2009


FDA Exempts Phase1 Investigational Drugs from GMPs

New Provisions Cover Formal Evaluation of the Production Environment as well as Training, Components and Production

On Jan. 17, 2006, the FDA issued a direct final rule that exempts most Phase 1 investigational new drugs from compliance with the cGMPs detailed in 21 CFR Part 211.(See Federal Register, Jan.17, 2006, Vol. 71, No. 10, pages 2458 to 2462). At the same time, the agency issued a draft-guidance "INDs-Approaches to Complying with CGMP during Phase 1." The guidance is available from the FDA Web site, The FDA action is "...intended to streamline and promote the drug development process, while ensuring the safety and quality of the earliest stage investigational drug products, those intended for use in Phase 1 clinical trials."

The new rule and the guidance provide an approach to establishing manufacturing controls for drugs at this stage of development. The need for cGMP compliance of investigational materials was established in 1978 when the cGMPs were issued (Federal Register Vol. 43, Sept. 29, 1978, pages 45014 to 45029, preamble comment # 49). In 1991, the FDA issued a "Guideline on the Preparation of Investigational New Drug Products" (human and animal). However, the guideline did not consider the variety of manufacturing facilities, small-scale or even laboratory-scale, that are used to produce Phase 1 investigational drug products.

The new rule adds a paragraph (c) to section 210.2 indicates that "(c) an investigational drug for use in a Phase 1 study, as defined in Sec. 312.21(a) of this chapter [21 CFR], is subject to the statutory requirements set forth at 21 U.S.C. 351 (a) (2) (B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter. However, this exemption does not apply to an investigational drug for use in a Phase 1 study once the investigational drug has been made available for use by or for the sponsor in a Phase 2 or Phase 3 study, as defined in Sec. 312.21(b) and (c) of this chapter, or the drug has been lawfully marketed. If the investigational drug has been made available in a Phase 2 or Phase 3 study or the drug has been lawfully marketed, the drug for use in the Phase 1 study must comply with part 211."

It is clear that at this time Phase 2 and Phase 3 investigational drugs must comply with the cGMPs for drug products, although the FDA has indicated that it is "considering additional guidance and regulations to clarify the agency's expecta tions with regard to fulfilling cGMP requirements when producing investigational drugs for Phase 2 and Phase 3 clinical studies."

The guidance presents the FDA's current thinking about controls for special production situations like a laboratory setting, exploratory studies, multi-product and multi-batch testing of investigational new drugs manufactured for use during Phase 1 trials. It recognizes "that some controls and the extent of controls needed to achieve appropriate product quality differ not only between investigational and commercial manufacture, but also among the various phases of clinical studies."

Provisions of the New Guidance

Appropriate quality control procedures in effect during product development maintain the quality and safety of investigational drug products. Therefore, the QC procedures must be written and well defined; adequate to control equipment; and ensure that data from production and testing are accurately and consistently recorded.

The sponsors/producers of the investigational drug are responsible for the safety, identity, strength, quality and purity of the drug and it is up to them to develop the QC procedures that will ensure those parameters.

The agency suggests that a number of technologies and resources are available to facilitate conformance with cGMPs. Those resources include the use of disposable equipment and process aids that reduce cleaning burden; prepackaged water-for-injection (WFI) and pre-sterilized containers that can eliminate the need for additional equipment or qualification of existing equipment; processing equipment that is closed to minimize cross-contamination and alleviate the need for stricter classification of room air quality; contract or shared production facilities and testing laboratories for production and testing of investigational product.

The sponsor, according to FDA, should also undertake a formal evaluation of the production environment to identify potential hazards and to take appropriate actions prior to and during production to minimize risks and ensure the quality of the investigational product. Special considerations should be given to the possibility of product contamination or cross-contamination with other substances, chemical, biological, viral or microbiological, that may be present from previous or concurrent research or production activities.

Training, Components and Production

Although strict compliance with Section 211 is not required for investigational drugs, the guidance makes it clear that some of the familiar provisions of cGMP compliance should still be considered. Thus, personnel should be appropriately trained in their job responsibilities and be familiar with the QC principles and acceptable methods for complying with the statutory requirements as outline in the guidance. Facilities and equipment should be appropriately sized, clean, and prevent cross-contamination and mixups. Equipment should not be reactive, should be calibrated and properly maintained and should be documented in the production record.

Components should be handled and accepted according to written procedures and should be segregated and labeled until they have been examined or tested and released for use in production.

Components should be stored so as to protect their integrity and relevant information, e.g., receipt date, quantity in the shipment, supplier's name, component lot number, investigational product batch number, storage conditions and expiration date should be recorded. Acceptance criteria for all components should be established, and the certificate of analysis for each lot of components should be reviewed to ensure that the acceptance criteria for specified attributes are met.

Production procedures should provide a record of the production data and laboratory testing that shows the components, equipment and procedures used. The documentation should allow replication of the process. If changes in procedures or processes are used for subsequent batches, the rationale should be given. Suitable microbiological controls should be implemented and documented.

Laboratory test procedures should be scientifically-sound (specific, sensitive, and accurate) and should be reproducible. Procedures should be written and followed. Specified attributes describing the identity, strength, potency, purity and quality of the investigational drug product should be monitored and applied appropriately. Laboratory equipment should be calibrated and be maintained following written procedures. System suitability testing should be performed on equipment to ensure that it is operating properly.

Samples of each batch, twice the quantity to perform the release testing (excluding pyrogenicity and sterility), should be maintained if possible for at least two years following study termination or withdrawal of the IND application under which the investigational drug was used. Stability testing of representative samples of the new drug should be performed to ensure the quality of the drug product that is being used in the clinic.

Responsibilities Defined

The key to compliance with the guideline and to product safety and quality lies in the written QC plan that the sponsor/producer establishes and follows. The guidance indicates that a sound QC plan should provide for the following responsibilities:

  • Examining the various components used in the production of a product (e.g., containers, closures, in-process materials, packaging materials, and labeling) to ensure that they are appropriate and meet defined, relevant quality standards;

  • Reviewing and approving of production procedures, testing procedures, and acceptance criteria;

  • Releasing or rejecting each clinical batch based upon cumulative review of completed production records and other relevant information (e.g., procedures were followed, product tests performed appropriately, acceptance criteria met);

  • Investigating and initiating corrective action if unexpected results or errors occur during production.

QC responsibilities should be independent of production responsibilities. If it is necessary for testing to be performed by production personnel, adequate controls that segregate the testing from production so as to prevent contamination or negatively affect test results should be in place. Depending on the size and structure of the organization, all QC functions could be performed by the same person, and it may be justifiable to have one person perform both production and QC operations, including release or rejection of each batch. In that situation, another qualified person who is not involved in production should periodically review the production records. Not surprisingly, quality should be the responsibility of all personnel involved in manufacturing.

Recordkeeping should include complete documentation of the quality and operation of the production processes, including all QC functions, equipment maintenance and calibration; and production, related analytical test distribution and component records.

The records must be retained for at least two years after a marketing application is approved for the drug or until two years after shipment and delivery of the drug for investigational use is discontinued and FDA is notified, if an application is not approved for the drug. �

Efrem Zaret, Ph.D., president of EZ Associates Inc. (Washington, N.J.), consults in GMP compliance and training, quality assurance and control, clinical supplies, logistics, regulatory affairs and product and package development. Reach him at 908-531-8148

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