FDA publishes new guidance for Phase I clinical trials.

FDA has issued a new guidance document for manufacturers of drugs used in Phase I clinical trials, replacing guidance issued 17 years ago.

The July-dated document, "Guidance for Industry: GMP for Phase I Investigational Drugs" represents FDA's current viewpoint on the application of GMPs to Phase I clinical trial drugs.

The document will replace the "Preparation of Investigational New Drug Products" guidance established in 1991, which "did not discuss all manufacturing situations, including, for example, small- or laboratory-scale manufacture of investigational products," according to FDA.

The agency said in many ways, the 1991 guidance "failed to meet FDA's expectations for safe manufacturing practices during the investigational stages of product development." Approaches described in the current document are specifically applicable to drugs manufactured for Phase I clinical trials.

FDA wrote: "This guidance applies to Phase I investigational drugs whether they are manufactured in small- or large-scale environments because Phase I clinical trials (21 CFR 312.21(a)) are typically designed to assess tolerability, or feasibility, for further development of a specific drug or biological product. Furthermore, if an investigational drug has already been manufactured by an IND sponsor for use during phase 2 or phase 3 clinical trials or has been lawfully marketed, manufacture of such a drug must comply (21 CFR 211.1) with 21 CFR Part 211 for the drug to be used in any subsequent Phase I clinical trials, irrespective of the trial size or duration of dosing. See 21 CFR 210.2(c).

Exempt from the guidance are the following Phase I investigational products:

* Human cell or tissue products regulated solely under [section] 361 of the Public Health Service Act;

* Clinical trials for products subject to the device approval or clearance provisions of the FD&C Act;

* Investigational products manufactured for phase 2 and phase 3 clinical trials;

* Already approved products that are being used during Phase I clinical trials (e.g., for a new indication);

* Positron emission Topography (PET) drugs that are subject to [section] 501(a)(2)(C) of the FD&C Act and/or the new PET GMP in 21 CFR Part 212 when finalized.

Drugs and biological products tested in Phase I investigational studies are intended to measure tolerability levels and practicality for further development. The suggestions presented in the new FDA guidance encourage drug manufacturers to thoroughly assess development and analysis sites, equipment, testing methods and documentation processes to identify potential dangers.

In applying appropriate GMPs, FDA said it recommends "that manufacturers consider carefully the hazards and associated risks from the manufacturing environment that might adversely affect the quality of a Phase I investigational drug, especially when the Phase I investigational drug is manufactured in laboratory facilities that are not expressly or solely designed for their manufacture.

"For example, of particular importance is the susceptibility of a Phase I investigational drug to contamination or cross contamination with other substances (e.g., chemicals, biologicals, adventitious agents) that may be present from previous or concurrent research or manufacturing activities."

The agency recommended the following steps to establish the appropriate manufacturing environment for Phase I investigational drugs:

* A comprehensive and systematic evaluation of the manufacturing setting (i.e., product environment, equipment, process, personnel, materials) to identify potential hazards;

* Appropriate actions prior to and during manufacturing to eliminate or mitigate potential hazards to safeguard the quality of the Phase I investigational drug. Any manufacturing environment, including a laboratory, should have adequate work areas that are properly equipped and controlled for the specific operation(s) needed to manufacture a Phase I investigatio drug."

As indicated in the document, manufacturers are expected to implement and maintain high quality regulations, adopt a willingness to evolve policies and procedures as needed and ensure controls are robust enough to be product-specific:

The document added: "Consistent with FDA's 'GMPs for the 21 Century initiative,' where applicable, manufacturers are also expected to implement manufacturing controls that reflect product and manufacturing considerations, evolving process and product knowledge, and manufacturing experience."

By addressing the variation of product controls between investigational phases and commercial manufacturing, the guidance promotes consistency throughout all stages of drug development and production to protect the safety of human subjects. Recommendations for safe and effective use of Phase I investigational drugs, including quality controls, record keeping and personnel regulations are also outlined.

The 1991 guidance will remain applicable to the manufacture of investigational drugs for use during Phase II and III clinical trials, and for the manufacture of non-exempt Phase I investigational drugs.

FDA said the new guidance is being published in accordance with a final ruling that drug manufacturers specializing in product development for Phase I clinical trials are not required to comply with the outlined strategies for prudent manufacturing processes.

However, manufacturers must be prepared to consult resources and seek out applicable information beyond the industry guidance in order to fully comply with GMP requirements. As stated in the FDA guidance:

"During product development, the quality and safety of Phase I investigational drugs are maintained, in part, by having appropriate QC procedures in effect.

Using established or standardized QC procedures and following appropriate GMP will also facilitate the manufacture of equivalent or comparable IND product for future clinical trials as needed. Adherence to GMPs during manufacture of Phase I investigational drugs occurs mostly through:

* Well-defined, written procedures;

* Adequately controlled equipment and manufacturing environment;

* Accurately and consistently recorded data from manufacturing (including testing).

FDA said manufacturers may have acceptable alternatives to meet the objectives described in this guidance, but added: "It is the manufacturer's responsibility to provide and use such methods, facilities, and manufacturing controls to ensure that the Phase I investigational drug meets appropriate standards of safety, identity, strength, quality, and purity."

Carrie Nathans, Special Correspondent (CMC)