James A. Taylor, PhD
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On January 17, 2006, the FDA released new regulations, effective June 1, 2006, which affect the production of most investigational
drug and biologic products intended for phase 1 clinical trials. These regulations are much broader in scope than the Exploratory
IND guidance released on the same day, and which apply only to low-risk, CDER-regulated clinical studies.
The new regulations, which acknowledge that manufacturing controls should be appropriate to each stage of development, apply
specifically to the section of the Code of Federal Regulations (Title 21 CFR Part 211) that refers to drug product manufacturing;
they extend, by implication, to the production of active pharmaceutical ingredient (API), i.e., bulk drug substance. The new
regulations apply to phase 1 clinical trials for all drug and biological products not previously tested in a later phase of
clinical testing, but do not apply to certain cell-based products.
In essence, the FDA has eased formal GMP regulations for phase 1 studies to assist small academic and commercial manufacturers,
who have limited personnel and facilities, produce initial batches of drug product. In practice, the regulations apply more
broadly to larger contract manufacturers and sponsors in the production of API and drug product as well.
In determining where to apply the new regulations most rigidly, FDA will consider patient safety and degree of risk as key
factors, and will apply the regulations when greater risk is present. For example, the farther away the production step is
from final product, the less risk will apply (assuming no substantive safety risks are introduced at the initial stage that
cannot be removed by appropriate downstream purification). In the preparation of a sterile parenteral product, on the other
hand, FDA reviewers will show greater concern with the final aseptic processing step than in the number of steps to produce
API, the choice of a starting material, or the level of early GMP compliance.
In lieu of full GMP compliance, FDA will require manufacturers to maintain proper safety controls in the form of tentative
release criteria. The FDA will also require manufacturers to maintain a series of written procedures for all manufacturing
processes and controls; to ensure that facilities and equipment are used properly; and to maintain an accurate production
record of all phase 1 clinical supplies. FDA has issued a guidance to describe this. When limited resources exist, contract
vendors are generally best suited to support phase 1 manufacturing.
Manufacturers should not presume that FDA will permit manufacturing of phase 1 clinical supplies outside the guiding principles
of GMP regulations. Manufacturers should assume that FDA will question or audit manufacturing operations when safety concerns arise. Consultation with FDA will still
be beneficial in certain situations and perhaps can be best handled through a pre-IND meeting.
The new GMP regulations for drugs in phase1 clinical trials are based on common sense, adherence to good scientific practices,
and continuing concern for patient safety. In this setting, contract manufacturers and sponsors should do the following:
- Establish written policies and procedures if they do not already exist
- Adopt a more rigid approach towards the final steps of drug product production
- Obtain a second opinion from an experienced consultant or FDA reviewer directly, as part of a pre-IND meeting. When in doubt,
err on the side of safety.
James A. Taylor, PhD, Partner,
Merchant-Taylor International, 162 S. Rancho Santa Fe Rd., Encinitas, CA 92024, (tel) 858.675.0808. (fax) 858 675.1047, jtaylor21@comcast.net
