GMP Guidance For Phase I IND Trials Will Benefit Drug Manufacturers, Labs

Manufacturers and laboratories producing investigational new drugs in Phase I studies are exempt from having to fully validate their manufacturing process under new FDA guidelines.

FDA's Jan. 12 ¹ draft guidance, "INDs - Approaches to Complying with Current Good Manufacturing Practices During Phase I," and a related ² direct final rule on IND GMPs, specifies that "the particular requirements in [21 CFR Part 211] need not be met for most exploratory products manufactured for use during Phase I clinical trials."

The exemption differentiates between small-scale laboratory production of investigational human drug products (including biologics) and large-scale commercial manufacture of pharmaceuticals. FDA amended 21 CFR Part 210 in its cGMP requirements to excuse drug and chemical manufacturers and laboratories from having to comply with Part 211.

"FDA believes this change in the cGMP regulations...is appropriate because many of the issues presented by the production of investigational drugs intended for use in relatively small Phase I clinical trials are different from issues presented by the production of drug products for use in the larger Phase II and Phase III clinical trials for commercial marketing," the direct final rule states.

During a Jan. 12 teleconference, FDA Deputy Commissioner for Operations Janet Woodcock said the new GMP guidelines are part of the agency's "Product Quality for the 21st Century" initiative to mend FDA's "one-size-fits-all approach to manufacturing."

"The regulations were written with factories in mind....The regulations really didn't fit laboratory production," Woodcock said.

The "direct final rule...allows FDA for the first time to give direction and advice to researchers on how to safely prepare and produce small quantities in the laboratory which then can be used in people."

The direct rule, under Part 211 exemptions, also excuses sponsors producing small batches of investigational drugs from having to rotate the stock for drug product containers, repackage and re-label drug products, and separate packaging and production areas.

These requirements are "not generally concerns for these very limited production of investigational drug products used in Phase I clinical trial," the direct final rule says.

The exemptions do not extend to Phase II and III trials, however. If an investigational agent has progressed to the later stages of development, then sponsors are "demonstrating an intent to expose more subjects to the investigational drug;" therefore, the drug will be required to meet cGMP regs and comply with Part 211.

Additionally, every IND will need to meet FDA's standards for safety, quality and purity characteristics.

The agency can place on clinical hold, terminate, seize or enjoin the production of an investigational agent if its "production does not occur under conditions sufficient to ensure the identity, strength, quality, and purity of the drug, which may adversely affect its safety."

In conjunction with the Jan. 12 release of the IND GMP draft guidance and direct final rule, FDA also released a ³ final guidance, "Exploratory Investigational New Drug Studies," granting researchers more flexibility to conduct micro-dose studies in human subjects (⁴ , p. 3).

The exploratory IND final guidance, along with the GMP documents, are part of FDA's Critical Path initiative to streamline drug development through early identification of promising new therapies.

"Putting these pieces together, the GMP and the exploratory IND, we hope to stimulate scientific study of new laboratory discoveries in light that it hasn't really been happening in the past. We think that this will help translate new discoveries into the hands of doctors and patients," Woodcock said.

She noted that the GMP guidelines will "really help with the safety of laboratory production...and be especially valuable for academic and NIH researchers and medical schools...who don't have large factories and facilities at their disposal."

National Cancer Institute Deputy Director of Advanced Technologies & Strategic Partnerships Anna Barker said the new guidances and regulations for IND studies will also be a boon for the commercial sector due to enhanced collaboration between academia, government and industry in early stages of drug development.

While "FDA lacks data to estimate the extent of cost savings...some manufacturers may realize savings because they no longer must meet certain requirements," the agency notes in the direct final rule.

"The savings to drug manufacturers that produce the Phase I drugs in-house will vary greatly from product to product," FDA said.

For manufacturers, cost savings at the level of testing and analyzing components and in-process materials can range from $50 to $1,200 per tested component.

The direct rule also stands to encourage large manufacturers to produce investigational agents in-house, instead of contracting out the work.

For large manufacturers, in-house production of investigational Phase I drugs would incur additional savings of approximately $129,600 per year or $1,440 per IND from reduced standard operation procedures and validation requirements.

In-house production can save large firms between 24 and 40 hours per IND.

However, the regs may mean increased hours for chemical manufacturers and laboratories in developing SOPs for quality, process and procedural controls.

"We estimate that an additional 12 to 24 hours may be required for these activities depending on the experience of the entity and its employees with our current cGMP rule," FDA notes.

The cost to chemical manufacturers and labs based on increased work hours would total $133,650 annually or $810 per IND.

The direct final rule's exemption from Part 210 and 211 will also reduce the Office of Management & Budget's review burden by 6%, from 848,625 hours to 798,132 hours.