Already in January 2006, the FDA published the draft of a Guidance for Industry intended to describe in detail the special cGMP requirements on the manufacture of investigational medicinal products for phase 1 in connection with a corresponding adaptation of 21 CFR 210 and 211. This guidance was meant to give assistance to the manufacturers in implementing the then planned legal requirements

However, after the FDA had encountered considerable contradiction to the planned new regulations, the planned changes to the CFR were withdrawn, and, for the moment, the draft guidance was abandoned.

Now the FDA is making a new attempt to implement the changes. According to the authority, the proposals of that time have been taken into account and the documents, adapted correspondingly. The note in the Federal Register of 15 July 2008 (Volume 73, No. 136) announces the adaptation of 21 CFR 210 and 211: Investigational medicinal products intended for use in phase 1 are to be exempted from complying with the "final rule". The text stresses that the cGMP requirements of 21 CFR 211 are applicable to phase 2 and phase 3 drugs. The changes are scheduled to come into force on 15 September 2008: http://www.fda.gov/cber/rules/gmpind.pdf

At the same time the revised Guidance for Industry was published under a new title. The document now titled "Guidance for Industry: cGMP for Phase 1 Investigational Drugs" describes FDA's proposals and expectations regarding the manufacture and control of phase 1 investigational medicinal products. Most of the changes are of editorial character and aim at harmonising and clarifying the wording as well as avoiding possible misunderstandings. Apart from that, the level of details has been raised. Instead of just listing the exemptions, the scope has now been defined exactly; it refers to, but is not limited to, the following products:

• Investigational recombinant and non-recombinant therapeutic products
• Vaccine products
• Allergenic products
• In vivo diagnostics
• Plasma derivative products
• Blood and blood components
• Gene therapy products
• Somatic cellular therapy products (including xenotransplantation products).

Products derived from human cells and tissue continue to be exempted.

Examples for increased or more detailed requirements compared to the draft of 2006 are:

• Environmental monitoring
• Separation of quality control and production
• Traceability
• Deviations and appropriate investigations
• Complaints
• SOPs in the fields of packaging, labelling and shipment

A comparison of the documents can be found here.
The new FDA Guidance can be found here:
http://www.fda.gov/cder/guidance/GMP Phase1IND61608.pdf

Author:
Wolfgang Schmitt
On behalf of the European Compliance Academy (ECA)