Everyone in the pharmaceutical manufacturing industry understands or has at least heard of current Good Manufacturing Practices (cGMP).  The requirements of the cGMPs are prescribed in Title 21 of the Code of Federal Regulations parts 210 and 211 (better known as 21 CFR part 210 and 211).  But there is a unique situation in which the requirements of 21 CFR 211 in the manufacture of a drug are exempt.  That is for the manufacture of Phase 1 investigational drugs.

So, how did we get here?

Section 501(2)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FC&C Act) requires drugs to comply with good manufacturing practices.  The FDA issued cGMP regulations for drug and biological products with 21 CFR parts 210 and 211.

The FDA understood that 21 CFR parts 210 and 211 were written for and directed at the manufacture of commercial batches.  These products typically are characterized as repetitive and large batches.  For several reasons, the FDA acknowledged that the production of phase 1 investigational drugs should be exempted from complying with all of the specific regulatory requirements outlined in parts 210 and 211.  So, in July 2008 the FDA issued guidance on this subject “Guidance for Industry – cGMP for Phase 1 Investigational Drugs,” and effective 15 September 2008, the FDA exempted phase 1 investigation products from the requirements of 21 CFR 211.

Excerpt from 21 CFR 210.2(c):  Applicability of current good manufacturing practice regulations.

(c) An investigational drug for use in a phase 1 study, as described in Sec. 312.21(a) of this chapter, is subject to the statutory requirements set forth in 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.

 

So, what does this mean?

Often, small pharmaceutical and biotechnology companies have their hopes riding on the success of one, maybe two, drugs.  And as is also often the case, these companies have limited funds to advance the drugs into trials.  Understanding the ramifications of this exemption and how to implement the desired manufacturing practices can save a company much time and money. 

What is a phase 1 investigational drug? 

21 CFR 312.21(a) describes phase 1 investigational trials.  Phase 1 clinical trials are typically small in size (20 to 80 patients), the patients are healthy, and the goal of the trial is to determine the metabolism and pharmacologic actions in humans, tolerability (i.e., side effects), and if possible, determine evidence of effectiveness and thus its potential for further development.  Additionally, Phase 1 trials are closely monitored by trained health care professionals. 

 

What does the FDA expect for cGMPs in the manufacture of Phase 1 investigational drugs?

The guidance document states the cGMP for the manufacture of Phase 1 investigational drugs will occur mostly through:

• Well-defined, written procedures
• Adequately controlled equipment and manufacturing environment
• Accurately and consistently recorded data from manufacturing (including testing)

What the FDA is suggesting is not to spend time and money on meeting all the requirements of 21 CFR part 211, but to spend effort, time, and money toward ensuring the equipment is functioning correctly (through a commissioning program), and develop clear and specific procedures and batch records that describe and record the manufacturing process.

In the guidance, the FDA recommends following the below two steps to establish an appropriate manufacturing environment for Phase 1 investigational drugs:

• Risk assessment: A comprehensive evaluation of the manufacturing setting (i.e., environment, equipment, process, personnel, and materials) to identify any potential hazards.
• Implement appropriate actions before and during the manufacturing to minimize or eliminate the potential hazards identified during the risk assessment.

The guidance describes the specific cGMPs for Phase 1 investigational drugs, and they are summarized below:

1. Personnel: All personnel should have the education, experience, and training (or any combination of the three) to ensure they can perform their assigned functions.
2. QC Function: Every manufacturer should have an established written plan that describes the QC responsibilities and functions.
3. Facility and Equipment: The facility used should have adequate work areas and proper equipment for the intended task. 
4. Controls of Components, and Containers and Closures: The company should have established written procedures describing the handling, review, acceptance, and control of material.
5. Manufacturing and Records: The manufacturer should follow written manufacturing and process control procedures.
6. Laboratory Controls: Laboratory tests used in the manufacturing should be scientifically sound, suitable, and reliable for the specific purpose.  The testing should be performed under controlled conditions and follow written procedures.
7. Packaging, Labeling, and Distributing: The packaging, labeling, and distribution operations should follow written procedures.  The packaging of the drug should be suitable to protect it from alteration, contamination, and damage.
8. Record Keeping: Manufacturers should keep complete records relating to the quality and operation of the manufacturing process. 

Let’s discuss the requirements for Facility and Equipment because by understanding what is expected, companies can save substantial time and cost.  What is not specified, or conversely what is exempt, is the need to ‘qualify’ the facility and equipment.  Through the use of the risk assessment, justification for facility and equipment commissioning can and should be justified.  The outcome of the risk assessment will drive the risk-reduction steps and necessary testing of facility and equipment.  The expected outcome is a solid commissioning program that tests equipment to ensure it is can reliably maintain environmental and process manufacturing conditions. This will result in a large savings of time and money over a qualification effort.

In summary, the FDA has allowed for an exemption to the cGMPs of 21 CFR part 211 for the manufacture of Phase 1 investigational drugs.  The FDA recommends a subset of those requirements, based on a risk-based approach that relies on procedures, facilities, and equipment that provide for the safe manufacture of the drug.  The FDA realizes that Phase 1 drugs are in their infancy and are investigational; the FDA wants the companies to spend their time and effort on ensuring a safe and well-documented manufacturing process, and it does not want to hinder the development of drugs due to manufacturing regulations. 

Companies that embrace this method of operation can use their limited time and financial resources for developmental activities that represent the most risk to the patient.

 

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About the Author

Daniel Carpenito has over 31 years of experience in process engineering, commissioning, project management, validation, and quality assurance.  His broad client experience ranges from small research sites to large biotech and pharmaceutical facilities to contract manufacturers.