FDA official clarifies cGMP expectations for investigational drugs

The US Food and Drug Administration (FDA) does not expect sponsors to have their commercial manufacturing processes finalized and fully compliant with current good manufacturing practice (cGMP) until a product is in Phase II studies. An agency official said it expects manufacturers to learn more about their manufacturing processes as they progress through the clinical development process.

On 4 September, the Small Business and Industry Assistance (SBIA) office at the Center for Drug Evaluation and Research (CBER) held a webinar offering regulatory tips to small businesses that may not have the same regulatory experience or resources as larger companies. The speakers broadly recommended that small businesses developing new drugs familiarize themselves with FDA guidances and, if they lack in-house regulatory expertise, reach out to outside consultants who may help fill the gap. They also strongly recommended using communicating with the agency about their product development plans.

During the Q&A portion of the presentation, Paresma Patel, a division director at the Office of Product Quality Assessment, noted that one of the top questions sponsors ask regulators during discussions about chemistry, manufacturing, and controls (CMC) is at what stage they should develop processes that conform to cGMP.

Patel noted that during early interactions with sponsors, FDA does not expect companies to have developed a manufacturing process that completely follows the cGMP requirements set out in the 21 CFR Part 210 and 211.

“These regulations are really focused on commercial manufacturing and may not be appropriate for Phase I studies,” said Patel, noting that FDA has specific guidance on cGMP requirements for investigational drugs in Phase I studies. FDA exempted investigational drugs in Phase I studies from most cGMP requirements in 2008 to “streamline and promote” drug development, while retaining greater manufacturing oversight for investigational drugs that reach Phase II and III.

“When it comes to understanding how much of your manufacturing process should actually be conducted under cGMP, what we recommend is sponsors come in and have a CMC-focused meeting to discuss their manufacturing process to support pivotal clinical studies and ultimately, commercialization,” she added. “We recommend this prior to those pivotal clinical trials being to run, so usually at the end of Phase II is when that happens.”

Patel noted that the FDA assesses sponsors' manufacturing processes based on guidance that conforms to the International Council for Harmonisation (ICH) Q11 guideline and added that sponsors should read up on the Q&A document associated with the standard.

“Usually, for Phase I studies, we do not expect that the manufacturing process at that stage is going to be your commercial process, and typically we see a minimal number of steps under cGMP for Phase I or the first-in-human study,” said Patel. “As development nears commercialization, we see additional steps that are added or needed in order to assure that the manufacturing process meets ICH Q11 requirements.”

During her webinar talk, Patel noted that a major challenge when assessing the manufacturing aspect of a drug application is that it covers the entire product lifecycle from the investigational new drug (IND) phase to commercialization. She noted that between the preclinical phase and the IND phase, there is typically very limited information on the CMC aspects of the drug production. She added that there is significant CMC development between the pilot study and pivotal study phase, that sponsors and FDA can learn from.

“CMC development has to be at a stage to ensure consistent manufacturability to support a marketing application,” said Patel. “Following approval, the CMC information continues to change as suppliers or manufacturers may change, and the manufacturing processes may continue to be optimized.”

“Throughout this process the CMC team is meeting with sponsors to advise on key aspects of CMC development as they move closer to commercialization,” she added.

SBIA webinar

FDA official clarifies cGMP expectations for investigational drugs

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