Early CGMP Guidance

Posing a question to members of our Editorial Advisory Board

What impact will the FDA’s new cGMP guidance have on the CMO & contract services industry?

The concept of microdosing has been endorsed by FDA for many years. The current guidance broadens the discussion from primarily one involving radiolabeled compounds (about the only way it could be done until recently) to one covering any compound. New technologies such as the more sensitive mass spectrometers, and specialized techniques such as accelerator mass spectrometry, make many of these studies feasible now.

The guidance will provide the ability to obtain some limited data early, which can help in the final selection of a drug candidate. Perhaps the biggest gain will be for academic institutions, since the guidance is not likely to radically change the approach large companies are taking to drug development. These studies could put a strain on the CRO industry, since the levels of detection of the methods needed to measure the drug in these studies will be very low. This will open up issues as to whether the methods should meet the acceptance criteria laid out in the current FDA bioanalytical guidance, or if more relaxed criteria are appropriate. This is uncharted territory, and I suspect that most groups will go slowly as they explore the boundaries of what is allowed and weigh the gains against the information to be gained and the time it takes to do these exploratory studies.

—Name withheld by request


I think the FDA’s new cGMP guidance will even out the playing field in the CMO industry as manufacturers try to comply by implementing quality control and quality assurance programs to close existing gaps. All customers indicate that quality and compliance are the primary qualifiers when selecting a CMO, however there are varying degrees of quality which, at the higher end, increase cost but provide greater security of supply. Therefore, as CMOs implement their programs they will also be increasing their costs, potentially bringing CMO pricing more in line across companies.

—Terry Novak, DSM Pharma


I’m not involved in producing API, but I strongly ascribe to the notion of faster in animal and faster in people to get a quick read on PK parameters below optimum therapeutic dose. With modern mass spectrometry one can often get a few hours of PK info with a 1 mg dose. Currently, going down to microgram doses in humans is going to be very rarely sensible. While interesting things can be done with accelerator mass spectrometry, that process can be too slow and too costly. The risk with an acute mg dose in humans is extremely low, as long as equivalent doses of 100 or, better, 500 times higher have not lead to acute toxicology in a couple of animal species. Judgment by wise people is required. The problem is many of us have clouded judgment or bias either due to medical or financial influences. I do not have a solution to this bias. One interesting solution would be that those who make such judgments themselves be the participants in the first human dose. That’s how it was done early in the 20th century.

At the end of the day, this approach is only good to cancel a project. If it is to go forward, all the conventional things will have to be done in any case. A criterion that may be good for failing is not likely to be good for passing! Some will then say, “Why bother?”

—Pete Kissinger, Ph.D., Bioanalytical Systems, Inc.


FDA’s new cGMP guidance should have no real impact on either a client or contractor’s ability to manufacture and release materials for Phase I clinical trials. They have assembled an outline that closely approximates what it takes for client companies and contractors to collaborate on the make/test/release process for initial clinical supplies. The guidance does not make absolute statements and allows some flexibility. For less mature client companies with less resources/experience in cGMP, this is a guidance that can help them understand the scope of work required for them and their CMO.

—Jack Regan, Corgentech


FDA’s new guidance on making early drug development activities under the same cGMP regulations should be very positive for the CMO and contract service industry. It is well known that more and more new molecules are being developed by the drug companies, so contract service providers with potent compound-handling capabilities will benefit from this regulation. There will also be the tendency in the Pharma industry not to “contaminate” their own equipment and areas and be saddled with cleaning issues and potential safety risks to their employees, if they can find a contract clinical developer who can take that responsibility for them. This also means that CMOs and smaller clinical development organizations will have to have fairly strong analytical groups well equipped to handle cleaning validation/verification services.

—Dilip M. Parikh


The new CGMP guidance draft carries with it the suggestion of potential impacts that may curtail the activities of some contract manufacturing facilities with regard to larger batches of early production GMP lots for clinical use. However, the same guidance could allow for substantially more projects underway at any given time if adequate, but limited production space becomes available. Of special interest is the potential for minimal quantity production lots for use in

a)    clinical screening studies under an exploratory IND with as many as five drugs administered, and

b)    minimal dosing amounts described as “microdose studies” where less than 1% of the calculated pharmacologically effective dose could be given up to 100 micrograms.

The guidance appears to basically uphold the requirements for production facility responsibility for reasonable controls, documentation and certification of standards of safety, identity, strength, quality and purity. Risk assessment of the methodology will become of paramount importance.

This new approach could prove to be very helpful in exploring preliminary metabolism of related members of a series of NCEs as FDA’s other guidances place greater emphasis on a better understanding of the metabolic fate of drug substances, and the potential for toxicity of key and prevalent biotransformation products.

Larger scale early CGMP production lots may shrink in size and, interestingly, larger amounts of material produced may be consumed for quality control and characterization testing, than for the dosage form itself. This could lead to substantial increases in the number of production runs, in total, being requested of various contract sites.

As long as safety does not become an issue over the long term, this approach, if adopted, would seem to suggest potential for increased services at quality CROs capable of:

1)    limited production of quality drug substance that could enter early phase testing;

2)    reliable analytical method development and execution to quantify ever decreasing levels of drug substances/ metabolites; and

3)    creative and sophisticated approaches to identifying drug metabolites of interest in a variety of bio-matrices.

—Neil J. Lewis, Ph.D., XenoBiotic Laboratories, Inc.