The US Food and Drug Administration has made some excellent efforts in recent years to modernize its manufacturing regulation
and guidance. However, its recent decision to move forward with its direct final rule exempting most Phase 1 investigational
drugs from complying with the regulatory cGMPs is not one of them. The rule casts too wide a net, capturing both sensible
changes and highly risky ones.
Many aspects of this rule (published in the Federal Register on July 15) and the accompanying guidance (cGMP for Phase 1 Investigational Drugs) simply codify what has already been agency practice for years. FDA leaders, speaking at conferences, have often said that
GMP requirements should be ramped up as a product progresses through clinical development, and agency enforcement has reflected
Indeed, many industry experts agree that some cGMP rules in 21 CFR 210 and 211 may not be necessary or appropriate in early development, such as the requirement for separate packaging and
production areas, as the rule mentions. It also makes sense to acknowledge, for example, that a manufacturing process will
not be fully validated at Phase 1.
The problem, however, is that in seeking to make some appropriate GMP adaptations for early development, the agency has gone
too far by relaxing quality control rules that are critical for ensuring drug safety.
The most troublesome change is the way the guidance waters down the importance of the quality control function. The document
goes so far as to say that in "very limited circumstances . . . all QC functions may be performed by the same individual(s)
performing manufacturing." This is alarming. Even in publishing, where the consequences of an error are much lower, we don't
proofread our own work.
Also missing are other important provisions from part 211, such as the requirements to validate autoclave sterilization (a
critical step to prevent patient exposure to nonsterile products) or to conduct identity checks on raw materials. Have we
already forgotten the heparin crisis of earlier this year, in which at least 149 people died?
In making important decisions, the FDA normally evaluates the balance of risks and benefits. So who will benefit from the
Large organizations, who already have robust quality systems in place, will most likely continue to follow full GMPs in Phase
1. So will many smaller companies, even if only for efficiency: Many firms manufacture a single lot for Phases 1 and 2, and
because Phase 2 drugs still must be manufactured according to full GMPs, those combined lots also must follow the strict rules.
So not much will change for these companies, either.
Thus, the primary beneficiaries of the change will be start-ups, spun out of university research environments, that are bringing
their first drugs to the clinic. Some of these companies will even be working in experimental areas like gene therapy. Those
are precisely the firms who are least likely to know what they are doing in terms of GMPs and quality control.
Annex 13 of the European GMP guidelines also acknowledges that good manufacturing practices should be "appropriate to the
stage of development of the product." Yet in contrast to the new FDA documents, the European guidance emphasizes that because
less is known about drugs in early development, quality systems are even more important at this stage. The FDA rules should
do the same.
Laura Bush is the editor in chief of BioPharm International,