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.
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 modified rules?
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,