On June 25, 2007, the Food and Drug Administration (FDA) published its final rule, 21 CFR 111: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. The FDA established a compliance date of June 25, 2008. However, for businesses employing 20-500 full-time employees, it established a compliance date of June 25, 2009, and for businesses that employ less than 20 full-time employees, June 25, 2010.
As the 483 dust settled during the three years following its publication of 21 CFR 111,
the Agency moved into the current Warning Letter phase. It began with a trickle, beginning with one Warning Letter in March 2010 and another in June 2010. Then, beginning in October 2010, the Agency’s issuance of Warning Letters ramped up. Below is a graphical representation of the average number of Warning Letters issued per month since 2010. It is now issuing Warning Letters at nearly five times the rate it did in 2010, with more than one per week on average.
Prior to 21 CFR 111, dietary supplements were regarded as food. In its preamble to 21 CFR 111, the FDA stated: “The agency has implemented separate, and more specific, CGMPs for various types of food products to provide for process controls in manufacturing that are not captured by the more general part 110 food CGMPs.” Despite the period following the FDA’s proposed rule on March 13, 2003, including an extensive outreach program until implementation on June 25, 2007, many firms in the dietary supplement manufacturing sector have demonstrated their inability or unwillingness to comply.
I performed an in-depth review of all dietary supplement Warning Letters since 2010. Specifically, the number of 21 CFR 111 sections cited in the Letters was evaluated and compiled. Not surprisingly, process controls (Subpart E) and master manufacturing and batch production records (Subparts H and I, respectively), among other Quality Systems, were severely lacking. The chart below shows that nearly two-thirds of Warning Letter citations fall within these areas.
The data show that the Agency is currently focusing on process controls and records. Increased scrutiny has begun in the areas of Quality Assurance authority and responsibilities (Subpart F) and equipment/utensils contamination control (Subpart D). It is clear from my analysis of Warning Letters that QA’s role in governing cGMP compliance is chronically inadequate. It is also clear that the Agency has begun to set its sights on contamination control.
The FDA has begun its injunction and seizure phase. Consider this… The Department of Justice recently granted a consent decree of permanent injunction against Kabco Pharmaceuticals Inc. on Long Island (http://www.justice.gov/opa/pr/2013/April/13-civ-391.html). Although I cannot independently verify, several dietary supplement manufacturers on Long Island that I’ve audited since April 8, 2013, recounted the same story: on or about April 11, 2013, armed Federal Marshals accompanied by a S.W.A.T. team descended on the company. With such a demonstration of “shock and awe”, there can be no doubt that the Agency is serious about enforcing cGMP compliance.
I have performed over 100 audits of dietary supplement manufacturers during the past three years. As someone with more than 25 years of cGMP experience, primarily in the pharmaceutical and biotechnology sectors, I am all-too-frequently surprised how poorly these manufacturers understand the current regulatory environment. And, as someone with extensive QC Microbiology experience, and based upon my analysis of dietary supplement Warning Letters and my experience in the field, the FDA will undoubtedly soon be focusing on contamination control.
I can performed a comprehensive gap analysis of all areas of compliance to 21 CFR 111, and provide consulting services to close these gaps. You may procure my consulting services by contacting The Microbiology Network Inc. at: http://www.microbiologynetwork.com/contact.asp. I also plan to author a more in-depth article on current regulatory enforcement trends in an upcoming PMF Newsletter. You can subscribe free of charge at: http://www.microbiologyforum.com/.