Displaying a re-enforcement of the agency’s resolve, the U.S. Department of Justice (DOJ) prosecuted a case that found the owner and key managers of a New Jersey-based manufacturer of dietary supplements guilty of criminal contempt of court for willful violation of a consent decree driven by failure to comply with cGMPs. During an inspection performed in late 2008 and early 2009, at Quality Formulation Labs and American Sports Nutrition, Inc., multiple violations of cGMPs were noted, including the finding of dead rodents. As a result of the legal action driven by the DOJ, the company was fined $1 million dollars and the defendants sentenced to federal prison. The sentences received by the defendants were:
- Mohamed S. Desoky: 40 months in prison, three years supervised release, and a fine of $60,000;
- Ahmad Desoky Esq.: 34 months in prison, three years supervised release, barred from practicing law during his period of supervised release, and a fine of $12,000; and
- Omar Desoky: 34 months in prison, three years supervised release.
Summary of 21 CFR, Part 111 Requirements
21 CFR, Part 111 was introduced to industry through a tiered approach for compliance. Manufacturers of dietary supplements, with a workforce of great than 500 employees, were required to comply with 21 CFR, Part 111 by June of 2008. Manufacturers with an employee base of 21 to 499 employees were required to comply with 21 CFR, Part 111 by June 2009; and small entities, with less than 21 employees, were required to comply with the new regulation by June 2010.
One of the salient requirements associated with 21 CFR, Part 111 is the need for manufacturers to perform analytical testing on products. According to Columbia Analytical Services, in some cases requirements for product purity of dietary supplements have been noted to be more stringent than pharmaceuticals. Other statutory requirements required by 21 CFR, Part 111 include: Proper employee training, hygiene, and qualifications; clean and sanitary manufacturing facility; adequate equipment suitable for the manufacturing of dietary supplements; a production and process control system supported by written procedures, records, testing, and sample collection and storage; written quality control procedures; written procedures for product packaging and labeling; creation of a Master Manufacturing Record (MMR); creation of Batch Production Record (BPR); written procedures for laboratory operations; written procedures for all manufacturing operations; written procedure(s) for product holding and distribution; written procedure(s) for handling product returns; and written procedure(s) for customer complaints.
The FDA employs warning letters as a tool to escalate serious regulatory issues. Warning letters issued to the manufacturers of dietary supplements require the immediate remediation of observations noted within the warning letter. Failure to do so can result in further regulatory action such as an injunction that forces withdraw from or preventing the entry into the U.S. dietary supplement market or a consent decree with oversight provided by the federal courts.
Common observations noted warning letters include: failure to prepare a Master Manufacturing Record (MRR); failure to test and identify dietary supplement components; failure to prepare a batch production record (BPR); and not having written procedures to support quality operations.
FDA inspections have increased as a result of the passage of the Food Safety Modernization Act (FSMA). Driving regulatory compliance with cGMPs continues to be one of the primary focuses of FDA. For example, during Q4-2011, the agency issued a total of 165 warning letters. Of these warning letters, 18 were issued to the manufactures of dietary supplements. It should be noted that 50% more warning letters were issued to the manufacturers of dietary supplements versus pharmaceutical manufacturers. According to FDA, fundamental reasons for driving the issuance of warning letters were: an inadequate response to the Form 483 observations issued during inspections and the failure to provide supporting documentation.
One of the most significant trends documented by the agency is the misbranding of dietary supplements. For example, if the manufacturer makes a claim that using the dietary supplement will reverse arterial sclerosis, then the supplement now migrates to control under 21 CFR, Part 211 as the supplement would now be considered a drug. One salient point to remember is that dietary supplements require no formal review and approval by FDA; however, pharmaceuticals do. To prevent issues associated with misbranding, the labeling for dietary supplements must be factual and not contain therapeutic cure claims. Other adverse data trends noted for manufacturers of dietary supplements include: adulteration with drug substances; illegal claims; and unsafe ingredients.
Areas FDA is Focusing On
Each year FDA focuses on certain aspects of an industry and uses inspections to drive compliance to regulations. For the dietary supplement industry, areas of increased focus include:
- Lack of master manufacturing records or significant requirements not included;
- Lack of finished product release criteria or failure to test (all or a subset of finished batches) or meet finished product release criteria critical to product safety and quality;
- For significant dietary ingredients (e.g., those that make up the bulk of the product), failure to establish specifications for incoming material or failure to conduct identity testing;
- No quality control review procedures or significant quality control procedures not implemented;
- No batch records; and
- Significant physical plant deficiencies.
In conclusion, increased enforcement efforts by FDA are forcing the manufactures of dietary supplements to comply with 21 CFR, Part 111 or face regulatory consequences. The agency has already shown its resolve by working with the Department of Justice and bringing willful violators of cGMP before the courts to atone for egregious violations.
The agency, as part of its increased vigilance, is employing the warning letter as a tool to obtain the attention of manufacturers failing to comply with all aspects of Part 111. The focus will continue to be on: product testing, MMR, BPRs, the establishment of written procedures and specifications for the testing of ingredients; lack of quality control procedures, and general facility violations.
Failure to comply with all requirements delineated within Part 111 will result in the issuance of a Form 483 observation; and may result in the issuance of a warning letter by the FDA. Failure to respond or adequately respond to Form 483 observations will definitely result in a warning letter. Failure to respond to a warning letter and the manufacturer of dietary supplements can expect time in court negotiating the terms of their consent decree. Remember, the prudent path to follow is one that results in ongoing compliance with all aspects of 21 CFR, Part 111.
Bob Mehta is principal consultant of GMP ISO Expert Services, a Los Angeles/Orange County-based consulting firm specializing in global supplier quality management, supporting quality systems for FDA and ISO regulated companies and helping with remediation of quality systems as a result of FDA’s warning letters to make the system compliant to regulatory requirements. Mr. Mehta has more than 22 years of experience in the fields of quality, regulatory compliance, regulatory and notified body inspections, supply management and risk management. He holds MSQA, MBA, B.S. (Chem), and ASQ - CSSBB, CQE, CRE, CSQE, CBA, CQA, CPA certifications. He serves on the committee of the Industry Board of Advisor for Medical Device Industry Education Consortium (MDIEC). He is heavily involved in remediating and implementing the risk-based quality systems and supplier audit program for Fortune 500 clients in a variety of industries, including food/dietary supplement, pharmaceutical, medical device and biotech.