For a number of years, many dietary supplements have been produced by contract manufacturers. As manufacturing processes become more sophisticated (e.g., complex probiotics) and FDA regulatory requirements continue to expand, it becomes more cost effective to use the knowledge, experience and expertise of contract manufacturers to produce these products. Due to increased costs in manufacturing and testing equipment, many companies find it is a more economical option.
Entering into a partnership with a contract manufacturer can offer many advantages. However, it also presents several challenges to ensure the products are being manufactured in accordance with all applicable laws and regulations. The following statement is often seen in warning letters regarding the manufacturing of dietary supplements.
“In cases where a distributor contracts with a manufacturer to manufacture a dietary supplement that the distributor then distributes under its own label, the distributor has an obligation to know what and how manufacturing activities are performed so that the distributor can make decisions related to whether the packaged and labeled product conforms to its established specifications and whether to approve and release the product for distribution.”
In addition to that FDA statement, court cases such as U.S. vs Dotterweich and U.S. vs Park clearly establish corporate officials must “devise whatever measures are necessary to ensure compliance with the Food, Drug and Cosmetic Act.” (from the Park case).
Some of the compliance issues identified by FDA and EAS consultants—and strategies the firm recommends for compliance—follow.
Contract Manufacturers’ Findings
FDA dietary supplement cGMP (current good manufacturing practice regulations in Title 21 of the Code of Federal Regulations (CFR), Part 111, “Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements,” were published in 2007. When looking at recent statistics for warning letters issued to the industry, the following were most often observed:
- 21 CFR Part 111.75, Testing
- 21 CFR Part 111.70, Specifications
- 21 CFR Part 111.205, Master Manufacturing Records
- 21 CFR Part 111.255, Batch Production Records
- 21 CFR Part 111.103, Quality Unit Operations
- 21 CFR Part 111.553, Product Complaints
- 21 CFR Part 111.453, Holding and Distribution
While this data is from all FDA inspections, the list is the same when looking solely at contract manufacturers. Interestingly, since 2008 or 2010, when most data collection began, no change has occurred in the priority order of observations. This suggests a need to change how monitoring and compliance is evaluated and achieved.
A supplement brand must develop a compliance plan and strategy to ensure a contract manufacturer is cGMP-compliant. The typical approach in the industry has been to have a written plan, or standard operating procedure (SOP), for the qualification of contract manufacturers. That plan has usually included the use of a quality questionnaire, followed by an onsite audit to observe and document how products are produced, controlled and tested. Certainly, these activities must continue. However, it’s important to think about the following as a company develops its own plan:
- Verify an onsite audit plan has emphasis on the aforementioned areas commonly cited by FDA in inspections and warning letters.
- Consider this relationship as being on a team. Both members of the team have strengths and weaknesses. Explore them, make sure they are understood and ensure both sides have the necessary knowledge, skills and abilities to comply.
- Teams must communicate. Confirm communication plans are in place and understood by both parties.
- Both sides have a responsibility for compliance. Make sure both sides understand which parts of compliance they are responsible for and systems are in place and monitored to ensure compliance. A quality agreement must be adopted to define these responsibilities.
- Verify specifications are written for all materials and finished products and both parties have reviewed and approved them for all products.
- The contract manufacturer must make available critical documents needed to verify compliance (specifications, master batch records, completed batch records, laboratory test results, investigations).
- All required SOPs must be in place and staff trained on them.
- Production and laboratory staff must have been thoroughly trained on the cGMP requirements. EAS finds the most common reason staff make mistakes is they were not fully trained on procedures or did not understand procedures, regulations and requirements.
- Conduct as many follow-up audits and visits as necessary to show due diligence and ensure compliance continues beyond just the time of an onsite audit.
In summary, the significant regulatory risks for noncompliance must be considered. While a warning letter does not put a company out of business, the adverse publicity from one can have a significant impact on the company’s bottom line. What’s more, further FDA action after a warning letter—namely an injunction—can put a company out of business. But with the proper plans and strategies, such an adverse outcome can almost always be avoided. Most warning letters in this area result from lack of knowledge, commitment or oversight.
Robert C. Fish joined EAS Consulting Group in 2006, after a decade consulting for FDA-regulated industries. He spent 33 years with FDA, the last six years of that service as director, division of field investigations (DFI) where he was responsible for general policy and guidance for the agency’s domestic and international investigation activities.