With the passage of the Dietary Supplement Health and Education Act of 1994 (DSHEA) and the subsequent adoption of the Code of Federal Regulations 21 CFR 111 and related chapters, the onus of proof for product potency, purity and viability at the end of assigned shelf life is now statutorily regulated—and the responsibility falls squarely on the shoulders of the manufacturing company—and in many instances, on the brands that purchase from the manufacturer under contract. Consequently, failure to conduct an audit on a potential contract manufacturing partner is essentially not a good practice.
What does an audit entail? To begin with, a customer should be well acquainted with the laws and regulations of the land, which are found in the federal register. Many of these are basic, such as licensure for the facility, registration of the facility, the existence of written policies and procedures that make up the day-to-day operational governance of the company, and finally, issues of personnel training and the quality attributes of the product in question.
Some of the basic questions on a punch-list that every manufacturer should have at their immediate disposal in terms of written answers are:
1. The full name of the company, its ownership and legal domicile.
2. The addresses of the manufacturing company plants that will be involved in production of the finished products.
3. Copies of regulatory filings, licenses, and certificates from local health departments and other municipal and state agencies.
4. Copies of foreign regulatory licensures or certifications from international authorities, such as the Australian Therapeutic Goods Administration (TGA) or Health Canada’s Natural and Non-prescription Health Products Directorate (NNHPD).
5. An organization chart dealing with the plant or plant(s) that will be making the product.
6. Copies of any FDA 483s or warning letters received in the past five years by the company along with copies of responses, redacted as appropriate to preserve confidentiality of other customer names and trade secret data.
7. Written standard operating procedure (SOP) manuals, along with up-to-date indexes and reference documents. This should be made available to the inspector conducting the audit at the beginning of the audit, and will be utilized by an auditor to verify the manufacturer is following actions enumerated in the document.
8. Written procedures for conducting an out-of-specification review, and determining disposition of materials or finished products that are out of specification.
9. Outside certifications by third-party auditors, such as certifications from NSF, UL, Fresenius, etc.
10. A facility diagram showing areas of operation under control of the SOPs. This is often overlooked by companies, and is an indication that careful attention to detail may be missing in other steps of the operation.
11. A list of key operating equipment and capacities.
12. A list of laboratory equipment and capabilities, along with an organization chart of the laboratory personnel.
Under 21 CFR 111, raw materials are no longer acceptable at face value by companies engaged in production of finished dosage forms of capsules, tablets, powders or liquid dietary supplements. This means raw material identity must be conducted or a statistical plan for acceptance based on other recognized criteria must be presented and defended by the company should the inquiry arise. Testing raw materials for identity against reference standards also means the company must have a means for securing reference standards acceptable to government agencies in terms of their authenticity. Having a Fourier transform infrared (FTIR) spectroscopy or Fourier transform near-infrared (FT-NIR) spectroscopy fingerprint measured against prior receipts is not satisfactory. The “fingerprint" that is being matched must be to an independent reference standard that has been authenticated and meets the requirements for suitability under the law.
No longer does a small room with some beakers and flasks and a warming plate with stirring apparatus cut it as an operational laboratory. Companies are required to demonstrate a process and have adequate equipment and personnel who have been properly trained conduct tests to ascertain if the material is what it claims to be. The simple failure to have this capability has led to dozens of form 483s being issued and subsequent warning letters being generated by the agency.
Depending on the nature of the finished products, careful attention must also be paid to handling allergens in terms of segregation, testing and labeling of finished goods to reflect the potential risk to sensitive customers. Likewise, the element of microbiological contamination must also be carefully monitored. Pathogenic bacteria such as salmonella and E. coli are responsible for outbreaks of foodborne illness. Since many materials are natural, high bio-burden may be inherent or may be introduced due to mishandling. Growing, harvesting and handling practices vary around the world, thus special care must be taken to qualify the supply chain and ensure the safety of the products being utilized in manufacturing. Failure to evaluate microbiological contents of finished products or even the starting raw materials has led to more than one expensive recall.
Audits of manufacturing plants look for organization in the facility and a rational linear flow of materials. Companies whose facilities have grown over the years often have “made do" with somewhat illogical segregation of processes, which may contribute to cross-contamination of products.
The quality of the production process must be evaluated in terms of the batch record. Careful attention to the generation of this document, involving the various disciplines of research and development (R&D), pilot work, stability testing both in real time and on an accelerated basis—in addition to the educational requirements for key positions held in the company—are a requisite for a solid audit interface.
The days of relying on certificates of analysis (CoAs) provided by raw-material vendors as the sole arbiter of material identification are over. Likewise, as a client of a manufacturing firm, one should insist on understanding fully how products that are being produced by a prospective supplier are being made and tested. The brand holder should understand the nature of the test, the equipment utilized, the schedule for calibration and the level of education of the people in the laboratory.
Spending time and resources at the front end of the dialogue with a potential supplier pays off in the end by helping to avoid common pitfalls or misunderstandings. Contract manufacturing firms should not greet the request for an audit with the same level of angst often encountered when receiving an audit notice from the IRS. An audit is the time for contract manufacturers to demonstrate their dedication to excellence. The audit will serve as an invaluable opportunity for the finished brand holder to glean an understanding of the production process, associated risks and all the mitigating controls the manufacturing firm has employed to ensure the safety, quality and compliance of finished product.
Mark A. LeDoux is founder, chairman and CEO of Natural Alternatives International (nai-online.com) Inc., an organization with world-renowned facilities in the United States and Switzerland engaged in the research, design and manufacture of nutritional supplement programs and products for multinational clients. He is immediate past chair of the Council for Responsible Nutrition (CRN) and current chairman of CRN-International. LeDoux has been a proud member of the Natural Products Association (NPA) since 1980 and serves on its board of directors. He is also a recognized participant of the Codex Alimentarius Commission, the United Nations' food and dietary supplement standard-setting body under joint supervision of its Food and Agriculture Organization and World Health Organization (WHO). LeDoux is president of the Marie A. LeDoux Charitable Foundation and a member of the Young Presidents' Organization graduates.