The dietary supplement Good Manufacturing Practice (GMP) regulation (21 CFR 111) is effective for companies with 20 or more employees, with the smallest companies due to come under the regulation soon. Inspections began last year on the largest companies and will begin to fold in the smaller companies as the law becomes effective for those organizational sizes. There have been numerous articles, seminars, Webinars and other industry educational opportunities for all of those involved in these companies to learn more about the GMP regulation details, what preparations are advised and on what aspects FDA inspectors might focus. The United Natural Products Alliance (UNPA) actually offered attendees to its May 2009 GMP seminar a chance to meet and question current FDA inspectors, in addition to other speakers detailing how to prepare for GMP compliance and future inspections. While all the education on the regulation’s finer points can help the basic foundation of compliance, there is much that can be learned from inspections that have already taken place.
If It Isn’t Written, It Doesn’t Exist; If it’s Broken, Fix It
In one inspection observations report (form 483), a dietary supplement manufacturer was told it did not establish written procedures for calibrating instruments and controls used in manufacturing or testing a component or dietary supplement. “Specifically, the firm conducts in-house calibration on all their electronic weigh scale instruments,” the inspector noted. “However, the firm does not have written standard operating procedures [SOPs] for conducting their in-house calibration operation.”
Every procedure your staff or crew undertakes has to be written down. This means every step in the manufacturing process, from releasing raw material for processing to checking the seal over plastic bottle openings.
In what might be an example of being completely unprepared, relative to written procedures, one dietary supplement manufacturer inspected in September 2009 did not did not prepare a written master manufacturing record for each unique formulation of a dietary supplement it manufactured. In addition, the inspector noted the company did not have procedures for holding and distributing operations, nor did it make and keep written procedures outlining quality control (QC) responsibilities for conducting a material review and making a disposition decision.
On the other hand, even when companies have written procedures for a certain process, they might not be thorough enough to cover all actions involved. Following one inspection, the auditor informed the dietary supplement contract manufacturer its records of examination and testing of raw materials and components did not include records of examination of finished product packaging and closures used for the dietary supplements. In another case, a juice manufacturer was given a 483 report that stated, “The written instructions in your master manufacturing did not include instructions for corrective action plans to use when specifications are not met.”
Daniel Fabricant, vice president of scientific and regulatory affairs at the Natural Products Association (NPA), which had more than a handful of its members undergo an FDA GMP inspection, echoed the 483s, saying written SOPs, master batch records and corrective action plans are some the key aspects of GMPs companies should focus on.
In fact, the 483 for the same contract manufacturer as above noted the company’s batch production records “did not include documentation that QC personnel approved and released, or rejected the packaged and labeled dietary supplement.” In addition to getting dinged for the absence of a corrective action plan in its master manufacturing record, the company also lacked sufficient documentation for production and process controls, results of testing and examinations, theoretical yields at various manufacturing stages, and periodic review of instrument calibration and controls.
The corrective action focus was evident in other 483 reports, including one where a juice/supplement manufacturer had a record of glass breakages, which it categorized as low risk, but had no record of segregating or evaluating the products after each breakage incident. There was also no corrective action plan for when the product was out of spec, such as when the pasteurization temperature or bottle core temperature did not meet spec.
