Part One of this article in Functional Ingredients' April issue concluded with a reminder that documentation and record keeping are the glue of cGMP-compliant dietary supplement manufacturing. Every procedure that occurs in the production of a dietary supplement must be documented in readily accessible records. This second part in the series will discuss the importance of record-keeping.
The Final Rule on Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements (21 CFR Part 111) is divided into subsections that contain the requirements for personnel practices; design and maintenance of manufacturing facilities; equipment sanitation; controls in the production process, quality control; laboratory operations; warehousing and distribution; handling of product returns and complaints. The rule states that records must be kept for all of these activities, and concludes with an entire subsection devoted to record keeping.
The first step toward cGMP compliance is to establish written specifications for the finished product that include its components, packaging, labeling and testing. Specifications—defined standards that, when met, ensure the identity, purity, strength and composition of the dietary supplement—are the blueprint.
Specifications include ingredients and potencies declared on the product label, along with product characteristics such as tablet size and weight, hardness and dissolution time; and, for capsules, the gross and net fill weight, with acceptable ranges for variation. Specifications must also be set for tolerance limits on contaminants. Testing methods should be defined for each specification, including analytical methods used to assay the finished product for ingredient potencies.
While on the subject of finished product testing to verify label claims, the new rule provides latitude in selecting one or more specifications for batch testing. Others may be skipped, which means it is not necessary to assay every ingredient in a multi-ingredient product. Indeed, in many cases it may not be technically possible to do so if a scientifically valid method does not exist for a particular complex matrix. (The FDA does not expect manufacturers to invent analytical methods, only to utilize methods that are scientifically valid.) There is a stipulation to this: the manufacturer must make a technically sound case that compliance of the specification chosen for testing ensures that other specifications are also met. On this basis, the label claim for ingredients not assayed may be verified "by input," which means quality control personnel attest that the correct amount of those ingredients were added to the batch. Though the "by input" verification is not explicitly mentioned in the Rule, the FDA has verbally stated that it is acceptable as part of a valid testing protocol. Manufacturers may test a subset of batches, according to a statistically valid testing plan. The rule of thumb is to take the square root of the number of lots produced and add one. For example, out of every 100 lots, 11 would be tested.
Batch to batch consistency
Specifications are incorporated into the Master Manufacturing Record (MMR). The MMR is the recipe that details process controls for ensuring the dietary supplement is produced consistently and reliably from batch-to-batch. Key required elements in the MMR include the product name, strength and concentration for each batch size; the identity, weight and measure of each component; statements of theoretical yield and intentional overages; sampling procedures and testing instructions; and descriptions of the package and label. The MMR must also prescribe corrective actions for batches that fall out of spec.
The central document, for verifying that a given lot was produced in compliance with cGMP, is the Batch Record. It verifies that all procedures prescribed by the MMR were carried out and verified by quality control personnel. The Batch Record provides a traceable history, without which, no one—neither the manufacturer nor the FDA—can know whether the lot conforms to specifications. In addition to the identity and weight of all components in the batch—along with two signatures verifying they were added correctly—the batch record must include the identity of equipment and processing lines, plus the date and time of cleaning and sanitation. Packaging and labels used are also recorded.
As mentioned in Part One of this two-part series, own-label distributors who outsource production to contract manufacturers bear the final responsibility for ensuring compliance of every SKU in the product line. The responsibility stops with the company whose name and brand appear on the label. All required records must be readily available when the FDA arrives for a GMP inspection.
Irfan Qureshi, ND is VP for Technical and Regulatory Affairs of AIBMR Life Sciences, Inc. http://www.aibmr.com. John R. Endres, ND is Chief Scientific Officer. Alexander G. Schauss, PhD is President and CEO. AIBMR Life Sciences offers consulting services in cGMP compliance and other technical and scientific matters to clients world-wide.