Upcoming Issue Highlights
Home Subscribe Advertise Sourcebook Free Product Info Home

FDA GMP Inspections Return to Pre-COVID Levels

Albion Minerals®
GMP Inspection GMP Inspection

Supplement industry compliance struggles remain.

Data recently released by FDA (U.S. Food and Drug Administration) indicates that for the second year in a row, the number of dietary supplement current good manufacturing practices (cGMP) related inspections of dietary facilities remains steady following a severe decline in 2020 and 2021 because of the global pandemic. Consistent with pre-COVID-19 data, nearly one-half of inspections of domestic (U.S.-based) firms resulting in the issuance of an FDA Form 483—Notice of Inspectional Observations—calling on the firms in question to provide a formal response to citations of potential violations of the cGMP regulations (found in Title 21, part 111 of the Code of Federal Regulations). And, consistent with pre-COVID data, failure to establish appropriate product specifications is by far the leading violation found by FDA investigators.

As we approach the 30th anniversary of The Dietary Supplement Health and Education Act of 1994 (DSHEA) which mandated the FDA promulgate cGMP regulations, this data brings several questions to mind. How did it take FDA 13 years to publish a cGMP regulation that 14 years after becoming fully effective (yes, that is a total of 27 years) that nearly one-half of regulated industry still cannot comply with? Is there a problem with the regulation? Is there a problem with industry? How is it that the same sections of the cGMP regulations are the most frequently cited in Form 483s year after year? What is it that the industry is not grasping about the requirement that it establish specifications for its products and ensure that those specifications are met for every product run?

It is vitally important that these GMP issues are of concern to companies who distribute products under their own label but contract out manufacturing to third parties. Indeed, FDA’s Small Entity Compliance Guide: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements provides that:

A distributor who contracts with a manufacturer to manufacture a dietary supplement, which the distributor then distributes under its own label, 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.

What are specifications? They are the most frequently cited source of enforced regulatory requirement of dietary supplement cGMPs dictated in 21 CFR 111, cGMP in Manufacturing, Packaging, Labeling or Holding Operations for Dietary Supplements, by FDA. Since 2010, when the cGMP requirements became affective for all the dietary supplement industry, the failure to establish specifications as required in 21 CFR 111.70 has been a constant source of consternation. In accordance to 21 CFR 111.70(a)-(g) specifications must be established for any point, step or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record (MMR), including specifications for each component (raw material), in-process material, packaging component, label (and labeling), finished product, and the final packaged and labeled finished product. A specification, established by the International Conference on Harmonization (ICH), is comprised of, at least, an assigned test parameter; acceptance criteria for the test; and a specific, designated and scientifically valid test method. The regulations further require documentation explaining why meeting the established specifications will ensure the quality of the finished dietary supplement in terms of identity, purity, strength, composition and limits of potential contaminants. In other words, a properly designed specification should be designed to describe exactly what a product (or component thereof) is supposed to be as supported by scientifically valid testing.

Why is this so challenging for the industry? The fact is that appropriately establishing these various specifications requires a significant amount of knowledge about the intended product label claims, product formulation, and manufacturing and packaging processes, as well as scientific expertise regarding the dietary ingredients, test methodologies, and product stability. In addition, specifications are fundamental cGMP documents that must be developed and implemented using a well-defined and controlled process that is part of a broader and comprehensive quality management system (QMS). QMS processes and documents all require the review and approval of an independent quality unit (QU) to adhere to the general cGMP principle of “quality by design” and the application of a check and balance system.

Specification Documents

Raw material, in-process and finished product specifications must individually address the categories of identity, purity, strength, composition and limits of potential contaminants. Packaging component specifications must evaluate safety, suitability for intended use, and reactivity and absorptivity. All these specifications must then work together to holistically ensure the safety and quality of the finished dietary supplement and that all product label claims, defined on the label specification, will be met. Label claim requirements are provided in 21 CFR 101, Food Labeling, and apply to both nutrient content claims and structure / function claims. The establishment of any specification must, therefore, always be considered in the context of the intended product label claims.

An understanding of the product formulation is also vital to the establishment of specifications because the chemical form and presence of potential contaminants in the ingredients will determine the potential contaminants in the finished product. The concentration of the ingredient and chemical constituents, and amount of the ingredient formulated into the product are the primary factor for determining whether the product label claims will be met, but the stability of the ingredients and the entire product stability are also important. Dietary supplement products must be formulated with ingredient overages to ensure that all dietary ingredients meet at least 100 percent of product label claims upon initial release and throughout the product shelf life as required in 21 CFR 101, and a stability program based on ICH guidance is necessary to determine this overage.

Manufacturing and packaging processes can be additional sources of potential contaminants to finished products and therefore, must be known and understood when specifications are established. Understanding the variability of these manufacturing and packaging processes is necessary to assist with the assignment of acceptance criteria for associated strength tests. However, the other significant factor that must be considered when assigning the acceptance criteria for all tests is the variability of the test method that will be employed. This test method variability will be ascertained as part of the method validation that is performed to demonstrate that the method is scientifically valid as required per 21 CFR 111.75(h) and 111.320(b). A scientifically valid test method is described by the FDA as accurate, precise, specific and consistently doing what it is supposed to (ruggedness) in the Preamble to the 21 CFR 111 Final Rule.

Specifications SOP

Guidelines that should be used to prepare each type of specification, considering all the relevant factors, and an explanation for why meeting the specifications will ensure the safety and quality of the finished dietary supplement, and that all product label claims will be met, must be dictated in a written procedure. This written procedural requirement is met by preparing a standard operating procedure (SOP) to describe the establishment of each type of specification along with an associated specification template. Specifications will then be established for each raw material, in-process material, packaging component, label (and labeling), finished product, and the final packaged and labeled finished product using that template. Again, the theme here is that procedures need to be in place to ensure that the finished dietary supplement is exactly what it is supposed to be.

Quality Unit

The specifications SOP, specification templates, and all established specifications must be reviewed and approved by the QU in accordance with the controlled processes of the QMS. This is one of the numerous QU responsibilities dictated in 21 CFR 111, which must themselves be designated in a written procedure. It is noted that when testing is performed to determine whether the established specifications have been met, only the QU can release material for use and product for distribution, and when necessary, has the authority to reject materials and products.

A New Regulatory Development

Until recently, much of the information relating to issues with FDA inspections for GMP compliance by individual companies were largely unavailable unless the problem escalated to the level of a warning letter (published weekly on FDA’s website) or more serious enforcement action such as an Injunction. This was due to the only way to access data relating for FDA 483s was through the submission of a Freedom of Information Act Request. Recently, however, FDA updated the quantity and quality available through its Compliance Data Dashboards https://datadashboard.fda.gov/ora/index.htm.

While data relating to dietary supplement GMP inspection data is not separated out from all food related inspections, that database is searchable by, among other things, company name, FDA classification of the violation and keywords. The availability of this information is potentially a sea change and issues related to compliance failures as the trade press, other media and competitors now can monitor compliance issues generally at a much earlier time than previously. NIE

Attorney Marc S. Ullman represents clients in matters relating to all aspects of U.S. Food and Drug Administration and Drug Enforcement Administration matters, regulatory issues, Federal Trade Commission proceedings and litigation. He practiced with one of New York’s leading white collar criminal defense firms for 10 years, where he represented clients in both federal and state prosecutions, as well as numerous related civil matters and other litigations. He can be reached at marc.ullman@rivkin.com. Tara Lin Couch, PhD is the owner of TLC Regulatory and Laboratory Consulting and is an Analytical/Organic Chemist who also possess a B.S. in mathematics. Couch has exceptional analytical abilities and more than 35 years of diverse laboratory and regulatory experience in academic, field, contract and manufacturing environments. She is a sought-after expert on issues pertaining to quality control in pharmaceutical, dietary supplement, tobacco manufacturing and the cannabis industries. As a consultant, Couch assists with the development, improvement and implementation of quality systems that are scientifically sound, efficient, practical and compliant with FDA regulations. She also helps clients with the conduct of FDA regulatory surveillance, follow-up, and pre-approval inspections including preparation efforts, direct support, and responding to FDA related communications such as the initial Form 4003—inspection records requests, Form 483—list of observations, warning letters, consent decrees, deficiency letters and other information requests.

Albion Minerals®