UNPA – University of Mississippi Conference Explores Dietary Supplement GMP Inspections and Compliance
On February 11th and 12th, the United Natural Products Alliance (UNPA) and the National Center for Natural Products Research (NCNPR) at the University of Mississippi cosponsored their fifth seminar on good manufacturing practices (GMPs) for dietary supplements.
Though Loren D. Israelsen, executive director of UNPA, was unfortunately unable to be present, Adam Ismail, interim executive director of UNPA, kicked off the seminar. Featured speakers included the following experts on GMPs, quality control, and medicinal plant analysis: Ikhlas Khan, PhD, assistant director of NCNPR; Carl C. Reynolds, senior advisor of the Division of Dietary Supplement Programs in the Center for Food Safety and Applied Nutrition (CFSAN) of the US Food and Drug Administration (FDA); Harry B. Rice, PhD, director of regulatory and scientific affairs at UNPA (the author of this article); and Bradford W. Williams, manager of the Division of Dietary Supplement Programs in the Office of Nutrition, Labeling and Dietary Supplements of CFSAN at FDA.
Similar to past seminars, all of the subparts of FDA’s final GMP rule for dietary supplements were discussed, but this conference gave special attention to the 483 forms from inspections conducted by FDA since June 25, 2009 (the compliance deadline for medium-sized dietary supplement facilities). For those not familiar with the 483, it is a form used by FDA inspectors to record their inspectional observations related to specific areas of noncompliance. The 483 is not meant to represent a final FDA determination regarding a facility’s compliance. In the event of such a determination’s needing to be formally documented, it would be detailed in an Establishment Inspection Report (EIR). While none of the 483s issued since the June 25, 2009 compliance date have progressed to an EIR, it will be interesting to see how this situation develops in the coming months.
Lessons Learned
By reviewing 483s from various companies that have undergone inspection, the yet-to-be-inspected dietary supplement businesses can gain key insights on how to assess their own state of GMP compliance or noncompliance. Observations thus far have fallen under 14 of the rule’s 16 subparts (i.e., subparts B-O). A common theme seems to exist for the 14 subparts: specifically, noncompliance was noted for failure to establish written procedures and keep written records. All interested parties should keep in mind a basic rule: If it was never written down, it never existed!
As depicted in the following graph, of the 483s reviewed, more inspectional observations were recorded for some of the GMP rule’s subparts compared to others. For example, 21% of the inspectional observations were specific to Physical Plant and Grounds (Subpart C), while only 1% of the observations was specific to Product Complaints (Subpart O). Because compliance with all subparts of the final rule is currently mandatory for large and medium-sized companies (and will be for small companies with less than 20 employees beginning June 25, 2010), all dietary supplement manufacturers would be well advised to use the information from the existing 483s to compare their compliance (and possible noncompliance) with how the inspectors are interpreting and documenting noncompliance with the regulations. While a company may be able to use the information to gauge how important FDA considers each of the subparts, a 483 report is only a snapshot in time. All manufacturers of dietary supplements are forewarned that as time progresses, inspectors will become more experienced and savvy and inspections will likely become more rigorous.
The above graph depicts the percentage of FDA inspectional observations that were recorded for each subpart of FDA’s dietary supplement GMP rule.
Examples of Documented Inspectional Observations Written in 483 Reports (The following examples appear exactly as written by FDA inspectors.)
Subpart B: Personnel
Personnel engaged in manufacturing, packaging, labeling, and holding dietary supplements do not have the education, training, or experience to perform the assigned functions.
The personnel you identified to perform quality control operations do not have distinct and separate responsibilities related to performing such operations from those responsibilities that the personnel otherwise have when not performing such operations.
Subpart C: Physical Plant and Grounds
You did not hold cleaning compounds, sanitizing agents, pesticides, pesticide chemicals, or other toxic materials in a manner that protects against contamination of components, dietary supplements, or contact surfaces.
You did not have separate or defined areas of adequate size or other control systems to prevent contamination or mix-ups of components and dietary supplements during receiving, identifying, holding, and withholding from use components, dietary supplements, packaging, and labels.
Subpart D: Equipment and Utensils
You did not follow written procedures for maintaining, cleaning, and sanitizing, equipment, utensils, and any other contact surfaces that are used to manufacture, package, label or hold components or dietary supplements.
Records are not kept for the cleaning, sanitizing, and inspection of equipment.
Subpart E: Requirement to Establish a Production and Process Control System
You did not conduct at least one appropriate test or examination to verify the identity of a dietary ingredient prior to its use.
You did not follow written procedures for the tests and examinations conducted to determine whether specifications are met.
Subpart F: Production and Process Control System: Requirements for Quality Control
The responsibilities and procedures applicable to the quality control unit are not in writing.
You did not make and keep written procedures for the responsibilities of the quality control operations for conducting a formal review and making a disposition decision and written procedures for approving or rejecting any reprocessing.
Subpart G: Production and Process Control System: Requirements for Components, Packaging, and Labels and for Product that You Receive for Packaging or Labeling as a Dietary Supplement
You did not identify each unique lot within each unique shipment of packaging in a manner that allows you to trace the lot to the date received, the status of the packaging, and the dietary supplement that you distributed.
You did not conduct appropriate tests or examinations or rely on a certificate of analysis to determine whether components met established specifications.
Subpart H: Production and Process Control System: Requirements for the Master Manufacturing Record
You did not prepare a written master manufacturing record for each unique formulation of a dietary supplement that you manufactured.
Your batch production records did not include the weight or measure of each component used.
Subpart I: Production and Process Control System: Requirements for the Batch Production Record
Your batch production records did not include the date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs.
Your batch production records did not include an actual or representative label, or a cross-reference to the physical location of the actual or representative label specified in the master manufacturing record.
Subpart J: Production and Process Control System: Requirements for Laboratory Operations
You did not make and keep written procedures for laboratory operations.
The documentation for laboratory tests and examinations did not include the results of the testing and examination.
Subpart K: Production and Process Control System: Requirements for Manufacturing Operations
You did not use effective measures to protect against the inclusion of metal or other foreign material in dietary supplements.
Subpart L: Production and Process Control System: Requirements for Packaging & Labeling Operations
You did not take the necessary actions to determine whether packaging for dietary supplements meets specifications so that the condition of the packaging will ensure the quality of your dietary supplements.
Subpart M: Holding and Distributing
You did not establish procedures for holding and distributing operations.
Subpart N: Returned Dietary Supplements
You did not make and keep records of written procedures for fulfilling requirements for returned dietary supplements.
Subpart O: Product Complaints
You did not follow written procedures for the requirements to review and investigate a product complaint.
—Harry B. Rice, PhD, director of regulatory and scientific affairs, United Natural Products Alliance
