Five most common GMP observations by FDA

Image | adobe.stock/wladimir1804

It’s surprising, but some companies still having difficulty comprehending the Dietary Supplement GMPs found in 21 CFR 111. After 18 years, one would expect that these regulations would be second nature to the other complexities of running a business in the industry. That said, in my experience, many companies in the Drug Manufacturing industry seem to have many of the same problems with compliance to the GMP regulations found in 21 CFR 210 and 211.

In reviewing many of the U.S. Food and Drug Administration’s (FDA) Warning Letters, I see the same observations cited from company to company. Here, I will list those non-compliance issues and provide feedback on them in order help manufacturers and distributors to better understand ways to avoid having issues cited by the FDA.

First, companies must understand that being certified by organizations as GMP Compliant means nothing to the FDA. The FDA will never walk away from an inspection or investigation simply because you provide them with a GMP Certificate. Their job is to determine by themselves if in fact you are compliant to the GMP regulations. So, let’s take a look at what commonly pops up in the FDA’s 483 Observation Reports and in their Warning Letters.

1. Failure to qualify suppliers of components used in the manufacture of dietary supplements. 21CFR111.75(a)(2)(ii)(A)

You must first qualify the supplier by establishing the reliability of the supplier’s certificate of analysis through confirmation of the results of the supplier’s tests or examinations.

This simply means that you must prove confidence in the supplier’s certificate of analysis. This can be done through testing in-house (if possible) or testing via a third-party testing laboratory. If the supplier has already tested the component through a third-party laboratory, you may request a copy of the test record for comparison to the certificate of analysis.

The good news is that the regulations only require you to qualify your supplier periodically. However, the interval you determine must be scientifically sound. So, it should not be one rule for all components. On a side note, if your company uses an FT-IR to aid in the identification of components, the lot number of the component you used for qualification of the supplier can now be considered your standard. I recommend you keep copies of the certificate of analysis with the test results in a master file designated for each particular component.

2. Failure to conduct at least one appropriate test or examination to verify the identity of the dietary ingredient prior to its use. 21CFR.75(a)(1)(i)

Before you use a component, you must conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient, unless you petition the agency under paragraph (a)(1)(ii) of this section and the agency exempts you from such testing.

Identification of ingredients can be as simple as organoleptic examination, although that cannot be used in every case. Scientific analysis via a spectrophotometer or other analytical methods can also be used.

You must establish two forms of documentation to satisfy the requirements for each component used in the manufacturing and packaging of a dietary supplement. Amazingly, many companies are still relying on the certificate of analysis alone to allow the release of a dietary ingredient for use in producing their products. The first form of documentation is your complete specifications for the component. This includes every specification you require from your supplier for the particular component. The second is your release criteria in the form of a test record that outlines the characteristics and specifications that you use to release the component for manufacturing or packaging. The “test” record documents the results of your in-house testing or examination for identification, plus any other internal requirements you may have established for acceptance. You may also include on the test record verification of results from the certificate of analysis.

3. Failure to prepare a Master Manufacturing Record for each product you produce and for each batch size of each product that you produce. 21CFR111.205(a)

You must prepare and follow a written master manufacturing record for each unique formulation of dietary supplement that you manufacture, and for each batch size, to ensure uniformity in the finished batch from batch to batch.

Surprisingly, many companies are using a recipe-style document to produce their products. Some are even handwriting the batch record as orders requiring the products are received. A Master Manufacturing Record (MMR) must contain all information necessary to produce and package a batch of dietary supplement. A portion of the MMR is your Batch Production Record (BPR), while the remainder includes:

• The full specifications of the product
• Your release criteria for the product in the form of a test record
• Your packaging record and specifications for packaging for each configuration that you may package the dietary supplement
• Finished packaging specifications and release criteria in the form of a test record for each configuration of the finished packaged product,
• An approved specimen label for each configuration of the finished packaged product.

The portion of the MMR that becomes your BPR has many requirements also found in 21CFR111.210 and 21 CFR 111.260. These requirements must be documented on each. All required forms included in the MMR must bear two or more signatures with dates identifying who created and who checked the formulation, specifications, test records, packaging record specifications, and labels.

4. Failure to establish a Production and Process Control System through sufficiently created Written Procedures designed to provide adequate instructions for cleaning and maintaining equipment and control procedures for the control of processing and packaging a dietary product. 21CFR111 Subpart E and 21CFR111.153 – 21CFR111.180

This covers a very broad area within the GMPs. The key here is adequate written procedures. Written Procedures are required for each task and responsibility and you cannot create procedures that encompass several tasks or involve several areas of responsibility. This is in contrast to Standard Operating Procedures, which are just that: “STANDARD.” They are designed to indicate what is done every time the particular task being performed. They are not processing procedures. Processing procedures are what you create as processing steps for the processing of a product. Processing procedures are not standard.

One must not conflate run-on procedures with standard procedures or processing procedures either. Run-on procedures are procedure that instruct the reader to complete several tasks as one step. This does not work. As an example, if a procedure is created for receiving components from a supplier or carrier, the task is to receive it from the truck or carrier and place it into a quarantine area. Several steps can outline the process in checking the material, completing paperwork, etc. But the procedure stops once the material is in the quarantine area. The next step of sampling, assigning lot numbers, etc. is a different task, thus, a different procedure.

It is important to understand that a sufficient production and process control system protects the dietary supplement throughout the production and packaging of the product. Thus, a Hazard Analysis and Critical Control Point HACCP program is not required for dietary supplement manufacturing.

5. Failure to establish an adequate Quality Control Unit. 21CFR Subpart F including 21CFR111.103 – 21CFR111.140

You must establish and follow written procedures for the responsibilities of the quality control operations, including written procedures for conducting a material review, making a disposition decision, and for approving or rejecting any reprocessing.

Quality control personnel must ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record. To do so, quality control personnel must perform operations that include: EVERYTHING.

Believe it or not, I have seen many 483 Observation Reports and Warning Letters that claim that the company’s Quality Unit is inadequate. The most common observation is that the Quality Unit is not given the proper authority to perform their duties. Top management of dietary supplement manufacturers must understand that the Quality Unit has the highest degree of authority within the company. That is what they are hired for. Their goal is to protect the product quality and the company’s reputation for the quality they process into their products.

The responsibility of the Quality Control Unit must be delineated in a written procedure and such written procedure must include the fact that they must approved everything within the documentation, processing, packaging, sampling, receiving, holding, etc. and etc. There is literally no area from start to finish regarding the operations of a dietary supplement manufacturer that can move forward without the approval of the Quality Control Unit.

I hope this article offers a “heads up” idea of what a company should consider prior to any inspections and what the FDA focuses on during an investigation. Our goal as members of the industry is to produce and supply our customers with the highest quality products available, and of course to make a profit while doing so. The only thing that can negatively affect that is to discover through an FDA investigation that your company is not up to par. That can negatively impact your reputation and your profitability.

Author Bio

Gary Callahan has over fifty years of experience in pharmaceutical and dietary supplement manufacturing. He’s been consulting manufacturers of drugs and dietary supplements since 2007. He is the Owner/CEO of GMP Consulting Services, Inc. GMP Consulting Services offers GMP Compliance Programs and GMP Maintenance Programs designed to meet and exceed the FDA’s GMP Requirements.