March 1, 2009

7 Min Read
Treating the FDA as your customer

RegCol_Sourcebook.jpgHow you approach the new dietary-supplements GMPs can ultimately affect the measure of success you have in designing a programme that will satisfy FDA requirements.

The publication of 21 CFR Part 111 in 2007 has evoked a spectrum of responses from members in the industry that range anywhere from abject fear and moderate ambivalence to complete denial. Realistically, however, all must accept the fact that the GMPs are here to stay and, from now on, will necessitate significant changes in the way that products are manufactured, advertised and sold to dietary-supplements consumers.

Bringing products to market that are safe and effective is the primary goal of the dietary-supplements industry. It needs to be recognized that this goal is also shared by the people at the FDA and, as such, should be considered when designing any compliance system.

Consider the case of an herbal manufacturer we recently met who receives some of his ingredients as whole herbs. He was aware that Paragraph 111.75 (h) (2) of the regulations allows for "gross organoleptic analysis" for identity testing, if this is appropriate. Although he was currently using this method, he was fearful that the FDA would not consider his results scientifically valid. Consequently, he was in the process of acquiring an expensive piece of HPLC equipment that he hoped would produce more acceptable results. Knowing that his current testing procedure would most likely be acceptable to the FDA, we encouraged him to contact it to gain clarification and direction, stressing that regulators always welcome this type of dialogue with industry members. However, he replied, apprehensively, that he could not possibly do that, because he did not want to bring attention to his company within the agency.

In a subsequent conversation with Brad Williams, assistant to the director, dietary supplements, CFSAN, at the FDA (while keeping the company's identity confidential), we learned that, in this case, organoleptic testing was appropriate and acceptable. Williams also stated that he would be very happy to speak to the company's representative in an effort to address any questions or concerns regarding this issue or any other part of the regulations. Unfortunately, the manufacturer would not reconsider his earlier decision, thus setting a specification that was overly restrictive and further binding himself to using a very precise, and difficult to manage, analytical technique that was probably unnecessary.

Taking the time to build a relationship with the FDA as you develop your compliance programme is well worth the effort, when faced with the eventuality of a regulatory inspection. If, during inspections, the FDA investigator finds conditions which, in the investigator's opinion, violate GMPs, he will provide these in writing on an FDA Form 483 (commonly called 'a 483'). These findings are typically responded to in writing, stating what the company will do to remediate the observations. However, if the response is determined inadequate or the observations are considered serious violations, the FDA may issue a warning letter, to which the company must respond within 15 working days of receipt.

These are difficult times and are seldom conducive to establishing your first contact with local FDA personnel, because the circumstances tend to be more confrontational. For this purpose, it is decidedly better to initiate discussions with the agency as soon as possible. Keep in mind that the FDA will still inspect your facility, and expect you to be following GMPs, but it is much easier to converse with people whom you already know.

As you begin to institute the new GMPs into your existing processes, take a proactive approach in your interactions with regulators. From this point forward, you should think of the FDA as one of your most important customers, and treat them as such.

Michael J Plover is president of Quality Systems Design (North Wales, Pennsylvania), a consulting firm specialising in assisting companies to develop robust and maintainable processes. He also is the author of Your Sourcebook for Dietary Supplement Compliance, which breaks down the regulations and offers insights for developing maintainable and affordable GMP compliance systems.

Who is in control?
The regulatory requirements outlined in 21 CFR Part 111 clearly dictate that an in-depth study of every process is essential to designing a compliance system that assures every batch yields a quality product.

Over the years, numerous companies in the pharmaceutical industry have learned costly lessons from their process ignorance, resulting in extensive 483 warning-letter observations and, in some cases, consent decrees from the FDA. Such regulatory actions can cause your operation a tremendous loss of time and profits while remediation plans are formulated and put into place.

The reactive approach to compliance always comes with a high price tag. So, in order not to place yourself in the position of playing 'catch up' with regulators, you must first determine if you control your process or if your process controls you.

Remember, no matter how insignificant an activity appears to the overall success or failure of your production operation, it can play a major role in defining the ultimate outcome of manufacturing a product that conforms to the requirements set forth in the regulations, as well as meeting all of your specifications.

However, it is impossible to set appropriate specifications without having sound process-control mechanisms in place. If you don't have good control of your operations, you will find yourself constantly fighting fires and preparing deviation reports.

Execution of a well-run compliance programme requires a full understanding and management of all processes from supplier control to distribution. This also includes a document-control system where only approved and current versions of documents are available for use.

So when setting your compliance goals, be proactive and show your process that you're in control.

The Cost of noncompliance
Suppose you receive a 10-item 483 after an FDA inspection. WITHOUT EXCEPTION, the agency will expect:

  • A written response to all items, explaining your action plan for improving your quality and compliance systems that precipitated these citations.

  • A written response that will detail the systems approach you plan to take for dealing with any manufacturing/process systems that are found noncompliant by the FDA.

To calculate the amount of time and person-hours required to prepare an acceptable response to the agency, realize that each item on the 483 will take about 10 hours of management's time to fully respond to. This will include preparation of the initial draft and re-writes, checking the response for feasibility and completeness, and the final polishing of the wording to assure precision and clarity. After you factor in the cost of management's person-hours, you can then calculate the cost of 100 person-hours to the company.

If the response is not thorough enough, or if the 483 items are serious enough, you may receive a warning letter from the FDA. The time required to reply to a warning letter is about triple to that of a 483. You will want the assistance of an experienced consultant when responding to citations of this nature. When you calculate all of the costs incurred for this type of situation, it adds up to thousands of dollars.

Lastly, warning letters are posted on the FDA's website for your competitors and customers to see. Can you really afford the loss of good will and business you would experience throughout the industry if you were the company highlighted on such a posting? As you can see, the cost of noncompliance is too high to risk.

The regulations require you to think about, understand and control your systems. This is also good business practice and will help improve your bottom line. Think of GMPs as 'Good Management Practices,' not just Good Manufacturing Practices. If you understand and control your operations better, you will have fewer rejections, fewer investigation reports, less rework, less scrap and a better bottom line. Yes, the GMPs are a lot of work initially, but the payoff is there.

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