Original Post Date: January 6, 2011
Author: John English
Everyone has their own way of starting the New Year. In my case, I was fortunate to catch an FDA colleague for a brief discussion. When I asked for an opinion about the large increase in Warning Letters posted in the last 15 months, the reply I got was – “When the new commissioner came in, I believe that she said “It’s all about Enforcement.” Warning letters are the measure of enforcement.” With those words fresh in my mind, I noticed the following item that appeared TUE morning in the CDER daily update. (Yes, it’s dated Monday but it wasn’t there late MONDAY afternoon)
• FDA Issues the following Warning Letters:
o Macco Organiques, Inc.
o Yuki Gosei Kogyo Co., Ltd.
o Synbiotics Limited c/o Ambalal Sarabhai Enterprises
There are several interesting parts to this. First, these weren’t “new letters.” All of them were “issued” last year! (OK, last month, actually, but still in December and not this week.) What else do they have in common? All of them are for ex-US API facilities in three different countries – Canada, Japan and India. This seems to show a clear focus on the issue of off-shore sourced API’s within the FDA-regulated area. Following up on those three, a fourth was posted on TUE – this API company (Klinge Chemicals Limited) is located in Scotland.
There is also some new focus point in two of the letters – the USP. Two of the companies had USP issues. Macco addressed that issue in a way that is simple, novel and one the FDA didn’t accept:
(Item 2) …In your response you indicate that your products will no longer have a United States Pharmacopeia (USP) claim on the label and that, therefore, you do not need to comply with the USP. We disagree with your response. These three APIs are all the subject of monographs in the USP …Removing the designation “USP” from your product labels does not eliminate the statutory requirement that your firm comply with the USP requirements. If your product fails to meet the standards of strength, quality, or purity in the USP, you may state on the label how your drug differs from these compendial standards. Either failing to comply with the USP compendial requirements or to state on the label how your drug differs from the compendial standards renders your drug adulterated under the Act.
Klinge has a similar problem but for a different reason. You may find it of interest.
(Item 3) …. the finished product assay determination and volumetric solution standardization procedures and calculation formulas do not at least meet the current USP standards. There is no assurance that the final result for all finished products released by your firm are within specification. The FDA investigator noted that your firm had no access to the USP.
Your response is inadequate because it failed to evaluate whether or not the lots of (b)(4) (API) that have been released were within specification according to USP monograph. …
The Synbiotics Ltd letter has a much different issue – they did not allow the investigator access to the site. Even ‘from a distance,’ the review did not go well:
On August 23, 2010, the U.S. Food and Drug Administration arrived at Synbiotics Limited, your manufacturing facility for active pharmaceutical ingredients (API), located at Plot Nos. 570, 571, 576A, Maitry Marg, Village-Luna, Tal Padra (Dt.), Vadodara, India, to conduct an inspection. YOUR FIRM DENIED OUR INVESTIGATOR ACCESS INTO THE FACILITY, and instead requested that the investigator remain in a business office located at Asence Pharma Private Ltd., Parshwa Pooja Complex, Akota, Vadodara, India. During August 23-27, 2010, information and limited documents provided to the investigator for review revealed significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs.
Let’s review one more common issue – both the Canadian and the Scottish firms were cited for issues with stability studies. In the case of the second firm, to quote the old song “Please don’t bother trying to find them, they’re not there.” Please consider the excerpt below:
2. Failure to establish a stability program to monitor the APIs manufactured at your facility.
For example, your firm has NOT COLLECTED or tested a batch of (b)(4) API IN THE LAST THREE YEARS. At least one batch per year of API should be tested as part of an ongoing stability program.
We acknowledge your response indicating that your outside contract for stability sample analysis was discontinued and that YOUR FIRM INTENDS TO PURCHASE EQUIPMENT and conduct stability testing onsite. However, you have not adequately addressed the specific issues cited on the FDA-483. Your firm failed to have written procedures that govern the stability program to address your annual commitment and analyses to be performed. …
Please note there are other issues covered – endotoxins for one and training for another but these are hopefully enough to encourage you to read them on your own. In the interest of getting this done, finally, all four letters do have this phrase in common:
Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA MAY WITHHOLD approval of any new applications or supplements listing your firm as an API manufacturer…..
Please note that the phrase is “may withhold?” If “enforcement” is the key reason for issuing a warning letter, what level of non-compliance is required to actually get a companies products refused entry? “Patience is a virtue” but please consider this observation, also taken from one of these letters as a measure of patience and inspection activity? (Oh yes, and ‘understatement!)
“We acknowledge that your firm is performing the second stage of qualification for this water system. However, this deficiency was brought to your attention DURING THE LAST FDA INSPECTION IN 2003. Your failure to correct then LEADS US TO QUESTION your commitment to manufacturing quality APIs.”
Please note that all highlights or font change are by this author. Specific references are available by request at John.T.English@prodigy.net or through this website email@example.com. In addition:
“Matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the letter recipient that may have changed the regulatory status of issues discussed in the letter.”
John English is a consultant to the life sciences industry.