BIOTECHNOLOGY 11


How to avoid and respond to FDA criticisms


Ken Appel reports on how manufacturers can keep on top of regulations for temeperature, humidity and controlled environments.


Ken Appeal signale comment les fabricants peuvent se conformer à la règlementation concernant la température, l’humidité et les environnements contrôlés.


Ken Appel berichtet darüber, wie herstellende Betriebe in Bezug auf die Vorschriften für Temperatur, Feuchtigkeit und kontrollierte Umgebungen die Oberhand behalten.


N


o cGMP (current Good Manufacturing Practice) manufacturer wants to


receive a Form 483 letter (Notice of Inspectional Observations) from the FDA. In such stringently controlled industries as pharmaceutical/ biotechnical development, manufacturing and warehousing, receiving a list of deficiencies can feel like a heavy blow to your quality system. Worse, with the 2009 increase in enforcement staff1


and


the September 2009 change to the response time - now 15 days-the FDA appears to be ramping up its enforcement mandate2


.


Below: Every monitoring system should have a detailed IQ/OQ change control document to make validation a straightforward process.


Te following article shows three excerpts from some of the more common ‘observations’ noted in Form 483 Letters during 2008- 2009. Te names have been left out in this article, but are a matter of public record3


. Each of these deviations involved environmental


conditions (temperature, humidity, etc) in a variety of cGMP settings; they range from failure to properly validate containers for Human Cell & Tissue Products to a lack of temperature records in an aseptic processing area of a drug manufacturing facility. None of the deviations excerpted here are unique, but all are avoidable.


After the excerpts, I will outline some best practices of a 483 response, providing you with a 10-point checklist that should make that 15-day time limit more manageable, and some links for further research. Finally, I will look at ways to simplify and automate monitoring, alarming and reporting on FDA regulated environments. Options range from low-tech manual methods, to hybridised systems that combine written and electronic methods of documentation, to fully automated systems.


Sample Deviation 1. To a contract Pharma manufacturer: “Requirements for stability testing of drug products are not being met. For example, you do not have, as part of the storage condition, any documentation that stability samples are maintained at the designated temperature [21 CFR 211.166(a)(2)]; and you do not have appropriate stability data to support the 4 year expiration date for the product. [21 CFR 211.166(b)]”


Sample Deviation 2. To a blood bank: “Failure to have quality control procedures and follow those procedures for periodic tests of containers to maintain proper temperature...as required by 21 CFR 606.160(b)(5)(iv)...”


Sample Deviation 3. To a major manufacturer of OTC Pharmaceuticals: “Failure to establish and maintain procedures to adequately control environmental conditions, as required by 21 CFR 820.70(c). Specifically, temperature conditions within the aseptic processing area are not being documented to ensure such conditions are consistently within established specifications...”


“For example, during the inspection we observed that your firm was recording the relative humidity (RH) in the processing room, but not in the sterilisation chamber. We also observed that your firm was not maintaining or reviewing the temperature recorder charts generated during your sterilization process of [product x]...”


Tere is no regulatory requirement to respond to a 483. According to the agency, they are merely “... inspectional observations, and do not represent a final agency


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