Review of FDA Warning Letters

Apr 01, 2011

The FDA provides an electronic reading room on its website that provides access to a great deal of useful information, including copies of Warning Letters issued by the FDA. Reviewing these letters can be useful because they provide insight into the inspection techniques and concerns of FDA inspectors. Additionally, they can be used to perform gap analyses of the processes used at your company in preparation for an FDA inspection. This article provides a summary of the review conducted for Warning Letters issued between 2000 and 2010 for products that are aseptically filled and for manufacturing processes identified as non-sterile.


Employee training in a pharmaceutical company almost always includes instilling a 'healthy fear' of regulatory agency inspections. Most, if not all, countries have established governmental agencies that are responsible for the safety and efficacy of the medicines manufactured, sold and distributed within their country. These agencies typically have the legal authority to go into production facilities to assess various aspects of the manufacturing and distribution facility. As such, employees learn that the company's viability is dependent upon successfully passing these inspections.1

The notification that a regulatory inspector is planning a visit to a company site can trigger concern regarding the expected outcome and frantic activities often take place in preparation. Since the implementation of the FDA's Systems Based inspection programme, however, it has become more difficult to successfully prepare for an inspection.

Originally, the Systems Based Inspection guide was introduced by the FDA as a pilot programme.2 The method for evaluation entailed a portion of the FDA's regional offices using the programme for a 6-month trial period in 2001. The results were successful and the FDA officially implemented the programme in 2002 as the Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections (Program 7356.002).2

Prior to the implementation of this guidance, companies prepared for inspections by thoroughly reviewing and assessing products with upcoming pre-approval inspections because these products tended to be the focus of the inspection. Under the new guidance, however, the FDA reviews companies in a systematic approach, which makes it more difficult to prepare. One valuable way to prepare for an inspection is to look at the FDA's inspection findings from other companies to determine which types of observations are also issues at your company.

For this study, the FDA's website was searched to review the Warning Letters issued between 2000 and mid-2010. The searches were limited to those referencing aseptic processing or non-sterile processing, and the data were summarised.2,3

Warning Letter review

Table 1: Number of FDA observations made per section of the Code of Federal Regulations, 21 CFR Part 211.
Data obtained from the Warning Letter review were analysed to determine the appropriate section of the GMPs, as stated in 21 CFR Part 211, that had been violated. This was then summarised to determine how many observations were made for each section of the GMPs. Following determination of the number of observations made, a ranking was performed to determine which section resulted in the most observations (rank = 1) and which resulted in the least (rank = 33 for aseptic; rank = 44 for non-sterile processing). Items with the same number of observations were given the same ranking within the type of processing used. These results are summarised in Table 1. The top ten categories of observations for each type of processing are summarised in Table 2.

Table 2: Top ten categories of FDA Warning Letter observations.
Although the product processing types were different (aseptic versus non-sterile), among the top ten categories of observations, several made the listing for both types of processes; for example: responsibilities of the quality control unit, equipment cleaning and maintenance, written procedures and deviations, general requirements (laboratory controls), testing and release for distribution, batch production and control records, and production record review.