The API warning letters of the last 21 months - facts and trends

The number of warning letters addressed to API (Active Pharmaceutical Ingredient) manufacturers has increased considerably over the past three years. 22 were issued in 2016; that is more than twice as much as in the year before, when 10 manufacturers of active substances received the unpopular FDA letter.

While the warning letters for pharmaceutical manufacturers are based on chapters of the "Code of Federal Regulations, 21 CFR, Part 211", the citations in API warning letters refer to regulations in the chapters of guideline ICH Q7. On the contrary to the 21 CFR 211 chapters in pharmaceutical warning letters, those are not specified explicitly; however, the wording of main deficiencies (usually in bold print) in API warning letters literally reflects the corresponding passages of guideline ICH Q7 most of the time, so that a clear allocation is possible in most cases. This also facilitates a simple statistical assessment in regards to frequency distribution of deficiencies and the trends over a specific period of time.

Hereafter, some facts about the warning letters issued to API manufacturers during the period of fiscal year 2016 (Oct. 15-Sept. 16) and the nine months of fiscal year 2017 (Oct. 16-Jun. 17) are listed.

Inspected Sites

The share of production sites located in India or China which received a warning letter is high in both considered periods.

Land   Number of WLs in FY 2016  Number of WLs in FY 2017 (9 months)
China  10 9
India  6 8
USA  2 1
United Kingdom 1 1
Canada  1 0
Italy  1 0
Germany  1 0
Spain  0 1
Japan  0 1


The numbers for the previous fiscal years are similar; this is a stable trend which will probably continue in the future.

It's interesting to take a look at the findings described in the warning letters of both periods.

Frequency distribution of quotes

Frontrunners in FY 2016 are deficiencies which refer to chapter 5 Process Equipment, subsection 5.4 Computerized Systems, paragraph 5.43 of guideline ICH Q7. This paragraph states:

"Computerized systems should have sufficient controls to prevent unauthorized access or changes to data. There should be controls to prevent omissions in data (e.g. system turned off and data not captured). There should be a record of any data change made, the previous entry, who made the change, and when the change was made."

In total, there are 12 citations in the warning letter which refer to the unregulated access to raw electronic data. Most cases describe fraud and data manipulation, e.g. deleting of "bad" analyses (HPLC) after choosing the ones with specification compliant results, manipulation of metadata in audit trail, changing the date of analyses etc. These deficiencies are described in warning letters issued to 6 Indian, 5 Chinese and one German manufacturer.

The second most frequent GMP violations the inspectors found were in quality management, relating to the ICH Q7 chapter 2 Quality Management. Particularly common with 6 citations were violations of the requirement for prompt recording of quality relevant activities as stated in paragraph 2.15:

"All quality related activities should be recorded at the time they are performed."

Here, the FDA inspectors observed incompletely filled-in batch protocols as well as the frequently practiced later transfer of measured values from memos to the official protocol (partly even "from memory", i.e. without memo). The corresponding warning letters were addressed to 4 sites in China and 2 in India.

The frequency distribution in FY 2017 looks a little different. With 11 citations referring to GMP violations of chapter 5 Process Equipment in total, the number of findings in this area is still relatively high. The number of citations directly referring to unauthorised data access as per subsection 5.4 Computerized Systems, paragraph 5.43 however has significantly decreased with only 5 citations (warning letters issued to 2 Indian, 2 Chinese and one Japanese manufacturer). 5 more citations refer to regulations concerning an entirely different issue: cleaning and maintenance. Subsection 5.2 Euipment Maintenance and Cleaning, paragraph 5.21 states:

"Written procedures should be established for cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. ..."

Warning letters that listed deficiencies in this area were issued to 3 companies in India, one in the USA and one in Spain. The warning letter issued to the Spanish manufacturer also described a GMP violation in relation to unsuitable Production equipment with reference to subsection 5.1 Design and Construction, paragraph 5.11 ("Equipment should be constructed so that surfaces that contact raw materials, intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the official or other established specifications").

The actual peak in frequency distribution of findings in FY 2017 are citations related to chapter 2 Quality Management.  Overall, the warning letters described 12 GMP violations of the principles of quality assurance and relating to the areas of responsibility in Quality Units (subsection 2.1 Principles, 2.2 Responsibilities of the Quality Unit(s) and 2.3 Responsibilities for Production Activities); twice as much as in FY 2016. Scenarios vary from complete lack of a Quality Unit (e.g.: "Your firm has no Quality Unit. ... Your salespeople signed your CoA under the title "QC Director". Without performing tests, your salespeople also signed under "Tested By"") to the lack of fundamental GMP documents (e.g.: "Your firm had no written procedures for supplier qualification, relabeling and repackaging operations, sampling, production release, stability, and document retention. ...").

12 more GMP deficiencies were found in the area quality control and laboratory. The incomplete or not at all conducted investigation into the reasons for OOS results especially caused the FDA inspectors reprimands in the warning letters. Recipients of the warning letters with GMP violations in the areas quality management and lab controls were - apart from a US American company - exclusively API manufacturers from India and China.

Taking a look at the complaints phrased in the warning letters shows a slight trend away from the GMP violation "non-existent regulation of access to electronical data and its manipulation" and towards "inadequately performed responsibility of Quality Unit and mistakes in the quality control laboratory". Still, the violation of data integrity will very likely remain a problem for the time being, especially at Far Eastern production sites. An analysis of warning letters when FY 2017 is over at the end of the year will show whether this prognosis proves to be true.

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