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The analysis of the Warning Letters of the fiscal year 2016 offers a surprise in several respects. On the one hand, with a total of 83 Warning Letters, the number of letters sent to pharmaceutical companies is very high. However, the main portion of this went to US "Compounding Pharmacies", i.e. institutions that produce individual medicinal products according to medical prescriptions, also including sterile preparations. After the deduction of these Warning Letters - 54 in number - 29 Warning Letters remain, almost half of which were addressed to pharmaceutical companies in China and India. The remaining Warning Letters went to companies in the USA, Latin America and Europe. From the Warning Letters directed at API manufacturers around 70% went to Chinese and Indian companies, which is a significantly higher share.

As is well known, FDA inspectors have been increasingly focusing on the GMP-compliant handling of production- related data for some time. Frequently, they find deficiencies concerning this matter in locations in Far Eastern countries.

24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 2 - in Berlin or online


Berlin, Germany27/28 October 2021

24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 2 - in Berlin or online


The following frequency distribution of the Warning Letters of the FY 2016 in conjunction with "Data Integrity Issues" reflects this situation:

It is interesting to take a look at the Warning Letters for companies producing pharmaceutical active ingredients. In the FY 2016, the FDA concentrated again on the facilities located in India and China. A total of 22 Warning Letters were sent to active substance manufacturers (of these, four are already included in the 29 Warning Letters addressed to pharmaceutical companies, since the companies concerned produce both active substances and finished medicinal products, and the same WLs cover the deficiencies in API and pharmaceutical production. The total number of Warning Letters for pharmaceutical and API companies is therefore 47). Here, the frequency distribution is as follows:

As this review shows, inspectors found  violations of data integrity requirements  especially in Chinese and Indian  companies. In most cases this was  not only a question of uncontrolled access to data storage, but often blatant  fraud in connection with the manipulation  and destruction of data.  The content breakdown of the Warning  Letters to the pharmaceutical  companies according to the most frequently  cited deficiencies results in  the following ranking of the "Top Five  Issues":  According to this table, the most common  deficiencies infringe basic GMP  requirements such as

24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 1 - in Berlin or online


Berlin, Germany26/27 October 2021

24th APIC/CEFIC Global GMP & Regulatory API Conference - Part 1 - in Berlin or online

  • The absence of written SOPs for  production and quality control
  • The absence of a quality unit that  establishes a minimum level of  such instructions, enforces compliance  and releases materials, intermediates  and products
  • The absence of the test to release  the final product
  • The absence of SOPs for the cleaning  and maintenance of the production  equipment 
  • The non-compliance of the quarantine  status of components, containers  and closures before their testing  and approval by the quality unit
  • The absence of written SOPs to prevent  microbial contamination in  sterile products and the lack of validation of aseptic processes and  sterilization procedures
  • The absence of scientifically based  test methods in quality control 

It is first of all surprising that medicinal  products are being produced in  pharmaceutical companies without  these minimum standards, which have  been known for several decades. A  partial explanation emerges from the  fact that the proportion of Indian and  Chinese companies receiving these complaints is high. But there are also always "black sheep" among US American  and European companies, which  do not meet the minimum standards  of Good Manufacturing Practice.

As the analysis of the warning letters  of the past fiscal years shows, the focus  of the FDA is continuously shifting.  A clear trend goes towards data integrity,  mainly for API manufacturers in  India and China. But "basic GMPs" is  also a focus of most FDA inspections  again.

A detailed evaluation of the API Warning  Letters is the subject of an investigation  in a later edition of the GMP Journal. 


Dr Gerhard Becker
... is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in analytical and compliance topics.

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