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Insufficient failure investigations, supplier qualification, stability testing – the most common GMP violations in the FDA warning letters



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An analysis of warning letters issued in the past fiscal year essentially shows the same pattern of frequently cited GMP violations. It also shows a noticeable increase in the GMP deficiencies relating to the qualification of suppliers and their certificates of analysis. Find out more,8489,S-QSB_n.html



The analysis of the warning letters issued in the last fiscal year shows no surprise at a first glance: as in recent years the FDA detected an insufficient investigation of unexplained discrepancies and deviations from defined standards and specifications in their inspections. The corresponding paragraph 21 CFR 211.192 requires that the drug maker clarifies the reason for the deviation, takes corrective actions and also creates a complete documentation. In the last 5-year period on average annually about 22 companies received a warning letter listing this GMP deficiency. This fact shows that many quality assurance departments’ understanding of deviations handling, failure investigations and corrective actions is frequently fragmentary.

Quite interesting is the detailed study of the warning letters referring to GMP violations with regard to 211.192. These warning letters take into account the drugs’ dosage forms. In particular manufacturers of oral dosage forms were addressees of warning letters containing citations with regard to 211.192, followed by parenteral drugs manufacturers, companies in the area of blood/blood products and manufacturers of topical drugs. The respective scenarios are quite different. However, main shortcoming is always the inadequate education and documentation in each incident.

A rather unexpected finding in the lineup of the most common GMP violations is the high number of citations with regard to 21 CFR 211.84 “Testing and approval or rejection of components, drug product containers, and closures”. This quote appears so frequently as never before: 16 out of the 32 companies that received a warning letter in the fiscal year 2013 for violations of part 211 had not implemented the provisions of paragraph 211.84 as expected by the FDA investigators. Interestingly, in this case most of these companies (12 of the 16) are manufacturers of topical products (ointments, creams, etc.).

The formulations in the warning letters in this regard are very similar (in some cases identical) and are usually limited to the following standard wording: “Your firm has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals” or “Your firm failed to withhold from use each lot of components, drug product containers, and closures until the lot had been sampled, tested, or exampled, as appropriate, and released for use by the quality control unit.”

Under the addressees of warning letters with quotations in the area of quality control – 21 CFR 211.166 “Stability Testing” and 21 CFR 211.160 “General Requirements” – there are also many of the companies that were already criticised due to non-compliances with regard to 211.84. This is not surprising as the thematic connection of all three paragraphs has a reference to the function of quality control. These two paragraphs 211.166 and 211.160 – just as 211.192 – have been in the top ten of GMP deficiencies for many fiscal years. Main shortcoming relating to 211.166 is the lack of a written stability test programme. Therefore, the following sentence can be read in almost all warning letters: “Your firm does not have an adequate written testing program designed to assess the stability characteristics of drug products in order to determine appropriate storage conditions and expiration dates.”

Information on infringements of 211.160 are more differentiated. Partly some interesting scenarios are described, as, for instance, “inappropriate visual particle inspection” or “switched off audit trail function in the chromatography system”. Here too Topika makers make the majority of addressees – even though not as clear as in the previous paragraphs of part 211. Main shortcoming in the implementation of the guidelines in 211.160 is the lack of scientifically sound and appropriate specifications, standards, test plans and test methods for products, intermediates, components etc.

The analysis of the warning letters of last fiscal year has shown that the FDA increasingly focuses on the subject “supplier qualification” and in this context on critically questioning analysis results and certificates of the suppliers. A detailed examination of the warning letters of the current fiscal year will show whether this trend further continues.

A more detailed analysis of the warning letters of the previous fiscal year will be available in the October issue of the GMP Journal.,8489,S-QSB_n.html



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  1. Salil Warior says:

    Excellent piece Dr Crasto. In line with the thought we have scheduled a training programme in Mumbai on 7 -8 August 2014. The topics to be covered in the same are:
    • What is Quality Metrics and importance of Risk based inspections
    • What is Data Integrity and methods to avoid Data Integrity issues
    • EU Data Integrity observations
    • Latest Analytical tools
    • Audit trails & its implementation to comply with Part – 21 CFR part 11
    • Methodology / various tools to resolve data integrity issues
    • US FDA x EU x WHO Process validation comparison
    Will keep you posted about the training subsequently. To know more, please drop a line on

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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