FDA Warning Letter to Lupin Underscores the Need for Top Management Involvement in cGMP Compliance

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Over a two-year period, FDA inspections at company facilities found repeat problems with quality systems including lack of written procedures, inadequate investigation of out-of-specification conditions and corrective and preventive action, and insufficient cleaning and cleaning validation.

In a September 2019 warning letter to Lupin Ltd., FDA noted that the company had failed to meet requirements for current good manufacturing practices (cGMP) at its facility in Mandideep, Madhya Pradesh, India. As stated in the letter, regulators found that many of these problems, which were documented in late 2018 inspections, had previously been pointed out in 2017, when FDA inspectors visited the company’s facilities in Goa and Indone. Specific compliance issues included inadequate investigation into the causes of out-of-specification (OOS) conditions, undocumented procedures, problems with corrective and preventive action (CAPA), and insufficient cleanliness. The letter underscored the need for greater oversight of cGMPs by top-level managers.  

According to FDA, the company did not sufficiently investigate the root causes (whether in the testing laboratory or in manufacturing) of OOS or batch failures, or any quality problems with batch ingredients, whether or not product batches had already been distributed. As the letter stated, although a number of OOS tests had been performed on numerous products since 2016, investigations were often closed before a root cause for the problems had been found. Once batches passed retests, the product was often released. 

FDA asked for an independent review of all invalidated OOS results for all United States drug products since July 1 2016, and an assessment of whether justification for each invalidated OOS result was conclusive. When manufacturing was found to be the cause of the problems, the regulators asked that the company review all aspects of production thoroughly, including batch manufacturing records, process capability, raw material variability, deviation, complaint, and batch failure histories.

In addition, the regulators asked for analysis of trends in operations and identification of “systemic factors” that might be leading to variation in testing and manufacturing results. The agency also asked that the company assess the way it investigates deviations, atypical events, complaints, OOS results and failures, and that it revisit its CAPA plan and assess its effectiveness. 

Another fundamental problem found was inadequate written procedures for control of production steps and product quality, including inadequate identification of potential reasons for variation in product quality. Regulators asked that the company examine process validation for manufacturing and for in-process containers, and that it have an independent third party assess its manufacturing processes to determine the state of control, touching on equipment suitability, raw material quality, and other issues.


Inspection of a tablet press at the facility found unknown residues on several contact surfaces, raising the possibility of cross-contamination. The company responded that it had addressed the problem and retrained the operators, but FDA’s letter demanded a more comprehensive assessment and documented improvement of cleaning and cleaning validation procedures, and an approach that utilizes “worst case” assumptions.

Because many of these violations had been seen at other company sites previously, FDA reaffirmed the need for greater management oversight of cGMP, and asked that the company assess its global manufacturing operations “immediately and comprehensively.”

Source: FDA Warning Letter to Lupin Ltd., September 10, 2019.