Today FDA posted a warning letter issued to Emcure Pharmaceuticals Limited on March 3, 2016 based on the outcome of an inspection ending February 4, 2015. Justin Boyd and Paul Bonneau were the investigators for this inspection. The site manufactures both sterile drug products and solid oral products. An import alert for the site was put in place July 13, 2015. This represents yet another warning letter issued over a year after the precipitating inspection. The 10-page form 483 for this inspection maybe be purchased from the FDAzilla store HERE. According to FDAzilla documentation, two Emcure Pharmaceuticals sites in Pune, India were also inspected in May, 2015 for 1 day and another for 3 days and no forms 483 were issued. This warning letter, and the accompanying form 483, addressed the frequent combination of aseptic processing deficiencies, concerns about cross contamination and the ever present data integrity failures. FDA indicated that “…data falsification and manipulation, and your reliance on incomplete records to release product to the market are repeat violations” which were documented in a February 2014 inspection of the same facility. The February 2014 5-page form-483 is available for purchase at the FDAzilla store HERE. The 2014 inspection was conducted by Peter Baker. Deficiencies identified in the warning letter include but are not limited to:
o Poor aseptic processing techniques, eight (8) examples including operators crawling on the floor under the filling line.
o RABS loading for sterilization did not follow the validated loading pattern for sterilization as observed during the inspection.
o EM evaluations are not reliable due to use of dried media place for surface and personnel monitoring. A total of 36 such plates were observed during the inspection. Also, the locations for EM sampling were not identified.
o Data Integrity: EM personnel monitoring is in question because documentation did not identify specific individuals who participated in the filling operations. Thus it is unclear which employees were monitored. FDA states that “…you acknowledged serious gaps ‘especially with respect to the suspected data integrity and falsification’ in data generated in your environmental monitoring program.” FDA references the firm to the 1994 Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products.
o Visual inspection process is inadequate because multiple operators failed to correctly identify defects such as incorrect fill volume, presence of fibers, presence of other particles. Staff were unable to correctly identify defects, and have the ability to subjectively determine whether they were critical or major without guidance.
o Data Integrity: Video’s of filling operations did not show active air monitoring as was documented in the laboratory. Results were falsified, and this was confirmed by one of the microbiologists. Two other microbiologics stated that samples were collected and submitted for incubation. FDA stated that the firm acknowledged problems, including that “data were fraudulent” but the overall response was inadequate because “…you have not demonstrated how you can ensure that EM records generated before the inspection were reliable and accurate, or how the falsification of some of your reported EM data may have affected the quality of your products.”
o Data Integrity: Activities were documented contemporaneous with their performance, and on occasion those signing as “checked by” did not observe the activity.
o Data Integrity: In addition to addressing the specific deficiencies the firm is also required to submit their third party assessment of the following, along with supporting documentation, which has become common ‘boilerplate’ language in warning letters associated with data integrity:
- A comprehensive evaluation of the extent of the inaccuracy of your recorded and reported data. Include a detailed action plan to fully investigate the extent of your deficient documentation and data management practices.
- A risk assessment of the potential effects of observed failures on the quality of your drug products, including the effects of deficient documentation and data management practices, aseptic processing breaches, and inadequate environmental monitoring program. Determine the effects of your failures on the quality of drug products released for distribution and the data supporting all associated submissions.
- A management strategy for your firm that includes the details of your corrective action and preventive action plan. Describe the actions you will take, such as contacting your customers, recalling drugs, conducting additional testing and/or adding lots to your stability programs, or other steps to assure the quality of your drugs manufactured under the deficient conditions discussed above. Also indicate measures you will take, such as revising procedures, implementing new controls, training or re-training personnel, or other actions to prevent the recurrence of CGMP violations, including breaches of data integrity.
An additional data integrity observations from the form 483 was not identified in the warning letter but identified a lack of control over computerized systems associated with laboratory instrumentation.