USFDA 483, Sun Pharma: Lapses in Chromatographic Integration, Investigations, Reduced Testing Procedures

Observation 4

Laboratory records are deficient in that they do not include a complete record of all data obtained during testing.

When an analyst processing chromatography data determines the existing processing method is not appropriate or chooses to use a different processing method the original chromatogram is not saved. Analyst document that the integration was inappropriate and get approval for different processing method, but the original chromatogram is not saved.

Observation 5

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.

1. The analysts can choose the integration algorithm and manually enter timed integration events into the processing methods. Procedures have not been established to ensure the appropriate and consistent use of these timed integration events.
2. In-housed prepared microbiology media plates used for testing samples collected on July 29, 2022, showed indications of desiccation on August 4, 2022, prior to the end of incubation. This included cracking of the media and media pulling away from the edges of the plate on eight of the plates.
3. Procedures have not been established to ensure the potential source of microorganisms identified from the environmental monitoring program are evaluated. Enterococcus faecium, an organism that may be associated with fecal contamination, was identified in Compression Room, included in isolate library and colonies with similar morphology do not need any additional identification.

Observation 4

Laboratory records are deficient in that they do not include a complete record of all data obtained during testing.

When an analyst processing chromatography data determines the existing processing method is not appropriate or chooses to use a different processing method the original chromatogram is not saved. Analyst document that the integration was inappropriate and get approval for different processing method, but the original chromatogram is not saved.

Observation 5

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.

1. The analysts can choose the integration algorithm and manually enter timed integration events into the processing methods. Procedures have not been established to ensure the appropriate and consistent use of these timed integration events.
2. In-housed prepared microbiology media plates used for testing samples collected on July 29, 2022, showed indications of desiccation on August 4, 2022, prior to the end of incubation. This included cracking of the media and media pulling away from the edges of the plate on eight of the plates.
3. Procedures have not been established to ensure the potential source of microorganisms identified from the environmental monitoring program are evaluated. Enterococcus faecium, an organism that may be associated with fecal contamination, was identified in Compression Room, included in isolate library and colonies with similar morphology do not need any additional identification.

• The regulatory and auditor expectations on Laboratory compliance and chromatography integrations is increasing. The chromatographic integration procedures should define and address:
  • Controls on using different (alternate) integration events for different chromatograms in a sequence, for different time ranges in a chromatograms should be established. There should be a documentation of rationale for the same with supervisory approval. This is required now not only for “manual integration” (traditionally understood as manually altering baselines, start or end of the peak etc.), but even when system integrations are performed with different set of integration events. And the initial chromatogram(s) should also be saved with initial set of integration events, not sufficient to save only chromatograms from which results are reported. (Also refer the post: Warning letter / Glenmark, Goa, India /FEI 3004672766 / MARCS-CMS 637314/ 320-23-04/ NOVEMBER 22, 2022/ Observation 3)
• In Microbiology analysis ensure adequate procedural controls, checks and balances and discipline of practices.
  • Desiccation and drying of media plates can happen due to various reasons:
    • Lapses (like inadequate mixing, overheating and so on) during preparation of media plates. A good alternate option is to use Prepared Media plates from reputed, approved suppliers
    • Inadequate sealing /closing  of petri plates causing loss of moisture from the media plates.
    • Excessive handling during incubation (for reading plates), leaving the plates outside the incubator for long; Inadequate humidity controls in lab. Ensure lab personnel follow good microbiology lab practices, train and coach people.
    • Malfunctioning of Incubators, excursions of temperature / humidity in incubators; Over incubation; Ensure appropriate environmental conditions in the lab, monitor the data electronically with alarm, alert systems for excursions.
  • After identification of environmental isolates, follow it up with documented evaluation and assessment – What are possible sources, whether current controls are sufficient to avoid excursions and contamination (hygiene and sanitization practices, disinfectants and their efficacy). Identify additional measures if necessary and implement.
• Reduced Testing procedures: When reduced testing procedures are implemented, it should have sufficient checks and balances. Reduced testing may not be always for completely eliminate all testing – critical parameters which can have an impact on process and product CQAs (like particle size), parameters which can be impacted due to storage handling (e.g. sensitive impurities) and so on may still get tested, while other parameters with low risk of failure can be skipped. Even when reduced testing procedure is established, there should be defined periodic evaluation (e.g. one in every five or ten batches); and in such evaluations if failures are reported, all earlier batches which are not tested become a suspect and should get evaluated. Most importantly when failure investigations (like a drug product OOS) indicate a potential issue with material where reduced testing is implemented, it should automatically trigger a reevaluation of the reduced testing implemented for the material, and revision of reduced testing criteria. This should be part of the CAPAs implemented for the failure investigation.

• Review and revise the procedure for control of Chromatographic integration defining documentation of rationale, control and approval process for using different chromatographic events for integration of chromatograms within a sequence. Chromatograms with initial integration events and changed integration events should all be saved, and reviewed during analysis review and release.
• Investigate the observation of desiccation of media plates, establish root cause (refer discussion under What companies should do.. above) and CAPAs. Based on the root cause perform an impact evaluation, whether any earlier results could have been impacted; Draw support from other controls / data to rationalize the conclusions.
• Evaluation and assessment of Contamination controls in place with respect to identified environmental isolates and enhancement where necessary.
• Review the Reduced Testing Procedure and materials for which the same is implemented. Evaluate whether any revisions are required based on potential risk, quality events trend.