In March, FDA posted five Form 483s to pharma firms and eleven to compounding/outsourcing facilities. The receiving pharma firms include two Biocon facilities, Immunomedics, Shilpa Medicare, and Dr. Reddy’s.

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483s Posted

Biocon Limited

Biocon Limited (Bangalore, India) received a form 483 at the close of inspection on January 24, 2020. The inspection of this API site by a single investigator resulted in a four-page, 5-observation form 483. More than a few data integrity-related failures.

Observations include but are not limited to:

Failure to document the diluent used in swab sample collection, the volume of the diluent, and total area swabbed as required by the validation protocol and the governing SOP.
Failure to adequately investigate deviations, particularly OOS events associated with impurities. While nicely redacted, it appears that the firm did not investigate manufacturing conditions as a contributing factor or cause of the OOS events. This impacts all product shipped to the US.
Equipment was not adequately qualified. For example, HMI recipe operational parameters were not verified during qualification or at any other time. The observation is well redacted.
The Quality Unit does not adequately control GMP documentation. For example: records are not generated supporting the review, application, and reconciliation of labels on finished API or in-process samples; Quality approved batch records that were missing documentation of critical process parameters; uncontrolled forms were found in various department and documents were observed with the date entered prior to the documented QA issuance rate; shipment of samples for microbiological testing does not require temperature conditions to be documented.
Inventory records were found to be not accurate: materials of different status were comingled (Note: I’m assuming they operate a paper system); material status placards misidentified the status of the storage shelf contents.

Immunomedics Inc.

Immunomedics Inc. (Morris Plains, NJ) received a 9-page form 483 with 10 observations at the close of an inspection on March 10, 2020. This represents a followup inspection to a PAI conducted in August 2018 that went badly awry and resulted in a complete response letter. Here is the form 483 from that PAI.

Observations identified in the March 2020 inspection include but are not limited to:

There is no procedure, gowning requirement, or QA review of smoke studies. Studies did not include worst-case type of interventions.
QA and microbiology release and approval for use of a manufacturing area was not finalized until March 2020 although the area was conditionally approved and was in use since December 17, 2019.
FDA identified that procedures are not adequate or are not followed. They provide 13 painfully detailed examples of these failures in a range of activities and processes.
Appropriate controls are not exercised over computer systems. Electronic data are not appropriately controlled. Continuing their focus started over a year ago on filter integrity test units, the investigators identified that tests had been either aborted or the data were discarded without documentation or explanation. FDA also provides additional examples of failure to adequately control electronic data for laboratory instruments including analysts granted “advanced user access.”
Interventions in the semi-automated bioreactor process suggest that the process may not be adequately validated based on the firm’s comment that “…interventions are routine in support of a successful (b)(4) cycle, with the process not always capable of meeting specifications without human intervention.”
Facilities and equipment are not adequately maintained.
Hold times in the purification process are not documented so it cannot be determined whether the process is operated consistent with how it was validated.
Analytical methods for pH determinations and visual appearance were not subject to method verification.
Qualification of equipment and procedural controls have not been established. FDA provides three detailed examples including refrigerators, freezers, and data acquisition systems.
Automated cell thawing equipment are not properly qualified to ensure that cell banks thawed using the system meet acceptable cell density and viability for commercial manufacture.

Biocon Snd Bdh

Biocon Snd Bdh (Malaysia) received a form 483 at the close of inspection on February 21, 2020. This is their new insulin manufacturing facility where the first and second PAI had resulted in a complete response letter issued to their partner Mylan. Here is the form 483 from the PAI inspection ending February 15, 2018. Regarding the February 2020 inspection, Biocon Limited informed the National Stock Exchange of India that FDA has issued a VAI status for the facility and the inspection is “closed.”

Observations from the March 2020 inspection include but are not limited to:

The duration of interventions made in the Grade A area were not documented in the batch records that were reviewed and approved by Quality. No investigation was initiated regarding the impact this may have had on product quality.
Performance re-qualification of laminar airflow in the Grade Q filling unit did not correspond to the filling process and did not document all critical aspects.
Quality does not always adequately perform their responsibilities. The Quality Unit could not prove OQ for the integrity tester used in the filling unit; the Quality Unit also closed a CAPA without completing the associated deviation investigation into an OOT result.

Shilpa Medicare Ltd

Shilpa Medicare Ltd (India) received a 25-page form 483 with 15 observations at the end of inspection on February 25, 2020. The sheer number and scope of the observations suggest more enforcement will come. The firm manufactures both sterile and non-sterile drug product.

The overall conclusion which FDA seems to have made is that the Quality Unit is seriously inadequate and not performing their responsibilities. The form 483 identifies multiple repeat observations from previous inspections. The FDA does not include any warning letters issued to the site. A selection of the observations is included below, though it’s worth reading the entire document. Observation 12.B is unusual in that it cites the lack of detail for IT system wiring and network diagrams with more granularity than I’ve seen in the past.

Investigation of both OOS events and customer complaints were not adequate. Numerous examples are provided for each.
Media fill simulations do not have documentation of interventions.
Sampling of vials for finished product is not supported by statistical justification.
Aseptic Processing areas are deficient with regard to environmental monitoring. The sites chosen for monitoring are not scientifically justified.
Field Alerts were not submitted with the required timeframe.
Laboratory records do not include complete records of qualification and periodic calibration of several instruments. An extensive list of examples is provided.
Visual inspection of finished parenteral product is performed by staff who are not challenged on the identification of particles nor are they trained to identify defects including cracks and appearance.
The Quality Unit failed to collect the appropriate number of reserve samples, consistent with their procedure. And the reserve samples were not stored in a manner consistent with commercial product because they were provided an extra level of protection. The firm also could not demonstrate annual visual inspection of these samples.

Dr. Reddy’s Laboratories CTO5

Dr. Reddy’s Laboratories CTO5 received a short 2-page form 483 at the close of inspection on March 5, 2020. This site manufactures APIs.