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USFDA Flags Quality, Procedural Lapses At Lupin’s Mandideep Facility

The U.S. FDA inspected Lupin's Mandideep facility from Nov. 14 to Nov. 23, 2022, the company said in an exchange filing.

<div class="paragraphs"><p>(Source: Unsplash)</p></div>
(Source: Unsplash)

The U.S. drug regulator has flagged quality and procedural lapses at Lupin Ltd.’s drug product and active pharmaceutical ingredients manufacturing facility in Mandideep, Madhya Pradesh.

“U.S. FDA inspected Lupin's Mandideep Unit-1 facility from Nov. 14, 2022 to Nov. 23, 2022," the company said in a Nov. 24 exchange filing. "The inspection of the facility closed with issuance of a Form 483 with eight observations each for the drug product facility and API facility at the site.”

A Form 483 is issued when investigators have observed any condition that, in their judgment, may constitute violation of the Federal Food, Drug and Cosmetic Act and related acts.

“We are committed to addressing the observations and will work with the U.S. FDA to resolve these issues at the earliest. We do not believe that this will have an impact on disruption of supplies or the existing revenues from operations of this facility,” the company said.

BQ Prime has obtained a copy of the observations from the U.S. FDA.

Here are the key highlights:

For Drug Product Facility

  • Failure to review any unexplained discrepancy and failure of a batch or any of its components to meet specifications. Two instances were noted.

  • Appropriate controls not exercised over computer or related systems to ensure changes in production and control records are made by authorised personnel only. Three instances were noted where procedures (SOPs) were deficient, common passwords were used and some manufacturing equipment-related data was not stored or recovered.

  • Written procedures are not established for evaluations conducted annually to review records associated with representative batches, whether approved or rejected specifically. The annual product quality review is deficient such that it does not have provision for review of uniformity data.

  • Records of production, control, distribution, components and labelling associated with a batch of products were not maintained for at least one year after expiration.

  • Documents related to marketed complaint reports were shredded and log books do not provide a detailed description on the good manufacturing practices documents and records that were shredded.

  • Equipment used in manufacturing, processing, packaging and holding of drug product lack appropriate design to facilitate operations for intended use and for cleaning and maintenance. Concerns were noted regarding current engineering practices, where there was a lack of diagrams, drawings and standard operating procedures that define good engineering practices.

  • Routine calibration of automatic and mechanical equipment is not performed, as per written program design, to assure proper performance. The metal detection challenge is not performed during re-qualification of some capsule standards, as per protocol.

  • The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. Specifically, SOP is silent about review and approval process for engineering drawings and diagrams, and content of trend evaluation process for handling deviations in GMP operations.

  • The dosage forms are manufactured in Grade D (ISO 8) manufacturing areas. There is no periodic particle level testing done prior to, during and post-manufacturing process to verify whether the area is Grade D compliant.

For API Observation

  • Investigations are inadequate to identify root cause of failure of batch of intermediates or API to meet specifications, whether or not the batch was distributed. Two instances were noted.

  • Critical process parameters identified in the manufacture of APIs and intermediates are not continuously monitored. No alarm system to monitor temperature excursions in critical manufacturing steps and investigations to identify root cause of out-of-specification and out-of-trend results are inadequate.

  • Computer systems do not have sufficient controls to prevent unauthorised access or changes to data. Certain records were deleted, despite there being no provision in the SOP for the same. Some manufacturing equipment-related data is not stored and cannot be recovered.

  • A marketed complaint from the customer indicated that "black powder found in API powder during sampling". Certain concerns were observed, which indicated that there was no data to document that the corrective action and preventive action was effective to control and prevent recurrence of such particles.

  • The validation batch production records do not provide any measurable value (e.g. kg) for loading of material and there is no record documenting the volume or quantity of material.

  • There are concerns around current engineering practices. There are no updated diagrams for HVAC (heating, ventilation and air conditioning units), no isometric diagram for pipes that provide utility in manufacturing and no standard operating procedures that define good engineering practices.

  • SOP is silent about review and approval process for engineering drawings and diagrams.

  • The API are manufactured in Grade D (ISO 8) manufacturing areas. There is no periodic particle level testing done prior to, during and post-manufacturing process to verify whether the area is Grade D compliant.

Lupin has yet to respond to BQ Prime’s emailed queries on the implications of the observations, the steps being taken to address these issues, the expected timelines for resolution, whether there are any pending approvals from the facility and would they get impacted.

Shares of Lupin were trading 2.33% higher, as of 3:22 p.m., compared with a 0.84% rise in the Sensex.