The U.S. drug regulator has flagged quality and procedural lapses across Biocon Ltd. subsidiary's three sites.
“The U.S. Food and Drug Administration conducted three on-site inspections of Biocon Biologics Ltd.'s seven manufacturing facilities spanning two sites in Bengaluru, India and one at Johor, Malaysia. These inspections started with the Bengaluru site on Aug. 11, 2022 and concluded with the Malaysia site on Aug. 30,” the parent said in an Aug. 31 exchange filing.
“At the conclusion of these inspections, the agency has issued Form 483s with 11 observations each for the two sites in Bengaluru and six observations for the Malaysia site.”
A Form 483 is issued when investigators have observed any condition that in their judgment may constitute violation of the Food Drug and Cosmetic Act and related acts.
These inspections, the filing had said, were triggered for three pre-approval inspections for biosimilar Bevacizumab (cancer), rh-Insulin and Insulin Aspart (diabetes) and a capacity expansion inspection for biosimilar Trastuzumab (stomach cancer). These included multiple drug substance and drug product facilities and other support infrastructure at these sites.
“The observations primarily relate to the need for improving strategies for microbial control, enhancing quality oversight, augmenting the use of software applications and computerised tools to aid risk assessment and investigations and other procedural and facility upgrades,” the company had said in the filing.
The drugmaker also said it would submit corrective and preventive action plans to the U.S. FDA in the stipulated time frame. “We do not expect the outcome of these inspections to impact the current supply of our products.”
The observations had caused Biocon's shares to decline on Sept. 1.
BQ Prime has obtained a copy of the observations from the FDA on the three drug substance and product manufacturing sites.
Bommasandra-Jigani Link Road, Bengaluru
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed. Setup of vial filling lines, set up of sterile components were not always performed aseptically to protect air and prevent cross contamination. Environmental and personnel monitoring the aseptic areas, operations, equipment used and procedures of sample collection followed are deficient.
Environmental monitoring program does not include appropriate measures to monitor and control fungal contamination, adequate corrective actions are not taken to address the persistent trend of fungal contamination. Lack of established cleaning and sanitisation program to prevent microbial contamination and facility and equipment are not of adequate design and were difficult to clean or rusted or corroded. These do not ensure prevention of contamination and can adversely impact product quality.
Written records of investigations into unexplained discrepancies and failure of batch to meet specifications (out-of-specification) do not always have conclusions and follow-up. The impacts of contaminations are not adequately assessed to identify root causes.
Quality unit has not been effective in ensuring that manufactured products are in accordance with current good manufacturing practices. Failures to control review of laboratory testing data, conducting investigations and conducting activities as per written procedures were identified. Deviations from written test procedures and laboratory mechanisms are not recorded or justified.
Quality unit's overseeing of GMP manufacturing and laboratory operations is inadequate.
Lack of assurance that cleaning procedures for shared product-contact process equipment at the facility are effective in preventing cross-contamination. There is failure to include all necessary surface swab samples or there is missing data in quality control studies.
Laboratory controls do not include establishment of appropriate standards to assure quality and purity of components and in-process materials.
Inadequate procedural controls to protect electronic data acquisition and/or manufacturing control systems. There is risk to original data protection, data backup and retrieval.
Computer systems used in testing of drug products are not of appropriate design for intended use. Inadequate written procedures for selecting software vendors and review of CCTV's installed.
GMP equipment is used outside its validated acceptance criteria (temperature) for critically controlled material.
Some critical utility used for manufacturing facility has not been sampled at the points of use and tested for purity, odour.
Hosur Road, Electronics City, Bengaluru
Drug substance manufacturing facilities are not adequate to ensure prevention of contamination of equipment or product by environmental conditions that could adversely impact product quality. This is specially with regards to the fermentation and cell manufacturing areas. Raw materials used are weighed in uncontrolled, unmonitored environment. Fermenters have experienced at least four failures due to microbial contamination since FY2020. No microbial monitoring performed on certain steps.
Lack of assurance that manufacturing operations are appropriately designed to prevent microbiological contamination of the drug substance.
Quality unit has not performed necessary assessments to ensure that objectionable conditions do not negatively affect manufacturing process and quality control tests not performed in support of finished drug substances. Also, electronic systems and data is deficient.
Handling of customer complaints with regards to drug products was inadequate. Valid customer complaints were incorrectly classified as queries and not adequately investigated.
Lack of assurance that fermentation culture contamination check is able to recover contaminating microorganisms as no data was provided to demonstrate the same. Certain contamination check plates were observed to be cracked.
Failure to ensure identification of appropriate root causes, assess potential product impact and implement suitable corrective action.
Lack of assurance that incoming raw materials are appropriately tested prior to use. Inadequate justifications or risk assessments for raw material not meeting quality expectations.
Inadequate assurance that cleaning procedures are effective to prevent cross-contamination for shared product-contact process equipment. Failure to include swab sampling and testing in fermentation and cell equipment cleaning validation study and inadequate instructions in manual cleaning procedures for operators.
Not established adequate procedural controls to protect electronic data acquisition and systems used on manufacturing control.
Lack of assurance that water used in manufacturing drug substances is suitable for intended use.
Quality unit's overseeing of GMP manufacturing and laboratory operations is inadequate. There is lack of security control to prevent access to GMP utility and equipment. Also, no quality agreement between Biocon Ltd. and Biocon Biologics that supplies water to the facility.
Johar, Malaysia
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed. No assurance that aseptic process simulation studies performed are representative of routine setup, spray sanitising of equipment was not done appropriately.
Lack of evidence that cleaning procedures used for non-product-contact process equipment in RABS (a barrier system for aseptic processing) is validated to prevent contamination.
Quality unit's overseeing of GMP manufacturing and laboratory operations is inadequate.
Deviation investigations are inadequate. Failure to adequately identify root cause of certain issues and implement appropriate corrective and preventive actions for OOSs (out-of-specification).
Lack of assurance that water used in manufacturing drug substances is suitable for intended use. Risk assessment evaluating the water used is inadequate.
Batch records for drug substance batches had multiple correction footnotes, calculation errors and incorrect justifications rendering them inadequate.
The drugmaker in response to BQ Prime's emailed queries said it had submitted corrective and preventive action plans within the stipulated time frame to the U.S. FDA, addressing the observations made by them following inspections of their manufacturing facilities in India and Malaysia.
“We expect the agency to review our responses and revert with their comments within a specific time frame. At the end of the inspection, the agency did not indicate any change in the approval timelines for our biosimilars. We do not expect any impact on the supply of our currently commercialized products.”
The company said it is confident of addressing the observations to the agency's satisfaction. “Biocon Biologics remains committed to global standards of quality and compliance.”
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