Mfg News: Abraxis, Lupin, Sandoz & Allogene OverlandBy
A roundup of manufacturing news from Abraxis Bioscience, Lupin, Sandoz, and Allogene Overland Biopharm. Highlights below.
* FDA Issues Warning Letter to BMS Subsidiary Abraxis Bioscience
* FDA Issues Warning Letter to Lupin’s API Mfg Facility
* Sandoz Investing $50.1 M To Increase Antibiotic Capacity
* Allogene Overland Biopharm Completes Buildout of CAR T-Therapy Mfg Facility in Shanghai
FDA Issues Warning Letter to BMS Subsidiary Abraxis Bioscience
The US Food and Drug Administration (FDA) has issued Abraxis Bioscience, a Los Angeles, California-based drug-product company, and a subsidiary of Bristol Myers Squibb, a Warning Letter following an inspection of the company’s finished pharmaceutical manufacturing facility in Phoenix, Arizona. The FDA’s inspection took place from March 28, 2022, to April 6, 2022, and the FDA issued the Warning Letter following the company’s April 27, 2022, response to a Form 483, whereby the FDA cited the company for cGMP violations.
The main cGMP violation cited by the FDA was the company’s failure to effectively implement corrective actions and preventive actions (CAPA) and return its aseptic processing line and manufacturing operations to a state of control following unexplained discrepancy or failure of a batch. The FDA specifically noted that multiple media-fill failures occurred between April and October 2021, when simulating aseptic processing operations on the filling line used for Abraxane (paclitaxel), the company’s anticancer drug. The FDA said the company’s investigations into the following media-fill failures were inadequate in that they lacked sufficient rigor in determining root causes and scope of impact after the media fills revealed serious non-sterility risks in the company’s aseptic process operations.
In response to the Warning Letter, the FDA is requiring the company to conduct a comprehensive risk assessment of all contamination hazards with respect to its aseptic processes, equipment, and facilities. The FDA is requiring the company submit a detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. It also is requiring that the company submit a CAPA plan to implement routine, vigilant operations and management oversight of facilities and equipment.
Additionally, the FDA is requiring the company to conduct a comprehensive, independent assessment of the company’s overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures and to provide a detailed action plan to remediate this system. It is also requiring that the company provide a detailed description of the degree of involvement of quality assurance (QA) staff in evaluation, oversight, performance, and guiding of the content and depth of its investigations, including explaining the role and authority of the QA function in assuring appropriate root-cause determinations and identification of an effective CAPA plan. The FDA is also requiring that the company provide a retrospective evaluation by a qualified third party of investigations and failure modes related to the capability of the company’s aseptic processing operation to robustly produce sterile drugs. Additionally, the FDA is requiring a complete list of complaints for Abraxane since January 2019, including the lot number, date of manufacture, sufficient narrative regarding the nature of the complaint, any CAPA steps taken, and conclusions.
Source: US Food and Drug Administration
FDA Issues Warning Letter to Lupin’s API Mfg Facility
The US Food and Drug Administration (FDA) has issued Lupin, a Mumbai, India-headquartered bio/pharmaceutical company, a Warning Letter for cGMP violations following an inspection of the company’s active pharmaceutical ingredient (APIs) manufacturing facility in Boisar, Palghar, Maharashtra, India. The FDA’s inspection took place from March 22, 2022, to April 4, 2022, and the FDA issued the Warning Letter following the company’s April 25, 2022, response to a Form 483, whereby the FDA cited the company for several GMP violations. In issuing the Warning Letter, the FDA said that company did not provide sufficient detail or evidence of corrective actions to bring operations into cGMP compliance. In issuing the Warning Letter, the FDA acknowledged that the company suspended production of drugs from the facility to the US market and requested the company clarify whether it intended to resume manufacturing of drugs at this facility for the US market in the future and to notify the FDA before resuming such operations.
Among the GMP violations cited by the FDA were inadequate written procedures and practices for cleaning equipment used in the release of intermediates and APIs. Specifically, the FDA said that the company performed multiple risk assessments with the purpose to verify whether existing cleaning procedures and practices eliminate or reduce genotoxic impurities. It also performed risk assessment to evaluate other impurities from cross-contamination by evaluating residues on non-dedicated production equipment and within recovered solvents. The FDA said that the company’s risk assessments lacked data to support that existing equipment cleaning procedures were effective in removing such impurities along with residual API from each respective piece of equipment to acceptable levels.
In response to the Warning Letter, the FDA is requiring the company to conduct a comprehensive, independent retrospective assessment of its cleaning effectiveness to evaluate the scope of cross-contamination hazards. Based on that retrospective assessment, the FDA is requiring the company to issue a corrective action and preventive action plan of its cleaning program to include appropriate remediations to its cleaning processes and practices and to provide and timelines for completion.
The FDA also cited the company for failure to establish written procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics of intermediates and APIs. It said that while the company’s benchtop data suggests its purging process is effective, its commercial manufacturing data show that its purging does not remove all genotoxic impurities to a consistent level. Given the variability found in impurities levels in API, which may stem from special cause variation, to add further testing procedures. It is requiring the company conduct a process capability analysis to evaluate the formation, monitoring, and control of genotoxic impurities in intermediates and APIs manufactured by the company and to perform a comprehensive risk-based review for currently manufactured products.
The FDA also cited the company for failure to identify and investigate all critical deviations including limit excursions, and out-of-specification (OOS) results. The FDA is requiring that the company provide a comprehensive assessment and remediation plan to ensure its quality unit (QU) is given the authority and resources to effectively function. The assessment should also include: (1) a determination of whether procedures used by the company are robust and appropriate; (2) provisions for QU oversight throughout the company’s operations to evaluate adherence to appropriate practices; (3) a complete and final review of each batch and its related information before the QU disposition decision; and (4) oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products. It also requiring retrospective review of all data used to qualify or validate processes associated with the manufacture of APIs within expiry or release materials within expiry to identify all instances of non-conforming results and ensure they are addressed appropriately.
The FDA issued the Warning Letter on September 27, 2022 and posted it on its website on November 1, 2022. In a notification to the Bombay Stock Exchange on September 29, 2022, Lupin said that it does not believe that the Warning Letter will have an impact on disruption of supplies or the existing revenues from operations of the facility and that it is committed to addressing the concerns raised by the FDA and will work with the FDA to resolve these issues.
Sandoz Investing $50.1 M To Increase Antibiotic Capacity
Sandoz, the biosimilars and generics division of Novartis, is investing an additional EUR 50 million ($50.1 million) for increased manufacturing capacity for finished dosage form (FDF) penicillins across Europe.
The new three-floor building will be connected to the existing penicillin production facility and will cover an additional area of 1,875 m². It will focus on bulk formulation and fill–finish activities for penicillins for global distribution. Sandoz said that the new building will be ready for operation by early 2024, and that the expansion will cause a double-digit increase in its future output capacity for penicillins.
The new investment follows plans announced last year (2021) to invest more than EUR 100 million ($100.2 million) in new manufacturing technology for the production of oral amoxicillin active pharmaceutical ingredient (API) in its facility in Kundl, Austria, as well as plans to invest an additional EUR 50 million ($50.1 million) for sterile API production in Palafolls, Spain. Combined with Austrian federal government plans to contribute or coordinate public funding of approximately EUR 50 million ($50.1 million), the total amount now being invested in the Sandoz antibiotics network across Europe is over EUR 250 million ($250.5 million).
Allogene Overland Biopharm Completes Build-out of CAR T-Therapy Mfg Facility in Shanghai
Allogene Overland Biopharm, a joint venture company of Overland Pharmaceuticals, a Shanghai-based bio/pharmaceutical company, and Allogene Therapeutics, a Lausanne, Switzerland-based clinical-stage bio/pharmaceutical company of allogeneic chimeric antigen receptor T cell therapies, has completed the build-out of its allogeneic CAR T therapy manufacturing facility in Shanghai, China.
The 68,000-square-foot GMP facility has a modular design for all types of cell-therapy production. This scalable approach allows for simultaneous manufacturing of several allogenic CAR T products and is intended for the manufacturing of products for Asia.
Source: Allogene Overland Biopharm