- Delivery Method:
- Via Email
Recipient NameMr. Robert Kramer
Recipient TitleChief Executive Officer (CEO)
- Cangene BioPharma, LLC dba Emergent BioSolutions
400 Professional Drive Suite 400
Gaithersburg, MD 20879
- Issuing Office:
- Division of Pharmaceutical Quality Operations I
Warning Letter CMS # 630316
August 10, 2022
Dear Mr. Kramer:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cangene BioPharma, LLC dba Emergent BioSolutions, FEI 1000512361, at 1111 South Paca Street, Baltimore, MD 21230, from February 7 to 11, 2022, and from February 14 to 18, 2022.
This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your March 10, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific violations including, but not limited to, the following.
1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and you failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and (b)).
Your system for ensuring suitable design and adequate control of equipment was deficient. Your firm failed to use suitable equipment for aseptic manufacturing, which led to particulate contamination of your sterile drug products.
Multiple customer complaint investigations related to the presence of foreign particulates (i.e., metal particulates) in your drug products determined that the root cause was associated with the (b)(4) and (b)(4) tray units, both equipment that are present in your manufacturing environment and used in your aseptic processing operations. One of the investigations documented that seven vials were found to have metal particulates and an additional vial was found to have silicone particulates. The investigation also deemed the metal and other particulates to be “intrinsic” to the manufacturing process and stated that no further action was required. Your investigation added that the metal particulates likely entered the vials through manipulation of your tray units.
You examined approximately (b)(4) tray units and found that most (b)(4) needed to be further evaluated due to apparent damage. Further evaluation of your tray units confirmed they were inadequate for use in sterile drug production and should have been removed as part of preventive maintenance.
Your procedure for maintenance of (b)(4) tray units was inadequate. Your procedure, “SOP 9087, Inspection, Cleaning, and Storage Procedures for Trays and (b)(4)” indicated that tray units should be visually inspected prior to use in the manufacturing process, however, it lacked specificity regarding how you document your activities for the inspection, identification, segregation, evaluation, and repair and/or retirement of defective tray units. Our investigator also noted that you lacked documentation and adequate reconcilability for the visual inspection of tray units.
In your response, you state you will initiate improved inspection of all tray units, and any confirmed unacceptable trays will be submitted for repair and/or replacement. You also commit to revise your SOP 9087, “Inspection, Cleaning, and Storage Procedures for Trays and (b)(4),” to include examples of conditions that require maintenance assessment for repair or replacement (e.g., excessive scratching, old age, and worn appearance).
Your response is inadequate. You did not provide substantive evidence that your tray units are suitable for their intended purpose. Your response also lacks a systemic review of the preventive maintenance program used by your facility, including but not limited to replacement frequencies. Furthermore, you did not provide documentation of the actions taken on the defective tray units you evaluated. Also, you did not provide sufficient details regarding how your firm will ensure tray units are effectively identified and tracked (i.e., with unique identification number) to ensure suitability prior to use in production.
Your response also fails to address how you will ensure adequate investigation of intrinsic and extrinsic visible particulate contamination issues. You do not commit to accurately define and categorize intrinsic and extrinsic particulates in your operation, and to properly evaluate visible particulate contamination in your parenteral products. It is important that intrinsic visible particulate contamination is appropriately evaluated and investigated. In addition, extrinsic or foreign particulate contamination should occur very infrequently and be thoroughly investigated.
In response to this letter, provide:
- Your corrective action and preventive action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
- A CAPA plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
- A comprehensive, independent review and remediation plan for the design, control, and maintenance of the (b)(4) units used in your manufacturing process.
- Your revised procedure(s) which include the identification of all (b)(4) tray units, and the process of tracking and tracing for maintenance and determining suitability for use.
- An independent review of your classification and investigation of particulate contamination in your products. The review should comprehensively assess your program, including but not limited to ensuring appropriate classifications of particulates (e.g., inherent, intrinsic, extrinsic), and appropriate investigations and CAPA.
- A comprehensive assessment and remediation plan to ensure your quality unit (QU) is given the authority and resources to effectively function. The assessment should also include, but not be limited to, evaluating:
o whether procedures used by your firm are robust and appropriate
o sufficiency of provisions used for QU oversight throughout your operations to evaluate adherence to appropriate practices
o whether an effective and complete final review of each batch and its related information is conducted before the QU disposition decision
o implementation of oversight and approval of investigations, as well as discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
Also, describe how top management at your company supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
Your aseptic filling line operations required extensive (b)(4) interventions during the manufacturing process. Our investigators observed numerous instances of poor aseptic technique by your operators while performing (b)(4) interventions during production runs. Examples of these poor aseptic techniques include, but are not limited to:
- An operator was leaning into the aseptic filling cabinet which caused blockage of the unidirectional airflow over open glass vials. Notably, there was no subsequent clearance of the vials on the line exposed to potential contamination hazard.
- An operator left the filling cabinet door open for an excessive period.
- Poor practices by operators when manipulating vial tray containers and the (b)(4) used for charging these trays.
In addition, sterile (b)(4) used for (b)(4) interventions inside the filling line cabinet were stored outside the cabinet, adjacent to the swing door. The inadequate storage location of the (b)(4) increases the potential for their contamination.
Your SOP 9002, “Personnel Conduct in the Sterile Core”, Section 6.3 (Material Handling), under subsection 6.3.2 states that personnel should “(b)(4)”. Also, sub-section 6.3.8 mentions that “(b)(4)...”. Your procedure is deficient in that it did not strictly instruct personnel to not disrupt the path of unidirectional air flow during sterile manufacturing process.
To safeguard sterility of the drug product in aseptic processing operations, you must establish robust operational design and procedures, and personnel must employ strict discipline. The poor aseptic techniques observed during the inspection could cause potential breaches in sterility assurance.
You state you have made improvements to your program for monitoring aseptic processing personnel behavior and classroom training on aseptic behaviors.
Your response is inadequate. You do not indicate whether you have conducted a risk assessment that encompasses all batches within expiry and reviewed available videos associated with the batches to identify any poor aseptic practices and associated risks to your marketed drug products. Additionally, you do not provide the procedure for the aseptic processing behavior monitoring program that describes how you will document and evaluate observation(s) to determine if identified aseptic deviations may have impacted drug sterility.
In response to this letter, provide:
- Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of QU oversight (e.g., audit) during aseptic processing and its support operations.
- A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
- A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
o all human interactions within the ISO 5 area
o equipment placement and ergonomics
o air quality in the ISO 5 area and surrounding room
o facility layout
o personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)
- A detailed remediation plan with timelines to address the findings of the independent contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.
Repeat Violations at Facility
Similar deviations were cited in a previous inspection, conducted from April 12 to 16, 2021, and discussed during the regulatory meeting held on October 6, 2021. You responded by proposing specific remediations to address these observations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
Ineffective Quality System
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective operations oversight to ensure reliable operations, we found that your QU was not fully exercising its authority or responsibilities. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and products manufactured by your firm conform to FDA requirements.
CGMP Consultant Recommended
Based upon the nature of the violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at email@example.com, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
Correct any violations promptly. Failure to address this matter promptly and adequately may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.
Failure to address violations may also cause FDA to withhold issuance of Export Certificates. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to address any violations.
This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
Send your electronic reply to ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter CMS # 630316 and include FEI: 1000512361
If you have questions regarding the content of this letter, please contact Jose Hernandez-Guzman, Compliance Officer at firstname.lastname@example.org or 631-787-3002 x1017.
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations Division I
New Jersey District