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WARNING LETTER
WL # 623476

April 11, 2022

Dear Dr. Eppen:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Brigham and Women’s Hospital Inc., FEI 3012030543, located at 75 Francis Street, Boston, MA from August 5 to September 16, 2021.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for positron emission tomography (PET) drugs. See Title 21 Code of Federal Regulations (CFR), part 212 (21 CFR part 212).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your PET 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 October 12, 2021 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 facilities are not adequate to ensure the prevention of contamination of equipment or product by substances, personnel, or environmental conditions that could reasonably be expected to have an adverse effect on product quality. Procedures to ensure that all equipment is clean, suitable for its intended purposes, properly installed, maintained, and capable of repeatedly producing valid results, are not adequately followed. (21 CFR 212.30(a) and (b)).

You manufacture PET drug products for parenteral administration in a facility that is not adequately designed or controlled for aseptic processing. In addition, you did not ensure that your equipment is suitable for aseptic operations.

Facility Suitability

You failed to provide adequate facilities for the prevention of contamination.

From about July 1, 2020 through October 1, 2020, your facility experienced a series of water infiltrations in and around your Technical Corridor. The water infiltrations occurred in this uncontrolled and unclassified area, which is located behind, and above equipment used in the PET aseptic production operation, including your hot cells, biological safety cabinet, and laminar flow hood. During the inspection, investigators also observed an overhead water supply pipe actively leaking onto the floor within your raw material storage area. Furthermore, your environmental monitoring (EM) program revealed several fungal species in your facility’s ISO 5 classified environments, such as your hot cell used for the manufacturing of drug product [¹⁸F]-Fludeoxyglucose for Injection. In your investigation, you attributed the fungal recoveries in the ISO 5 classified environment to the water infiltrations. Your investigation states that the water infiltrations were due to multiple failures associated with the mechanical suite above your manufacturing area and with the roof penetrations leading into the plenum spaces above your cleanroom areas. Notably, the EM data indicates that the water infiltration problem preceded the date of detection and manifested as a loss of environmental control in your aseptic production facility. The failure to appropriately design and maintain the facility led to a lack of control and subjected drug products to the risk of contamination.

Equipment

From June 29, 2020 to November 25, 2020, your EM program repeatedly recovered microorganisms, including several fungal organisms, from your facility’s ISO 5 areas. Air monitoring in critical areas should normally yield no microbiological contamination. Your EM program also recovered many of the same organisms in the adjacent ISO 7 areas. During this time, you manufactured drug products including (b)(4) batches of [¹⁸F]-Fludeoxyglucose for Injection and (b)(4) sub-batches of [¹³N]-Ammonia for Injection. You acknowledged in your response that you failed to apply the appropriate minimum contact time for a sporicidal disinfectant used within the ISO 5 area of your biological safety cabinets and hot cells. Additionally, we observed an operator insert their upper torso and head into your biological safety cabinet while performing the cleaning and disinfection process. Furthermore, you failed to ensure all operators completed their media fill qualifications within your established requalification periods, which is a repeat issue from your 2019 inspection. Finally, you failed to adequately follow your procedures to investigate each ISO 5 EM result exceeding action level to determine product impact, identify root causes, and to implement effective corrective actions and preventive actions (CAPA).

In your response, you stated that your engineering department conducted responsive emergency remediations for each water infiltration, and that your facility was returned to a state of control in November 2020. However, you halted any further remediations in favor of a “comprehensive” repair project to be completed in February 2022. Your response also indicates that you will continue PET drug manufacturing while remediating your facility. You did not discuss your plans to proactively assess your facility and the Technical Corridor for its adequacy to manufacture PET drugs, including the prevention of contamination. Your response is inadequate because you did not include a sufficient plan for ensuring that your facility is robustly designed and maintained. Furthermore, you did not explain what additional steps you would take to prevent contamination while you continue manufacturing during remediations. Your response also failed to sufficiently address your ISO 5 decontamination program to improve its robustness such as assessing the potential for increasing disinfection frequency, ensuring more comprehensive application of disinfectants to all surfaces in critical environments and surrounding environments, and other steps that would ensure more effective disinfection.

Your response also acknowledged the need to investigate each quality related event. As a correction, you revised your Quality Management Systems SOP to reinforce investigation and reporting of all quality related events as required by your Environmental Control SOP and your Interpretation/Investigation of Positive Media Results SOP. Your response is inadequate because you did not describe why you failed to follow your established procedures nor indicate how you intend to assure that your written procedures will be consistently followed in the future.

PET drug products have short expiry periods. Consequently, PET drug products are released and administered before the results of batch specific sterility testing and EM are known. Your ongoing EM program is essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.

In response to this letter, provide the following:

• 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 ISO 5 areas
o Equipment placement and ergonomics
o Air quality in ISO 5 areas and the surrounding areas
o Facility layout
o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)
o Facility management systems and environmental controls (e.g., temperature, humidity, air handling, interactions of areas of differing classifications)

• 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, control, and maintenance.
• Your plans and results evaluating whether an adequate state of control was maintained for PET drug production during your facility remediation activities.
• A list of all environmental monitoring results outside alert and action limits for ISO 5 and ISO 7 areas since November 2020.
• Your 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, timely upgrades to equipment and facilities, adherence to appropriate preventive maintenance schedules, effective execution of repairs, and improved systems for ongoing management review.
• Your procedures for conducting routine facility walkthroughs, at appropriate frequencies, to assess the state of repair of your facility in order to mitigate contamination hazards.
• Evaluation whether cleaning and disinfecting methods (e.g., agents, procedures, frequency) used in all classified areas are effective.
• Your facility qualifications, media fills, and most recent static and dynamic smoke studies performed for both the biological safety cabinet and laminar flow hood during and since completion of the facility remediation.
• Complete investigations into all batches with potential microbial contamination. The investigations should detail your findings regarding the root causes of the contamination.
• Appropriate microbiological raw material, in-process, and batch release specifications (i.e., sterility, endotoxin, total counts, appropriate identification of in-process bioburden flora) for each of your drug products.
• Your plan to ensure your staff will adhere to your established procedures.

2. Your firm failed to conduct adequate investigations and take appropriate corrective action when a failure of a production batch or any component of the batch failed to meet any of its specifications. (21 CFR 212.20(d)).

You failed to conduct adequate investigations into multiple out-of-specification (OOS) endotoxin results, including implementing appropriate and effective CAPAs.

For example, analysis of drug product [¹³N]-Ammonia for Injection, batch 13NNH3210511-A revealed an OOS result for endotoxins, and the batch was released without an adequate investigation. An initial OOS test result was invalidated due to a system suitability failure. A second analysis, which met system suitability criteria, obtained an OOS result of 30.7 EU/mL (exceeding your (b)(4) EU/mL specification). You resampled from the final product vial and conducted another test, which met the specification. You repeated the analysis, which also yielded a passing result. You released the batch and subsequent sub-batches based on the passing results.

You invalidated the OOS result without conducting an adequate investigation for potential sources of contamination, and concluded that “concerns with (b)(4) were confirmed using a new bottle of (b)(4)”. Your investigation failed to include testing of the initial reagent bottle of (b)(4) to support your assumed cause of the OOS. Your investigation also did not clearly identify errors by the laboratory in the handling of the (b)(4) as the cause of the OOS. Your investigation also identified neither corrective nor preventive actions. Despite a failure to clearly establish a laboratory cause, you did not extend your investigation into potential manufacturing causes. The investigation failed to evaluate the potential sources of endotoxin contamination from the upstream process including contamination from manufacturing equipment, raw materials, processing conditions, or the working environment.

In your response, you revised your Quality Management System SOP to include concepts from FDA’s Guidance for Industry, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production and standardized your reporting format. However, your response is inadequate because you did not provide a retrospective evaluation of OOS endotoxin testing results. It is also unclear whether you revised your Pyrogen Testing SOP to reflect revisions to your Quality Management System SOP, as your Pyrogen Testing SOP still allows the testing of OOS endotoxin results until (b)(4) passing results are obtained without limiting the number of retests that can be conducted.

For more information about pyrogen and endotoxin testing, see FDA’s Guidance for Industry Pyrogen and Endotoxins Testing: Questions and Answers https://www.fda.gov/media/83477/download.

In response to this letter, provide the following:

• A retrospective review of all invalidated OOS (including in-process and release/stability testing) results for PET drug products and a report summarizing the findings of the analysis, including the following for each OOS:

o Determine whether the scientific justification and evidence related to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

• A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:

o Quality unit oversight of laboratory investigations
o Identification of adverse laboratory control trends
o Resolution of causes of laboratory variation
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o Adequately scoping of each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations

Guidance on Positron Emission Tomography (PET) Drugs

See FDA’s guidance document, PET Drugs—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing, at https://www.fda.gov/media/71026/download.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations 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.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility in connection with your products. 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 drugshortages@fda.hhs.gov, 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 promptly and adequately address this matter 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.

If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.

Send your electronic reply to ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter # 623476 and include FEI: 3012030543.

If you have questions regarding the content of this letter, please contact CDR Liatte Closs, Compliance Officer, at liatte.closs@fda.hhs.gov.

Sincerely,
/S/

Craig Swanson
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations Division I
New Jersey District

CC: Peter Holton, Director of Operations BICOR
Brigham and Women’s Hospital Inc.
75 Francis Street
Boston, MA 02115
Email: pholton@partners.org