Sanofi MARCS-CMS 690604 — January 15, 2025

WARNING LETTER

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• Delivery Method: Via Email
• Reference #: 320-25-22
• Product: Drugs

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• Recipient: Mr. Paul Hudson; Chief Executive Officer; Sanofi; 54, Rue La Boétie; 75008 Paris; France

• Issuing Office: Center for Drug Evaluation and Research (CDER); United States

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Warning Letter 320-25-22

January 15, 2025

AMENDED
(This letter replaces Warning Letter No. 320-25-22 dated December 16, 2024.)

Dear Mr. Hudson:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Genzyme Corporation (a Sanofi subsidiary), FEI 1220423, at 8, 31, 45, 49, 51, 55, 68, 74, 76, 80 New York Ave., Framingham, MA, from June 12 to July 9, 2024.

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your APIs 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 July 29, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

1. Failure to investigate all critical deviations.

FDA documented that approximately 20 percent of bioreactor runs attempted between January 2022 and July 2024 were rejected for contamination or other quality failures. This rate is excessive and calls into question the state of control of your process. You failed to conduct adequate investigations into critical deviations, including multiple microbiological contamination events recorded in this timeframe. For example:

A. Two lots of (b)(4) and three lots of (b)(4) were out-of-specification (OOS) for appearance due to the presence of (b)(4) particles and were not adequately investigated.

B. Three in-process high-pressure events associated with product leakage during the transfer of bulk (b)(4) through a (b)(4) to (b)(4) L shipping bags were not adequately investigated.

Your investigations failed to identify all potential contributing causes, did not consider the conclusions of an engineering study that contradicted your assigned root cause for the OOS appearance events, and did not document all investigational activities, including the collection of at least one sample found in a storage room by FDA investigators.

In your response, you reference numerous corrective actions and preventive actions (CAPAs) initiated to address the inadequate investigations into the microbiological contamination and the in-process high-pressure events including:

• “… additional quality oversight of significant deviations…,”
• implementation of “… an investigation job aid” for (b)(4) technology items that help determine product impact,
• and revising your procedure governing appearance testing of APIs to ensure the observation of particles will result in an investigation that includes particle characterization.

Your response is inadequate. You did not provide the completed investigations alluded to in your response, identify the root cause(s), justify each CAPA, or explain how the effectiveness of the CAPA will be determined. You also did not address the impact of excessive (b)(4) particles in your drug substances potentially reducing the ability of (b)(4) to successfully remove objectional microbiological contamination.

In response to this letter, provide:

• An update on your investigation into reducing particle load in your process. Include in this update both an updated control and removal strategy, including an analysis of load, (b)(4) capacity, (b)(4), and parameters to monitor to ensure (b)(4) used to remove microorganisms are not adversely affected by (b)(4) from particulates.
• A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit (QU) oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A retrospective, independent review of all investigations into unexplained discrepancies or the failure of a batch or any of its components to meet any of its specifications for U.S. products, irrespective of whether the batch was ultimately distributed in the U.S. market, and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each investigation: o Determine whether each investigation was thorough, described all investigational activities, including sampling and analysis of samples, identified root cause(s), identified scientifically justified CAPA and appropriate means of determining CAPA effectiveness.
  o Determine whether the scientific justification and evidence relating to an invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
  o For investigations that conclusively establish root cause, provide rationale and ensure that all other methods, procedures, processes, and materials 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.

2. Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes.

You repeatedly deviated from your validated manufacturing process for the production of (b)(4). For example:

A. You performed (b)(4) of the (b)(4) during (b)(4) of the (b)(4) bioreactor runs while the manufacturing process was validated with (b)(4). You identified the (b)(4) process as increasing the risk of microbiological contamination events in an investigation into a March 2024 in-process contamination event.

B. Your manufacturing personnel were observed to use a written work instruction (Pre-Job Briefing) describing itself as “… not a GMP document/process…” to deviate from your validated manufacturing procedure by replacing the (b)(4) with (b)(4) L shipping bag to control the frequency of high-pressure and in-process leaking events. The (b)(4) manufacturing process described in the electronic batch record used by manufacturing personnel was validated using a (b)(4) to process the transfilling of all (b)(4) L shipping bags used in a batch.

In your response, you commit to executing a protocol intended to identify additional CAPA to increase control of upstream processing and thereby reduce the incidence of microbiological contamination events. In addition, you commit to prohibiting the practice of replacing the (b)(4) with (b)(4) L shipping bag during the manufacture of (b)(4). You also state the Pre-Job Briefing document was used incorrectly to implement the change to the validated manufacturing process and commit to identify and correct any other manufacturing instructions that rely on a Pre-Job Briefing document to deviate from the validated manufacturing process.

Your response is inadequate. There is no indication you initiated an investigation into your deviating from the validated manufacturing process by replacing the (b)(4) filling bags on multiple occasions. In addition, there is no retrospective review of batch records for batches within expiry, to identify any other process deviations performed without the appropriate corresponding documentation including risk assessment(s). You did not provide your rationale for ending the practice of replacing the (b)(4) for (b)(4) L shipping bag during the manufacture of (b)(4). Furthermore, you did not identify an alternative control strategy to address the high-pressure events that resulted in the in-process product leakage events. You also did not investigate or describe your CAPA to address your QU’s roles in these deviations from validated manufacturing processes.

When significant variability is observed in a drug manufacturing process or in its input materials, it is essential for executive management to support and implement effective actions to promptly address the source(s) of the variation and ensure a continued state of control.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In response to this letter, provide:

• An assessment of each drug production process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.
• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.
• Timelines for completed further process performance qualification studies on remediated processes for marketed drug products for which a state of control has not been adequately/fully established.
• Process performance protocol(s), and written procedures for qualification of equipment and facilities.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility.

3. Failure to have equipment of the appropriate design and suitability for their intended use for the manufacture of APIs.

Your firm used equipment unsuitable for its intended use in microbiologically controlled manufacturing environments. For example:

A. Mobile carts used in the setup of (b)(4) units required operators to get down to the floor and manually lock and unlock the cart brakes despite previously determining equipment proximity to the floor as a contributing root cause in microbiological contamination events.

B. (b)(4) used to establish temporary sterile boundaries for tubing continue to be used despite being identified in a June 2023 microbial contamination event investigation as possessing a “design flaw” that may allow microbial ingress.

In your response, you commit to removing all brakes from the (b)(4) carts, assessing potential design improvements to the carts, and you note supplemental contamination control training to manufacturing personnel. You explain the previous documented description of a design flaw in the (b)(4) was incorrect, and the problem is a “design limitation” that requires specific instruction to fully mitigate the risk of microbiological contamination. You also commit to verification of the (b)(4) usage by a second operator.

Your response is inadequate. You disregarded your previous conclusion that equipment and personnel proximity to the floor is a contributing root cause in microbiological contamination events and state the design of the mobile carts is “… fit for purpose when used per the SOP and in a manner consistent with manufacturing training.” You do not commit to reassess manufacturing equipment to ensure it is of appropriate design to minimize the risk of microbial contamination. You do not describe the (b)(4) “design limitation” or explain why this “design limitation” was not previously mitigated. You also do not discuss how the revised instructions for usage and verification will mitigate the risk associated with their use.

In response to this letter provide, your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, ensuring suitability for use, 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.

4. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.

Our inspection documented approximately 84 open and past due deviation investigations existed as of June 21, 2024. For example:

A. QE-000270 (187 days past due)
B. QE-004069 (179 days past due)
C. QE-004896 (129 days past due)
D. QE-023790 (45 days past due)

Multiple past due investigations also lacked procedurally required extensions to the due date.

The procedure governing deviation handling requires non-significant deviations be closed within (b)(4) and significant deviations be closed within (b)(4). The procedure further requires a documented and approved request for extension in the event a deviation investigation cannot be closed within the specified timeframe.

In your response, you identify four contributing root causes: excessive personnel attrition of trained investigators, process knowledge gaps amongst newer investigators, prioritization of investigations associated with lots pending release, and inconsistent communication of “deviation performance metrics.”

Your response is inadequate. Although you identified CAPA, for each contributing root cause, you did not provide sufficient detail for their implementation. You commit to adding resources to your “Compliance Engineer and QA team to sustain the deviation quality system…” and assess this action “… against adherence to performance metrics and the (b)(4) planning exercises for resource allocation.” You also commit to reassigning existing personnel and to bring in subject matter experts to assist with addressing the investigation backlog but do not explain how this will impact other operations, how these personnel will be trained to conduct specific aspects of the investigations, and how their performance will be monitored and assessed.

In response to this letter, provide:

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources, including adequate training, to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate.
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
o A complete and final review of each batch and its related information before the QU disposition decision.
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.
o Also describe how top management 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.

5. Failure to ensure all production deviations are reported and evaluated, and that critical deviations are investigated, and the conclusions are recorded.

Multiple production deviations went unaddressed until our investigators informed facility personnel of the issues. For example:

A. An (b)(4) line used for aseptic processing was observed to be touching the floor during (b)(4) setup activities. The batch record specifically includes an instruction for personnel to ensure production lines do not contact the floor.
B. An operator was observed to touch their gown and hairnet with their hands and then handle sterile manufacturing equipment without sanitizing their hands.
C. The (b)(4) located between the (b)(4) L (b)(4) and a (b)(4) L shipping bag was observed to be oriented (b)(4) during processing of (b)(4) lot (b)(4). The batch record specifically instructs personnel to orient the (b)(4).

In your response, you commit to conducting additional training for all facility personnel and to revise your (b)(4) contamination control training to include additional instructions on when to use (b)(4) and when gowning changes are appropriate. You also commit to making procedural changes associated with equipment management and using additional resources for operational coaching and oversight.

Your response is inadequate. You do not provide your investigation(s) into the objectionable behaviors, assess your training program, or assess your oversight of setup and manufacturing operations.

In response to this letter, provide:

• Your investigation(s) into the objectionable behaviors.
• Your revision(s) to personnel training and written procedures that instruct personnel on proper aseptic practices including situations requiring sanitization of gloves.
• An assessment of training program effectiveness for all training given to personnel performing activities in, and in support of, production activities. Your assessment should include identification of specific CAPA, date(s) of implementation, and the means of determining CAPA effectiveness.

Quality Unit Authority

Significant findings in this letter indicate that your QU is not able to fully exercise its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

Conclusion

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

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 deviations 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 deviations may also prevent other Federal agencies from awarding contracts.

Failure to address deviations 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 deviations 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 deviations.

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 deviations 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 CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1220423 and ATTN: Jason F. Chancey.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research