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  5. Toyobo Co. Ltd. - 614177 - 08/19/2021
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Toyobo Co. Ltd. MARCS-CMS 614177 —

Delivery Method:
Via Email

Recipient Name
Mr. Hidehiko Kanae
Recipient Title
General Manager
Toyobo Co. Ltd.

2 Chome 1, Katata
Otsu, Shiga

Issuing Office:
Center for Drug Evaluation and Research | CDER

United States

Warning Letter 320-21-55

August 19, 2021

Dear Mr. Kanae:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Toyobo Co. Ltd., FEI 1000251214, at Toyobo (Kabu) Sogokenkyusho, 2 Chome 1, Katata, Otsu, Shiga, from February 15 to 19, 2021, on February 22, 2021, and from February 24 to 25, 2021.

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 product is 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 18, 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.

Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

A. You did not adequately investigate significant particulate defects in your sterile drug product, including recurring incidents of extrinsic particle contamination.

During 2019 and 2020, multiple batches of (b)(4) injection solution were found to have significant particulate contamination defects, many of which are defined in your procedure and response as “foreign” (i.e., extrinsic). When extrinsic particulates were identified within batches, you failed to initiate a timely investigation to determine root causes and assess the drug product impact. Our review revealed that your in-process quality standards, limits, categories, and triggers for investigations do not sufficiently differentiate intrinsic from extrinsic particulate contamination.

A recent investigation update, submitted to FDA on June 18, 2021 (four months after FDA’s inspection), indicates that you have improved your procedures and are performing supplier audits. While your investigation concluded that it is “highly possible” that your washing and sterilization processes could not remove certain particles adhered to the (b)(4) stoppers or vials, you failed to adequately address the upstream root causes of the contamination and implement timely corrective action and preventive actions (CAPA).

In addition, you failed to address multiple instances of a ferrous-(b)(4) complex that was found during visible particle identification studies, including the potential for this contaminant to induce adverse events because of immunogenic response. Your firm indicated that the (b)(4) appears to be from the drug formulation.

Your response discussed the 12 batches cited during the inspection that were found with visible particulates such as cellulose fibers, glass fibers, (b)(4), black and white “particles,” and “stain-” like particles of various colors. You also expanded the investigation to encompass (b)(4) batches that remained within expiry and identified further instances of extrinsic or “non-stopper material.” Notably, stopper “stain” defects were also investigated in 2017. However, your stopper supplier indicated that their process was not the cause of the problem at the time, and your CAPA was inadequate to resolve the problem.

Your response is inadequate. You failed to adequately investigate both extrinsic and intrinsic particulate contamination issues. You did not determine the root cause and implement a timely and effective CAPA to address persistent incidents of extrinsic particulate contamination in your sterile injectable product. Extrinsic particulate contamination should occur infrequently and be fully investigated.

In response to this letter, provide:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification 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.

• An updated risk assessment regarding marketed batches, including:
    o An evaluation of extrinsic particulates found in batches within expiry period.
    o Protocol or sampling procedures and criteria used to select the vials examined as part of your investigation.
    o The potential impact of iron-(b)(4) complexes on safety (e.g., immunogenic response) and efficacy of your product.

• An independent review of all injectable defect limits that includes but is not limited to:
    o Limits and associated rationales for both 100% inspection and Acceptable Quality Levels (AQL).
    o Provide a comprehensive list of all items that could trigger the initiation of an investigation related to foreign particulates.

• An updated investigation into the extrinsic particulate contamination for (b)(4) injection solution, including root causes and all CAPA activities.

B. Your investigation into data integrity breaches, reported to the agency in a (b)(4), was insufficient to determine the scope of the problems at your facility.

Your firm identified recurring instances of the following:

• Operators failed to consistently ensure that personnel monitoring plates contacted gowning surfaces before leaving the ISO 7 area (Grade B).

• Operators failed to consistently ensure that environmental monitoring plates contacted equipment surfaces located in ISO 5 (Grade A) and ISO 7 (Grade B) areas.

• When surfaces were monitored, operators wiped equipment surfaces with (b)(4) before sampling the equipment surface.

• Nonviable particle data for ISO 5 (Grade A) was reported as ISO 7 (Grade B) when particles results were higher than alert levels.

• Operators failed to report ISO 5 (Grade A) airborne particulates values using a portable particulate counter, instead they repeated the monitoring of airborne particulates.

Your investigation lacks sufficient information regarding the extent of the breaches of data integrity. Your investigation lacked a comprehensive assessment into the extent of the “falsification of airborne particles measurement records” and other breaches of data integrity occurring in the facility. Environmental monitoring (EM) data related to operators, equipment surfaces, and non-viable particulate monitoring was unreliable and raised product sterility assurance concerns.

Your investigation also indicates the data integrity breaches were not isolated. You found that (b)(4) of (b)(4) operators were involved in manipulation of contact plate measurements, while all (b)(4) environmental monitoring operators were involved in the manipulation of non-viable particles measurement data.

Our inspection also cited additional weaknesses in the reliability of your documentation, including uncontrolled testing worksheets and deficient systems for reconciliation of laboratory documents.

Based on your investigation, a total of (b)(4) batches of (b)(4), manufactured from 2016 to 2020, could have been impacted by these practices. However, there was insufficient data in your response to support a full determination of the scope of potentially affected batches.

Accurate microbiological data is fundamental to evaluating and maintaining the state of control of an aseptic processing operation. Awareness of microbial excursions in an aseptic processing operation is essential to trigger prompt actions that maintain environmental control. Additionally, timely and thorough evaluation of action level excursions, identifying potential routes of contamination, as well as identifying appropriate follow-up measures are necessary to prevent contamination risks to the product. Your failure to report accurate data compromised the sterility assurance of drug products released from the facility and may have increased risks to patients.

Your response stated that a product impact risk assessment was conducted and that product sterility was not compromised. However, you lacked adequate justification for this conclusion, given the extent and nature of the data integrity breaches that occurred in the facility. In addition, while your response focused on environmental data and a review of “aseptic practices and sterility assurance training and oversight,” its scope did not sufficiently address other areas of deficient data integrity.

Your response mentions that the root cause is associated with “employees not understanding CGMP, the importance of data integrity, and pressure in handling deviations.” We acknowledge your efforts to date of identifying data integrity deficiencies and actions toward improving accountability of all staff at your facility. However, further actions are needed to ensure competency of employees in performing and overseeing aseptic operations and improve quality systems effectiveness and data integrity oversight throughout your entire manufacturing operation.

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., daily activities, audits) 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 rooms
    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 contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

• A plan to perform testing (including sterility, as well as any other test identified by your risk assessments) of retain samples for all batches of sterile drug products manufactured at your facility that remain within expiry in the U.S. market.

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources 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

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.

• 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 or documentation issues, appropriate staffing to perform activities robustly, improvements in capability when needed, adherence to appropriate preventive maintenance schedules, effective execution of repairs, timely technological upgrades to the equipment/facility infrastructure, and improved systems for both daily production supervision and overall operations management.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance with Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download

We acknowledge that you are using a consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide the following:

A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
• A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
• Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
• An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
• A comprehensive retrospective evaluation of the nature of the manufacturing data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

B. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

C. A management strategy for your firm that includes the details of your global CAPA plan. Your strategy should include:
• A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
• A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
• Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
• Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
• A status report for any of the above activities already underway or completed.

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 and to assist your firm in meeting CGMP requirements. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and that the consultant evaluates the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA. 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 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. 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 any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Toyobo Co. Ltd., at Toyobo (Kabu) Sogokenkyusho, 2 Chome 1, Katata, Otsu, Shiga, Japan into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated or misbranded may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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 since our inspection to correct your 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 CDER-OC-OMQ-Communications@fda.hhs.gov.

Identify your response with FEI 1000251214 and ATTN: Rafael E. Arroyo.


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

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