Marcus Research Laboratory, Inc.

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Marcus Research Laboratory, Inc., FEI 1950348, at 1820 Delmar Blvd., Saint Louis, Missouri 63103, from May 3, to May 14, 2021.

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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 June 4, 2021 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.

Your firm manufactures povidone iodine (PVP-I), API which may be used by your customers to produce presurgical preparatory products. During the inspection, we observed that your Quality Unit (QU) released API lots 100017872R and 100017911C without adequate procedures and processes to ensure that critical deviations are investigated and resolved.

During the production of PVP-I lot 100017872R, on March 4, 2020, your production personnel observed PVP-I in reactor cabinet (b)(4) was smoldering. In response to the risk of imminent fire, production personnel used a fire extinguisher. Due to this incident, production did not proceed as normal. Associated drugs experienced inconsistent temperature exposure and additional processing and hold times. Your firm only tested the affected drums of material for percent of available iodine and released them for further processing.

Similarly, on August 18, 2020 during the production of PVP-I lot 100017911C, your production personnel noted reactor cabinet (b)(4) was smoking. Production was ceased, and the material was held in unknown conditions. Your firm again, solely tested the affected drums of material for percent available iodine and released them for further processing.

In both instances, your firm created deviation reports but released drugs based solely on composite results of percent available iodine. Your drugs were exposed to excess heat, fire, smoke, and debris. Additional contaminants or other particulates from the use of the fire extinguisher may have also compromised the material. In addition, the associated drugs experienced processing parameters beyond the normal validated state.

Your firm did not perform additional testing on lots 100017872R and 100017911C to confirm that the API was not contaminated with harmful particulate matter or other contamination. Additionally, your firm lacked a risk or impact assessment to evaluate the exposure of the API to the extraneous debris or contamination resulting from the incidents. The QU released lots 100017872R and 100017911C without ensuring the critical deviation was fully resolved, and any residual chemical contaminants and particulate risks were fully addressed.

In your response, you stated that you are “currently seeking advice from a consultant to determine the best path forward on addressing this matter.” Your response is inadequate. You did not provide any supporting documentation that evaluated the impacted lots that you released. Specifically, you did not provide supporting documentation that would ensure the material was free of potentially harmful particulate matter and other extraneous contamination given the intended use of the API, including the potential for use in sterile drug products.

In response to this letter, provide:

• 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 Provide concurrent stability data for the affected lots 100017872R and 100017911C.

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.

• Your action plan to address any product quality or patient safety risks for batches of povidone iodine in U.S. distribution, including potential customer notifications and recalls or market withdrawals.

Your equipment construction was inadequate because your product contact surfaces may alter the quality of the product in that they were additive, absorptive, or reactive. During the inspection, we observed that critical povidone iodine manufacturing equipment, such as the (b)(4) blender, (b)(4), hoppers, and (b)(4), were discolored and rusty. Furthermore, your firm hired a third party to (b)(4) your equipment to remove corrosion and rust (b)(4). Given that you must (b)(4) corrosion from product contact surfaces (b)(4), your contact surfaces are deficient as they can lead to contamination of your product, specifically, particulate matter (e.g., rust).

Additionally, you use trays to further process your product during a (b)(4) stage. During this processing, you wrap the trays with plastic liners. These plastic liners come into direct contact with povidone. FDA investigators observed the plastic liners were tattered and torn, exposing product to plastic particulate matter.

In your response, you stated that (b)(4) is adequate to remove corrosion and that you would evaluate the use of plastic liners. Your response is inadequate, because it lacked scientific justification or supportive documentation for your assertion that (b)(4) is adequate. Furthermore, FDA raised these concerns during the December 2019 inspection and July 2020 regulatory meeting, and you have failed to adequately address them.

In response to this letter, provide:

• Full evaluation of materials of construction of all drug contact surfaces in the facility, with specific focus on additive, absorptive, or reactive factors, and whether they can lead to contamination of the drug distributed. • 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. Your plan should also ensure that appropriate actions are taken throughout the company network.

FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.Q:ov/downloads/Drugs/.../Guidances/ucm073497.pdf.

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and 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 corrective actions and preventive actions 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 deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility/in connection with your product. You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations.

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 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.

Please address your reply via email to: ORAPHARM3_RESPONSES@fda.hhs.gov

Attention: Tina M. Pawlowski, Compliance Officer U.S. Food and Drug Administration Division of Pharmaceutical Quality Operations III

Your written notification should refer to the Warning Letter above (WL #615153). If you have questions regarding the contents of this letter, please contact Tina M. Pawlowski at (313) 393-8217.