Nephron SC Inc. MARCS-CMS 634647 — October 11, 2022

WARNING LETTER

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• Delivery Method: VIA Electronic Mail
• Product: Drugs

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• Recipient: Ms. Lou W. Kennedy ; Chief Executive Officer and Owner; Nephron SC Inc.; 4500 12th Street Ext.; West Columbia, SC 29172; United States; lkennedy@nephronpharm.com

• Issuing Office: Office of Pharmaceutical Quality Operations, Division II; United States

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October 11, 2022

Case # 634647

WARNING LETTER

Dear Ms. Kennedy:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Nephron SC Inc., FEI 3010892830, at 4500 12th Street Ext., West Columbia, SC from March 28 to April 20, 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).

In addition, the inspection revealed that your firm failed to submit an NDA Field Alert Report to FDA within three working days of receipt of information concerning significant chemical, physical, or other change or deterioration in a distributed drug product, as required by section 505(k) of the FD&C Act, 21 U.S.C. § 355(k) and stipulated by the regulation 21 C.F.R.§314.81(b)(1)(ii).

We reviewed your May 11, 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 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).

Your firm failed to conduct adequate and timely investigations relating to products made by both terminal sterilization and aseptic processing.

Cross Contamination
Your firm manufactures products that undergo moist heat sterilization, including Sterile Water for Injection, USP, Ketorolac Tromethamine Injection, USP, 60 mg/ 2 mL, Sodium Chloride Injection 0.9%, USP, as well as pending application products undergoing development studies.

Your firm’s testing found cross contamination of drugs in at least three lots of drug products. You failed to adequately identify the root cause or scope of potentially impacted lots in a timely manner.

Your investigation was initiated on April 2, 2021, when you detected the presence of the drug Bupivacaine, produced from your outsourcing facility (under section 503B FD&C Act), in a lot of drug product pending application approval, (b)(4). You attributed the root cause to a combination of the nature of terminal sterilization cycles and the permeability of the container closure system (CCS) used to produce your drug products.

It is essential that your firm does not introduce risks through overlap of your outsourcing and conventional production operations by sharing equipment, facilities, processes, or personnel, as the applicable standards significantly differ in certain respects. The attempt to mix these operations and follow two different standards increases complexity and product hazards. Notably, your firm uses common equipment, including blow-fill-seal (BFS) machines and your sterilizing equipment, for 503B compounding operations as well as conventional drug manufacturing operations. You found flaws in your IV bag CCS, including high permeability in the CCS that allows for contamination of the autoclave and infiltration into the containers (e.g., LDPE vials and IV bags) of subsequent batches of drug products produced in the common sterilization equipment.

A phase two investigation related to the cross-contamination was opened on April 30, 2021, and remained open at the time of the inspection, which was initiated on March 28, 2022. Our inspection found that you continued to manufacture drug products with the same CCS and autoclave cycles. Only after FDA’s inspection did you perform additional investigation and CAPA. Your lack of a timely and comprehensive investigation failed to identify the extent of the cross-contamination hazard to marketed drug products.

In your response, you provide an updated investigation. It extends the evaluation to other drug products using the same CCS, and includes limited studies within the sterilizing equipment and limited testing for cross-contamination of potentially affected drug products.

Your response is inadequate. Your investigation does not consider other sources of contamination. With only limited data, you conclude that the measured level of cross-contamination was “negligible.” Furthermore, you indicate that the identified corrective action of running (b)(4) autoclave cycles between products to “clean” this equipment found “a statistically significant reduction in carry-over.” However, your investigation does not adequately consider flaws related to your CCS (including, but not limited to, material quality and compatibility with the manufacturing process), and determine whether it provides suitable protection against egress and ingress of cross-contaminants. Your response lacks a commitment to review your CCS for raw material quality and vendor reliability. This concern not only relates to your current drug products but also your pending application drug products.

You also do not sufficiently address other potential root causes, such as a leak due to a CCS breach, that could be a potential source of cross-contamination within an autoclave. In addition, your investigation does not fully consider the impact of container-closure permeability on sterility assurance or product potency.

Contamination is generally nonuniformly distributed as your own data indicates. The test data in your investigation is limited to a small number of units, and the extent of contaminated units in a batch remains unknown. The number of contaminated units and degree of contamination may far exceed levels identified by your firm. Your study with limited testing shows cross-contamination of Bupivacaine active in Sterile Water for Injection with a wide range of variability of contamination levels (i.e., a four-fold range). However, you conclude that the cross-contamination between medicines is uniform and not at a sufficient level of concern.

Your firm does not consider that the highest result in the range from a very small sample is unlikely to reveal the highest contamination level in a batch. Furthermore, for the drug products tested and reported with results of “not detected,” you assume that the result is representative of the entire lot. Testing of your retain samples alone is insufficient to determine the scope of the contamination issues and mitigate risks associated with the contamination. You also state, “The data were assessed within alignment of ICH Q3B impurity thresholds” and “Impurities analysis is governed by ICH Q3B wherein thresholds are set to dictate the level of concern and identification required for impurities.” This is an inappropriate interpretation of the ICH Q3B¹ guideline, as it applies to impurities classified as degradation products and excludes extraneous contaminants.

You continued to observe cross-contamination in your drug products without adequately evaluating the scope of impacted lots nearly a year after you initially identified the contamination. On May 27, 2022, approximately a year after the investigation was initiated, you submitted Field Alert Reports (FARs).

On August 2, 2022, FDA held a teleconference with you about your contaminated drugs. On August 10, 2022, you conducted a voluntary recall of lot 023011 of Ketorolac Tromethamine Injection, USP, 60 mg/ 2 mL (and 4 lots of products made as part of your outsourcing operation), as noted on the following FDA website: https://www.accessdata.fda.gov/scripts/ires/index.cfm?Product=195477

Microbial Contamination
Your investigation into process simulation (media fill) failures was inadequate as you failed to implement appropriate CAPA to prevent microbial contamination. Your firm experienced two media fill failures, in which Pseudomonas aeruginosa (gram-negative rods) was detected in your BFS mandrel cooling water. It is highly atypical to have gram-negative microbes in the aseptic production cleanroom environment or identified in a media fill. For example, media fill lot M02801 identified Pseudomonas aeruginosa in a large number of turbid units ((b)(4)). You conducted a single repeat media fill to requalify the BFS for production after repairing the water leak from the mandrel, and cleaning and disinfecting the outer surfaces of the BFS. A single media fill is insufficient to support the requalification of your aseptic operations. In this situation, a comprehensive CAPA should be implemented followed by three successful and consecutive runs to requalify your aseptic process after a media fill failure.

You also detected this organism elsewhere in your operation including routine environmental monitoring (EM) and water samples.

For example, following the maintenance of your water for injection (WFI) system on June 4 and June 5, 2020, you identified several instances of Pseudomonas aeruginosa and other species including seven samples that yielded too-numerous-to-count (TNTC) CFU/100mL results. Your investigation attributed the results to laboratory error, due to a presumed contaminated (b)(4), and invalidated the results without clear evidence establishing laboratory error as the cause. You also based your investigation conclusion on other test results from batches formulated between June 4 to 6, 2020, that did not “recover” Pseudomonas aeruginosa and indicate that drug product testing on June 21, 2020, identified Pseudomonas spp. using the vacuum manifold. You did not confirm the source of the contamination and your CAPA was limited to retraining your microbiology laboratory personnel. Notably, you identified no CAPA for the autoclaving of the (b)(4). Your SOP requires the (b)(4) to be autoclaved (b)(4) but you failed to follow your SOP, determine why the step was not documented and caught in time, and explain how you will be improving your laboratory system to prevent similar future errors.

Your minimal retrospective review of batch data for the presence of Pseudomonas spp. is also inadequate. The presence of highly pathogenic microorganisms in your environment can present severe risks that can be potentially fatal to patients. Their presence should receive urgent and effective remediation. It should also be noted that finished product testing alone cannot establish sterility of all units because contamination is typically episodic and not uniformly distributed. Larger contamination problems may go undetected for substantial periods if your firm is placing too much reliance on the final quality control test for sterility to become aware of a problem in aseptic manufacturing.

In your response, you commit to flush the BFS cooling water reservoirs (b)(4) to reduce bioburden to limit the potential for biofilm formation, establish a clean-in-place (CIP) program for the cooling water systems, and conduct trending to determine the optimal flush frequency. Your response also includes a preventative maintenance procedure for your BFS machine that requires a pre-check to inspect for the presence of moisture in the (b)(4). Relying on visual inspection of (b)(4) to detect the presence of moisture is insufficient to prevent the ingress of mandrel cooling water into your BFS filler, and will not robustly prevent contamination of sterile medicines made by your firm. Your response is inadequate because you did not review the fundamental design and integrity of your BFS machinery (including, but not limited to, the suitability of the BFS cooling system for its intended use).

In response to this letter, provide:

• A comprehensive, independent 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 assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted. An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final quality assurance decisions, and is fully supported by executive management.
• A procedure for your water system monitoring that provides for appropriate daily microbial testing of water to ensure its acceptability for use in each lot of drug products produced by your firm.
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets Purified Water, USP, and WFI USP, monograph specifications and appropriate microbial limits.
• In addition to this holistic remediation, provide specific CAPA activities that are being undertaken to effectively remediate the conditions that caused the specific cross-contamination incidents discussed above. Provide an independent review by your consultant that determines the effectiveness of your CAPA, including but not limited to:

    o A list of all enhancements to cleaning and maintenance procedures including specific frequencies and locations to be cleaned in all relevant equipment
    o Identify any other sources of cross contamination other than the sterilizing equipment
    o Determine the adequacy of your analytical methodology to identify residual carryover
    o Supporting evidence to demonstrate that the challenges identified during your study, such as interference of product matrix and co-eluting peaks, were adequately resolved
    o Adequacy of scope of the investigation and its related CAPA

• The latest update on your improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:

    o Drugs with higher toxicities
    o Drugs with higher drug potencies
    o Drugs of lower solubility in their cleaning solvents
    o Drugs with characteristics that make them difficult to clean
    o Swabbing locations for areas that are most difficult to clean
    o Maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of a new drug product or new manufacturing equipment.

• A commitment to conduct testing between lots of autoclaved drug products using sensitive testing techniques such as liquid chromatography mass spectrophotometry (LCMS) prior to release to determine whether there is any cross contamination with your mixed operations.
• An independent assessment to include, but not limited to, the suitability of material composition, reliability of suppliers, fabrication process, and all other factors that influence the CCS quality and integrity. The assessment should evaluate all aspects of CCS suitability including its permeability and ability to provide protection from external factors affecting the sterility assurance or potency of batches of products manufactured in an autoclave or other sterilizing equipment.
• An independent, comprehensive review of the adequacy of design, control, and maintenance of your BFS machinery. When describing the maintenance program, provide all failure modes of water ingress that can occur, a description and the purpose of the (b)(4) in your BFS mandrel design. Based on this comprehensive review, provide a CAPA to prevent recurrence of BFS system contamination with water-borne gram-negative microbes.

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)).

You did not establish appropriate environmental monitoring (EM) action levels for the ISO 5 critical area where drugs are most vulnerable to contamination. Samples from the ISO 5 critical area should normally yield no microbiological contaminants. Because of the inappropriate action level, you failed to investigate three of six ISO viable EM samples that were > 1 CFU in your BFS lines. Appropriate ISO 5 action levels are a critical part of a robust EM program to prevent microbiological contamination of sterile drug products.

In your response, you state that you have revised your ISO 5 action levels for air, surface, and some personnel monitoring (PM) to (b)(4) CFU/plate. You also state that you investigated microbiological contamination from air sampling within the ISO 5 critical areas that exceeded the action level and conclude that the contamination “posed no negative risk” to the sterility assurance of the lots. However, your response is inadequate because you did not conduct a comprehensive retrospective assessment of historical EM data for actionable events and you failed to provide an assessment of your established EM and PM alert and action levels (e.g., settling plates, chest, head, goggles, forearms) to assure your levels are appropriate to monitor your manufacturing environment.

We also note that your firm has been applying the ISO 5 action level for active air monitoring from USP <797> (Pharmaceutical Compounding – Sterile Preparations) to your sterile drug production operation. USP < 797> is not an appropriate regulatory standard for your operations. If your firm continues to conduct outsourcing activities and conventional drug manufacturing operations at the same site, the higher CGMP standard needs to be followed in the event there are any overlapping (where appropriate) activities. While overlapping activities should be avoided, if any common facilities, personnel and equipment are used, they must be designed, maintained, and controlled in compliance with the standards for conventional manufacturing under the CGMPs for finished pharmaceuticals, 21 CFR 210 and 211. Otherwise, you should fully separate your operations.

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements for establishing appropriate EM and PM action levels when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

In response to this letter, provide:

• 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 contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.
• Your investigations into all environmental data that reached alert and action levels for the past two years.
• Your plan to review and ensure EM/PM alert levels, action levels, procedures, and CAPA are robust and appropriate.

3. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

Sampling of the BFS machines in your EM program for ISO 5 active air viable and non-viable monitoring is deficient. You failed to demonstrate that the method used for sample collection for EM (e.g., use of tubing with a length of about (b)(4) and material) provides a meaningful and representative sample of conditions during production. The air sample tubing was held between the door jamb and the door to your BFS, potentially disrupting the air flow to your sampling instruments. Furthermore, your established procedure fails to adequately describe the configuration of the tubing used to monitor viable and non-viable samples to address the potential of compromised airflow within the tubing.

In your response, you provide rationale for the sampling procedure and agree that the sampling should be collected as close to the point of fill as possible without impacting the airflow within the blow fill seal machine environment. In addition, your response includes the manufacturer’s recommendation that tubing is free of bends with a radius of less than (b)(4) to minimize the loss of larger particles by impaction and prevents the possibility of tubing collapse.

Your response is inadequate because, you did not provide supportive studies evaluating whether your sampling method is capable of adequality monitoring your ISO 5 environment as intended. You did not revise your procedures to establish the proper configuration of your tubing to assure the airflow path is not impeded. Furthermore, EM instruments should be located and placed in an orientation demonstrated to obtain a meaningful sample.

In response to this letter, provide:

• A thorough, independent assessment, and CAPA for your EM and facility monitoring program. Include a comprehensive evaluation of monitoring, recording, alarm documentation, deviation investigation, data retention and overall environmental control in your assessment.
• 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, 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.
• The actual length of the EM sampling tubing and the distance from the sampling location to the point of fill on your BFS with supporting photographs.
• Studies evaluating whether your program for viable and non-viable EM operates as intended with the configurations you have established.
• Revised procedures that assure EM sampling tubing configuration is suitable for collecting reliable environmental data.

Additional Guidance on Aseptic Processing

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

Recall and Temporary Suspension of Manufacturing

We acknowledge that you recalled lot 023011 of Ketorolac Tromethamine Injection, USP, 60 mg/ 2 mL drug product as well as four outsourcing facility compounding drug products after the FDA contacted you via telephone on August 2, 2022.

We acknowledge your commitment to temporarily suspend production of some drug products (terminally sterilized by moist heat) at this facility. You indicated that you planned to resume operations on August 23, 2022. Resumption of manufacturing your drugs terminally sterilized by moist heat should only occur once you have implemented effective CAPA and completed appropriate submission requirements.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of all identified 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.

Field Alert Reporting Violations

The NDA/ANDA Field Alert reporting requirements in 21 CFR 314.81(b)(1)(i) and (ii), effective since May 23, 1985, require holders of NDAs and ANDAs to submit information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product to the appropriate FDA district office within three working days of receipt by the applicant. The intent of the 21 CFR 314.81(b)(1) regulation is to establish an early warning system so that significant problems are brought to the FDA’s attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential safety hazards with drug products manufactured in the future. FARs must be submitted for confirmed and unconfirmed problems meeting the definition of the regulation within three working days of becoming aware of the problem.

From this inspection, in addition to the aforementioned CGMP violations, your firm is in violation of the Field Alert reporting requirements set forth in 21 CFR 314.81(b)(1)(ii). Specifically, on April 2, 2021, you initiated an investigation into the out-of-trend results for stability samples at 6-months related to extractables and leachables for your pending ANDA for (b)(4), USP 10mg/ml, that identified bupivacaine active in your drug product.

On May 27, 2022, you submitted three initial FARs for your approved ANDA products, Sterile Water for Injection, USP, Ketorolac Tromethamine Injection, USP, 60 mg/ 2 mL, and Sodium Chloride Injection 0.9%, USP, notifying the Agency that you were investigating the potential residual active ingredient carryover into manufactured lots for these drug products. The submission of these FARs is more than one year from your initial investigation identifying the potential carryover of drug active.

We are concerned with the CGMP violations demonstrated at your facility and failure to submit FAR-related events within three days of becoming aware of a problem. Please include in your written response the corrective action you plan to take regarding distributed products manufactured at your facility that may be affected by the violations.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations 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. 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 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.

Please electronically submit your reply on company letterhead to Mark W. Rivero, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to Mr. Rivero.

If you have questions regarding the contents of this letter, you may contact Mr. Rivero via (954) 527-4239 or mark.rivero@fda.hhs.gov.

Sincerely,
/S/

Frances de Jesus
Acting Program Division Director
Office of Pharmaceutical Quality Operations,
Division II

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1 Guidance for Industry Q3B(R2) Impurities in New Drug Products is available at: https://www.fda.gov/media/71733/download