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WARNING LETTER 649198

May 11, 2023

Dear Mr. Zilner:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, RemedyRepack, Inc., FEI 3005841768, at 625 Kolter Drive, Suite 4, Indiana, PA, from November 7 to November 10, 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).

We reviewed your November 21, 2022 response to our Form FDA 483 in detail, and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. Your firm failed to establish adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

Your cleaning processes for drug manufacturing equipment, including those used for blister card and liquid repacking operations, were inadequate. For example, your quality control checks failed to identify contaminated surfaces of your (b)(4) blister card packaging equipment. You also noted multiple occurrences of visibly contaminated tablets and capsules. Furthermore, you lacked chemical testing to confirm your cleaning procedures sufficiently removed product residues and cleaning agents from your equipment.

In addition, we note you lacked adequate studies to support your clean hold times.

In your response you commit to updating your current cleaning validation procedures and performing new cleaning validations. You also state you will re-clean machines that have been stored more than (b)(4) prior to use.

Your response is inadequate. You fail to provide scientific evidence demonstrating your interim cleaning procedure will sufficiently remove potential contaminants, such as product residues, cleaning and sanitizing agents, and objectionable organisms. You also did not provide your cleaning validation protocol indicating the relevant sources of risk, predetermined acceptance criteria, acceptable amount of time for storing dirty equipment, and other considerations relevant to your equipment cleaning program. Furthermore, you fail to assess the impact of your inadequate cleaning processes on product that is currently on the market and within expiry.

In response to this letter, provide:

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

• A corrective action and preventive action (CAPA) plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe improvements to your cleaning and disinfection program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning and disinfection execution for all products and equipment; and all other needed remediations.

• Appropriate 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 each piece of equipment

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

• A summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

• A detailed risk assessment addressing the hazards posed by distributing drug products manufactured using shared equipment that may have been improperly cleaned. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.

2. 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 investigations lacked sufficient root cause determinations, CAPA, and assessment of all potentially affected batches. For example, you identified multiple deviations for numerous broken tablets caused by your packaging equipment between October 20, 2021, and November 8, 2021. You treated these similar deviations as individual occurrences and did not address this adverse pattern. Your investigations, each of which was signed by quality assurance staff, determined no further action was necessary, and did not provide any explanation for this conclusion. In one instance, you stated these tablets “are tiny and do not run well” on your repackaging equipment, though you lacked adequate root cause determination and did not implement any CAPA.

Inadequate investigations can lead to unidentified root causes, ineffective CAPA, and recurring problems that compromise the ability to manufacture safe and effective drug products.

In your response, you state “relevant” employees will be retrained in conducting proper assessments and investigations, and new employees will receive thorough training to ensure they fully understand the requirements.

Your response is inadequate. It fails to provide a comprehensive investigation into the broken tablet deviations, and you do not extend your investigations to other batches to determine the full scope and product impact of the deviations. Furthermore, you do not implement CAPA plans to prevent these issues from reoccurring. In addition, your response does not specify whether the “relevant” employees to receive investigation training will include manufacturing operators, supervisors, management, quality personnel, or other staff.

In response to this letter, provide:

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

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

You failed to provide adequate data to demonstrate you validated your drug packaging processes to ensure consistent product quality. For example, you packaged and distributed various drug products which lacked product-specific packaging validation protocols with pre-approved acceptance criteria.

You also experienced numerous deviations for tablets that broke during packaging, and your firm was aware that small tablets do not run well on your (b)(4) packaging machine.

You also failed to adequately qualify your drug packaging equipment. Though you provided a procedure titled, “Validation Protocol,” you lacked adequate equipment-specific protocols to reveal the limits of capability of the equipment you use to package drug products.

Without adequate process validation, incorporating all manufacturing inputs and parameters that can affect product quality, your firm lacks basic assurance that you can reproducibly deliver products that meet specifications. See FDA's guidance for industry, Process Validation: General Principles and Practices for general principles and approaches that the FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In your response, you state you are enhancing your validation and qualification programs to include protocols, acceptance criteria, additional testing, and a final summary of your findings.

Your response is inadequate. You fail to include or otherwise address your risk assessment for any marketed drug products manufactured and distributed with unvalidated packaging processes. You also do not provide an assessment of the product quality impact on distributed drug products you packaged on equipment that lacks adequate qualification studies.

In response to this letter, provide:

• A timeline for performing appropriate process performance qualification (PPQ) for each of your marketed drug products.

• Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

• Provide 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.

• An assessment of each drug product 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, and 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.

4. Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)).

Your facility design is inadequate to prevent cross-contamination. You repackage non-penicillin beta-lactam drugs in the same facility as non-beta-lactam drugs, rather than in separate dedicated facilities. Complete and comprehensive separation of beta-lactam repackaging operations is essential due to the severe patient risk posed by cross-contamination.

Contamination of non-beta-lactam drugs with beta-lactam drugs presents great risk to patient safety, including potential anaphylaxis and death. No safe level of beta-lactam contamination has been determined to be a tolerable risk. Severe allergenic responses can occur in susceptible patients exposed to extremely low levels of beta-lactams.

In your correspondence of March 3, 2023, you state you have “never experienced a breach in containment of beta-lactams.” However, you also explain you have not performed environmental sampling for beta-lactam contamination. In your reasoning for this decision, you explain most beta-lactam products you process are in capsule form, in small quantities, and repackaged (b)(4) in an “isolated” environment with HEPA filtration. You also include rudimentary floor plans and photos of your production areas, which indicate that your non-penicillin beta-lactam operations are not conducted in a separate building or comprehensively sealed-off facility.

Your facilities and practices are inadequate. You state you have not had a breach in beta-lactam containment, but you lack data to support this conclusion. You also have not initiated environmental monitoring or assessed the product quality impact of potential breaches on distributed product. You also fail to implement a design at your site that ensures complete and comprehensive physical separation of your non-penicillin beta-lactam operations.

Notably, you use a separate building on your campus to repackage penicillins. Similarly, it is essential that your firm use separate facilities for the processing of non-penicillin beta-lactam drugs.

Separation of non-penicillin beta-lactam drugs nearly always necessitates use of a building dedicated to only those drugs. In very limited instances, two facilities could potentially be housed in the same building. However, in such rare cases, a continuous solid impervious wall separates two comprehensively distinct facilities which are fully sealed-off from each other. These two separate physical facilities exist within an external building structure, but with separate entries, exits, facility infrastructure, air handling, personnel, and which by design completely preclude any potential for incidental air, personnel, materials, or other interactions. Under the limited cases in which this design concept could be considered, a rigorous risk assessment would demonstrate that the design provides as much protection against cross-contamination as is achieved by manufacturing in a separate building.

Because of the extremely low threshold dose at which an allergic response could occur, beta-lactam facilities need to be completely and comprehensively separated from non-beta-lactam facilities. For more information, see FDA’s guidance document, Non-Penicillin Beta-Lactam Drugs: A CGMP Framework for Preventing Cross-Contamination, at https://www.fda.gov/media/79971/download.

In response to this letter, provide:

• Your plan to fully dedicate your facility to beta-lactams or cease any beta-lactam production in the building. Regarding the latter, if you intend to attempt decontamination so that your facility can resume solely non-beta lactam production, facility decontamination would be necessary and you will need to develop a comprehensive decontamination plan for the facility. Your plan should include all equipment and facility parts that will be removed. The design and remediation plan should be premised on the knowledge that it is profoundly difficult to completely decontaminate a facility of beta-lactam residues.

• A comprehensive, independent assessment by a qualified third party regarding future measures to prevent risk of beta-lactam cross-contamination. The assessment should identify any inadequacies in assuring complete physical facility separation of beta-lactam and non-beta-lactam production, as well as controls to prevent personnel use of common areas. Describe the extensive remediations to design and controls that support dedicated facilities with complete and comprehensive separation (i.e., isolated and sealed off). Details regarding the remediated site should include but not be limited to air intake and exhaust, vacuum systems, HVAC filter locations, entry points, egress points, people/material/equipment flow, personnel gowning, physical containment devices for packaging equipment, material storage, common area separation, decontamination practices, monitoring containment, and testing.

• Provide timelines for the independent assessment and how you intend to evaluate the effectiveness of your CAPA.

• Your immediate plan to perform environmental sampling of your facility for beta-lactam cross-contamination, including frequency and sampling locations using robust and validated methodologies. In addition, provide any testing performed to date. Assure your method for detecting beta-lactams provides appropriate sensitivity to detect very low levels of contamination; see FDA’s published analytical method which has a LOD of 0.2 ppb at https://www.ncbi.nlm.nih.gov/pubmed/29766324. If such testing reveals recovery of beta-lactams, take rapid corrective actions, such as notifying customers, and initiating recalls.

• A list of all decontaminant solutions used in your facility, including validation data to support that the decontaminant solutions can break the beta-lactam ring of the beta-lactam drug products repackaged.

• A program for future monitoring of beta-lactam residue throughout the site.

• Floor plans for each building and facility where repackaging operations occur, clearly illustrating the flow of materials and personnel, as well as areas used for cleaning, air locks, or other purposes relevant to drug production. Also describe which specific product types can be repackaged, sampled, or otherwise manipulated in each of the buildings and facilities, as well as which product types are not permitted.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 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. 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 days¹. 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.

Send your electronic response to orapharm1_responses@fda.hhs.gov. Your written notification should refer to Warning Letter CMS # 649198 and include FEI: 3005841768.

If you have any questions, contact Compliance Officer Samina Khan at samina.khan@fda.hhs.gov.

Sincerely,
/S/

Lisa Harlan
Program Division Director
Office of Pharmaceutical Quality Operations Division I

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1 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.