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Delivery Method: Via Email Reference #: 320-26-28 Product: Drugs Over-the-Counter Drugs

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Recipient:

Recipient Name

Mr. Darren J. Birkelbach

Recipient Title

Chief Executive Officer

Integrity Partners Group

1111 Industry Avenue SE Roanoke, VA 24013 United States

dbirkelbach@integritypartnersgrp.com

Issuing Office: Center for Drug Evaluation and Research (CDER)

United States

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Warning Letter 320-26-28

December 15, 2025

Dear Mr. Birkelbach:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Chemisphere Corporation, FEI 1000158477, at 2101 Clifton Ave., Saint Louis, MO, from June 16 to 24, 2025.

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 July 16, 2025, response to our Form FDA 483 in detail.

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

1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release, and for each batch of drug product required to be free of objectionable microorganisms, appropriate laboratory testing, as necessary (21 CFR 211.165(a) and 211.165(b)).

Your firm failed to adequately test your over-the-counter (OTC) **(b)(4) **drug products for strength (assay) of each active ingredient prior to release and distribution. You also failed to ensure adequate microbiological testing for each batch of your (b)(4) and (b)(4) drug products prior to release.

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Testing is an essential part of ensuring that the drug products you manufacture conform to all predetermined quality attributes and are appropriate for their intended use. Without adequate testing, you lack basic data to support that each drug product batch conforms to appropriate specifications before release.

In your response, you state that you will develop test methods or identify a contract testing laboratory to ensure product integrity and revise your product release standard operating procedures (SOPs) to require assay for active ingredients and microbiological testing “clearance.”

Your response is inadequate. Because you lack adequate testing of each batch of your drug products, you do not know whether they conform to all appropriate finished product specifications and are suitable for release to consumers.

In response to this letter, provide:

• A comprehensive independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• A list of chemical and microbial specifications, including test methods, used to analyze each batch of your drug products before a batch disposition decision. o An action plan and timelines for conducting full chemical and microbiological testing of reserve samples to determine the quality of all batches of drug product distributed to the United States (U.S.) that are within expiry as of the date of this letter. o A summary of all results obtained from testing reserve samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).

Your firm failed to perform adequate testing for your raw materials that were used to manufacture the following:

• OTC (b)(4) and (b)(4) drug products
• Specially (b)(4), an in-process material used in (b)(4) prescription drug products

For example, you did not adequately test for identity of each incoming shipment of each lot of raw materials (e.g., (b)(4)) used in the manufacture of your OTC drug products, drug components, and in-process material. In addition, you relied on your suppliers’ certificates of analysis (COAs) without establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Products Containing (b)(4)

Your firm failed to adequately test for (b)(4) in your incoming component (b)(4) used as an active pharmaceutical ingredient (API) and as a component in an in-process material. The use of (b)(4) contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4)

Products Containing (b)(4)

Your firm also failed to adequately test your incoming components at high risk of (b)(4) contamination for identity before using them to manufacture your drug products and in-process material. This includes, but is not limited to, testing of (b)(4) to determine its appropriate identity, prior to use in manufacturing your OTC (b)(4) drug products and in-process material for prescription drug products.

Identity testing for (b)(4) and certain other high-risk drug components includes a limit test in the United States Pharmacopeia (USP) to ensure the component meets the relevant safety limits for (b)(4) levels. Because you did not perform identity testing on each shipment of each lot using the USP identification test that detects these hazardous impurities, you failed to assure the acceptability of these components for use in the manufacture of your drug products and in-process material.

The use of ingredients contaminated with (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document (b)(4)

In your response, you state that you will develop a test method and/or use a contract testing laboratory to test incoming (b)(4) for (b)(4) and incoming high risk drug components, including but not limited to, (b)(4) for (b)(4). Your response is inadequate because you do not provide adequate details that ensure identity testing for raw materials will meet all USP monograph requirements.

In response to this letter, provide:

• A comprehensive, independent review of your material system, including but not limited to: o Evaluating all suppliers of materials (components, containers, and closures) to determine if they are reliable and appropriately qualified. o An assessment of all materials to determine whether they are consistently of acceptable quality. o A review to ensure assigned expiration or retest dates are appropriate (supported by data). o Adequacy of the supplier qualification program, and its selection, qualification, and disqualification provisions. o Based on a thorough review, provide a summary of your systemic corrective actions and preventive actions (CAPA) to remediate the vendor qualification program and prevent use of unsuitable components, containers, and closures.
• The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.
• A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your SOP that describes this COA validation program.
• A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
• A commitment to provide (b)(4) test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of incoming (b)(4) within expiry of manufactured drug products. Alternatively, if a retain of a component lot is unavailable, perform reserve sample testing of all implicated finished drug product batches for the presence of (b)(4).
• A commitment to provide (b)(4) test results, no later than 30 calendar days from the date of this letter, from testing retains for all lots of high-risk drug components used in the manufacture of drug products. Alternatively, if a retain of a component lot is unavailable, perform reserve sample testing of all implicated finished drug product batches for the presence of (b)(4).
• A full risk assessment for drug products that are within expiry which contain any ingredient at risk for (b)(4) contamination (including, but not limited to, (b)(4)). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain (b)(4), including customer notifications and product recalls for any contaminated lots. Identify additional appropriate CAPA that secure supply chains in the future, including, but not limited to, ensuring that all incoming raw material lots are from fully qualified manufacturers and free from unsafe impurities. Detail these actions in your response to this letter.
• A description of how you will test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity. If you intend to accept any results from your supplier’s COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your supplier’s results through initial validation as well as periodic revalidation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot. In the case of (b)(4), and certain additional high-risk components we note that this includes the performance of (b)(4) of USP monograph.

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

Your firm failed to adequately validate your equipment cleaning process to demonstrate its effectiveness to prevent potential cross-contamination between your OTC drug products and non-pharmaceutical products. You manufactured your OTC (b)(4) drug products on non-dedicated equipment, e.g., your (b)(4) tank. This equipment was also used to manufacture (b)(4) including, but not limited to, (b)(4) that is intended for (b)(4).

Inadequate removal of residues from manufacturing equipment during cleaning can lead to contamination of drug products subsequently manufactured on the non-dedicated equipment. It is unacceptable as a matter of CGMP to manufacture drugs using the same equipment that you use to manufacture non-pharmaceutical products due to the risk of cross-contamination.

In your response, you state that you will develop and implement a site-wide cleaning validation master plan including, but not limited to, identifying equipment and establishing analytical methods and acceptance criteria. You also state you will determine worst-case products and most difficult to clean manufacturing surfaces based on solubility, potency, toxicity, and cleanability.

Your response is inadequate because you do not provide a risk assessment for the drug products manufactured on shared equipment potentially impacted by inadequate cleaning. In addition, your target timeline for completing cleaning validations is not until August 2026, you do not provide your interim plan to ensure that your non-dedicated equipment is adequately cleaned prior to manufacturing your drug products.

In response to this letter, provide:

• Your commitment to discontinue manufacturing drugs on shared equipment with non-pharmaceuticals in your facility. If you intend to resume manufacture of both pharmaceutical and non-pharmaceutical products at your facility, provide a plan to show how you will separate the areas in which you will maintain dedicated manufacturing equipment for your pharmaceutical manufacturing and (b)(4) product manufacturing operations.
• Your risk assessment for all drugs you have previously manufactured on equipment shared with non-pharmaceutical products. For each product, assess the risk of potential contamination due to shared equipment and provide your plans for addressing the product quality and patient safety risks for any product still in distribution, including potential recalls or market withdrawals.
• A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.
• A complete assessment of documentation systems used throughout your equipment use and cleaning operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
• 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 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 SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

4. Your firm failed to establish 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)).

Lack of Process Validation

Your firm failed to adequately validate your manufacturing process for each of your OTC drug products and qualify the manufacturing equipment used for their production. Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluates batches to determine whether an initial state of control has been established.

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. 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/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.

In your response, you state that you will develop and implement a process validation for all OTC drug products and qualify manufacturing equipment among other corrective actions, as applicable. You also state that your timeframe for completion of validation activities is February 2026.

Your response is inadequate because you did not provide your interim plan for drugs distributed before process validation activities are complete to ensure you produce drug products of acceptable quality.

Inadequate (b)(4) System Validation

Your firm failed to adequately qualify your (b)(4) system to ensure it produces (b)(4) that meets appropriate chemical and microbial attributes for use in your OTC drug products manufacturing and equipment cleaning. Specifically, you used “(b)(4)” as a component to manufacture your OTC drug products and to clean the associated manufacturing equipment. You have not established that your (b)(4) system is adequately designed, maintained, and monitored to ensure that it consistently produces (b)(4) suitable for its intended use.

Additionally, you obtained microbial growth as recently as this year from the (b)(4) holding tank and (b)(4) sampling port locations that exceeds your set action limit of (b)(4) CFU/ml. You did not perform microbiological identification for the microbial growth results and did not sanitize your (b)(4) system following these excursions. The inadequate control of your (b)(4) system poses a potential risk for objectionable microbiological contamination into your drug products.

Furthermore, (b)(4) for pharmaceutical use must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. Routine monitoring of microbial counts and identity of microbiological contamination in the system is integral to ensuring oversight of ongoing state of control and suitability of (b)(4) for use in manufacturing operations.

In your response, you state that you will develop and implement a validation plan to qualify your (b)(4) system. You also state that you will develop a deviation and out-of-specification investigation procedure for (b)(4) system related excursions. The procedure will include speciation of microbial contaminants and sanitization protocols for observations of any contamination or foreign matter.

Your response is inadequate because you do not provide adequate details regarding your plan for performing (b)(4) system validation, nor do you provide your interim plan to ensure that the (b)(4) for your drug product manufacturing and equipment cleaning is suitable for its intended use prior to manufacturing your drug products.

In response to this letter, provide:

• 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.
• A timeline for performing process performance qualification for each of your marketed drug products. Also provide a risk assessment and any follow up actions to be taken for the distributed drug products produced without performing any process validation studies.
• 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.
• A comprehensive, independent assessment of your (b)(4) system design, control, and maintenance.
• A thorough remediation plan to install and operate a suitable (b)(4) system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces (b)(4) adhering to (b)(4), USP monograph specifications and appropriate microbial limits.
• Regarding the latter, ensure that your total microbial count limit for (b)(4) is appropriate in view of the intended use of the products produced by your firm.
• A detailed risk assessment addressing the potential effects of the observed (b)(4) system failures on the quality of all drug product lots currently in U.S. distribution within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.
• A procedure for your (b)(4) system monitoring that specifies routine microbial testing of (b)(4) to ensure its acceptability for use in each batch of drug products produced by your firm.
• A procedure governing your program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces (b)(4) that meets (b)(4), USP monograph specifications and appropriate microbial limits.

Quality Systems

Your firm’s quality systems are inadequate. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-systems-approach-pharmaceutical-current-good-manufacturing-practice-regulations.

Responsibilities as a Contractor

Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.

You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry.

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.

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.

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 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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 1000158477 and ATTN: Christina Alemu-Cruickshank.

Sincerely, /S/

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