FDA – Warning Letter – 10 JUNE 2022

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals

1. The company 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).

The company failed to adequately investigate out-of-specification (OOS) results for both drug components and finished drug products.

The company invalidated microbial OOS results based on limited and inadequate investigations.

For example, Company tested additional samples and released batches based on subsequent passing results when Burkholderia cepacia complex (BCC) was detected in several aqueous-based drug products.

Company investigations into these OOS result consistently referenced improper equipment cleaning. However, the root cause remains uncertain. Also failed to ensure that appropriate corrective actions and preventive actions (CAPAs) were adequately implemented to prevent the recurrence of BCC contamination.

Furthermore, the company concluded that the passing retest results provided proof of the effectiveness of the preservative in the product.

The company’s conclusion is inadequate. As per USP <51>, antimicrobial preservatives should not be used as a substitute for good manufacturing practices or used solely to reduce the viable microbial population of a nonsterile drug product. Research has shown that at a later point in the shelf life of some drug products, BCC may adjust to the conditions and proliferate in the preserved drug, even if it was not recovered during initial testing. While initial release testing results provide critical quality control information, those test results may not provide a full understanding of the microbial quality of a given batch or be predictive of stability characteristics.

In addition, contamination may not be uniformly distributed in a system, and a sample may not be representative of the type or level of contamination that may exist in other individual units of a batch. Therefore, a passing re-test is not sufficient to invalidate the initial OOS result without a sound scientific justification and supporting evidence that clearly establishes causative laboratory error. Furthermore, timely investigations are essential when data indicates a problem with a system or process.

Additional examples of inadequate investigations include:

• Failure to thoroughly investigate multiple out-of-limit microbial results in both your old and new water systems. You also failed to adequately address potential root causes when an adverse pattern of BCC contamination was observed between November 2019 and May 2021. Numerous aqueous-based drug products were manufactured and released during this period.
• Failure to extend microbial contamination investigations to other, potentially impacted drug products. For example, when BCC was detected in swab samples collected from the  Tube Filler on March 3, March 11, and April 27, 2021, the investigation did not include an evaluation of the drug products manufactured immediately before and after BCC was detected.
• Failure to initiate an investigation when OOS results were obtained during stability testing. For example, investigations were not initiated in responses to an OOS assay result for Sodium Sulfacetamide (10%) and Sulfur (5%) Cleanser batch, at the 18-month stability testing interval and OOS viscosity results for Urea Cream 40% in batch at multiple stability testing intervals. You failed to promptly address the stability failures and take appropriate remedial actions to ensure that all distributed batches maintain their quality attributes through the labeled expiry.

Your response is inadequate. For example, you performed BCC testing after the inspection only on retain samples from the specific drug product batches cited by the FDA investigators that were within expiry. You also failed to address stability sample chemical testing failures and water microbial contamination failures, and implement systemic corrective actions and preventive actions (CAPA).

Your response failed to provide a comprehensive plan for ensuring investigations are conducted in a timely manner, comprehensively investigate potential root causes, and extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy.

For more information about handling failing, OOS, out-of-trend, or other unexpected chemistry test results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download.

For further information regarding the significance of BCC and other objectionable contamination of non-sterile, water-based drug products, see FDA’s advisory notice posted on July 7, 2021, at https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm.

In response to this letter, provide:

• Detailed risk assessments addressing the hazards posed by marketed drug products with microbiological contamination, including:

A retrospective, independent review of water system failures, batch failures, rejected batches, returned drug products, complaints, and deviations that may have been related to microbiological contamination for the last three years.

Full microbiological testing of retain samples to determine the quality of all batches of drug products formulated with water that are within expiry. Testing of each batch should be completed, and include total counts and identification of bioburden to detect objectionable microbes, including but not limited to BCC. Provide a summary of all results obtained.

If the test results or risk assessments indicate the substandard quality of your drug products, take rapid corrective actions, such as customer notifications and product recalls.

• A retrospective, independent review of all OOS (including invalidated, in-process, and release/stability testing) results and a report summarizing the findings of the analysis, including the following for each OOS:

Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.

For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.

For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/ facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing the following:

Quality unit oversight of laboratory investigations
Identification of adverse laboratory control trends
Resolution of causes of laboratory variation
Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
Adequately scoping each investigation and its CAPA
Revised OOS investigation procedures with these and other remediations

2. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that are of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).

Company water systems and manufacturing equipment used to manufacture drug products are not designed, cleaned, and maintained appropriately. For example:

•  On several days, water samples collected from multiple points-of-use (POU) of your water system yielded “too numerous to count” (TNTC) results.
• Monitoring and testing of your previous water system between November 2019 and January 2021, detected BCC in approximately 101 samples.
• Notably, BCC was detected in two water samples from the same POU over the course of seven days for your new water system installed in February 2021. Other microorganisms were also detected in several POU ports numerous times between February and June 2021. water produced from this system has been used to manufacture drug products without assurance that the system is operating as intended.
• BCC was found in swab samples collected from cleaned  Tube Filler pumps and parts on March 3, March 11, March 23, and April 27, 2021. Staphylococcus aureus was found in the swab sample collected from the hopper on July 13, 2021, and mold was found in the swab sample collected from room hoses on May 25, 2021.
• BCC was found in swab samples collected from cleaned Packaging filler nozzle and hoses on June 28, 2021, and filler on July 19, 2021.

In your response, you acknowledged that the new water system performance qualification protocol was insufficient in many aspects and shared your plan to develop and execute a new protocol. You also stated that you intend to revise your production procedures to address microbial contamination on equipment and to conduct cleaning validation for your manufacturing equipment.

Your response is not adequate. It is your responsibility to ensure adequate systems and procedures are in place prior to manufacturing your drug products. Your response did not include a risk assessment to thoroughly remediate the design, control, and maintenance of your water systems. You did not provide a timeline for completing equipment cleaning validation. We remain concerned about the design, control, cleaning, and maintenance of your water system and equipment based on your persistent findings of objectionable microorganisms.

In response to this letter, provide:

• A comprehensive, independent assessment of your water system design, control, and maintenance.
• A thorough remediation plan to install and operate a suitable water system. Include a robust ongoing control, maintenance, and monitoring program to ensure the remediated system design consistently produces water adhering to  Water, USP monograph specifications, and appropriate microbial limits. Include an assessment of your system to ensure it is properly designed to minimize any potential areas for stagnant water or dead legs to be present. A review of the adequacy of your cleaning procedures with appropriate chemical and microbiological acceptance limits. Also include 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.
• 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:
• Drugs with higher toxicities
• Drugs with higher drug potencies
• Drugs of lower solubility in their cleaning solvents
• Drugs with characteristics that make them difficult to clean
• Swabbing locations for areas that are most difficult to clean
• Microbial risks related to equipment, cleaning procedures, and maximum hold times before cleaning

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

• A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards and a CAPA plan that describes improvements to design and control.

3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22) and the company failed to prove this procedure.

Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products.

For example:

• Multiple drug products that did not meet their specifications were released.
• Testing for BCC was not performed as required per established specifications for numerous non-sterile, aqueous-based drug products.
• Batch production records were not established and followed for reprocessing.
• CGMP records, such as microbiological notebooks, logbooks, and BCC-related microbiological laboratory investigation reports (MLIRs) were missing, and no investigation was initiated.

Your QU is responsible for fully exercising its authority and responsibilities. Further, data integrity is critical throughout the CGMP data life cycle, including in the creation, modification, processing, maintenance, archival, retrieval, transmission, and disposition of date after the record’s retention period ends.

In your response, you stated your prior Quality Assurance (QA) and Research and Development (R&D) executives were inexperienced which resulted in confusion and quality deficiencies. You provided an updated quality manual, procedures, and product specifications. You also committed to initiating investigations for missing MLIRs and performing a risk assessment for any released product associated with missing MLIRs.

We acknowledge that you recalled all batches identified during the inspection that did not meet specifications and were within expiry, including Hydroquinone USP 4% Cream, and Sodium Sulfacetamide 10% Wash. We also acknowledge that you tested retention samples for BCC in batches that were cited by our investigators.

Your response is inadequate as you failed to identify root causes and evaluate the full scope and impact of the CGMP deficiencies as well as the associated risks to product quality (including batches in distribution). In addition, your QU did not provide a comprehensive CAPA plan with a systematic approach to correct these deficiencies.

In response to this letter, provide:

• A comprehensive, independent 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:

• A determination of whether procedures used by your firm are robust and appropriate.
• Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
• A complete and final review of each batch and its related information before the QU disposition decision.
• Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

Also describe how top management supports quality assurance and reliable operations, including but not limited to the timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

• Provide a comprehensive independent review of investigations and other CGMP records to show when drug reprocessing occurred and the drug product batches impacted. This list should note if the drug product batch was released, whether or not it still remains within expiry, and, if so, a risk assessment on the impact on product quality and any potential hazards to patients.

4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use the results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)) and the company failed to prove this procedure.

Your firm failed to establish an adequate stability program and determine appropriate expiration dates.

For example:

• Your labeled expiration dates are not supported by stability data provided during the inspection. For example, the labeled expiration date is 18 months for Sodium Sulfacetamide (10%) and Sulfur (5%) Cleanser, and the initial batch placed on stability failed assay testing at 18 months.

Your stability data provided during the inspection also demonstrated viscosity failures at multiple testing intervals during the labeled expiry period of 18 months for  Urea Cream 40% and 24 months for Selenium Sulfide 2.25% Shampoo.

• Reprocessed drug products were not placed into your stability program and there is no assurance that they conformed to established specifications throughout their life cycle.

In your response, you described your plan to review and revise expiration dating based on supporting data and to update your procedure so that reprocessed batches are placed on stability.

Your response is inadequate. For example, the scope of your planned review to ensure expiration dates are supported by data was limited to only batches cited by our investigators and did not include all products manufactured and distributed by your firm.

In response to this letter, provide:

• A comprehensive, independent assessment and corrective action and preventive action (CAPA) plan to ensure the adequacy of your stability program. Your remediated stability program should include, but not be limited to:

• Stability indicating methods.
• Stability studies for each drug product in its marketed container-closure system before distribution is permitted.
• An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
• Detailed definition of the specific attributes to be tested at each station (timepoint)
• Expiration dating of all your drug products, including all container-closure systems

All procedures that describe these and other elements of your remediated stability program.

A comprehensive plan to assess the stability of all batches of your drug products, including reprocessed batches, on the market within expiry.

Unapproved New Drug Violations

Your products Hydroquinone USP, 4% Skin Bleaching Cream, Sodium Sulfacetamide 10% Wash, Sodium Sulfacetamide 10% and Sulfur 5% Cleanser, and Selenium Sulfide 2.25% Shampoo prescription products are drugs within the meaning of section 201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and intended to affect the structure or any function of the body of man.

Examples of the claims observed on your product labels that provide evidence of their intended uses (as defined in 21 CFR 201.128) include, but may not be limited to, the following:

• Hydroquinone USP, 4% Skin Bleaching Cream indicated for “the gradual bleaching of hyperpigmented skin conditions such as chloasma, melasma, freckles, senile lentigines, and other unwanted areas of melanin hyperpigmentation.”
• Sodium Sulfacetamide 10% Wash indicated for “topical application in the following scaling dermatoses: seborrheic dermatitis and seborrhea sicca (dandruff). It also is indicated for the treatment of secondary bacterial infections of the skin due to organisms susceptible to sulfonamides.”
• Sodium Sulfacetamide 10% and Sulfur 5% Cleanser indicated for “use in the topical control of acne vulgaris, acne rosacea, and seborrheic dermatitis.”
• Selenium Sulfide 2.25% Shampoo is indicated for “the treatment of seborrheic dermatitis of the scalp, dandruff and tinea versicolor.”

The above drug products are considered new drugs within the meaning of section 201(p)(1) of the FD&C Act, 21 U.S.C. 321(p)(1) because they are not generally recognized as safe and effective for their labeled uses.

Under sections 301(d) and 505(a) of the FD&C Act, 21 U.S.C. 331(d) and 355(a), a new drug may not be introduced or delivered for introduction into interstate commerce unless it is the subject of an application approved by FDA under either section 505(b) or (j) of the FD&C Act, 21 U.S.C. 355(b) or (j).

There are no FDA-approved applications on file for these products. Distributing these products (or other new drugs) in interstate commerce without approved applications, therefore, violates these provisions of the FD&C Act.

Misbranding and Listing Violations

We also found that your Hydroquinone USP, 4% Skin Bleaching Cream (b)(4), and Selenium Sulfide 2.25% Shampoo (b)(4) are not properly listed with FDA as required by section 510(j) of the FD&C Act, 21 U.S.C. 360(j). Although during the 2021 inspection Monarch PCM, LLC was established as the contracting manufacturing facility for these drugs, the drug listing submissions do not include the manufacturing establishment, which is required under 21 CFR 207.49(12).

Failure to properly list a drug product is prohibited and will render a drug misbranded under sections 301(p) and 502(o) of the FD&C Act, 21 U.S.C. 331(p) and 352(o). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(a) of the FD&C Act, 21 U.S.C. 331(a).

In addition, is required to list the drug it manufactures for Private Label Distributors (PLDs), using an NDC that includes the Monarch PCM, LLC’s own labeler code. This is regardless of whether the drug is commercially distributed under Monarch PCM, LLC’s own label or trade name or under the label or trade name of the PLD. Sodium Sulfacetamide 10% Wash (b)(4) is listed for the PLD (b)(4) under PLD’s NDC, but there is no current listing submission under Monarch PCM, LLC’s NDC. In addition, Selenium Sulfide 2.25% Shampoo (b)(4) is listed for the PLD (b)(4) under PLD’s NDC, but the listing submission under Monarch PCM, LLC’s NDC is inactivated due to lack of listing update or certification as required under 21 CFR 207.57.

Additionally, we note that you manufacture OTC drug products, which are labeled as topical anesthetics, including “(b)(4)” and (b)(4) Rx Only. While we acknowledge that neither product currently appears to be available for purchase or distribution in the US, we want to advise you of their regulatory status under the CARES Act.

“(b)(4)” and “(b)(4) Rx Only,” are considered to be drugs as defined under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as external analgesics. Section 505G of the FD&C Act, 21 U.S.C. 355h, governs nonprescription drugs marketed without an approved application.

Under section 505G of the FD&C Act, 21 U.S.C. 355h, certain nonprescription drugs without an approved application —commonly referred to as “OTC monograph drugs”— may be legally marketed if they meet applicable requirements. In particular, topical products intended for use as an external analgesic are deemed to be generally recognized as safe and effective (GRASE) and not a “new drug” if, among other things, they conform to the tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330.

We note that OTC topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. The 1983 external analgesic TFM, in combination with subsequent determinations, was deemed to be a final administrative order

However, your “(b)(4)” product does not conform to the conditions of use specified in the final administrative order, because the concentration of the product’s active ingredient, (b)(4), exceeds the amount permitted under the 1983 external analgesic TFM. (b)(4) is allowed in concentrations from 0.5 to 4% in an external analgesic drug product under the 1983 external analgesic TFM. Thus, your “(b)(4)” does not meet the requirements under section 505G of the FD&C Act, 21 U.S.C. 355h, for marketing without an FDA approved application.

In addition, your product, “(b)(4) Rx Only” bears the statement, “Rx Only.” However, considering its toxicity, other potential for harmful effect, and collateral measures necessary for its use, the product is not a prescription drug as defined in section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1). In fact, given its intended use as an external analgesic, the formulation and indications for this product appear to be consistent with the external analgesic TFM. Therefore, this product would be misbranded under section 503(b)(4)(B) of the FD&C Act, 21 U.S.C. 353(b)(4)(B), because it inappropriately bears an “Rx Only” statement.

Furthermore, we note that you manufacture several OTC drug products that include “(b)(4)” and “(b)(4) Rx Only,” which are labeled as topical anesthetics. While we acknowledge that neither product currently appears to be available for purchase or distribution in the US, we want to advise you of their regulatory status under the CARES Act.

“(b)(4)” and “(b)(4) Rx Only,” are considered to be drugs as defined under section 201(g)(1)(C) of the Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 321(g)(1)(C) because they are intended to affect the structure or any function of the body. Specifically, these products are intended for use as external analgesics. Section 505G of the FD&C Act, 21 U.S.C. 355h governs nonprescription drugs marketed without an approved application.

Under section 505G of the FD&C Act, certain nonprescription drugs without an approved application —commonly referred to as “OTC monograph drugs”—may be legally marketed if they meet applicable requirements. In particular, topical products intended for use as an external analgesic are deemed to be generally recognized as safe and effective (GRASE) and not a “new drug” if, among other things, they conform to the tentative final monograph (TFM) that is the most recently applicable proposal or determination for such drug issued under 21 CFR Part 330.

We note that OTC topical external analgesic products were addressed in the TFM for External Analgesic Drug Products for Over-the-Counter Human Use (external analgesic TFM; 48 FR 5852, February 8, 1983) and subsequent rulemakings. The 1983 external analgesic TFM, in combination with subsequent determinations, was deemed to be a final administrative order.

However, your “(b)(4)” product does not conform to the conditions of use specified in the final administrative order, because the concentration of the product’s active ingredient, (b)(4), exceeds the amount permitted under the 1983 external analgesic TFM. (b)(4) is allowed in concentrations from 0.5 to 4% in an external analgesic drug product under the 1983 external analgesic TFM. Thus, your “(b)(4)” does not meet the requirements under section 505G of the FD&C Act for marketing without an FDA approved application.

In addition, your product, “(b)(4) Rx Only” bears the statement, “Rx Only.” However, considering its toxicity, other potential for harmful effect, and collateral measures necessary for its use, the product is not a prescription drug as defined in section 503(b)(1) of the FD&C Act, 21 U.S.C. 353(b)(1). In fact, given its intended use as an external analgesic, the formulation and indications for this product appear to be consistent with the external analgesic TFM. Therefore, this product would be misbranded under section 503(b)(4)(B) of the FD&C Act, 21 U.S.C. 353(b)(4)(B), because it inappropriately bears an “Rx Only” statement.

Quality Unit Authority

Significant findings in this letter indicate that your QU is not fully exercising its authority and/or responsibilities. Your firm must provide the QU with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.

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/media/86193/download.

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.

In response to this letter, provide the following:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed. Include a detailed description of the scope and root causes of your data integrity lapses.
• 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.
• A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

FDA – Warning Letter