WARNING LETTER

Westwood Laboratories LLC MARCS-CMS 674728 — April 17, 2024

Delivery Method:: VIA EMAIL CONFIRMED DELIVERY
Product:: Drugs

Recipient:: Recipient Name

Mr. Paul A. Schirmer; Recipient Title

Chief Executive Officer; Westwood Laboratories LLC; 710 S. Ayon Avenue
Azusa, CA 91702
United States

Issuing Office:: Division of Pharmaceutical Quality Operations IV; United States

WARNING LETTER

April 17, 2024

Dear Mr. Schirmer:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Westwood Laboratories LLC, FEI 2020372, at 710 S. Ayon Ave., Azusa, from October 30 to November 20, 2023.

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 December 11, 2023, 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 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).

You failed to adequately investigate complaints received for the over-the-counter (OTC) drug products you manufacture. For example,

A complaint for Advanced Protection SPF 30, Lot (b)(4), reporting the “entire batch is separating.” Your investigation failed to review relevant manufacturing records, including the processing parameters used to produce an emulsion of intended quality and evaluate other lots or drug products to determine the extent of the problem. Your investigation determined the product was “not properly emulsified” without adequately evaluating the processing parameters used to produce an emulsion of intended quality. You then failed to take appropriate corrective actions and the lot was reprocessed, assigned a new expiration date, refilled into the original containers, and released.
A complaint for (b)(4), Lot (b)(4), reporting the product was “watery thin.” During your investigation, you obtained an out of specification (OOS) result for viscosity from a retain sample that was not adequately investigated and documented in the complaint report. Notably, your complaint report did not acknowledge the OOS and stated, “The product does not feel like it is watery thin and would apply correctly as per the retains of the lot that were pulled and evaluated.”

Your response states you will revise the investigation and complaint procedures to include the pulling and testing of retain samples and retrain staff with the procedural improvements going forward. Your response is inadequate as you did not provide supporting documentation of these changes. Furthermore, you do not commit to evaluating your quality unit’s (QU) processes and procedures to determine whether your investigations are effectively identifying the causes of deviations and product failures to implement appropriate corrective action and preventive action (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 response to this letter, provide:

An independent, comprehensive review of your company’s complaint handling program that identifies deficiencies and a corresponding CAPA.
An independent, retrospective review of all complaints, including the associated investigations of drugs within expiry as of the date of this letter. Include the drug product name, batch number, date of manufacture, production line number, a summary of the complaint, description of likely root causes, CAPA plan, and status of CAPA.
A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

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

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.

2. Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality. 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)).

You manufacture OTC drug products without adequate assurance of the quality of your raw materials. For example, you failed to test propylene glycol for diethylene glycol (DEG) and ethylene glycol (EG) used in the manufacture of your OTC (b)(4) drug product. Identity testing for propylene glycol and certain other high-risk drug components¹ include a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of DEG or EG. 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. You also rely on your suppliers’ certificate of analysis (COA) without adequately establishing the reliability of your component suppliers’ test analyses at appropriate intervals.

Your response states that you will revise your specifications for components at high-risk of DEG or EG contamination to test for DEG and EG. Your response is inadequate because you did provide sufficient detail or adequate evidence of corrective actions and did not consider retrospectively testing your retained components for DEG and EG. Further, you also do not discuss how you will verify the reliability of your suppliers’ COAs nor how you will perform qualification of your suppliers.

Without adequate testing, you do not have scientific evidence that the components conform to appropriate specifications prior to use in the manufacture of your drug products.

The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s guidance document Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol to help you meet the CGMP requirements when manufacturing drugs, including repackaged drugs at high-risk for DEG or EG contamination at https://www.fda.gov/media/167974/download.

In response to this letter, provide:

A commitment to provide DEG and EG 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 retain sample testing of all implicated finished drug product batches for the presence of DEG and EG.
A full risk assessment for drug products that are within expiry which contain any ingredient at risk for DEG or EG contamination (including, but not limited to, glycerin). Take prompt and appropriate actions to determine the safety of all lots of the component(s) and any related drug product that could contain DEG or EG, 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 suppliers’ COA instead of testing each component lot for strength, quality, and purity, specify how you will robustly establish the reliability of your suppliers’ 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 glycerin, propylene glycol, and certain additional high-risk components we note that this includes the performance of parts A, B., and C of the United States Pharmacopeia (USP) monograph.
The chemical quality control specifications you use to test each incoming lot of high-risk drug components to determine acceptability for use in manufacturing.
A comprehensive, independent review of your material system to determine whether all suppliers of components, containers, and closures, are each qualified and the materials are assigned appropriate expiration or retest dates. The review should also determine whether incoming material controls are adequate to prevent use of unsuitable components, containers, and closures.
A summary of your program for qualifying and overseeing contract facilities that test the drug products you manufacture.
A summary of results obtained from testing all components to evaluate the reliability of the COA from each component manufacturer. Include your standard operating procedure (SOP) that describes this COA validation program.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Appropriate Control over Laboratory

You failed to exercise appropriate controls over your high-performance liquid chromatography (HPLC) software system, such as requiring employee-specific logins, appropriate assignment of administrative privileges, and ensuring the audit trails are enabled. Furthermore, you could not locate the system’s validation documentation during the inspection.

Your response states that the validation documentation is available on your HPLC software system, but that you require the assistance of your vendor to retrieve it. You also state that you identified an IT system administrator, trained employees enable the audit trail, and will establish a work instruction. Your response is inadequate because you failed to provide supporting evidence. You are responsible for the validation of your HPLC system despite your vendor having completed it on your behalf.

There must be adequate document controls in place to assure product quality. CGMP compliant record keeping practices prevent data from being lost or obscured and ensure that activities are documented at the time of performance.

Verification of Microbial Testing Methods

You revised your microbial testing methodology to utilize rapid detection media plates for aerobic and yeast and mold counts without appropriately verifying whether your revised methods are suitable for testing of your drug components and drug products. Your revised methods included shortened incubation times and failed to demonstrate your new method's ability recover organisms. Notably, the uses of the rapid detection media plates are intended for use “in the food and beverage industries.”

Your response states that you will develop protocols and procedures for testing microbial attributes of your drug components and drugs using the rapid detection plates, and that you will validate the suitability of your alternative rapid methods following the USP. Your response is inadequate because you did not provide sufficient detail or adequate evidence of corrective actions (e.g., protocol or procedure). Your revised methods must be properly verified giving equivalent or better results when substituted for USP compendial testing.

The ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product must be established and validated. Results generated using unverified or unvalidated methods may put consumers at risk.

Moreover, 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:

A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. 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 the FDA.
A complete assessment of documentation systems used throughout your manufacturing and laboratory 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.
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 lot of your drug products before a lot disposition decision.

o An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States that are within expiry as of the date of this letter.
o A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

4. 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)).

Your firm uses water as a component in your OTC drug products. Your water system is not adequately qualified, controlled, maintained, and monitored to ensure that the system is operating properly and continuously producing water suitable for its intended use. For example, you did not test for objectionable microorganisms. You also failed to conduct adequate conductivity testing to ensure that your water met (b)(4) USP monograph specifications. We also observed inadequate maintenance of your water system (e.g., utilization of ultraviolet lamps beyond established usage times, leaking water tank) and inadequately validated system changes (e.g., new points-of-use and the adding of (b)(4) were not validated).

Your response states that you will qualify your water system according to USP <1231> and develop a validation master plan to address the qualification life cycle of the system and events. You state that procedures and methods will be implemented to determine whether the (b)(4) water complies with established specifications including objectionable organisms. You provided a revised water system diagram, but no other supporting documentation. Your response is inadequate because you did not systemically review your water system to ensure that it is capable to produce water suitable for its intended use. You also did not consider retrospective testing of retained finished drug products that used water from this system.

Water for pharmaceutical purposes must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes. The lack of adequate validation provides no assurance that the system performs as intended and subsequent use of inadequately (b)(4) water in pharmaceutical manufacturing can adversely impact drug product quality and patient safety.

Furthermore, you manufacture human drugs on equipment shared with animal drugs, medical devices, and cosmetics, but failed to perform appropriate cleaning validation using your in-house cleaning and sanitizing agents. You also did not adequately evaluate difficult to clean surfaces of your shared equipment. Inadequate cleaning may result in residual product and detergents on shared equipment, risking cross contamination with various products manufactured on this equipment.

In response to this letter, provide:

A comprehensive remediation plan for the design, control, and maintenance of the water system.

o A (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.

Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your products.
A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or 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 water system monitoring that specifies routine microbial testing of water to ensure its acceptability for use in each batch of drug products produced by your firm.
The current action/alert limits for total counts and objectionable organisms used for your (b)(4) Water system. Ensure that the total count limits for your (b)(4) water are appropriately stringent in view of the intended use of each of the products produced by your firm. Total microbial count limits for (b)(4) Water systems are generally tighter than your current action limits for the topical dosage forms produced by your firm.
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.
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.

Quality Systems

Your firm’s quality system is 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/media/71023/download.

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 evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive (b)(4) audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with the 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.

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 the FDA to withhold issuance of Export Certificates. The 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 send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
19701 Fairchild Road
Irvine, CA 92612-2506

Please identify your responses with the unique identifier: CMS 674728.

If there are any questions about the released information, please contact Yumi Hiramine, compliance officer, at Yumi.Hiramine@fda.hhs.gov or at 818-226-1839.

Sincerely,
/S/

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
________________________

1 Components with higher risk of DEG or EG contamination compared to other drug components.