Avaria Health & Beauty Corp.

Warning Letter 320-24-59

September 3, 2024 Dear Dr. Burk:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Avaria Health & Beauty Corp., FEI 3014583374, at 650 Jamieson Parkway, Unit 5, Cambridge, Ontario, from April 22 to 30, 2024.

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 May 17, 2024 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.

Your firm manufactures over-the-counter (OTC) (b)(4) drug products without adequate assurance of the quality of components used in their manufacture. For example, you failed to adequately test your incoming components, including identity testing, of each shipment of each component lot used in the manufacture of your OTC drug products.

(b)(4)

You failed to adequately test each shipment of each lot of (b)(4) for identity, a component at higher risk for (b)(4) and (b)(4) contamination. We note that (b)(4) is an ingredient used in your OTC (b)(4) drug products. Identity testing for (b)(4) and certain other high-risk drug components include a (b)(4) limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits. 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 ensure the acceptability of these components for use in the manufacture of your drug products.

The use of ingredients contaminated with (b)(4) or (b)(4) has resulted in various lethal poisoning incidents in humans worldwide. (b)(4).

In your response, you state that you would include identity testing of your raw materials, including (b)(4). Your response is inadequate. You failed to provide sufficient details regarding how you will ensure adequate identity testing for each lot of each shipment of (b)(4). Further, you do not address potential impact on drug products distributed to the United States that are within expiry.

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. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate quality.

In response to this letter, provide:

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 certificate of analysis (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 parts A, B, and C of the USP monograph.

The chemical and microbiological 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 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.

A summary of your program for qualifying and overseeing contract facilities that test the components and drug products you manufacture.

2. 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 data demonstrating that you have adequately validated your manufacturing processes used to manufacture your OTC drug products and that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality. Additionally, you failed to provide data to demonstrate the qualification of your manufacturing equipment. Indeed, your Quality Assurance Manager stated that it is not the firm’s practice to have validation studies for the manufacturing process and/or equipment qualifications regarding the manufacture of OTC drug products for the U.S. market.

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 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 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 regarding process validation, you state that anticipated deliverables associated with the validation master plan are currently being fulfilled for OTC drug products for the U.S. market. Your response regarding process validation is inadequate because you failed to provide a detailed plan or supportive documentation for validating your drug production process.

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 (PPQ), and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

A timeline for performing appropriate PPQ for each of your marketed drug products.

Include your process performance protocols, 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.

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).

Your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. For example, your QU failed to ensure:

Verification of testing methods to ensure accurate, precise, and reliable results (21 CFR 211.194(a)(2)).

Performance of routine calibrations of equipment used in the manufacture, processing, packing, and holding of a drug product (21 CFR 211.68(a)).

Performance of annual product reviews (21 CFR 211.180(e)).

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/media/71023/download.

In response to this letter, provide:

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

A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

In a previous warning letter (#320-23-21) issued on August 3, 2023, FDA cited similar significant CGMP violations. You proposed specific remediation for these violations in your response. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

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 if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPA before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

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.

FDA placed your firm on Import Alert 66-40 on April 14, 2023, after your response to our 704(a)(4) Request for Records sent to you on January 25, 2023, demonstrated CGMP violations related to controls for (b)(4) and (b)(4) in high-risk components used in your drugs.

The inspectional findings detailed above further demonstrate your firm’s noncompliance.

Your firm remains on Import Alert 66-40.

Correct any violations promptly. 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 any violations.

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at 650 Jamieson Parkway, Unit 5, Cambridge, Ontario into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

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 3014583374 and ATTN: Kevin Maguire.