WARNING LETTER

Generitech Corporation MARCS-CMS 618333 — March 01, 2022

Delivery Method:: VIA UPS
Product:: Drugs

Recipient:: Recipient Name

Mrs. Norma D. Daliva-Banks; Recipient Title

President; Generitech Corporation; 4967 E Lansing Way
Fresno, CA 93727-7408
United States

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

WARNING LETTER

March 1, 2022

Dear Mrs. Daliva-Banks:

The U.S. Food and Drug Administration inspected your drug manufacturing facility, Generitech Corporation, FEI 3002994577, at 4967 E Lansing Way, Fresno, California from July 6 to 28, 2021.

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).

In addition, (b)(4) Hydroquinone Cream and (b)(4) are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act, 21 U.S.C 355(a), and are also misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee). Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(d) and (a) of the FD&C Act, 21 U.S.C. 331(d) and (a). These violations are described in more detail below.

We reviewed your September 15, 2021, response to our Form FDA 483 issued July 28, 2021, in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.

During our inspection, our investigator 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 investigate out-of-specification (OOS) assay results for several lots of your topical over-the-counter (OTC) drug products. For example, assay testing for salicylic acid in your (b)(4) drug product Lot (b)(4) revealed results including 1.93% and 1.90% (retest). Your specification for this critical product attribute was (b)(4)% - (b)(4)%.

Your quality system for investigations is inadequate and does not ensure consistent production of safe and effective products.

In your response, you stated you lack the resources and personnel to adequately investigate. You also stated you will develop a more comprehensive corrective action and preventive action (CAPA) program and train your personnel. Your response is inadequate. You failed to appropriately investigate to determine a root cause or assess the impact of your OOS results. You also failed to implement an appropriate CAPA to mitigate and prevent recurrence. Further, you did not provide a retrospective review of all distributed batches within expiry to ensure all potential discrepancies have been adequately investigated.

In response to this letter, provide the following:

• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for US products irrespective of whether the batch was ultimately distributed in the United States for the last three years from the initial date of inspection and a report summarizing the findings of the analysis, including the following for each OOS:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o 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.
o 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 of the following:
o Quality Unit (QU) oversight of laboratory investigations
o Identification of adverse laboratory control trends
o Resolution of causes of laboratory variation
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o Adequately scoping of each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether the program includes effective root cause analysis, ensures CAPA effectiveness, analyzes investigations trends, improves the CAPA program when needed, implements final QU decisions, and is fully supported by executive management.

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 (2)).

You failed to perform an identity test for each component lot used in the production of your drug products, including for the salicylic acid active pharmaceutical ingredient in your (b)(4) drug product Lot (b)(4). Further, you did not establish the reliability of each of your suppliers’ certificates of analyses (COA) for component specifications and characteristics.

This is a repeat observation from the previous April 2013, FDA inspection.

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

In your response, you stated you will develop a standard operating procedure (SOP) that includes component testing for purity and identification. You also stated you will train a technician on how to handle raw material components. Your response is inadequate. You failed to provide adequate details of your procedure that will ensure appropriate incoming testing will be performed for each component, i.e., complete testing against the COAs or appropriate justification to perform reduced testing of selected quality attributes (other than identification) based on supplier reliability. You also did not describe other elements of your supplier qualification program beyond a vendor questionnaire. Additionally, you failed to provide a plan to test retain samples of previously used drug product components to ensure all quality attributes were met.

In response to this letter, provide the following:

• 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.

• The chemical and microbiological quality control specifications you use to test and release each incoming lot of components for use in manufacturing.

• 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 re-validation. In addition, include a commitment to always conduct at least one specific identity test for each incoming component lot.

• 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 components for the drug products you manufacture.

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

You failed to appropriately validate your processes and adequately qualify the equipment used to manufacture your topical OTC drug products. Specifically, you have not completed the appropriate process performance qualification (PPQ) studies for multiple topical OTC drug products, and you do not have a rigorous ongoing program to monitor process control to ensure stable manufacturing operations and consistent drug quality. You also failed to appropriately conduct performance qualification on your compounding and filling equipment.

Without appropriately validating your processes and qualifying your equipment, you cannot demonstrate that your manufacturing process can consistently manufacture drug products that meet predetermined quality attributes.

This is a repeat observation from the previous April 2013, FDA inspection and a violation listed on the Untitled Letter issued to your firm on January 24, 2014.

In your response, you stated you will implement a comprehensive production and process control program and train your employees. You also stated you will develop a performance qualification process to integrate into your installation and operational qualification procedures. Your response is inadequate. You failed to provide adequate details of your new procedures and protocols. You also did not provide a timeline for the implementation of these plans.

In response to this letter, provide the following:

• 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 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 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.

• An assessment of each drug product process to ensure that there is a data-driven and scientifically sound program that identifies and controls all sources of variability, such that your production processes, and will consistently meet appropriate specifications and manufacturing standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, sufficiency of detectability in your monitoring and testing systems, quality of input materials, and reliability of each manufacturing process step and control.

4. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

You failed to demonstrate that your cleaning and disinfection practices are adequate to remove contaminants from the shared equipment used to manufacture both topical OTC
drug and cosmetic products. For example, the equipment used to manufacture your (b)(4) is the same equipment used to produce your (b)(4) and (b)(4) drug products, and you lacked cleaning validation studies.

Inadequate removal of active ingredients and residues from manufacturing equipment during cleaning can result in cross-contamination of your drug products.

This is a repeat observation from the previous April 2013, FDA inspection and a violation listed on the Untitled Letter issued to your firm on January 24, 2014.

In your response, you stated you will develop and conduct cleaning validation for all equipment used for OTC manufacturing. Your response is inadequate. You failed to provide adequate details of your validation plan. You also did not provide timelines for the implementation of this plan.

In response to this letter, provide the following:

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

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

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:
o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning

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.

Unapproved New Drug and Misbranding Violations

Unapproved New Drug Violations

(b)(4) Hydroquinone Cream and (b)(4) are “drugs” as defined by 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 skin bleaching drug products. Examples of claims observed on your product labels, that provide evidence of the intended uses (as defined by 21 CFR 201.128) of your products include, but may not be limited to, the following:

(b)(4) Hydroquinone Cream
(b)(4)

(b)(4)

(b)(4) Hydroquinone Cream and (b)(4) skin bleaching drugs are subject to section 505G of the FD&C Act, 21 U.S.C. 355h, which governs nonprescription drugs marketed without an approved application. Specifically, your skin bleaching products fall under section 505G(a)(4) of the FD&C Act, 21 U.S.C. 355h(a)(4), because they are subject to a determination to be not generally recognized as safe and effective (GRASE) in a proposed rule that is the most recently applicable proposal issued under 21 CFR part 330.¹ Thus (b)(4) Hydroquinone Cream and (b)(4) are deemed to be new drugs under section 201(p)(1) of the FD&C Act and subject to the requirement to have an approved new drug application under section 505 of the FD&C Act, 21 U.S.C. 355, beginning on September 23, 2020.²

No FDA-approved application pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, is in effect for (b)(4) Hydroquinone Cream or (b)(4). Accordingly, your skin bleaching drug products are unapproved new drugs and their introduction or delivery for introduction into interstate commerce violates section 505(a) of the FD&C Act, 21 U.S.C. 355(a). Introduction or delivery for introduction of such products into interstate commerce is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. 331(d).

Misbranded Drugs

Further, (b)(4) Hydroquinone Cream and (b)(4) are misbranded under section 502(ee) of the FD&C Act, 21 U.S.C. 352(ee), because these products are nonprescription drugs subject to section 505G of the FD&C Act, 21 U.S.C. 355h, are not the subjects of applications approved under section 505 of the FD&C Act, 21 U.S.C. 355, and do not comply with the requirements under section 505G.

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).

Quality Unit Authority

Your inspectional history and 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.

Repeat Observations and Violations at Facility

In a previous inspection dated April 5, 2013, and an untitled letter dated January 24, 2014, the FDA cited similar CGMP observations and violations. You proposed specific remediation for these observations and violations in your responses. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

Test Results Out-of-Specification

For more information about handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see the FDA’s guidance document Investigating OOS Test Results for Pharmaceutical Production at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigating-out-specification-test-results-pharmaceutical-production.

Process Controls

Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See the FDA’s guidance document 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/regulatory-information/search-fda-guidance-documents/process-validation-general-principles-and-practices.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm and because you failed to correct repeat violations. We strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

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 identify your response with unique identifier CMS 618333. Electronic responses may be submitted to ORAPHARM4_Responses@fda.hhs.gov with ATTN: CDR Steven E. Porter, Jr. or send your written responses to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food and Drug Administration
1907 Fairchild Road
Irvine, CA 92612

If you have questions regarding this letter, please contact LCDR Rumany Penn, Compliance Officer, at (949) 608-4409, or by email at Rumany.Penn@fda.hhs.gov.

Sincerely,
/S/

Lance M. De Souza
Acting Director, Division of Pharmaceutical Quality Operations IV

_________________

1 On August 29, 2006, FDA issued a proposed rule (71 FR 51146) setting forth a determination that OTC skin bleaching drug products, including but not limited to those that contain hydroquinone, are not generally recognized as safe and effective.

2 FDA did not determine that it was in the interest of public health to extend the period during which any drugs subject to section 505G(a)(4) may be marketed without such an approved new drug application.