WARNING LETTER

The W.S. Badger Company, Inc. MARCS-CMS 622318 — April 12, 2022

Delivery Method:: Electronic Mail
Product:: Drugs

Recipient:: Recipient Name

Ms. Rebecca Hamilton and Ms. Emily Schwerin-Whyte; Recipient Title

Co-CEOs; The W.S. Badger Company, Inc.; 768 Route 10
Gilsum, NH 03448-7503
United States

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

Warning Letter 622318

April 12, 2022

Dear Ms. Hamilton and Ms. Schwerin-Whyte:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, The W.S. Badger Company, Inc., FEI 3009946959, at 768 Route 10, Gilsum, NH, from August 30 to September 14, 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).

We reviewed your September 28, 2021 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 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 distributed various over-the-counter (OTC) drug products, but you failed to adequately validate your drug manufacturing processes and lacked adequate process validation studies for multiple products. In multiple batches of your sunscreen products, including those intended for infants, quality control testing yielded out-of-specification (OOS) results. Without process validation, your firm lacks basic assurance that you understand the adequacy of manufacturing inputs and parameters that affect product quality, and can ensure robust operations that reproducibly deliver products that meet specifications. In addition, you lacked adequate cleaning validation.

During the time period that you lacked adequate process validation, you manufactured, released, and distributed at least (b)(4) batches representing at least 23 unique drug product item codes. This is a repeat violation.

Your response stated that you were working with a consultant to complete your process validation studies, and that your plans were partially complete. You planned on completing your studies by (b)(4). You also stated that you planned to complete cleaning validation by the same date.

Your response was inadequate because your proposal to address your missing or inadequate process validation studies did not specify whether you planned to continue distribution of products produced from processes still lacking initial validation studies (process performance qualification (PPQ)). Similarly, your proposal for cleaning validation lacked adequate details. You had committed to performing process and cleaning validation for your products in response to the previous inspection and at a regulatory meeting held with FDA on November 19, 2019. However, from the time since your previous inspection, you had only performed PPQ studies for one of your products (SPF30 Baby Sunscreen), and had not yet completed the validation report for that product. It is difficult for the Agency to have confidence in your current commitments to comply with the FD&C Act when you failed to adhere to previous process and cleaning validation commitments.

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.

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 sound design, process performance qualification, and ongoing lifecycle monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

• The latest update and timelines for performing appropriate process performance qualification (PPQ) for each of your marketed drug products. Explain whether your firm plans to further distribute any products for which process validation studies have not yet been completed. Also, include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

• 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 procedures that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

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/media/71021/download.

2. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods (21 CFR 211.165(e)).

You released finished OTC drug products based on release testing performed by a third-party contract testing laboratory (CTL). The analytical test methods had not been validated for accuracy, specificity, and reproducibility. For example, the zinc oxide release test method that your CTL used was validated for another customer’s zinc-based products, but not for yours. Additionally, these same unvalidated test methods lacked scientific evidence to demonstrate that they were stability-indicating for your specific formulations. FDA initially made you aware of your lack of method validation over two years ago during your previous inspection and since then, you manufactured, released, and distributed numerous batches from multiple product codes without having adequate release and stability method validation data. This is a repeat violation.

Your response stated that you became aware that your CTL was using a method that was not specific for your formulation of OTC zinc-based products during an audit of your CTL on August 10, 2021. You also stated that you only then started working with your CTL to perform the necessary method validation studies for your products.

Your response was inadequate because you did not address why it took so long to initiate corrective actions and preventive actions despite having been cited for lack of method validation at your previous inspection. You did not have adequate zinc oxide release and stability test method validations during your May 2019 inspection, and committed to completing method validation at the November 19, 2019 regulatory meeting. It is difficult for the Agency to have confidence in these current method validation commitments when you failed to adhere to your previous commitments.

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 your drugs regardless of agreements in place with your contract facility. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure 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.

In response to this letter, provide the following:

• A detailed, independent assessment of all test methods to ensure they include specific instructions to ensure repeatability, are supported by adequate validation (or verification, for USP compendial methods) studies, and are appropriate for their intended use. The assessment should also determine whether test methods used in the stability program are stability-indicating. The scope of the assessment should encompass any tests conducted by your firm or its contract laboratories.

• A status report and timelines for completing validation (or verification, if appropriate) for all analytical test methods.

• A comprehensive independent review of your entire laboratory system, and a corrective action and preventive action (CAPA) plan that ensures full remediation of the laboratory operation. For example, the review of your laboratory system should include, but should not be limited to, the suitability of all laboratory equipment, a fully remediated calibration program, staff competencies, supervisory oversight, data systems, and other elements of laboratory control. This need for a compliant laboratory system also extends to any laboratory performing testing on your behalf.

See FDA’s guidance document, Analytical Procedures and Methods Validation for Drugs and Biologics, for general principles and approaches that FDA considers appropriate elements of analytical method validation at https://www.fda.gov/media/87801/download.

3. 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).

Your investigations were inadequate. You implemented ineffective corrective actions and preventive actions as you repeatedly obtained OOS viscosity and high water activity results. During an approximately two-year time period, you recorded at least 25 OOS results for viscosity. During the same time period, you also recorded at least 45 OOS results for high water activity. If the water activity exceeded your specifications, you would then test for bioburden. Several of these high water activity batches were also OOS for bioburden and failed release. In addition, you have received at least 29 complaints regarding product consistency and at least 129 complaints regarding lack of effect since March 2018. This is a repeat violation.

For example, you investigated an instance of OOS high water activity in your SPF30 Baby Sunscreen Cream finished product on June 9, 2020. You determined the root cause to be moisture in the (b)(4), and implemented (b)(4) to achieve greater control of moisture in the (b)(4), subsequently closing the investigation on August 17, 2020. However, even after applying the (b)(4), you observed 30 additional OOS results for high water activity, with some batches later failing for bioburden.

One of the subsequent 30 high water activity results occurred in your SPF35 Kids Clear Face Sunscreen Stick. Bioburden testing performed after the high water activity result showed the total aerobic microbial count failed specification at 390 cfu/mL. You rejected this lot, but your investigation did not determine the root cause of the microbial failure or extend the investigation to determine if any additional lots may have been affected. It is also concerning that you obtained OOS results for high water activity and failing results for bioburden in a product that does not appear to contain water as a component.

In your response regarding the failing viscosity results, you stated that you do not consider viscosity to be a critical quality attribute. You also stated that you would amend your investigations program to ensure investigations are more thorough.

Your response was inadequate because it discounted the significance of the viscosity specification without performing an adequate investigation into factors that caused the failures. You did not identify adequate CAPAs to resolve the potential root causes, and you did not sufficiently assess how other batches may have been compromised. Viscosity is a meaningful quality attribute for topical drug products, such as sunscreens and creams. Your range of viscosities varied substantially during the course of batch processing and may have contributed to your product complaints. Viscosity is important to drug product stability and in the application of your drug products to the skin, and should be measured using validated methods, e.g. USP <911> Viscosity.

Your response regarding the high water activity results and failing bioburden results acknowledged that the documentation of your investigations was inadequate. You attributed the continued high water activity results to the same root cause of high moisture in your (b)(4) and your follow-up CAPA was to (b)(4) to the (b)(4). You also stated that you would review your investigation procedures to include an assessment of whether the identified issue could have affected other lots.

Your response was inadequate because it lacked suitable impact assessment of your many OOS and failing results on your products on the market within expiry. FDA informed you, more than two years ago, that your investigations were not enabling effective CAPAs. At the time, you made similar commitments to improve your investigation process. However, you failed to adequately improve your investigation process since then. At the time of inspection, you had not yet initiated follow-up CAPAs in response to the excessive water activity and failing bioburden results. At the time, you also stated you were exploring adding (b)(4).

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 products currently in the U.S. market and within expiry as of the date of this letter 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 should not be limited to addressing the following:
o Quality unit 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 each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations

CGMP Consultant

Based upon the nature of the violations we identified at your firm, 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 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 ORAPHARM1_RESPONSES@fda.hhs.gov. Your written notification should refer to Warning Letter #622318 and include FEI number 3009946959.

If you have questions regarding the content of this letter, please contact us through ORAPHARM1_RESPONSES@fda.hhs.gov, and “cc” Compliance Officer Nancy Scheraga (Nancy.Scheraga@fda.hhs.gov).

Sincerely,
/S/

Craig Swanson
Acting Program Division Director/District Director
Office of Pharmaceutical Quality Operations
Division I/New Jersey District