Sovereign Pharmaceuticals, LLC

DATE: 10/5/2022 Case #: 634233

Mr. Hafey:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sovereign Pharmaceuticals, LLC, FEI 3003229412, at 7590 Sand Street, Fort Worth, from April 13 to 22, 2022.

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).

Information and records gathered during the course of the inspection reflect that your products are intended to treat a disease or condition. Therefore, your products, (b)(4), are drugs as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 321(g)]. Your products, which contain (b)(4), are also biological products as defined in section 351(i)(1) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)(1)] because they are a “protein” as defined in 21 CFR 600.3(h)(6), or are “analogous” to a protein because the identified biological product (i.e., protein) component in these naturally derived mixtures is necessary for the activity of the product and contributes to achieving the intended therapeutic effect.

Based on the information obtained from the inspection performed between April 13 to April 22, 2022, Sovereign Pharmaceuticals LLC. has been identified as the manufacturer of the bulk tablets for (b)(4). The drug listing submission for these products, however, does not reference Sovereign Pharmaceuticals LLC. as one of the manufacturers. Under section 510 of the FD&C Act as amended and 21 CFR (21 U.S.C. 360(j)(1), 21 CFR 207.17 and 207.41), all drugs manufactured, prepared, propagated, compounded, or processed for U.S. commercial distribution must be appropriately listed with FDA. Failure to list these drugs with FDA with the correct manufacturing establishment as required by section 510 of the FD&C Act, 21 U.S.C. 360(j), and as required under 21 CFR 207 (a)(12)(ii) is prohibited under section 301(p) of the FD&C Act, 21 U.S.C. 331(p). Failure to properly list a drug with the FDA will also render it misbranded under section 502(o) of the FD&C Act, 21 U.S.C. 352(o).

We reviewed your May 13, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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, and your firm’s quality control unit did not review and approve those procedures, including any changes (21 CFR 211.100(a)).

Your firm failed to adequately validate the manufacturing processes for bulk (b)(4) tablets. Specifically, during process performance qualification (PPQ) for in-process blend powder drum assay testing, several out-of-specification (OOS) results were obtained for at least one of your active ingredients, (b)(4) and/or (b)(4).

In addition, OOS tablet active ingredient assay and tablet weight results were observed in your validation report. The observed tablet assay result is outside of the United States Pharmacopeia (USP) (b)(4) Tablets monograph acceptance criteria.

These multiple OOS results, obtained during PPQ for your bulk (b)(4) tablets, also demonstrate a failure to meet the critical quality attributes defined in your protocols and a process that is not in a state of control.

Additionally, because of the narrow therapeutic range of this product, uniformity is critical; it is especially important to prevent patients with hypothyroidism from receiving insufficient or excessive doses.

Appropriate controls and understanding of your manufacturing processes are essential to ensuring a safe and effective drug product. The blend process is a critical step in the manufacture of oral solid dosage forms, particularly for narrow therapeutics like (b)(4) tablets. Inadequate handling of blends can promote segregation, increase moisture levels, cause aggregation of particles, and lead to inconsistent flow characteristics.

In your response, you indicated that your investigation required a review of ongoing data from (b)(4) tablet testing, that additional drum samples failures did not require investigations, and that blend sampling continued “as is” through commercial operations pending completion of the (b)(4) tablet test data review. You also committed to initiating a revalidation of the blend process and eliminating the drum sampling process, replacing it with a “reliable sampling process.”

Your response is inadequate. Your firm did not provide sufficient data to show where variability in your process was occurring. Your manufacturing process failures indicate that you do not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality.

Your manufacturing process must be designed to consistently maintain a state of control so that it meets all of its chemical and microbiological attributes. 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/regulatory-information/search-fda-guidancedocuments/process-validation-general-principles-and-practices.

In response to this letter, provide:

A data-driven and scientifically sound analysis that identifies all sources of variability including, but not limited to, material transfer, sampling and use of an overage. Determine the capability of each manufacturing process step and provide your corrective action and preventive action (CAPA) plan to reduce process variation.

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 (b)(4) tablets drug products.

Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.

A review of all other drug products that you manufacture to determine whether the specifications are appropriate and justifiable. Conduct a risk assessment for any products and corresponding lots lacking appropriate and justifiable specifications. If any products are found to be outside of compendial standards or other appropriate specifications, indicate the corrective actions you will take, including notifying customers and initiating recalls.

A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all hazards that may impact chemical and microbiological attributes of your (b)(4) tablet drug products. For example, regarding microbiological attributes, the assessment should include, but not be limited to, total counts and objectionable microorganisms such as Bacillus cereus in your incoming active pharmaceutical ingredients (API) lots. Include a CAPA plan that describes improvements to design and control.

2. 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 firm failed to adequately perform a timely and thorough investigation into the in-process OOS results obtained for your (b)(4) tablet drug products. For example, FDA investigators found that approximately 27 validation and commercial batches of (b)(4) tablets with different strengths failed your blend powder drum assay acceptance criteria and were compressed and released before being adequately investigated.

During the inspection, your firm generated a technical report explaining the OOS results were related to your drum sampling process. Specifically, it stated that the angle of insertion of the sampling thief was insufficiently shallow and resulted in the application of extra force.

In your response, your firm provided investigation INV-21-0017. The investigation is deficient in that it only considered (b)(4) batches and not extended to all similarly impacted drug product. Furthermore, your response concluded that additional OOS results for the drum samples tests did not require investigations. We acknowledge that you included a Risk Assessment report, dated May 12, 2022.

Your response is inadequate. Your firm is responsible for conducting a thorough investigation when you become aware that a product fails to meet any of its established specifications. Your firm failed to assess other sources of variability, allowed the continued use of flawed sampling processes and did not identify correct CAPAs. Furthermore, timely investigations are essential when data indicates a problem with a system or process.

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected 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/regulatory-information/search-fda-guidance-documents/investigating-out-specification-oos-test-results-pharmaceutical-production-level-2-revision.

In response to this letter, provide:

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 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 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 of each investigation and its CAPA o Revised OOS investigation procedures with these and other remediations 3. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)).

During the inspection, we observed that your quality unit (QU) was not effectively exercising its responsibilities to oversee the quality of your drug manufacturing operations. In addition, the established procedures applicable to the QU were not properly followed. For example:

A. Your firm’s QU failed to provide adequate quality review and approval for your (b)(4) tablet validation reports. Specifically, your QU approved validation reports for varying strengths stating no deviations were recorded in the execution of the validation protocols. However, a review of the validation reports showed significant errors and omissions, including but not limited to, drum assay failures and a failure to perform required RSD calculations for drum assay data.

B. Your established procedures require initiation of deviations to investigate and determine the impact of stability chamber excursions greater than (b)(4). This procedure also states to consider alternate storage for excursions expected to exceed (b)(4). However, in multiple instances, your firm did not initiate investigations involving excursions lasting more than (b)(4), and up to 10, days.

Your QU is responsible for fully exercising its authority and responsibilities.

In your response, you stated that a deviation was opened for the excursions cited by our investigators. You committed to initiating (b)(4) checks of the stability chambers and to review the entire system to assess improvements in monitoring system devices. You acknowledged the QU’s role and responsibilities in deficiently reviewing the validation reports.

Your response is inadequate. You failed to provide sufficient data to show that your stability samples were not negatively impacted by the excursions listed in the observation. In addition, you did not perform a retrospective review for other potential similar excursions to take appropriate CAPAs and product impact evaluations. You also failed to perform a comprehensive review of similarly impacted systems by a deficient QU.

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 of adequacy of your stability samples representative of product in the market through shelf life for all drug products you manufacture that may be similarly impacted by stability chamber excursions.

A detailed risk assessment on the impact to product quality and any potential hazards to patients because of inadequate quality review and approval of CGMP records.

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

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.

Based upon the nature of the violations we identified at your firm we strongly recommend engaging a consultant 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.

Based on the information your firm submitted to FDA's electronic Drug Registration and Listing System and the information collected during the April 2022 inspection, FDA has determined that your firm is distributing (b)(4), a biological product, without FDA approval or a valid biologics license.

We encourage you to contact FDA's Unapproved Drugs Coordinator, Dr. Sally Loewke, at Sally.Loewke@fda.hhs.gov for assistance in communicating with the FDA on the application process for your unapproved biological product.

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.

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of APIs and/or finished products produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances in your drug manufacture under 21 U.S.C. 356C(a)(1) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

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.

Your written notification should refer to case # 634233.

Please electronically submit your reply, on company letterhead, to Shawn Larson, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov. In addition, please submit a signed copy of your response to Shawn.Larson@fda.hhs.gov and ORAPHARM2ActingDCB@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Shawn Larson via phone at 214-253-5216 or email at Shawn.Larson@fda.hhs.gov.