FDA -WARNING LETTER -March 30, 2023

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, ALI Pharmaceutical Manufacturing, LLC, FEI 1920841, at 4410 S. 102nd Street, Omaha, from September 26 to October 3, 2022.

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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 October 21, 2022, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

1. Failure to demonstrate that your manufacturing process can reproducibly manufacture an intermediate and API meeting its predetermined quality attributes.

You failed to adequately validate your porcine thyroid API manufacturing processes, including the (b)(4) of (b)(4) intermediates. Additionally, the (b)(4) process validation was not representative of your current manufacturing process. For example:

• You based your (b)(4) process for (b)(4) intermediates on your (b)(4) room temperature mapping report. However, you performed the study with (b)(4) porcine thyroid which lacked evidence to address possible variation when (b)(4) intermediates are (b)(4). Further, this report indicated that your target material temperature was only reached after (b)(4) of (b)(4). Your report also lacked information about the material of construction (e.g., thickness and composition) of the drums, whether liner bags were used in the drums, and the quantity of intermediate in each drum.
• You determined the (b)(4) room processing time for (b)(4) porcine thyroid intermediate based on a retrospective evaluation of data obtained from previously (b)(4) lots. You concluded that a single log reduction of microbes takes (b)(4) in the (b)(4) room. However, your raw data show multiple instances of less than one log reduction in more than (b)(4).
• Your (b)(4) process performance qualification (PPQ) report failed to sufficiently correlate test data for the initial microbial load with the total time each lot was in the (b)(4) room. Further, you lacked justification for only sampling (b)(4) of each PPQ lot. You did not demonstrate material uniformity, including chemical and microbiological attributes.
• You lacked justification for holding times between stages of (b)(4), and final blend of porcine thyroid API. You stored (b)(4) intermediate in the (b)(4) room for up to (b)(4).

The porcine thyroid, USP API you manufactured is used to produce drug products to treat hypothyroidism. Because of the narrow therapeutic range of these products, proper blending and manufacture of your intermediate that is appropriately evaluated through process validation is essential to prevent patients from receiving insufficient or excessive doses.

In your response, you provide a retrospective evaluation of your microbiological results for the full-strength porcine thyroid API that you state is the only API you currently manufacture. You state that you implemented a worst-case interim sampling procedure to obtain samples from the top, middle and bottom of each container. You also commit to implement a fixed length of time of the (b)(4) by applying a worst-case analysis from the results of the (b)(4) intermediate.

Your response is inadequate. You do not address the impact of microbial results on your other distributed porcine thyroid API ((b)(4)) that may still be within their reevaluation date. Although you commit to evaluate intra-batch variability for (b)(4) intermediates, you do not provide sufficient rationale to demonstrate that (b)(4) lots provides a representative sample size to evaluate your process. These studies will be conducted for in-process (b)(4) and in-process (b)(4) samples and do not include final blended API. You do not provide sufficient details of your plans to assess and remediate your validation program.

In response to this letter, provide:

• 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 API. Regarding microbiological attributes, the assessment should include, but not be limited to, total counts and objectionable microorganisms such as Bacillus cereus.
• A detailed risk assessment addressing the hazards posed by distributing API with potentially objectionable contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
• Complete investigations into all lots with potential objectionable microbial contamination or an out-of-specification (OOS) microbiological result whether or not later invalidated. The investigations should detail your findings regarding the root causes of the contamination.
• Appropriate microbiological lot release specifications (i.e., total counts, identification of bioburden to detect objectionable microbes) for each of your API.
• A list of chemical and microbial specifications, including test methods, used to analyze each lot of your intermediate and API before lot disposition decision.
• A summary of results from testing retain samples of all API lots within expiry. You should test all appropriate quality attributes including, but not limited to, identity and strength of active ingredients and microbiological quality (total counts and identification of bioburden to detect any objectionable microbes) of each lot. If testing yields an OOS result, indicate the corrective actions you will take, including notifying customers and initiating recalls.
• 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-lot and inter-lot variation to ensure a continuing state of control. This should include the process for selecting API lots to achieve the final API blend.
• A timeline for performing appropriate (PPQ) for each of your marketed API.
• Include your process performance protocol(s), and written procedures for qualification of equipment and facilities.
• An assessment of each API 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.
• Timelines for completed process performance qualification for marketed porcine thyroid API (b)(4) and (b)(4) processed.

2. Failure to establish and follow written procedures for investigating critical deviations or the failure of intermediates and API lots to meet specifications.

You failed to adequately investigate OOS results. For example:

• You received a customer complaint for an OOS microbial result for full-strength porcine thyroid API. The complaint lot was composed of (b)(4) sublots of (b)(4) intermediate, two of which were reprocessed due to potential Escherichia coli (E. coli) contamination. Your investigation consisted mainly of a retrospective evaluation of similar complaints received at your firm. You did not sufficiently extend your investigation to the manufacturing process and there is no evidence that you evaluated retain samples.
• You reported an OOS microbiological result, of six times the allowable limit, for a porcine thyroid API lot manufactured for stability studies. Your limited phase 2 investigation concluded the OOS result was most probably due to a contamination during sampling. The manufacturing process of the lot was not sufficiently evaluated as part of the investigation and no additional actions were taken.
• You initiated two OOS investigations into high (b)(4) results for porcine thyroid API. You did not identify a root cause for each investigation. Your investigations did not sufficiently extend to manufacturing operations that could affect the OOS lots as well as other lots of porcine thyroid API. Although the investigations were both associated with similarly high OOS (b)(4) results, the conclusions of each investigation were different. In the May 2021 investigation, you stated that the lot could not be further processed and should be rejected. However, the August 2021 investigation concluded that the lot could be reworked. No corrective action and preventive action (CAPA) was opened for either investigation. In addition, the lot associated with the August 2021 investigation was rejected during our inspection, one year after the investigation was closed and without establishing a documented reason for its rejection.

In your response, you state that you revised your investigation procedures to include trend analysis, bracketing, and a more robust root cause determination, including operator interviews. You initiated multiple CAPAs to further investigate the root cause of the (b)(4) failures and to provide additional information for microbial OOS results.

Your response is inadequate. Your response to the complaint investigation does not address your failure to adequately evaluate your manufacturing process. It also does not include any commitment to evaluate retain samples. Although you commit to further investigate the root cause for your microbial and (b)(4) OOS results you fail to provide the evidence. It is not clear if you evaluated the manufacturing process and extended the investigations to other lots that may have been potentially impacted.

In response to this letter, provide:

• 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, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for porcine thyroid API lots manufactured and release in the last three years and a report summarizing the findings of the analysis, including the following for each OOS:

 Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.

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.

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., lot manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, lot failure history). Provide a summary of potential manufacturing root causes for each investigation and any manufacturing operation improvements.

3. Failure to ensure that API lots meet specifications prior to blending with other lots.

You failed to perform analytical testing prior to the final blend of (b)(4) intermediate lots. Your final blend consisted of up to (b)(4) intermediate lots. This practice may result in the blending of lots not meeting specifications and unreliable results reported for your finished API.

In your response, you commit to implement top, middle, and bottom sampling of each container for in-process (b)(4) intermediates of your finished full strength porcine thyroid API.

Your response is inadequate because you do not sufficiently explain why you will only test (b)(4) intermediates for microbial load and (b)(4). You did not commit to perform full testing of (b)(4) intermediate lots prior to blending. In addition, your response lacks a commitment to evaluate lot uniformity of other strengths of distributed porcine thyroid API previously manufactured at your firm that may still be on the market.

In response to this letter, provide:

• A comprehensive, independent assessment of your in-process monitoring and sampling operations, focusing on each upstream process step that can introduce variability. Provide your remediation plan to improve: (1) in-process detection of variation; (2) upstream controls; and (3) sampling plans.
• An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all lots of API distributed to the United States that are within expiry as of the date of this letter.
• A summary of all results obtained from testing retain samples from each lot. If such testing reveals substandard quality API, take rapid corrective actions, such as notifying customers and product recalls.

Process Validation

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.

Process Controls

Your firm lacks an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. 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-guidance-documents/process-validation-general-principles-and-practices.

Quality Systems

Your firm’s quality systems are inadequate. For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances: Q8(R2) Pharmaceutical Development at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development, Q9 Quality Risk Management at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9-quality-risk-management and Q10 Pharmaceutical Quality System at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-quality-system.

Test Results Out-of-Specification

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.

A possible laboratory error is insufficient to close an investigation at Phase 1. Whenever an investigation lacks conclusive evidence of laboratory error, a thorough investigation of potential manufacturing causes must be performed.

Contractor’s Responsibilities

During the inspection, a review of microbiological results for five porcine thyroid API lots showed identical results, which is not typical for microbial testing. Your firm did not perform an evaluation of the validity of these atypical results. It is your responsibility to use a qualified contract testing laboratory that produces accurate and reliable results.

We also noted that your contract laboratory provided you with certificates of analysis (COA) that you used to release your lots, even though the COA stated, “results are not suitable for GMP release for clinical or commercial use.” This testing does not support the release of your API for human use.

FDA considers contractors, such as contracted laboratories, as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the drugs you test for your clients. It is essential that you understand your responsibility to operate in full compliance with CGMP, and that you inform all your customers of any out-of-specification results or significant problems encountered during the testing of these drugs.

Additional API CGMP Guidance

FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-q7a-good-manufacturing-practice-guidance-active-pharmaceutical-ingredients.

CGMP Consultant Recommended

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations 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

Reference: FDA warning letter

FDA – Warning Letter