Aurolife Pharma, LLC MARCS-CMS 607087 — October 16, 2020

WARNING LETTER

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• Delivery Method: Certified Mail
• Product: Drugs

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• Recipient: Mr. Madan Mohan Reddy; Director of Operations; Aurolife Pharma, LLC; Plot No. 11, Survey No. 9 The Water Mark Building; Kondapur, HiTech City; Hyderabad 500084; Telangana; India

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

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WARNING LETTER
CMS# 607087

October 16, 2020

Dear Mr. Reddy:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, AuroLife Pharma, LLC, FEI 3005796917, at 2400 Route 130 North, Dayton, New Jersey, and 6 Wheeling Road, Dayton, New Jersey, from January 13 to February 12, 2020.

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 March 5, 2020, 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 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 invalidated initial out-of-specification (OOS) impurity testing results for your olanzapine active pharmaceutical ingredient (API) and finished drug product without sufficient investigation to determine the root cause of the failures.

For example, during impurity testing of olanzapine tablets, batch #56119018, an impurity at relative retention time (RRT) (b)(4) was calculated at a concentration of 0.3%, which exceeded the specification for any unidentified impurity (not more than (b)(4)%). You did not adequately investigate this impurity result.

During the OOS investigation, you confirmed the OOS results twice using the original sample. Then you tested a new sample from the same batch with a passing result, and only reported the passing re-test result. Without supporting evidence, you concluded that the impurity results were due to contamination from the mortar and pestle.

Furthermore, you failed to investigate impurity OOS test results for olanzapine API used to make your olanzapine tablets. For example, six lots of this API exceeded the specification limit of (b)(4)% for an unknown impurity at RRT (b)(4).

You did not adequately investigate these impurity test failures. You released five of these API lots for finished drug production and rejected one. In the rejected lot, (b)(4), you observed a high unknown impurity at another RRT. During the inspection, firm personnel indicated that this lot had experienced high temperature excursions while in storage.

You had prolonged problems assuring maintenance of the required temperatures of the refrigerated storage unit in which this API was stored.

While you attributed the OOS results at (b)(4) RRT to HPLC method issues that included lack of column prewashing, you failed to implement the corrective action in a timely fashion. Following our inspection, you tested at least (b)(4) more lots before making this correction to the method.

In your response, you wrote that your firm will re-evaluate the OOS results for batch #56119018 and recall the batch if necessary. Regarding the olanzapine API, you wrote that your “QC management verified all the tested and released lots for the subject peak at (b)(4) RRT” and determined the API lots were within specifications. You also wrote that you agreed that your OOS investigation procedure was inadequate and needed revision.

Your response is inadequate. We disagree with your conclusion that there was sufficient evidence to invalidate the OOS results for the five lots of olanzapine API. You also did not perform a retrospective assessment to identify all OOS results that were invalidated by your laboratory without strong scientific justification and clear evidence. Additionally, your revised OOS procedure remains insufficient. For example, it failed to ensure a thorough investigation of potential manufacturing causes is initiated whenever a laboratory cause cannot be conclusively identified.

In response to this letter, provide:

• The identity of the impurities at RRT (b)(4) and (b)(4) seen in lot (b)(4) of olanzapine API that failed for unknown impurities (specification NMT (b)(4)%). After you identify these impurities:
    o Determine if these impurities were potentially seen in forced degradation studies
    o Determine which root cause(s) was most likely to be associated with the degradant(s) found
    o Expand your investigation of OOS results at similar RRT in other batches of olanzapine API, and perform identification and proper root cause analysis

• A review of all batches of olanzapine API that were stored, or potentially stored, under the same conditions as the failed batch.

• A summary of all test results for each lot of olanzapine API received by your firm, regardless of whether the data was invalidated or if the lot was rejected. Test results for each lot should include each data point generated.

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

• 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 corrective action and preventive action (CAPA) plan 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 each investigation and its CAPA
    o Revised OOS investigation procedures with these and other remediations.

2. Your firm failed to maintain buildings used in the manufacture, processing, packing or holding of drug products in a good state of repair (21 CFR 211.58).

You failed to adequately maintain your facility in a good state of repair.

For example, in 2018, you had four incidences of water leakage from the ceiling of your encapsulation room (b)(4). Gabapentin capsules, USP 100 mg, were exposed to these leaks during multiple batch encapsulation operations. You also experienced water leaks during encapsulation operations of phentermine capsules.

In addition, there were at least five instances of water leaks in your packaging area (rooms (b)(4) and (b)(4)). Some occurred while you were filling tablets into open containers. Some of these leaks occurred above the packaging lines.

Your failure to ensure that your facility is adequately maintained may pose a risk to the quality of your finished drug products, including the moisture sensitive drug, pioglitazone HCL tablets.

Your firm failed to ensure that the root cause of these leaks was addressed promptly and to adequately assess the risks due to exposure of products to elevated ambient moisture.

In your response, we acknowledge you have committed to recalling the batches that were specifically listed on the Form FDA 483 in Observation #1. You also wrote that you plan to add a requirement to examine CAPA effectiveness and develop a new procedure for handling production anomalies. Your response failed to address why your executive management failed to fully recognize the risks from these leaks, and adequately address how you will ensure that facility repairs are addressed promptly.

In response to this letter, provide:

• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review. Your plan should also ensure that appropriate actions are taken throughout the company network.

• A retrospective review of drugs that may have been negatively impacted, including both chemical (e.g., dissolution, degradants) and microbiological attributes. The review should include factors such as elevated moisture levels due to leaks, and also include assessment of
all records that would yield such information, including records on maintenance, deviations, and facility repairs.

• Test retain samples of moisture sensitive drugs manufactured during periods that leakage occurred in your facilities.

3. Your firm failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

During the inspection, our investigators observed surfaces covered in powder throughout your facility including API sampling rooms, raw material dispensing rooms, common production corridor areas, granulation rooms, and compression rooms.

For example, in a (b)(4) granulation room documented as “major”-cleaned, we observed a powder residue coating the surface of the (b)(4) panel, the floor of the room, and the control panel of a (b)(4).

The visible powder observed in numerous areas of your facility could lead to cross-contamination of your finished drug products. Notably, the hazard posed by this deviation is heightened because you manufacture high potency drug products.

In your response, you stated you will revise your cleaning procedures and train your personnel. Your response failed to address the root cause of inadequate powder control in your facility and propose adequate corrections.

In your response to this letter, provide:

• Your CAPA plan to ensure that you have effective powder control (e.g., exhaust) systems in your facility.

• 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 in facility design, cleaning procedures, or cleaning practices. It should encompass each production room and piece of manufacturing equipment used to manufacture more than one product.

4. 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)).

To reduce the manufacturing process time for three strengths of acetaminophen and codeine phosphate tablets, you implemented a manufacturing process change. Using this new process, you manufactured (b)(4) process performance qualification (PPQ) batches. You rejected (b)(4) batches for uniformity failures (e.g., blend, content uniformity) and released the remaining (b)(4) batches.

You did not have data to support that your process was in a state of control prior to releasing those (b)(4) batches.

Your evaluation of the process change after implementation concluded that the new process resulted in a non-uniform blend, your previous manufacturing process was more consistent and robust, and the remaining batches should be held pending further discussion. Eight months after this initial evaluation you made the decision to revert to the old process. However, your firm determined that the quarantined batches could be distributed.

In your response, you wrote that you would review these lots and recall if necessary.

You also wrote that only the first (b)(4) consecutive “successfully manufactured” PPQ validation batches can be considered for release into the market and that any prior failed PPQ batches can be considered “(b)(4).” You added if any failure is observed in PPQ batches “with unassignable root cause then the failed batch and the batches manufactured prior to the failed batch shall not be released in to the market.” Your response is inadequate, because your proposed validation strategy fails to ensure all PPQ batches are properly evaluated when determining whether or not your process is in an initial state of control.

We acknowledge you have recently made the decision to recall the PPQ batches made using the new process.

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 ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies can result in product quality attribute failures. 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 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.

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

• A determination of whether the PPQ for each of your marketed drug products was properly executed and used the appropriate criteria.

Consultant recommended

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 these violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, 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 or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also 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.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.

Please send your electronic reply to Yvette Johnson, Compliance Officer at ORAPHARM1_RESPONSES@fda.hhs.gov and CDER-OC-OMQ-Communications@fda.hhs.gov. Please identify your response with FEI 3005796917.

Sincerely,
/S/

Diana Amador-Toro
Program Division Director/District Director
OPQO Division I/New Jersey District Office

cc:
Mr. Sanjay Singh
Associate President of Operations
AuroLife Pharma, LLC
2400 Route 130 North
Dayton, NJ 08810