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  5. Novel Laboratories, Inc. d.b.a LUPIN - 613385 - 06/11/2021
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Novel Laboratories, Inc. d.b.a LUPIN MARCS-CMS 613385 —

Delivery Method:
Via Email

Recipient Name
Ms. Vinita D. Gupta
Recipient Title
Group President-CEO
Novel Laboratories, Inc. d.b.a LUPIN

B/4 Laxmi Towers
Bandra Kurla Complex, Bandra (E)
Mumbai 400051

Issuing Office:
Office of Pharmaceutical Quality Operations Division I

United States

Warning Letter
CMS # 613385

June 11, 2021

Dear Ms. Gupta:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Novel Laboratories, Inc. d.b.a. Lupin, FEI 3006271438, at 400 Campus Drive, Somerset, New Jersey from September 10, 2020 to November 5, 2020.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 Title 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 November 30, 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.

CGMP Violations

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

Your cleaning procedures for non-dedicated equipment, including your tablet presses and (b)(4), are inadequate. Our investigators observed drug residue from previously manufactured drug product inside the (b)(4) on one of your tablet presses documented and released as clean by your quality unit. You used this tablet press to manufacture several potent and non-potent drug products. Investigators also observed residue on the (b)(4), as well as in the (b)(4) duct of your (b)(4). Cleaning and preventative maintenance procedures for your (b)(4), installed in 2008, did not include cleaning instructions for these areas or a regular inspection of the air ducts.

In your response, you stated that you performed analytical testing of the residue collected from the tablet press (b)(4), which confirmed the presence of active drug residue from the previously manufactured drug product. You also stated that analytical testing of the residues collected from the (b)(4) duct of the (b)(4), confirmed the presence of two different active ingredients, trimethoprim and tinidazole.

Your response is inadequate because you did not test reserve samples of drug products released to the U.S. market and within expiry, that were manufactured on these pieces of non-dedicated equipment, for cross-contamination. You stated that the results of the (b)(4) residues are below your maximum allowable carryover (MACO) limits; however, that does not assure that cross-contamination did not occur. In addition, (b)(4) was observed covered with residue, which provides no assurance of its integrity to prevent cross-contamination.

There is no assurance that you can prevent cross-contamination because your corrective action and preventive action (CAPA) plan fails to include cleaning the (b)(4) duct at drug product changeover.

In response to this letter, provide the following:

• A commitment to test all reserve samples of drug products, within expiry and released to the U.S. market, that were manufactured on your tablet press and (b)(4), as identified above, for potential cross-contamination. Your investigation should include an assessment of all potential sources of contamination. In addition, testing should include analyses using validated test methods that are fit for purpose and demonstrate that the drug products are of the strength, quality, and purity they purport to be. Provide a summary of the results that include but are not limited to, drug product name, batch number, expiration date, test performed, name of the test method, specifications, and test results. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

• 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 drug 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 drug product.

• A CAPA plan, based on the retrospective assessment of your cleaning and preventative maintenance programs, that includes appropriate remediations to your processes and practices, assessment of frequency, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and preventative maintenance. Describe improvements to these programs, including enhancements to effectiveness; improved ongoing verification of proper execution for all drug 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 Residues for use in recovery studies
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 drug product.

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

2. 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 adequately validate the manufacturing processes for temazepam 15mg and 30mg capsules before the transfer of product manufacturing to a new building. You did not adequately assess the process and equipment changes (e.g., charging order of the active pharmaceutical ingredient, different model (b)(4)) you made to your manufacturing operations, and failed to identify their impact to product quality. You manufactured batches with these changes implemented and released drug products to the U.S. market. Several batches manufactured with these unvalidated changes had out-of-specification (OOS) results for content uniformity.

Your OOS results suggest that your process is not robust. You did not adequately demonstrate that your manufacturing processes are reproducible and controlled to consistently yield drugs of uniform character and quality.

In your response, you stated that you recognized the occurrence of suboptimal process performance for your temazepam capsule manufacturing operations, which was the root cause of the OOS results. You also stated that you completed a (b)(4)-batch validation study, with equipment and process changes implemented, for both the 15mg and 30mg strengths, and that each of the batches met all specifications. In addition, you stated that you initiated a continuous process monitoring verification sampling protocol to monitor (b)(4) batches, for each strength, that were manufactured with your implemented improvements.

Your response is inadequate because you did not provide assurance that the batches released to the U.S. market, manufactured before validation, are of the appropriate strength and quality. The additional content uniformity testing performed for these batches does not ensure that all other product quality attributes are in conformance.

In addition, your firm does not have an adequate ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. Your continuous process monitoring verification sampling protocol only assesses dose uniformity. Out-of-trend (OOT) results for assay were identified when you made changes to manufacturing operations at the time of product transfer.

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 the following:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Include your validation report, continuous process monitoring verification sampling protocol for temazepam 30mg, and risk assessment reports for temazepam 15mg and 30mg. 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 timeline for performing appropriate process performance qualification for each of your marketed drug products.

• Improved in-process testing and monitoring to enhance detection of variation during production of each batch. Include remediated in-process quality standards, including but not limited to enhanced sampling, that will more robustly monitor upstream process control. Describe how the improvements will ensure early detection of process variation and manufacturing defects, and prevent consumer exposure to substandard quality drug products.

3. Your firm failed to establish and follow adequate written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).

Your quality unit (QU) failed to adequately establish and adhere to written procedures to ensure the strength, quality, and purity of the drug products you manufacture. For example,

• Your cleaning validation protocol procedure for the review and approval to change the MACO limits did not require adequate QU oversight. Specifically, this procedure did not require QU review of the test methods and the approved cleaning MACO limits, for potent and non-potent drug products manufactured on non-dedicated equipment. You did not ensure that each of these test methods had the capability to quantitate the newly established limits.

• You failed to adequately complete annual product reviews (APR) as required by 211.180(e) and your established procedure. Several drug products with a 2019 APR due date remained pending at the time of inspection. Your procedure required APR completion within (b)(4) of the drug product’s anniversary date.

Your firm previously made corporate-wide commitments to strengthen analytical method equivalency, cleaning validation procedures, and APR procedures across all sites and to have corporate quality assurance oversight of these areas.

In your response, you stated that you acknowledged a need for more robust QU oversight of your cleaning validation program and have revised your procedure, SOP NL-VA-002, Cleaning Validation and Verification Procedure to include a risk assessment and method impact assessment. You also identified that laboratory management, and not your QU, has the authority to review and approve individual standard operating procedures (SOP) pertaining to test method validations. You stated that these SOPs are being harmonized for alignment and consistent execution. In addition, you stated that individuals primarily responsible for APR are also responsible for additional QU tasks and that the (b)(4) tabulated process was replaced with a (b)(4) system.

Your response is inadequate because you failed to provide a comprehensive assessment of all written procedures to ensure that procedures impacting the identity, strength, quality, and purity of the drug products manufactured, grant the responsibility of approval to the QU.

Significant findings as detailed 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.

In response to this letter, provide the following:

• 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 A determination of whether your QU has the adequate education, training, and experience, or any combination thereof, to perform assigned QU responsibilities
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

• 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.

Repeat Violations at Multiple Sites
FDA cited similar CGMP violations at this facility in your company’s network.

• On September 10, 2019, Lupin Limited Mandideep (Unit 1), FEI 3002807511, was issued a warning letter for violation of, among other items, 21 CFR 211.67(a) for inadequate cleaning of manufacturing equipment and 21 CFR 211.100(a) for inadequate process validation.

• On November 6, 2017, Lupin Limited Goa (FEI 3004819820) and Lupin Limited Indore (FEI 3007549629), were issued a warning letter for CGMP violations and in response made corporate-wide commitments to strengthen corporate quality compliance and global quality governance.

Repeated violations at multiple sites demonstrate that your company’s corporate oversight and control over the manufacture of drugs is inadequate. You should further comprehensively assess your company’s global manufacturing operations to ensure that systems and processes, and ultimately, the drug products manufactured, conform to FDA requirements at all your sites.


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 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 supplier or 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 since our inspection to correct your 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 response to orapharm1_responses@fda.hhs.gov. Your written notification should refer to Warning Letter CMS # 613385 and include FEI: 3006271438.

If you have any questions, contact Compliance Officer BarbaraWilimczyk-Macri at barbara.wilimczyk@fda.hhs.gov or 973-331-4951.


Diana Amador-Toro
Program Division Director/District Director
Office of Pharmaceutical QualityOperations Division I/
New Jersey District

Mr. Ronald W. Overhiser
Vice President-Operations and Site Head
Novel Laboratories, Inc. d.b.a. Lupin
400 Campus Drive
Somerset, NJ 08873

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