Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EL End: 1/25/2023 TABLE OF CONTENTS Summary. Administrative Data. History Interstate (L.S.) Commerce. Jurisdiction (Products Manufactured and/or Distributed) Individual Responsibility and Persons Interviewed ... Firm's Training Program. Manufacturing/Design Operations Manufacturing Codes .nnmmmnennnnnnnnnnin Complaint Recall Procedures . Objectionable Condit Refusals, General Discussion with Management ‘Additional Information.. Samples Collected .. Voluntary Corrections jons and Management's Response SUMMARY 9f this testing laboratory was conducted as part of the CDER’s IOG Work-Plan for FY’23, in accordance with CPGM 7346.832, Pre~ Approval Inspections and CPGM 7356.002, Drug Manufacturing Inspections, under eNSpect Operation ID 238610. The profile covered was LCP. ‘This was firm’s initial inspection. ‘The three primary inspectional objectives of the PAI, ANDA[___](Sponsor (1 Pharmaceuticals /[ ————1Pharmaceutical as CMO, | |Tablets) “Readiness for Commercial Manufacturing, Conformance to Application, Data Integrity Audit, and Commitment to Quality” were covered. After reviewing the information along with the supporting data stated in the foregoing paragrap! Page | of 13Establishment Inspection Report 3016632979 REVIN LABS PRIVATE LIMITED. 1/23/2023, Hyderabad, Telangana, 500090 India 1/25/2023, This inspection covered Quality, Facility and Equipment, and Laboratory systems, The PAI inspectional coverage are discussed under each system as appropriate. An Inspectional Observations (FDA-483) was issued to Revin Laboratories at the close of the inspection. The observations include: Performing analytical testing for release purposes prior to completion and approval of the method validation by the QA. *+ Performing analytical testing for release purposes px which are used during raw data calculations * Discrepancies between the analytical procedure and validated methods *+ Lack of Quality Unit responsibilities procedure Lack of change control on the specification change for the impurity and its justification to validation the Excel sheets No samples were collected and no refusals were encountered during this inspection. The firm’s drug registration is current. ADMINISTRATIVE DATA Inspected firm REVIN LABS PRIVATE LIMITED. Location: Plot 84, 3rd Floor; 2nd & Hyderabad, Telangana, 500090 India Phone: FAX: Mailing address: Plot 84, 3rd Floor; 2nd & Hyderabad, Telangana, 500090 India Email address: Dates of inspection: 1/23/2023-1/25/2023 Days in the facility: 3 Participants: Saied A Asbagh, Investigator During this inspection, I, Investigator, Saied A. Asbagh presented my credentials to Mr. Nagarjuna Reddy, Managing Director who stated that he was the most responsible person at the firm. 1 indicated to Mr. Reddy that the reason for the inspection was to conduct a Pre-Approval inspection and GMP inspection, Mr. Reddy introduced his team members including Mr. Dharma Raju, Head Quality, and stated that they would assist him during the inspection, Page 2 of 13,Establishment Inspection Report FEL 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EI End: 1/25/2023 Official correspondence or FMD information to: Mr. Nagarjuna Reddy ‘Managing Director Road No. 8, Plot No. 84, 3" Floor ALEAP Industrial Estate Gajularamaram, Hyderabad, India 500055 Phone: 91 40 29881685, 91 9989320685 (C) Email: denagarjuna@re HISTORY The firm was founded in 2018 and has secured several accreditations and certifications since its establishment. The firm's main core function is to provide analytical services to its clients including pharma sector. ‘The firm has 80 employees. The firm’s business hours are from 9:30 AM to 6:30 PM, Monday ‘through Friday and testing laboratory runs in 3 shifts, 6 AM - 2 PM, 2 PM —10 PM, and 10:00 PM~6:00 AM. Currently, there is no pending recall or regulatory actions against the firm. INTERSTATE (LS.) COMMERCE ‘The firm serves as a contract-laboratory and tests [Tablets for its sole US client (Pharmaceuticals / [~~ whose product will be marketed in the US pending, approval (EXhibitill/Gistomers). Although the firm only has one US customer but it provides its services are offered outside the US (Bxhibiti2)/Overall Customer List). JURISDICTION (PRODUCTS MANUFACTURED AND/OR DISTRIBUTED) The firm’s QC site performs contract-testing for the ANDA product, Tablets, ‘This product is regulated by the FDA under the FD&C Act. INDIVIDUAL RESPONSIBILITY AND PERSONS INTERVIEWED The following personnel provided relevant facts, documentation and/or assistance during the EI. ‘The organizational chart was provided (EXhibit 3) Organizational/Chart). ‘Nagarjuna Reddy, Managing Director- Mr. Reddy is one of the company founders. Mr. Reddy hhas been with the firm since its conception four years ago and has 10 direct reports. He is responsible for all company functions and quality-related activities. He was present throughout the inspection, Page 3 of 13,Establishment Inspection Report FEL 3016632979 REVIN LABS PRIVATE LIMITED El Start: 1/23/2023 Hyderabad, Telangana, 500090 India ELEnd: 1/25/2023 Dharma Raju, Head Quality Mr. Raju reports to the Mr. Reddy, Managing Director. Mr. Raju has been with the firm in the past 5 months and has 8 direct reports. He is responsible for the firm’s quality functions. Mr. Raju was present throughout the inspection and assisted with documentations. ‘Chandravama Reddy, Assistant Manager QA~ Ms. Reddy reports to the Deputy QA. Ms. Reddy has been working at the company for almost a year. She is responsible for all quality-related activities and investigations. She was present throughout the inspection and was instrumental in providing the requested documentation. Rambabu Jetti, Deputy GM QC ~ Mr. Jetti reports to the Head Quality. Mr. Jetti has been ‘working at the company for the past 3 months and manages the entire QC staff. He is responsible for all QC functions. He was present throughout the inspection. U.S. Regulatory Agent: Firm does not have own US agent as a Contract Lab Refer to customer information below: FIRM'S TRAINING PROGRAM The firm’s training program is governed by RLPL/QA/SOP/003, 8/24/22. ‘Training is sub- divided into different sections, ie., induction training, training needs identification, On-The-Job ‘raining, ongoing training, and Analyst qualification and evaluation. The experienced new employees may only be trained on the job for 7 days pending their evaluation and QA approval. The firm administers GLP training during the induction training. Analysts go through refresher ‘raining semiannually. ‘The analyst evaluation procedure includes trainer evaluation of the employee. Reviewers are also qualified by being provided dummy templates. I reviewed the training files for several employees and noted some deficiencies as some employees lacked the proper training on procedures (OBSERVATION 3). MANUFACTURING/DESIGN OPERATIONS Quality System Page 4 of 13Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED. EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EIEnd: 1/25/2023 The firm’s Quality Unit head is responsible for the QA, QC, and Microbiology functions. The QA department with a staff of 19 handles all quality-related matters including complaints, deviations, OOS, and quality agreements with their clients. The firm's quality management uses hardcopies using MS Office software and there is no LIMS system. The procedures are managed by SOP RLPL/QA/SOP/001, 8/31/21. The firm has mainly established procedures with respective SOPs to ensure reliability of test data. I reviewed a list of quality procedures without comments. The internal audits are performed semi-annually per SOP RLPL/QA/SOP/OLI. The firm also has a vendor qualification program which I reviewed with the QA. The firm does not. have a procedure which would outline the Quality Unit responsibilities (OBSERVATION 2a). Complaint Reviews: The procedure is outlined in SOP RLPL/QA/SOP/010, 1/19/23. I reviewed 2 complaints, RLPL/CC/07/21/01 dated 7/20/22 and RLPL/CC/12/01 dated 12/27/22, No major deficiencies were noted. Discrepancy & Failure Investigations: The procedure for deviations is outlined in SOP QAD/00901, 3/7/22. I reviewed several deviations and discussed the pursuing investigations with the firm’s management for some improvements. No major deficiencies were noted though. RLPL/U/PDR/GEN/22/001, 2/8/22 RLPL/U/PDR/GEN/22/002, 3/11/22 RLPL/U/PDR/GEN/22/003, 9/3/22 DEV/QC/22/002, 11/7/22 Change Controls: The procedure is outlined in SOP RLPL/QA/SOP/005, 10/27/22. ‘The procedure outlines the steps such as proposal, review, and approval of the change. Changes are classified as minor and major depending on the nature and extent of the changes and change effect on the systems and processes. Trending of change controls are performed annually. 1 reviewed alist of change controls. Deficiencies were noted during my review of the specification change for an impurity which is further discussed in the laboratory section. CCF/QC/025/22, 10/13/22, completed 1/12/23 (CCF/MB/038/22, 12/5/22, completed 1/11/23 Qut-Of- Specifications: ‘The procedure is outlined in SOP RLPL/QA/SOP/017, 10/27/22. 1 reviewed the procedure without comments. No OOS was reported for the subject ANDA PAI. Training: Please refer to the “TRATNING” section in this report. ‘Readiness for Commercial Manufacturing and Commitment to Quality: The firm has established Quality System with pertinent SOPs to manage the product quality, the quality elements, and investigations. Upon my review of the firm’s quality system, no major deficiencies were noted. Page 5 of 13Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023, Hyderabad, Telangana, 500090 India ELEnd: 1/25/2023, The firm has a commitment and Quality System which would support the testing of the ANDA filed product for the specific tests mentioned in the ANDA. Facility and Equipment System Facility The facility isin a 4-story building of which the firm occupies 3 floors with a 4000 square footage area allotted for each floor totaling 12000 square feet. The administration and cafeteria are on the ground floor. ‘The sample registration room and instrumentation rooms are on the second floor. The microbiology lab with additional instrumentation rooms is on the third floor (Exhibit 4, Facility Layout). Equipment I reviewed a list of analytical laboratory instruments. The main analytical instruments include 3 ‘Water HPLCs with Empower 3 software, 1 Perkins HPLC, and 2 Perkins GCs, 1 LC-MS/MS, 1 GCHS/MS, and 1 FTIR (ERHibitSY Analytical Instruments). Equipment qualification, maintenance and calibration procedures are outline in SOP RLPL/QA/SOP/032, titled, “Handling of Instruments/Equipment”. I reviewed the procedure without comments. | reviewed the following instruments qualification which are also used in testing of the subject, ANDA product. + LC-MS/MS, RLPL/QC/LCMSMS/0011Q/0Q 10/31/18 + GC-HS, RLPLIQC/GCHS/007IQ/OQ 10/30/18 + HPLC, RLPL/QC/HPLC/165, 12/13/21 + FTIR, RLPL/QC/FTIR/009, 1Q/0Q 10/20/18 Readiness for Commercial Manufacturing: The firm’s Facility and Equipment System is, commercial-ready to test the ANDA product, [—______] Tablets for its impurities, ——} [———— Witroso. No major deficiencies were noted. Laboratory System ‘Asa contract laboratory, the firm conducts analytical testing according to the request made by its clients. The firm only has one QC laboratory. As mentioned in the facility section, the QC lab is in a 3-story building with a 4000 square footage area allotted for each floor. Each floor has its own sample preparation room. Samples are received in the sample registration office by the Page 6 of 13Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India ELEnd: 1/25/2023, designee and are assigned sample registration number, The laboratory is climate-controlled at NMT30°C. ‘The QA issues sample Worksheet (Test Data Sheet) including the analytical procedure along with the customer sample request form (TRF) and the sample to the QC who in-turn assigns to the respective analyst. All analytical calculations are performed in the worksheet. Printed chromatograms are attached to the worksheet. The firm has 2 servers and one of which is used for data backup purposes. The server | is used for Empower 3 during batch analysis. The data is backed up daily to the server and monthly to an external hard disk. All computers have access-authorization. The user privileges are outlined in the user ‘management SOP, RLPL/IT/SOP/004, 1/12/23, titled, “User Management”. The user groups are Administrator /IT Administrator (Level 1), method developer / Lab Manager / Supervisor / Reviewer (Level 2), Analyst (Level 3), and QA Reviewer (Level 5). Computer validation was only recently completed on 1/12/23. The firm stated though that all instruments had been previously qualified for all tests which had been performed earlier. According to the ‘management, the Excel sheets used during submission batch calculations have not been validated yet and the work is ongoing (OBSERVATION 1b). ‘The analytical instruments such as UV, Dissolution apparatus, FTIR, PSD, and Karl Fisher (KF) are on the second floor and the HPLCs, GC, LC-MS/MS, and ICP-MS are located on the third floor. The firm also has a small microbiological laboratory which has 4 incubators, 2 autoclaves, and laminar air flow hood. I had a quick glance at the lab which is environmentally monitored using active and passive air control and annual particle count for non-viable. I spoke in detail with the microbiological lab supervisor who explained the laboratory operation without comments. ‘There is no LIMS system used by the firm and all documents are handled using hardcopies. The reference standards are maintained by the sample registration officer and stored in respective storage cabinets according to their storage conditions. Reserved samples are maintained with access-control. Reserved samples are checked for any visual deterioration annually with proper logbooks. During my walkthrough, the laboratory appeared clean and organized. The instrument qualifications and calibrations including LC- MS/MS and GC-MS were current with the chemicals and reagents well-within their expiry dates. All instrument qualifications and calibrations were current with proper logbooks. No deficiencies were noted. Conformance to Application and Data Integrity Since this assignment was the subject of the PAI for| Tablets ANDA for its impurities, | reviewed the following and compared against Page 7 of 13Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EILEnd: 1/25/2023 the submitted data as deemed appropriate. In addition, per my request, the firm provided a ‘comparative table in which any changes since the submission batches on analytical methods and specifications with rationale and justifications are noted for the ANDA (Exhibit) Comparative Table). [Tablets ANDA for impurities, reviewed the method validation protocols for[_—_________—Jjimpurities executed on 3/15/22 and 3/10/22 with the completed reports on 3/22/22 and 3/18/22, respectively. The methods had been developed in-house, The method validation had been performed using LC- MS/MS to demonstrate its adequacy for intended purpose including system suitability, LOD and LOQ, Linearity, Specificity, method Precision, Precision at LOQ level, and Accuracy. There had been no protocol deviations (Exibit’7%[____}TabletsiImpurities Method Validation REPO). As I reviewed all the instruments validated parameters, I noted that the stock solution ‘quantity had differed from the validated quantity (OBSERVATION 1c). In addition, the method. validation had been conducted concurrently, ie., the method validation had not been completed prior to performing testing on the submission batches (OBSERVATION 1a). The diluent quantity added during testing had not been initialed, dated, or verified and the source of the addition was unknow (OBSERVATION 14). ‘As I reviewed a list of changes since the submission batches, I noted that the specification for the ‘VC-09 Nitroso impurity had been changed from 13 ppm to 48 ppm. The firm stated that it had been due to the request made by the customer and their evaluations (OBSERVATION 2b). I also reviewed the quality agreement which had been executed between the firm and [—_] Pharmaceuticals on 1/19/22 and between [___]Pharmaceuticals and [—_] Pharmace{—MO for Aarkish) on 3/23/21 without comments. 1 also reviewed a list of submission batches for which the firm had performed testing which included Batch Numbers 121020, 121021, 121022, 121023, 121024, 121025 by the requesting customer, *harmaceuticals in New Jersey (Exhibit 8) Listiof Sulbnil fehies Tested), 1 reviewed the raw data for Batch No, 121020 versus the validated procedure and noted @ discrepancy which was mentioned earlier. I also reviewed the audit trail reviews without comments. I also compared the specifications against the filed specifications of 5/5/22 and reviewed the analytical procedure against the filed of 5/5/22. 1 also reviewed the COAs for all 6 submission batches along with the COAs for the reference standards (Exhibit 9)(COAS Submission Batches ‘iid RS). No major deficiencies were noted. Page 8 of 13,Establishment Inspection Report FEL: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EIEnd: 1/25/2023 In conclusion, based on my review of the above, the data conformed to the submitted data in the application. The QC lab is commercial-ready to test and release the[ tablets. for its impurit{ ——}09 Nitroso. 1 should, however, note that this should be pending the reviewer input on the concerns stated earlier considering the observations. MANUFACTURING CODES ‘The product samples received by the firm are assigned registration numbers as follows: RLPLR2200001 RLPLR: Revin labs private limited R: Registration 22; Year 00001: Sequential until the year end COMPLAINTS. ‘The procedure is outlined in SOP RLPL/QA/SOP/010, 1/19/23. I reviewed 2 complaints, RLPL/CC/07/21/01 dated 7/20/22 and RLPL/CC/12/01 dated 12/27/22, No major deficiencies ‘were noted. RECALL PROCEDURES N/A. The firm is a contact-laboratory. OBJECTIONABLE CONDITIONS AND MANAGEMENT'S RESPONSE, Observations listed on form FDA 483 OBSERVATION 1 The accuracy, sensitivity, specificity and reproducibility of test methods have not been established and documented, Specifically, a. Your firm performed testing and release of [Tablets [impurity hrity, batch no. 121020, on 3/19/22 and 3/14/22, respectively, before completion and approval of the method validation by the QA. The latter tested batch was used in product submission batches. In addition, the test data sheets do not include the complete product name and the specific test. Page 9 of 13Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EIEnd: 1/25/2023 b. The excel sheet used in the| area calculations during testing of }!21020, 121021, 121022, 121023, 121024, and 121025 were used prior to validation. Your firm stated that the validation of excel sheets is in-progress. . During testing of[_______]Yablets for the [——}mpurity, batch no. 121020, the test data sheet, page 3, showed that 0.80 mL of stock solution was used for dilution. ‘The stock solution quantity used during the method validation was 0.2 mL. 4, During testing of rte no. 121020, it appeared that the diluent, Methanol, had been later added by handwriting. ‘The adding person and the date of entry had not been documented. Reference: 21 CFR 211.165(¢) Supporting Evidence and Relevan: During my review of the method validations for the I noted that the method validations had been performed and completed during testing of the submission batches and the methods had not been validated to ensure their suit testing of the submission batches. For example, the subr tested on 3/19/[ 9 Nitroso impurities, respectively (EXHIbitTO(Observation 1a). The method validations had been reported complete on 3/22/22 and 3/18/22, respectively. also noted that the Excel sheets which had been used during analytical calculations for submission batches had not been validated. The firm stated that they are in the process of conducting worksheet validations and provided a statement that the validation had not been performed for submission batches (Bxibitlllj Observation ib). As I was reviewing the submission batch testing for] impurity, batch no. 121020, I noted that on test data sheet, page 3, 0.80 mL of stock solution had been used for dilution. The stock solution quantity used during the method validation was 0.2 mL. In addition, during te{__] VC-09 Nitroso impurity, Methanol had been added as diluent by handvvriting and the source or date was unknow (Bxhibit)12) Observation 16114). Discussion with Management: 1 discussed with the firm that the methods must be validated to ensure their reliability, reproducibility, and suitability prior to their release of submission batches and most definitely prior to product release for commercial purposes. We also discussed that all addition or deletions ‘must be initialed and dated for information accuracy. The management concurred and acknowledged the observation and stated that they would internally review the findings, decide on action plans. and respond in writing within 15 days es appropriate. Page 10 of 13Establishment Inspection Report FEL 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India EIEnd: 1/25/2023 OBSERVATION 2 The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. Specifically, a. Responsibilities of the QCU is not documented. bb. The firm failed to produce change control and justification for the tablets impurity| by LC-MS/MS specification change from NMT 13.25 ppm to NMT 48 ppm on 10/28/22. In addition, the firm failed to produce documentation on the initial specification change for the latter impurity from 13 ppm to 13.25 ppm. The specification after completion of the method validation and submission batches had been established at 13 ppm. Reference: 21 CFR 211.22(d) ‘Supporting Evidence and Relevance: Per my request, the firm could not product responsibilities for the Quality Unit and stated that they had none. In addition, during my review of the product impurities specification! _—] Nitroso, I observed that the specification had been considerably changed from its originally submitted 13 ppm to 48 ppm on 10/28/22. As I queried the firm on the rationale, the firm stated that they had changed initially from 13 ppm to 13.25 ppm and was later changed on 10/28/22 from 13.25 ppm to 48 ppm due to the customer request. They also a Aarkish Pharmaceuticals had based this change on their risk-assessment. Th addition, no change control could be produced and the firm said they did not initiate a change control. Due to time constraints, I quickly glanced at the risk assessment document but found it important to be further reviewed due to its carcinogenic nature (EXHibit 13, Observation 2b). Discussion with Management: ‘The management stated that they would further discuss the observation with their client and respond in writing within 15 days as appropriate. OBSERVATION 3 Employees are not given training in the particular operations they perform as part of their function Specifically, ‘The firm failed to provide training on several revised SOPs including Training, Change Control, Handling of Complaints, Assuring Quality, OOS, for Ms. Chandravarna Reddy, Mr. Nagarjuna Reddy, and Mr. Dharma Raju. Page 11 of 13,Establishment Inspection Report FEI: 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023 Hyderabad, Telangana, 500090 India ELEnd: 1/25/2023, Reference: 21 CFR 211.25(a) Supporting Evidence and Relevance: ‘When I requested the training of the mentioned individuals, no updated training could be produced by the firm, Discussion with Management: ‘The management acknowledged the observation and stated that they are in-process of making improvements to their training program, would decide on action plans. and respond in writing within 15 days as appropriate, REFUSALS No refusals were encountered. GENERAL DISCUSSION WITH MANAGEMENT On 1/25/23, a closeout discussion was held with Mr. Reddy, Mr. Dharma, and additional ‘management staff. I presented to the firm’s management a summary of my inspection and findings. ADDITIONAL INFORMATION ‘There is no additional information for this inspection. SAMPLES COLLECTED There were no samples collected during this inspection, VOLUNTARY CORRECTIONS During this inspection, the firm made no voluntary corrections, Page 12 of 13Establishment Inspection Report FE 3016632979 REVIN LABS PRIVATE LIMITED EI Start: 1/23/2023, Hyderabad, Telangana, 500090 India EIEnd: 1/25/2023 EXHIBITS COLLECTED Customers, { page Overall Customer List, 2 pages Organizational Chart, 6 pages Facility Layout, 6 pages Analytical Instruments, 1 page Comparative Table, 1 page Varenicline Tartrate Tablets Impurities Method Validation Reports, 67 pages List of Submission Batches Tested, 1 page 9 COAs Submission Batches and RS, 8 pages 10 Observation 1a, 66 pages 11 Observation Ib, 2 pages 12 Observation Lc, Id, 3 pages 13 Observation 2b, 13 pages ew aMeene ATTACHMENTS 1 Issued 483, 4 pages seegangen Page 13 of 13