‘DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION 12420 Parklawn Dive, Room 2032, 12/13/2022. 12/23/2022 eokvil, MD 20857 Sea ORAPHA Refoteratonal4Besponses@la.ths gov 3010258278 Oo SET TVET EIS Mr. Sanjay Kumar Jaia, Ph.D. Amngal Pharmaceuticals Private Limited Plot na. 15, PHARMEZ (Special Econario Zane) Sarkhej- Bavie Highway No:BA, Meto¢a, Ta: Sanand District Alunedabad, Gujarat 382213, Indie Pharmaceutical Parenteral Manufactares “This document ist observations made by the PDA epresentativa() dung the inspection of your facility: They are inspectional ‘obse-vations, and do rot wpreseat final Ageacy determination cegercing your comalignce. Ifyou have on objection regarding. an ‘bse-vation, or have impinnenied, or pian implement, corrective setion in response 20 an observation, vou may discuss the objection ot action withthe PDA repreertative(s) daring he inspection or submit this information fo FDA at the eddress above. Ifyou have any ‘questions, plesse canta: PDA atthe phone number and addeess above The observations noted inthis Form FDA-483 ave not an exhaustive listing-of chjectionable conditions. Uider the lau firm ia responsible for conducting internal self audits to kdentify and correct any dnl all violations of the quality systems ‘roguirenonts, DURING AN INSPECTION OF YOUR FIRM L OBSERVED: 1. The Personnel behavior and practices in aseptic process area, document rember APSMC-020, esteblish the responsibility of the In Process Quality Assurance (LPQA) department, for example, “To verify the practices in acepriz process atea as per checklist.” This includes to," in aseptic area. according to the do’s and don'ts checklist” and as confirmed by the Senior General Manager Quality Assurance the visval verificat’on is performed “at least" The IPQA Manager & Senior General Manager QA explained that the visuel verification js normatty accomplished in about” for both the eseptie {il line and the area, There are no docuirents to describe the rationsle to support how and why the! “verification” of the aseptic filling process and the separatc™ process, is adequate; and the do's and don'ts verification records-do not delineate ™ Grade A arees, Inraddition, a. Mindful of the once! QA visual verification of the do's and don'ts checklist, please see the summary table below. The suumary table list the number 6f mentifacturing days during the year that ‘were used to manufacture the finished sterile. drag products and the number of times that QA performed a _yisuel verification ofthe assptic filling provoss. Excluding the numberof visual verifications performed soled in the summary, QA does not routinely observe the aseptic filling process opetations for ‘the remaining days of the year, ‘SEE REVERSE | | ‘Thomas J. Arista — Investigator/NE Ow 1a/23fzo22 OF THIS PAGE | . Moe resin snout NSPECTIONALORSERVAGIONN! Page tofDEPARTMENT OF HEALTH AND HUMAN SERVICES 12420 Parklawn Drive, Roem 2032 12/13/2022-12/73/2022 ‘Reclevitle, MD 20857 ORAPHARMIntermational483 responses @e.is.g0v 3010254278 ‘Mr. Sanjay Kurtar Jain, Pb.D. Ampeel Pharmaceuticals Private Limited Plot no, 15, PHARMEZ (Special Eeonemic Zone) Sarkhe)- Davia Higiay No 8A, Matoda, Ta: Sanand Dist Abmedebad, Gujarat 382213, India Pharmaceutical Parenteral Manufacturer Paranteral Year | Visial Verifications | Year Visual verifications Ja Unit | Floor | 2022 | performed by O4 | 2022 performed by OA 2. To perform the requisite aseptic set up operations of the aseptic fill ine!" Parenteral, the production opefator accesses the” Restricted Access Barrier System (ABS) via the fiN equipment access panel fez | that is approximately" ‘A production operator was abserved heving fo raise both arms and by taming the entire body sideways wes able to enter and exit this specific Grae A area. Due to the size of the access pane! opening, it appears that it provides production personnel limited space to‘perform the required aseptic set up activities, 3, Prodvtisn operators wear protective eyewear (ie... gogeles) during the aseptic processing of finished drug product. With the Senior General Manager of Quality Assurance, we observed four production operators ‘wearing goggles during the aseptic processing in the” RABs, The gozeles were not appropriately worn e.g, there were open spaces observed where the goggle straps are tightened and an open spece at the bottom of the goggles sitch that the face of the operators could be observed. 4. The Summary Report for Disinfectant Qualification, document number AP-QCM-MIS-43-00, dated Avg 23, 2022; consists of summation regarding the “obtained results for the execution of the disinfectant validation and to have a documentary evicence-and conclude that!" area capable enough to achieve acceptance criteria mentioned. in the approved protocol when microorganisins are challenged with defined contact time and concentration. Shelfiife/hold time is also established and summarized in this summary report.” There were various “clean room work surfaces that were used in the, study”. However, the disinfectant qualification studies did not include the following materials i.e, the sart's wheels, the!" that is used to seal the! the” that are vsed in the Bl 2ABS, the” _gowning material, and the specific type of a used in the study is not known. In addition, SEE REVERSE | Thomas J. Arista —lovestigator/NE, 32/23/2022 OF THIS PAGE. | iDEPARTMENT OF HEALTH AND HUMAN SERVICES OUD AND DRUG ADMINISTRATION 12420 Parklaivn Drive, Rocun 2032 12/13/2022- 17/28/2022 Reckville, MD 20857 Tote ORAPHARMInternational483responses @fia.nhsgov 3010254278 ‘Mr. Sanjay Kumar Jain, Ph.D. Amineal Pharmaceuticals Private Limited Plot no. 15, PHARMEZ (Special Econotaie Zone) Sarkhe}- BavleHighivay No.8A, Matoéa, Ta Senand Distret Abmedebsd, Gujarat'382213, India Pharmacoutioe! Parenteral Manufacture: 1 There is a senarate Vslidation study to evaluate the effectiveness of disinfectant for surfaces document nuimber AP-QCM-MIS-039-00, dated 8 Feb 2020. “The purpose of study is to establist the doctimented evidence to demonstrate the efficzey of disinfectant egents to-reduce the microbiel load from the surfaces when used at recommended dilutions for the routine cisinfection epplications.” The study did not include all of the clean roomn surfaces as in the Auzust 2920 disinfection quelification validation studies c.e., 3. The escptic fill Hines inf" include the ugg of that assist to diffuse the HEPA filter air into the Grade A\ of tite RABS, The Vice President Sterile Manufacturing, & Operations confirmed that the [" ‘re not cleaned and sanitized. 6, The Rationale for Environmental Monitoring dated, 14 April 2015, establishes that “A well-defined comprehensive cavironmentat monitoring arogram is regarded as an essential part of aseptic processing. A ‘good énvironmental monitoring program will provide evidence that the facility and its equipment are Operating: under defined controlled conditions. I will provide ihlbimation on the effectiveness of applied controls measures such as” for exemple, “eseptic technique, gowning practices, process controls, facility design and maintenance” as, yell as “cleanine/sanitization procedures.” "The following are not included in the EM samoling program ec, oe for the aseptic fil lines in the IL, Inaddition, A cart is used when performing the EM sampling in aseptic fil line in Parenteraf™!’ With-the. Senior Vice President India Quality Management, we observed the trolley wheels with what appeared-to ‘be a build-up of some form of dirt liké material. The Senior General Manager of Quality Assurance confirmed that the cart’s wheels are not subject to EM sampling. >, ‘There is an!" Unit (speaker, ), with asemivenneable polyester gemibrane is Used to chmmunicate From the Urade B area, that surrounds the aseptic fill line (Grate AY arid the control non-élassified (CNC) personnel corrider. With the President of Operations & the Senior Vice President of Quality Management India we observe in the 8 anit's metal interior suzface an unknown subsiance with a dark color, which appeared to havea mold like appearance. It was confirmed that the is not subject to any form of EM sampling, SEE REVERSE | Thomas J. Arista Investigator/NE_ 12/23 f20z2 OF THIS PAGE | = PonmsoAes om rere rmomatuns INSPECTIC AM, OBSERVATION, Page 3 of 9‘DEPARTMENT OF HEALTH AND HUMAN SERVICES 2000 AD DRUG ADRINISTRATION. 1220 Painen Drive, Room 2032 1sy20a9- 12/23/2022 | Roti, aD 20857 anol ORAPHARMIntemalioraltresponces tains gov 3010258278 TE AAR Mr. Sanjay Kumar Jaia, Ph.D. Amneal Pharmaceuticals Private Limited lotro. 15, PHARMBZ (Special Economic Zone) Sarkiej- BavlaHighivay Nog, Matoéa, Ta: Sanand Di Ahmedebad, Guiarat 382213, India Pharmaceutical Perenteral Manufacturer 7. An EM sample is taken ftom the aseptic fill line i the Bt of the access panel is sampled. The EM sampling does not ‘consist of any other area within the confined spate of where the production operator was observed raising both crms and turning the entire body sideways to entor and exit this specific Grede A area, The Haniling of Microbial Isolates, document nurriber, ACM-QCM-004, dated 1 § Jun 2022, the generat procédurefiéquirement establish that the “Microbial identification shall be carried out fot data trending. Purpose and to assist product and facility. contamination ‘investigations and in the development of effective countermeasure and to main‘ain the acea/process/system in the State of control.” ‘The “Microbial identification of environment isoiate aids in the evaluation of cleaning’ senitization effectiveness, personnel training, deterioration and malfunction of AHU system and facilities." The EM and giersonne) moritoring sariples for the Grade B.2tea is described in the Prequency of Microbial Isolate Exhibit-I ic, for routine plates observation 10 a The Assistant Manager QC Microbiology explained the EM samples are visually compared to the isolate library, which consist of approximately" photogrephs of previously isolated microorganisms that aro” media. The ‘Assistant Manager QC Microbiolegy added, if the microorganisms look like the™® photograph, then no forther micrebiological identification is performed. Regarding the saniple, is it used to determine, for example, if clearing is acceptable, evaluate the movement of persorme), ifthe EM program is recovering the samé microbial flora from!" ‘The identification of the unknown microbial Isolates” genus and species are based on the!™ photographs. ‘The Eavitonment Monitoring Program ‘Aseptic Manufacturing Are dated 21 Mer 2017-deseribes the intent “isto evaluate the potential risk prominent to aseptic areas” end “wo capture.the potential viable contaminants in the aseptic areas ‘with respect to, Risk identification: and justificetion for environment monitoring location and frequency” and “To evaluate the existing and additional location to, identify the worst and representative location”. The document lists “Site Justification”. The Assistant General Manager QC Microbiology confirmed that there are no written evaluations regarding’ the EM sample site locations to support the "Site Jistfieation”. ). ‘The. 18 Dee 2020 Quality Risk Management —document Environment Monitoring Location at!" of a describes an evaluation was performed “to determine current rationalizec sample Iocations for viable and non-viable monitoring during environmental monitoring programme is adequate.” SEE REVERSE | Thomas 3. Arista —investigatorNE—t-—~ 42/23/2022 OF THIS PAGE fay soe snot nsrcrioGt oration Page dotDEPARTMENT OF HEALTH AND HUMAN SERVICES FO2D AND DANG ADRNLSTRATION RT RET TOROS RESP 12420 Parklesin Drive, Room 2032 #9/13/2022-12/23/2022 Rockville, MD 20857 ORAPHARMIstemational¢S3recponses(@fda bhs gov 3010254278 Mr. Sanjay Kumar Jain, PhD. Ames] Pharmaceuticals Private Plot no. 15, PHARMBZ. (Special Eeorioniic Zone) Sarkhe}- Davla Highway No.8A, Metoda, Ta: Sanatd Disirict Ahmedabad, Gujarat 382213, India Phanmnacetitical Parenteral’ Manufacturer “The QRM assessment document is silent with respect to providing language thet instructs to,cbserve the clessified manufaetating areas and the eseptie pracessing operations. The lack of observing the aseptic filling process provides a limitation with tespect o performing a comprehensive trend analysis of the EM sample locations. ‘The Senior Manager of IPQA eonfied that the QRM assessment consisted of reviewing the 21 ‘Mar 2017 Envitcnmental Monitoring Program” Aseptic Manufacturing Area” document, 11. The Non-viable pattiole monitoring is cleanrooms of facility, document number AP-QCM-087 describe the frequency of monitoring ths Unidirectional air flow (UAF) Grade A" Grido A clean sir stations. Hovever, as confirmed by Senior Manager of IPQA, the NVP monitoring does not include obtaining particle measurements during the aseptic filling process e.g., when production personnel are performing the various maaual activities in an ‘ln Overation” (@ynamic) state. Please note forthe aseptic il dine in the there are” and for the aseptic. ill line in the" that are used Guring the eseptic filling processes. In addition, a, Thereare!”” AF units (Grace A) that are used in the eforementioned aseptic processing filling, lines. The Senior Manager of IPQA confirmed there is no NVP-monitoring of UAF Grade A areas during the éynamic operations e.g,, when production personnel pérfarm their fespective responsibilities. bb. ‘There is ng recerd to document the location & height of where the NVP monitoring is perZormed for the Grade A’ area to assure that the patticle measurements are near the critical aseptic operations. ‘that are performed curing the") srocess. c. Regarding the tecetion and distance of the ‘or aseptic fill jine int and for the ™” aseptic fill ling there is an” located near the *™ Station and an!” Jocated at the capping station. The distance between the” is.approximately""sm.and”” am, respectively. There is n0 ‘within the a ‘in order to monitor for the presence of particles, which precludes the company from assuring ‘that Grade A conditions are maintained and to assure that the finished drug products are in a state of contrat prior to the glass vials being sealed. d. There are that are used, for examp'e, to transfer" material, fill room ‘equipment perts from the! ‘Grade A) area to the aseptic fil Hines inthe’ a tanufueturing operations. The Senior Manager of IPQA SEE REVERSE | Thomes J. Arista —lnvestigator/NE_y* 1238/2022 OF THIS PAGE eae D ona ra das em) neswnousinind sen nnsrrona | OBSERVATION Page $ of 9‘DEPARTMENT OF REALTH AND HUMAN SERVICES STROKES ESPERO a oT 12420 Packlewn Drive, Room 2032 12/13/2022 22002 Rockville, MID 20857 i ORAPHARMIntemational483responses@fdahhs.gov 3010254278 Mr. Sanjay Kumar Jain, Ph.D. Amneal Pharmaveuticals Private Limited Plot no. 15, PHARMEZ (Special Economic Zane) Sarkhej- Bavia Llighway No:8A, Matoda, Ta: Sanand District ERT TT Sfrasaaisveme neh Abmedabad, Gujarat'382213, India Phirmacewical Paréateral Manufacture: confitmee there is no NYP monitoring performed of the ™ Grade AM) during dynamic operations. 12, The Air Flow Visualization Study & Recovery Study, document sumber AP-SM-MIS-05-04, describes the purpose for the air flow, for example” The Air _ Flow Visualization Study, document number AP-SM-MIS-01.07, objective is tof a Ihe sesenianes tea cha fr exanie." ‘The airflow visualization stedies (Video) docusitent niaierous instances where the unidirectional aiiflow and the personnel’s manual operations impact upon the airflow that could not bs observed due to either the angle and position of the video camera, or due lo an obstructed view cassed by the filling equipment. and/or due to @ {ack of smoke over the production perscnnel’s manual ams é& hands operations. The concern is.appiicable for the aseptic pypgess fll tines for ‘The fotlowing are examples of the aseptic fill Line (please note this is not intended to be etvallinclusive Est of examples), a. During the machine’ breakdown & maintenance work, the yideo documents airflow" and the creation of.” b. During the assembling of vial sealing machine, there are" onthe” of the fe equipment base. om _ vw [ithe capping station there are atthe!" ofthe shaped structure thet is box. 4, Regarding the Grade A"™ that are used during thie eseptic filing process, there were no “In Operation” (dynamic operations) personnel activities performed to demonstrate thatthe manual, operations do not negatively impact upon the unidiregtional flow of ar, ©. Daring the storile API from dispensing containers to unable to observe the matiual activities perfoimed by production personnel to assure and verify that the unidirectional airflow is maintained, £ During the aseptic connection & transfer of "unable to observe the aseptic manual operations performed by production personnel fo assure and verify thet the unidirectional airflow is maintained. SEE REVERSE | Thomas J, Arista ~Investigator/NE 12j23/2022 OF THIS PAGE he) Forse oaas wor seksarorowtintin ervcnaide ossnvation Page 6 of 9DEPARTMENT OF HEALTH AND HUNAN SERVICES OCD AKD DRUG ADMINISTRATION 32420 Parklawn Drive, Room 2082 ¥2/13/2022- 12/93/0002, Rockville, MD 20857 a ORAPHARMintemational483responses4@fda.hhs gov ‘Mr. Sanjay Kumar Jain, Ph.D. Amneal Pharmaceuticals Private Limited Plot ra. 15, PHARMEZ (Special Beonorie Zone) Saekhe}- Bale Highway No,SA, Matove, Tat Sasand Distt Ahmedabad, Gujarat 382213, India Pharmaceutical Parenteral Manufacture: g. There is an air flow evaluation to demonstrate that air exits & moves iromt a positive air pressure aree toward a less positive ar pressure avea. However, the evaluation did not include simalation of a routine operations eg. to allow the entry of prodiiction personnel end entry ofa!" Rather the ais low visualization consisted of by sbout 13, There are individual Air Flow Visualization Study & Recovery Studies performed for the aseotic fill lines, the UAF units, and the mictobiology sterility tests areas in that have been reviewed ond approved by personne! froin IPQA, Maintenance, Production and ‘Validation Departments, However, as confirmed by the individuals who reviewed and approved the air flow visualizetion stucies there are no written evaluations regarding the above departments” assessments, 14, There is a!" in aseptic fll tine™ ihat is used by peisonnel (o move from she filixoom to the area and capping station. ‘The Intervention Trend Repott for Vial Filling Line from 01 Feb-2022 10,31 Jul 2022, dated. 16 Sep 2022, document that the minimum & maximum ftmber of atervention occurrences consisted of 07 and 37 times, respectively during the manufacturing processes. The Intervention Trend Report for Viel Filling Line ™ from Jen 2022 to Jun 2022, dated 16 Aug 2022, document that the minimum & meximum number of intervention occurrences consisted of NIL and 22 times, respectively during the manufacturing processes. The intend of the intervention trend reports is'“To evaluate the actual executed interventions in the GMP batches with respect to allowed or pertuitted iaximum number of interventions” sod that the “Evaluation ‘helps to control on the actus requifement of interventions or to identify any new interventions.” Notwithstanding the above considerations, there is no airflow evaluation performed for the™ io demonstrate that the unidirectional air flow is acceptable ard that the air flow is not cOmpromsed within the Grade A area. 15, As previously reported in the preceding observation. nfeduction personnel access te aseptic fil fine! via the” RABE access panel [2.2 ‘that is approximately!" ‘The body movements performed by the production operator to enter and exit the Grade A environment have a direct impact upon the znidirectional ait flow. "There is no air flow evaluation regarding the above production personnel avtivity to assure that the air flow is unidirectional ani to assure that there are a0 and/or air turbulence created by the body iiovements while in the Grade‘A area. SREREVERSE | Thomas J. Aristd~Investigator/NE_- 12/23/2022 OF THIS PAGE ue vomarroactten06) remanence INSPRCTIOMAT, ORSERVATION: Page 7 of 9DEPARTMENT OF AEAUTIVAND HUMAN SERVICES FOOD AND DRUG AUBENISTRATION. 12424 Parklawn Drive, Rocim 2032 12/137202-12/23/7022 Rockville, MD 20857 wei ORAPHARMIitemational48respouses @fla.ths.zov 3010254278 Mr, Senjey Kumar Jain, Ph.D. Amneal Pharmaceuticals Private Limited Plot ro. 15, PHARMEZ (Spécial Economie Zone) Sarkineje Bula Highway No.SA, Motoca, Ta: Sanund Disitiet Ahmedebad, Gujarat 382213, India Pharmaceutical Parenteral Manufacturer 16. Asconfirmed by the Assistant General Manager Project & Enginegring Department, there are no Architectural Layouts (As Build) engineering diagrams forthe HVAC uaits in manufacturing facilities. In addition, 4. There i not Architectural Layouts for the)I™|l//JRestreted Access Barrier System (BRABS) thpt is used ‘to aseptically manufacture finished drug products inthe!” asoptie fill Line in Por for the ABS aseptic fil fines in!™ b. There ia Piping & Instrumentation Disgram (P&ID), identified as PR-2612496 4026295 ~ Arancal dated 19 April 2016, regarding the /"2ABS inthe” ‘The Senior General ‘Manager of Quelity Assurance confirmed that the Original Equipment Manufacture’s (OEM) 2016 P&ID ‘has not been reviewed and approved by the Quality Unit. 2. Change Control decument number CC-AMN-21-2316, dated 1 Nov 21, required shat the a Which included a change of ‘The'above AHUs are used in the aseptic fill 190m on the! AS confirmed the Assistant General Manager Project & Engineering Department, there are no engineorieg diagrams rogarding the changes that were mace, a. Regarding engineering diagrams of the mariufacturing facility and production equipmeit eg, Architectural Layout (As Built) or P&ID diagrams, the Assistant General Manager and Vice President Project & Engineering confirmed that there is no cocument/standard procedure (e.g., good engineering, practices) to desoribe and establish basic & fundamental engineering requirements, “DATES OF INSPECTION 12/43/22, 1214/22, 12/5/22, 12/16/22, 12/47/22, 12/19/22, 12/20/22, 12/21/22, 12/aa/22, 12/2322 ‘SEE REVERSE | Thomas J. Acista—Investigator/NE, 32/23/2022 OF THIS PAGE ‘roms un ns ve Page 8 of 9 | |The observations of objectionable conditions end practices listed on the front of this form are enoried: 4, Pursuant to Section 704{b) of the Federal Food, Drug and Cosmetic Act, or 2. To assist firms inspected in complying with the Acts arid reguiations enforced by the Food and Orug Administration. ‘Section 704(b) of the Federal Food, Drug, and Cosmetic Act (27 USC 374{b)} provides: "Upon completion of any Such inspection of factory, werehouse, consulting laboratory. of other establishment, and prior to leaving the’ premises, the officer or employee making the inspecfion shall give to the owner, operator, or agent in charge 2 report in wating setting forth any conditions or practices observed by him which, in his judgment, indicate thet any food, drug, device, or cosmetic in such establishment (1) ‘consists in whole or in part of any fithy, putrid, or decomposed substance, or (2) has been prepared, packed, or held under insanitary ‘conditions whereby it may have become ‘contaminated with filth, or whereby it may have’been rendered injurious to health, A copy ‘of such report shall be sent promptly to the Secretary.”