Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology 14 KABI Kishanpuira, B PROCESS SIMULATION PR ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCE CYTOTOXIC STERILE INJECTABLE FACILITY (LINE) Do b Erecerive Date: 07 ASEPTIC PROCESS SIMULATION (MEDIA FILL) PROTOCOL FOR ASEPTIC LIQUID AND LYOPHILIZED MANUFACTURING AND FILLING PROCESS Revision Index Date | _ Reason for revi a 27_|Changes made as pef Ghange control no. CHG-Baddi 2-2014-06 '4 | Nov.2014 include recommendation of CAPAs (Ref, No. CAPA-Baddi2-2014-0433) Revision as per chafige control CHG-Baddi 2-2015-0498: - 1) Incubation. period of media fill vials from 21 days to 14 days that is: is | 30duly [Initialy 7 days wt 20-25°C in upright condition than at 30-35°C in inverted 2015 |position, forrest of the 7 days. 2)Frequeney of inspection of media fill vials from observation on 3rd 7th,1Oth , 14th & 2ist to 7th day of incubation & 14th day of ineubation Revision as per change control CHG-Baddi 2-2015-0859: - 1g | 18Dec. [Container closure integrity Test removed from the protocol 2015 | |Annexure-I (Sampling Plan) revised to exclude Container Closure Integrity Test sampl Changes made as per Change Control no, 23213 I. Usage of commercial grade PPM in Media fill batches. . Usage of Alternative Thioglycollate Medium instead of Normal FM 29 June f. Removal of forceful simulation of Power failure and Particle count 17 | “2016 | excursion interventions. kt, Worst case filing duration revised from single run to Multiple SKU from common bulk. I. Revision of Annexure-V & VI. Fern No: SOPIQA0002-0037.002 CONFIDENTIAL On Signa na hex it a: NTIPSBIALFO-221P1; Poa By: Jtndra Xuma; Print On: 0108/2020 13:08; Copy Ne: * of 1: Copy To: Quality Assurarce (Genera) Primer Name: MOA PRINTER 4248 @; Dive Nae: Caron RADY 42454261 UFR KKPO-JTENORAKL); Pint Type ese Coe.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 ‘th FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL, ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LiNt-1) Document No: PSB/ALF/OL REVISION No.: 2 Page 2 of 29 Errective Date ] [Changes made as per Change Control no, 28617 & 28811 | 1. The hold time of Manufactured Media bulk will be considered from the 1g | 234uly |_ start of addition of Medium in WEI till end of filtration of Medium. 2016 | 2. Revision of Annexure-II for additional sample of Bio burden analysis after completion of first filtration of Media Bulk. 3. Revision of Annexure-IV. - (Changes made as per Change Control # 76944, ‘« Intervention classification/coding aligned with revised SOP/QAD/107, Rev. 19, * Revision of Annexure-I for change in sampling plan for In-process samples, * Revision of Annexure IV & V for change in Intervention classification 19. 30 June and codes. 2017 | Revision of Annexure VI for change in schedule of ATM simulation, * Annexure-I is made Obsolete, as incubation of vials is done as per SOP/QCM/074, Annexure- III, V and VI is made obsolete as annexures is available in SOP/QAD/107 Changes made as per Change Control # 98481 + Usage of gamma irradiated sterile media instead of non-sterile media ‘Changes made as per Change Control # 658611 1. Incorporation of Protocol #PSB/ALE/02 (Aseptic Lyophilization oa 09 Mar. process) 2020 2. Reftamed and harmonized of protocol, 3. Revision of Annexure-II and IV, 21 [Changes made as per Change Control # 783893, replace 100 mi Lyo pack size with S0ml Lyo at point number 7.14. Form Nos SOPIQAD/0002-0037.002 CONFIDENTIAL {QA Sinitiny ut Das WAary Pint kt NTIPSBIALFION-021P1; Prine By: Rene Kumar; Printed On: 108120201808; Copy Not; Copy To: Gy Assurance (Gene Prite Narn: MOA PRINTER «245 @; Drive Name: Canon R-ADY 424514253 UFR KFO-TENORAKU); Put Type: keues CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Yh see 1.0 APPROVAL SIGNATURES... 2.0 Opsective. 3.0 Score. 4.0 ReFereNce Docu 5.0 Resronsimity:. 6.0 Pre-REQuisiTE: 7.0 PROCESS SIMULATION TesT PROCEDURE. 8.0 ACCEPTANCE CriTeRIA. 9.0 DisPosAL OF MEDIA/ MEDIA FILLED VIALS, 10.0 Post CLEANING 11.0 Documenration, 12.0 OPERATOR QUALIFICATION sss 13.0 14.0 Form No.: SOP/QAD/0002-0037-002 Fresenius Kabi Oncology Ltd. Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) DOCUMENT No: PSB/ALF/O1 REVISION No.; 21 Page 3 of 29 EFFECTIVE DATE: t)"? Sef a TABLE OF CONTENTS CONFIDENTIAL [“* msg Pa mo yin Pine INTIPSBIALFION-0211; Prine By Mena Kur Pint On: 1018/2020 19:08 Copy No 4a: Copy To: Qualy Assurance (General Pinar Nara: MA PRINTER 4245 @ Diver Nema: Canon R-ADV 424514251 UFR I{KPO-ITENORAAUy Pint Type: neve Copy.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 th FRESENIUS KABI ASEPTIC LIQUID AND LYOPHILIZED FI Fresenius Kabi Oncology Ltd. Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) Docume No: PSB/ALF/01 1 REVISION No, Page 4 of 2 Eprective Date: 1.0 APPROVAL SIGNATURES the Liquid and Lyophilization process at line-1. Further if any changes in this protocol are required, protocol will be revised and duly approved, Prepared By ce ‘Name/ Designation Date Tiewsdlsy |S. Chvecotive 1D ALg rer [CheckedBy a Name/ Designation | Signature Date Vbst Re La Kone Mae Se eel %)— °C = E SN Gmeid | SD Gu ~ Owe . Dro Dora | porno Wy Aug r0 |Fhcal, _Kumaon, | Wtanagex _} “Wet JAA Qyys020. [ZowU Leth | Execuive— QA \Wor 14 Ay 2.0% ee ee < Sighature Date 7 TA Sag mane Form No. SOPIQADI0002-0037-002 CONFIDENTIAL, Prin INTIPSBIALFION-021 Prine By enc Kumar Pinte On: 01087200 13:08; Copy No: to 1: Copy To: Quaty Assurance (Ganra Printer Nama: MA PRINTER 4245 @ Over Naa: Canon R-ADY 42484281 UFR INKPD-ITENORAKL Prt Type ee Copy. Signing of this protocol indicates agreement with the Aseptic Process simulation approach for | [ey | | | 4'ssuance Code; INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology KABI Kishanpura, Badd PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS Cytotoxic § ERILE INJECTABLE FACILITY (LUNE-1) Document No: PSB/AL FIG REVISION No, Page sa Erpective Date: O7S¢p 254 2.0 Opsecrive To validate the aseptic processing of liquid and lyophilized inj on Formulation line-1) i.e, filling, half stoppering, Lyo loading and unloading activities Lyophilization processing (Io case of Lyophilization) fill stoppering and sealing through aseptic process simulation b substituting the product with a able growth medium. This activity aims to: ‘© Ensure that the manufacturing processes’ used for aseptically filled products in Cyto Sterile injectable facility line-! of Fresenius Kabi Oncology Ltd. have the capability to produce sterile drug products, * Establish that the procedures. followed are in compliance with the GMP requirements, ‘* Provide a measure of the likelihood of microbiological contamination arising in the process. 3.0 Scope, This protocol is applicable for the aseptic process simulation of liquid and lyophilized injection formulation and filling activities i.e. filling, half stoppering, Lyo loading and unloading activities Lyophilization processing (In case of Lyophilization) full stoppering and sealing to be carried out in the Cytotoxic Sterile Injectable facility line-1 at Fresenius Kabi oncology Ltd. Kishanpura, 4.0 REFERENCE DOCUMENT Following documents were referred during preparation of the protocol: Document Name Document Number Proces PDA Technical Report #22 NA \Wiyar" 7 Form No : SOP/QAT/0002-0037-002 CONFIDENTIAL, QA Sinus i “G \ rin INIPSELALFIO-221P 1; Ped By.Stendra Kum: Pretad On: 10082020 19.08; Copy No 1 Copy To: Quay Assurance (Gere) PritorName: MOA PRINTER 4248 @ Drier Nama: Canon I-ADV 4248/42 UFR IIKPOATENORAKU}; rit Type: lsved CoyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Ny FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALP/O1 REVISION No.: 21 Page 6 of 29 EFFECTIVE DATE Document Number | Aseptic Processing Sep.2004. EU Annexure-I Manufacture of sterile medicinal products NA WHO Annexure 6 Good manufacturing practices for sterile NA pharmaceutical products Aseptic Process Simulation (Media Fill) SOP/QAD/O107 | Quality Risk Management i SOP/QAD/0020 Inspection of Media Fill Vials and Qualification of Inspectors. SOP/QCM/0074 Microbial monitoring of cyto sterile facility SS Y SOP/QCM/0031 | Operation of Sterilization In Place of Manufacturing Tank and SOP/CSP/0065 Holding Tank. Operation of Cleaning In Place of Manufacturing and Holding SOP/CSP/0066 Tanks | Procedure for cleaning after media fills. SOP/CSP/0092 | Operation and Cleaning of MAR Make Vial Filling and Sealing SOP/CSP/0031 Machine | Event Handling Process SOP/QAD/0162 HandingofFieldAlet = ~~~ | gSOP-PH-QM-001 5.0 RESPONSIBILITY: The process simulation needs representatives from each of the following departments and will be responsible for the overall compliance of this protocol: Production ‘© Support QA in the preparation of the risk assessment resulting from batch record review to ensure all interventions since the last media fill study are identified Form No.: SOP/QAD/0002-0037-002 CONFIDENTIAL, A Sir {Vv Pat NTIPSBIALFION-021P1 Pate By: Jeena Kumar Prt On: 10872029 12:08; Copy No +o; Copy To: Quty Assurance (Gents Peta Name: MA PRINTER 4245; Ove Narra Canon RADY 4248426: UPR IKPO-ITENORAALU Pot Type eed CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (Lint-1) Document No: PSB/ALE/O1 REVISION NO.; 21, of 29 EFFECTIVE Date * Support QA in the preparation of process simulation protocol to ensure all interventions since the last media fill study are included. * Review of the media fill protocol and report. * Preparation of media fill batch records * Execution of the media fill protocol, © Handling of any incident or event during media {il * Involvement in investigation against failure of the study. * Training of personnel taking part in the-media fill and ensuring that required personnel participate in the media fill program. Quality Assurance + Lead in preparation of the tisk assessment resulting from batch record review to ensure all interventions since the last media fill study are identified. ‘© Preparation of process simulation protocol to ensure all interventions since the last media fill study are included in correct number. ‘+ Preparation and approval of the media fill protocol and report © Approval of media fill batch records. * Communication of media Fill planning and execution details to all concerned departments through Annexure- VII of SOP/QAD/0107 containing the mandatory information, ‘© Oversight of the execution of the media fill, including the monitoring for withdrawal of samples at different stages and CAPAs generated from the previous niedia fill failure investigations are assessed for its completion/implementation, * Incident or event is investigated and managed through event handling process SOP/QAD/0162, Form No.: SOP/QAD/0002-0037-002 CONFIDENTIAL rd Da 40% ~ Rie J are Print: NTIPSBIALF01-02 UP: Prt By: Jtendta Kumar; Pinto On: 1008/2020 13:08; Copy No of; Copy To: Guat Assurance (Gena Printer Name QA PRINTER 4245 @ vr Name: Canon R-ADN 424514261 UER WIKPD-JTENORAKU, Pit Type: ses Cory.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS. CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-L) Document No: PSBVALE/OI REVISION No. Page 8 of Errective Date + Review and approval of master list of Personnel Qualified for working in the aseptic area, including new person’s joined/gowning qualification for aseptic aren, Corporate Quality Assurance * Media fill failure will have to be reported immediately to the global operations Quality Management and Divisional pharma QA’ Competence Center Microbiology & Aseptic Technique. In addition to be formally reported by the corporate monthly KPI reporting system. © Review and approval of media fill failure investigation report by regional QA (FK- India) Microbiology © Part of the risk assessment team. * Review of media fill protocol and report + Environmental monitoring as per SOP/QCM/0031 «Sampling as defined in the media fill protocol. ‘+ Analysis of samples and preparation of analytical report. ‘+ Involvement in any media fill failure investigation. Engineering # Part of the risk assessment team. + Ensuring preventive maintenance of all machines as per schedule * Assurance of all required utilities throughout the study. * Simulation of maintenance intervention as per the media fill protocol * Rectification and documentation of any breakdown during media fill Forin No.: SOP/QAD/0002-0037-002 ‘CONFIDENTIAL, QA Sienatury pnd Dae yf Pint et INTIPSBIALFI'-02 11; ited By Soa Kumar, Print On: 1008/2020 1:08 Copy Noto Copy To: Gully Assuance (Genoa) Pte Nar: MOA PRINTER 4245 Drive Nar: Canon R-ADV 4248/65 UFR IKPD-JTENDRAKU}: Pri Typ: ese Cony,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. 6.0 70 KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOK, ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALE/01 REVISION No.; 21) Page 9 of 29 EFFECTIVE Dave: 07 $eb:2220 PRE-REQUISITES Media Fill study will be * HVAC Qualification. jated with review of the following: © Suitability of equipment and their qualification, * Training of Personnel, required for Manufacturing and Filling of aseptic process simulation, PROCESS SIMULATION Test PROCEDURE Aseptic Process simulation (Media Fill) is'the performance indicator to demonstrate the process capabilities of an aseptic. manufacturing process. Following activities will be performed for the Aseptic Process Simulation (Media Fill) for aseptically filled liquid and lyophilized products for verification of performance attributes 7.1 FREQUENCY OF ASEPTIC PROCESS SIMULATION Aseptic process simulation activity is executed in every six month. The entire step in the aseptic process simulation study will be performed as per media fill batch record and SOP/QAD/0107 “Aseptic Process Simulation (Media Fill)”. The number of replicate trials, required of the aseptic process simulation for new facility (startup) as well as for addition of @ new container closure system/size will be as per the Aseptic Process Simulation (Media Fill) SOP/QAD/0107. 7.2 PROCESS SIMULATION MATRIX During revalidation selection of pack size, fill volume and process to be simulated will be planned as per the media fill execution plan (annexure-VI of SOP/QAD/0107).. Form No.: SOP/QAD/90002-0057-002 CONFIDENTIAL, tk INTIPSBIALEIO'-024PI rad Bye Kura; Pete On: 100912020108; Copy No 1 of Copy To: Cty Axsiance (Caner) PitocName: MOA PRINTER 4245 @ Driver Nam: Canon -ADY 4245/4251 UFR I{KPD-JTENORAKU} ah TYP: ete CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd, KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTONIC STERILE INJECTABLE FACTLITY (LINF-1) Document No: PSB/AL Fa 7.3 PROCESS SIMULATION RUN 7.3.1 REVALIDATION PROCESS SIMULATION RUN - DESIGN: + Follow the media fill execution plan (Annexure-VI of SOP/QAD/0107) for Media fill activities, * Minimum & Maximum vial size to be cover every six month and other Intermediate vials sizes to be planned in periodic fills. ‘+ Each intermediate vial size will be taken for the process simulation (in rotations basis) as per Annexure-VI of SOP/QAD/0107. ‘© The pack sizes which are same for the liquid injection and lyophilized product may be split during filling after manufacturing of a single media bulk, * Only commercial grade Primary Packaging Material will be used for media fill © The worst-case filling duration of Media fill will be based on the review of the last six months of commercial batches. + The filling duration of different SKUs from a common bulk will be longer than the longest duration fill that occurred in the past six months. + The filling duration will be calculated from the filling start time of the first SKU to filling end time of last SKU from common bulk. 7.4 PRocepuRe: * The process simulation run is designed to cover all the normal processing operations and include inherent as well as corrective (Opened/Closed CRAB Door) interventions that could realistically be encountered during routine filling operations, * The following table will provide the comparison of normal manufacturing steps as well as the process simulation steps: Form No. SOPIQADI0002-0037-002 CONFIDENTIAL QA Signatyyyand Date en rng Pit kt INTIPSBIALFION-021t; rine By rca Kumar; Pit On: 1008/2020 1308; Copy Noo: Copy To: Qulty Assurance (Genera Pitr Nara: MOA PRINTER 4245 @ Ove Nera Canon R-ADV 4248/4261 UFR I{KPD-ITENDRARLY; Pit Tye: ese Coo,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINr-1) Document No: PSB/ALF/OL Revision No.: 21 Page 11 of 29 EFFective DATE: Normal Process Se ane pene | siadiice Justification [Dispensing TOC NA Formulation (Mixing & Dissolution) | v [ v NA Sterile Filtration - 1 & Bi Soluti Sey ulk Solution P 7 i Sterile Filtration -2 (In the filling CRABS) |v NA Vial Filling i ini T= v NA 'Half-Stoppering (In case of Lyo Filling) ¥ v | NA Tray loading (In case of Lyo F a ava NA Lyo loading (In case of Lyo Fil a v NA 7 | ~ | Freezing may Lyophilization: (In case of Lyo Filling) | [arrest microbial 1. Freezing v vat 20°C) | Broth 2. Primary Drying v « ene vega 3. Seeondary Drying y x | yatr on aresig 4, Vacuum 4 “Cartial) | microbial growth | _ By filter Comp. | Other gases may | | Air in case of arrest the growth | Vacuum break: (In case of L.yo Filling) ByN; SCDMand of organism | By filter Nitrogen Air in = o pee AT By Comp. Air in | Other gases may case of SCDM | arrest the growth Vial purging ByN2 | and By Nitrogen | of organisms /Ox/COr | Air in case of | ATM om Nos SOPAQAD/0002-0037-002 CONFIDENTIAL, Prt ae NTIPSBIALEON-0210 Print Name: MOA PRINTER 4245 @ Drs Na ‘Canon R-AOV 424814251 eed By stoner Kurar, Prited Cn: 100820201308; Copy No: of Copy To: Guy Asirance (Caner I{KED-ATENORAKU} Put Ty: ete Copy.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALF/01 Revision No.: 21 Page 12 of 29 Eprective DATE: ()°7Sp: 20% Normal | Process — | Manufacturi ti | ng Operations/ Steps | peeuction | simutation | %#ifeation Rubber Stoppering v4 v | NA Rubber Stoppering inside Lyophilizer (in| | NA v v | case of Lyo Filling) | Unloading of Vials (In case of Lyo Fi rail v NA Aluminum Cap Over sealing vy v NA i? ‘All integral vials Exterior Vial Washing & Visual | Y peoubaeap aed Tana Alen ve | cosmetic defects a Ae too. | | Vial labeling is not | | required in media Vials labeling y * fill as batch no. | and serial no, is | | coded on the neck I oe | of each vial Required for Vials Incubation * v incubation of, organisms 100% visual Media fill vials inspection after 7" day and "1 v inspection to verify 14! day of incubation microbial | contamination Normal "Process ‘i Manufacturing Support Process(s) Production | _ Simulation Sustifie: Product and Vent Filters Sterilization | =~ | | NA Product and Vent filters Integrity Testing v Y | (Pre& Post Use) | | NA Filling Machine Parts Sterilization lv y | NA Porm No.: SOP/QAD/0002-0037-002 CONFIDENTIAL QA Signy ad Ooms Vis Gi Pt ks NTIPGBIALP/‘-02 1: ead By Nena Kumar Pied On: 101082020 1:08 Copy Noto : Copy To: Gully Assen (Genes) Pre Name: MA PRINTER 4245 @ OrverNune: Canon R-ADY 4248/4251 UFR {KPD.JTENORARL); Prt Type: lesbo CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Ny FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALE/O1 REVISION No.: 21 Page 13 of 29 ErrectiveDate: ©76P | Normal | Process — : Mi 4 Ianafacturing Operations/ Steps | Un | sioutetion Justification | Vials Washing & Depyrogenation v v NA | Rubber Stoppers and Over seals | Sterilization a 4 NA Preparation Vessels Cleaning & | v y A Sterilization _ — | Mobile (collection) Vessels Cleaning | 7 m Sterilization ea ‘Manufacturing Support Process(s) Normiat | Process | Justification Production | Simulation | Product and Vent Filters Sterilization | v | NA Product and Vent filters Integrity Testing | oe en (Pre & Post Use) | | Filling Machine Parts Sterilization v v | NA ‘als Washing & Depyrogenation v v | NA. | Rubber Stoppers and Flip-off Seals| ¥ | mA Sterilization | eo Po et - ' Solution Preparation Vessels Cleaning & |, ys = Sterilization | = Holding Vessels Cleaning & Sterilization | ¥ v | NA Lyophilizer Cleaning & Sterilization y | v ne as | | In-Process Controls I 7 . Panne pH and |Bulk Solution Sampling for Chemical] y gravity | Testing process | Bulk Solution Sampling for Bioburden v v 7 Foxm No: SOP/QAD/0002-0037-002 CONFIDENTIAL, Pt: INTIPSBIALFIO"-0211; Peto By Meneame; Pinta On 1010812020 19.08 Copy Nt of 1; Copy To: Quality Assurance (Sonera Ptr Nana: MOA PRINTER 42¢8 @ Orv Naa: Canon R-ADV 42484251 UFR IKPO-ITENORAKU Pit Type: ued Copy,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 wh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS: CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALF/01 REVISION No: 21 Page 14 of 29 Errective DATE: 07 6¢h Jodo : Normal | Process Manufasturig Support Process) Production |Stuvtetion | ustifieation Pre-fill Growth Promotion Test (from | ‘As part of bulk x v holding tank) acceptance criteria Growth Promotion ” y As part of bulk = | acceptance criteria Environmental Monitoring (Viable & Non- TNA : vy | v Viable) | TA nondestructive | approach willbe taken for the " sampling of vials Fill Volumes Check v v aoe Sea 1 the vials will be visually inspected - and incubated, Personnel Monitoring - vA NA ‘Surface Monitoring 7 vy NA cRAB Glove Dab Monitoring Ch [Na + The procedures for preparation and sterilization of the equipment, containers and closures will be done using the appropriate SOP(s), which are followed for the routine production of batches. 1S INTERVENTION SIMULATION ACTIVITIES: * The process simulation will closely simulate the aseptic processing operations incorporating, the inherent and corrective (Opened/Closed cRAB door) interventions as per Annexure-IV of the protocol. + Based on the approved risk assessment, a consolidated list of interventions along with category and frequency in the form of a matrix will be incorporated into the Form No.: SOP/QAD/0002-0037-002 CONFIDENTIAL Print: NTPSBIALFION-02 1; Printed By Stace Kumar; Prt On: 1008/2020 13.08; Copy No: 1 of; Copy To: QullyAssuranes (Gores) Prt Name: MA PRINTER 4245 @; Over Nem Canon R-ADY 42484251 UFR IKKPD-ITENORAKU Pit Type esd CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 wh FRESENIUS Fresenius Kabi Oncology Ltd KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL, ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) Document No: PSB/ALEO1 Revision No.: 21 Page 15 of 29 ECTIVE Dat media fill protocol (Annexure-IV) will be issued to the production department along. with the batch record for understanding and tracking execution of interventions during media fill. 7.6 PROCESS SIMULATION Batu Size 7.6.1 Process simulations to support batch sizes $000 or greater. © The normal batch size for process simulations will be 5000 units. * The normal batch size for process simulations in lyophilization process will be NLT 5150* units (Total filled units before lyophilization) Note: In case the capacity of the Lyophilizer for a particular vial size is less than 5150 units then the number of units filled will be according to the full capacity of the Lyophilizer chamber. © In order to ensufe that the target batch size is achieved for a process simulation run it is normal to target a higher target fill number, e.g. 110% of the target value. e.g 5,500 for a nominal 5,000 unit run, to allow for rejects, losses etc. *As per a rational of rejection trend of 10 lyophilization Batches the average rejection is 2.3% which is rounded off as 3.0%. 7.6.2 Process simulations to support batch sizes of < $000 units © For operations with production sizes under 5,000. the number of medic filled units will be at least equal the maximum batch size made on the processing line. + If the target number is not achieved the batch may still be used to support the processes, providing: © The duration of the fill is consistent with that of the planned process. * The cause of the low yield has been identified and does not invalidate the run. Form No: SOP/QAD/9002-0037-002 CONFIDENTIAL QA Siang ght Date f Chorney? Yur Print ee NTIPSBIALFOY.0211P: Printed By: Senea Kumar; ried On 10882020 13:8; Copy No ft Copy To: Quay Assurance (Gene Printer Name: HOA PRINTER 4245 @ Drive Name Canon ADV 42454251 UFR I(KPD-ITENORAAU), Pit Type: sued Coy.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 th iy 78 FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) Document No: PSB/ALF/01 Revision No.: 21 Page 16 of 29 Errective Date: * The total number filled is greater than 90 % of the target number MEDIA SELECTION * The media selected for process simulation test will demonstrate the capability to promote recovery of wide spectrum of microorganisms. * The medium growth promotion properties will be evaluated using Pharmacopeial methods. * For Aerobic Microorganism, Gamma irradiated (sterile) Soybean Casein Digest Medium (SCDM) — 3.0.% w/v will be used * For Anaerobic Microorganisms, 2.9% Gamma irradiated (sterile) Alternative Thioglycolate Mediu (ATM) 2:9% w/v will be used. PROCESS SIMULATION BATCH MANUFACTURING PROCEDURE 7.8.1 COMPOUNDING / MANUFACTURING Form No.: SOP/QADI0002-0037-002 CONFIDENTIAL QA Siu nucyppibe © Use gamma irradiated (Sterile) soybean casein digest medium or Alternative Thioglycolate Medium (ATM). * Prepare 3 % w/v solution of soybean casein digest medium ot 2.9% w/v solution of Alternative Thioglycolate Medium in WFI at 50-60°C as per batch manufacturing record. © Follow the solution preparation method as per the respective batch manufacturing record, Use same filter media and same porosity filter batch. used in the regular production © Collect the sample of media bulk before filtration for Clarity, pH, Specific Gravity & Bioburden test as per annexure-IL * Filter the media into the sterilized holding tank. iV @ wy Print i INTIPSEVALFD.024I*; Panta By: Jtendea Xuma; Pied On 101872020 19:8; Copy No: tft Copy Ta Quality Assurance Genera Printer Name: Wak PRINTER 4245 @ Dvr Nene: Canon R-ADY €2454251 UFR NKPD~ITENORAKU): Pit yo 18 opy.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 th FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALF/OL REVISION NO,: 21 Page 17 of 29 EFrEctive DATE 7.8.2 FIRST FILTRATION * The unfiltered liquid growth medium will be sterilized by passing through sterilizing grade filters in a manner similar to the production process being simulated, + The bulk compound (Soybean Casein Digest Medium or Alternative Thioglycolate Medium) will be sterilized through sterilizing grade filters (same es normal production process) within the time period of 8 houts (i.e. From the start of addition of Medium in WFT till the end of filtration) to avoid any undesirable failure (as the growth promoting media can lead to proliferation of microorganisms if retained unfiltered for prolonged time period.) * After sterilization, the growth medium will be passed through the equipment drain as it was during the actual produetion batch and all routine procedures used in the manufacture of the batch are’ performed, such as in-process sampling, filter integrity testing, etc. © After first filtration of the media, collect the sample for, GPT, pH & Bioburden test as per Annexure IL. The filters used for filtration were tested for integrity before and after filtration. 7.8.3 SECOND FILTRATION © The filtered bulk solution stored in holding vessel was again filtered through on-line 0.22um sterilizing grade cartridge filter and filled into the vials under ¢RABs © The filters used for filtration were tested for integrity before and after filtration, 7.8.4 FILLING SPEED Form No: SOPIQAD/0002-0037-002 CONFIDENTIAL QA Signatu Pint ts NTIPSBIALFI0-021P1: Ped Bytes be set to address the different risks « The filling speed to be used in Media Fills associated with fil speed (minimum speed-longer exposure, higher speed-turbulence, vial spillage etc.). 5 qd Date Ginn ura: Pintea On 0108/2020 19.08; Copy Na: tf 1 Copy To: Cuaty surance Gaara Printer Nama: MOA PRINTER 4245 Driver Name: Canon iR-ADV 424514251 UFR I{KPD-JITENORAAU) Pint Type ss Copy,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) DOCUMENT No: PSB/ALFV/OL REVISION No. 21 Page 18 of 29 Errective Date © For minimum (2 ml) and maximum (100 ml) vial sizes the media [ill line speed will be set to simulate the allowed validated range (maximum and minimum vial per minute) used during routine manufacturing ‘+ For other vial sizes the standard filling speed used during routine manufacturing will be simulated. * The media filled Vials will be sealed and collected in sequentially numbered trays / boxes, and the time of collection / filling will be recorded. 7.8.5 FILLING DURATION ‘+ The overall length of the processing run (Collective filling duration of different SKU from common Bulk) will be similar to or greater than that normally encountered in routine manufacturing * The last six month commercial batches will be reviewed to decide the filling duration of upcoming media fill © After completion of Media fill, Media fill batch records will be reviewed to ensure that pre decided filling duration achieved during Media fill ‘* The process simulation tests will be of sufficient duration to include a representative ‘number of common interventions, which might occur during an actual product filling operation. Where they are part of normal operations, gown changes, shifi changes, breaks etc. will be simulated « [fall normally expected interventions are not covered with the normal operating line speed for the desired media vials, this must be achieved by running the filling machine at a slower speed. Fon No: SOmrADON2 087-08 conFipexriat OA Sip ( ve |__Ayingy Pit et INTIPSBIALFIO"-021Pt; rita Bena Kumar Prt On: 1008/2020 13:08; Cooy Not of 1: Copy To: Qual Assure (Canta, Pinte Name: MOA PRINTER 4245 @ Diver Nam Canon R-ADV 42454261 UFR IKPO-JTENDRAKLD, Pit Type sued CoryIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh,Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS ‘ CYTOTOXIC STERILE INJECTABLE FACILITY (LINt-L) Document No: PSB/ALE!0 Revistos Ne P. 9 of 29 Errective Dae: 0°? SCP 20.20 7.8.6 FILLING VOLUME © The fill volume should be sufficient to assess potential micrdbial contamination and to ensure the complete contact with all sterile surfaces inside the container when inverted, © The set volume used will provide sufficient container headspace (due to foamin, the media) to support potential contaminant growth and sufficient volume to visually detect growth, © The filling speed will be adjusted to leave the units open under the filling head for the same time as they would be in routine filling, © Fill volumes per vial size are ptovided in Annexure-V1 of SOP/QAD/0107 and the same will also be defined in the Batch Filling Record. 7.8.7 HALE STOPPERING IN LYO PROCESS + The filling process i followed by the stoppering process under the cRAB ~ 1 ‘The bungs will be partially stopperred to simulate the lyophilization process, * Slotted rubber stopper will be used for half stoppering process 7.8.8 TRAY LOADING IN LYO PROCESS - ‘+ After the stoppering operation, vials will be transported to the tray loading system for Joading in to the lyophilizer without sealing under the cRAB - 4. + The trays will be completely filled and then transported into the lyophilizer. The arrangement of the vials will be as per below diagram. Form No.: SOP/QAD/0002-0037-002 CONFIDENTIAL Print: NTIPSBIALFO1-021P: Pint By: Jtnda Kumar; Ped On; YO!UE2C20 1908; Copy No 1 of Copy To: Guy Assurance (Gene) Print Name: MOA PRINTER 4245 Orver Nee: Cao RADY 42454261 UFR IIKPOITENDRAKU); Pr Type latued Cony.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Document No: PSB/ALF/O1 Revision No. 21 Page 20 of 29 Errective Date Incorrectly loadad shelves 7.8.9 LYOPHILIZATION ‘The Lyophilization process will be as follows: + Partially stopperred vials are loaded into the lyophilizer. * The freezing phase in normal production is simulated by maintaining 20°C temperature for 2 brs «A partial vacuum of 400 mbar will be applied within the chamber and this level will hold for a period of 6 hours at ambient temperature. © Then the chamber will vent with filtered compressed/Nitrogen air and stoppers will close completely within the chamber of lyophilizer before opening the door. © The lyophilized stopperred vials will be removed from chamber for sealing. 7.8.10 SEALING, EXTERNAL WASHING AND OPTICAL INSPECTION © The lyophilized stopperred vials will be removed aseptically from lyophilizer chamber to sealing station for sealing and then transported to external decontaminating machine for washing of the external surface of the vials. «All the filled vials will be optically inspected with trained operator. Form Ne: SOPIQADIN002-0037-002 CONFIDENTIAL OA Seige | "| Venn Pent ks: NTIPSBIALFION.0211; Peed By Menara Kura, Pinte On 1010872020 1306; Copy No + of Capy To ually Aasurance (Genera Petr Nome: MQ PRINTER 4245 @ One Nema: Conon R-ADV 4245281 UFR KPO-ATENORAKU) Pit Type: sued Copy.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 i FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-D) DocumENt No: PSB/ALF/01 Revision No. 21 age 21 0 Errective Date: 7.8.11 ENVIRONMENTAL MONITORING © Environmental monitoring including non-viable airborne particle count. scttle plates, tive cir monitoring, swabs / contacts plates at the end of processing will be performed as per the defined SOP/QCM/0031 7.8.12 SAMPLING PLAN + Sampling will be curried out during the progess Simulation run as per Annexure-tI. 7.8.13 INTERVENTIONS + The process simulation will essentially include the activities that occur and / or being. followed during normal vial-filling operation or forced situations will be created during process simulation for checking the robustness of the aseptic process. * The interventions 6 be'executed as per procedure mentioned in SOP/CSP/0129 andl are listed in Annexure-IV of media fill protocol. ‘+ Before each media fill, a risk assessment as per SOP/QAD/0020 is to be prepared by referring the media fill execution plan annexure-VI of SOP/QAD/0107 along with the assessment of interventions of commercial batches since the last media fill i.e Once in six month. Note: Conveyor speed of depyrogenation tunnel will be set at the speed as during commercial production for respective pack sizes. 7.9 Post FILL VISUAL INSPECTION * Perform visual inspection of filled vials as per the SOP No. SOP/CSP/0025, ‘© The standard of inspection and criteria used for rejection will be the same as used in routine manufacturing. Fom No: SOP/QADI002-037.002 CONFIDENTIAL On Semicgr ne iY ya Pint: NTIPSBIALFION-021Pt; Printed By-enda Kumar, Pinte On: 1018/2020 1.9; Copy Not a1: Copy To: Quality Assurance (Gana Petr Name: MR PRINTER 4245 @ Drie Name: Canon R-ADV 4245/4251 UFR IKPO-JTENORAKUy Pit Type: sed Cory.Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 N FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-1) Document No: PSB/ALF/01 Revision No.: 21 Page 22 of 29 EFFECTIVE DATE: * Cap coding - The media filled vials will be serially coded on the cap for identification purpose. © Non-integral vials - Vials that would be excluded during routine production especially related to the integrity of the container closure, such as capping rejects. cracked or chipped vials will not be considered for incubation, as they are not representative of the microbial quality of the product, The containers will undergo a double check before discarding. The reason for discarding all such units will be documented. © Only clearly non-integral units (e.g. crack in glass, leakage) are to be rejected * Defect vials that would be rejected during normal manufacturing visual inspection (€.g, incomplete or loose crimpitig) are to be considered as part of the media fill vial counts. + Non-integral filled Vial rejects will be documented in following categories: ype of Rejection | lled and ut oppered without eap/erimp | Filled and stoppered without cap/crimp led and stoppered with cap/erimp, but broker/cracked/leaking as detected during manufacture (incl. photo evidence) led and stoppered with caplerimp, but brokervcracked/lecking as detected during visual inspection (incl, photo evidence) © Integral vials - All integrally filled and sealed vials will be collected in trays, ‘© Trays will be subjected to 100% visual inspection. Fern No; SOPRQADOMc¥7.002 CONFIDENTIAL Gh Scie Oa Viary Print: NTIPSBIALFIOY-0211; Printed By tend Kumar Pend Or: 110912020 13:08 Copy No 1a; Copy To: Quaty Assurance (Gene Pre Name: MQ PRINTER 4248 @ Drier Nar: Canon R-ADY 4248/4251 UFR WKPD-ITENORAKL Prt Type: sued CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh,Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LiNt-1) Document No: PSB/ALF/OL REVISIONNO.: 21 Page 23 of 29 EFFECTIVE Dare * Integral media fill vials send to micro with status label indicating media batch number and date of filling for incubation, 7.10 INCUBATION © All media filled vials will be incubated in a suitable and qualified room for a minimum of 14 days. + For Aerobic media fill: © Media filled vials will be incubated at 20-25°C for 7 days in upright position. * After 7 days inspect for any contamination as per SOP/QCM/0074. If all the vials are clear, invert and incubate for 30-35°C for further 7 days. © Atthe end of 14th day, inspect the vials for any contamination, ‘+ For Anaerobic media fill: © Media filled vials will be incubated at 30-35°C for 07 days in upright position. * After 7 days inspect for any contamination as per SOP/QCM/0074. If all the vials are clear, invert and incubate for 30-35°C for further 7 days. * Atthe end of 14th day, inspect the vials for any contamination * The vials will be transferred to a temperature-controlled room as quickly and practically possible after the completion of the filling process. Note: If there is a delay of more than 24 hrs. between the filling and incubation steps, the incubation time will be counted from the start of incubation only ‘© Invert and swirl the media filled vials in order to have contact of media to entire internal surface of the vials as per procedure defined in SOP/QCM/0074. Record the date of incubation in the report. TAL STAsis Test (POST INCUBATION GROWTH PROMOTION TEST) ‘The media filled vials after the incubation will demonstrate the capability to promote recovery of wide spectrum of microorganisms, Form No: SoPrqAb/0G2 2037-02 CONFIDENTIAL oe {yerd Pent: NTIPSBIALFIO-021Pt; Printed By: Mena Kuma: Printed On: 1108/2029 19:08; Copy Note 1; Copy To ually Assurance (Genera Pinte Name: MQA PRINTER 4245 @; Diver Nema: Canon iR-ADY 42454261 UFR WKPO-ITENORAKL), Pit Type sued ConyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi $s SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Documtnt No: PSB/ALFDT Revision No: 21 Page 24 of 20 ERrECTIVE DATE: 07 «fo Qe * The medium growth promotion properties will be performed as per SOP/QCM/0043. and the inclusion of environmental organisms. © In general at least 5 vials for each test organism will be considered for stasis test 7.12, POST INCUBATION INSPECTION © Inspect 100% of vials on 7 and 14" day. of incubation period as per SOP/QCM/0074. 7.13 EXAMINATION OF MEDIA FILLED VIALS * Each media-fill vial will be examined for microbial growth by qualified inspectors with appropriate training, + The following methodology will be applied to detect the microbial growth as per SOP/QCM/0074 If any vial is found contaminated during the routine inspection, identify the vial/tray and record the details in the format attached as Annexure-I of SOP/QCM/0074. * Remove the contaminated vial/vials, inform QA, initiate the event as per SOP/QAD/O162 and immediately proceed for identification in microbiology laboratory, « All suspected vials identified during the examination, will be brought to the immediate attention of QA. At the end of incubation period, these vials will be examined in laboratory, for contamination characterization / identification. ‘* Affer incubation is underway, any unit found to be damaged will be included in the data for media fll run, because the unit can be representative of handling problem Any decision to exclude such incubated unit from the final reconciliation will be decided by QA and will be fully justified and appropriately explained in the provess simulation report. Form No: SOP/QADION2 607.02 CONFIDENTIAL OA Sis een a Vii") Pik NTIPSBIALFIO'-021P1; Ped Sy: Mena Kurar Prd On: 1008/2029 1308 Copy Nota 1; Cony To: Quit Assurance (Gara) Peter Name: MQA PRINTER 4268 Dror Name: Canon R-ADV 4248/4251 UFR I(KPD-ITENORAKL Pit Type: sued Cop. wyofanl Date,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Ny FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS. CYTOTOXIC STERILE INJECTABLE FACILITY (LiNE-1), Document No: PSB/ALI01 Revision No.: 21 Page 25 of Errective DATE * The final inspection will include accurate count of the number of units inspected ancl reconciled against the actual number of manufactured units from the manufacturing records. 7.14 MEDIA FILL PROCEDURE FOR ANAEROBIC ORGANISM WITH GAMMA IRRADIATED (STERILE) ALTERNATIVE THIOGLYCOLATE MEDIUM, + The overall Media Fill approach for media fill procedure for anaerobic organism will remain same as per the approach defined above for Media fill with SCDM © The worst case pack sizes (2 ml and $0 ml) will be taken into consideration uncer the scope of performing Media fill with Altemative Thioglycolate Medium for Anaerobic organism. © The media fill will be executed with 2.9% wiv Alternative Thioglycolate medium Dissolve the medium coimpletely in the WFI at $0-60 °C as per batch manufacturing record, * The Nitrogen purging /Nitrogen use as applicable will be performed in different stage of media fill procedure. Frequency: © During routine validation, alternate pack sizes (2 ml or $0 mil) will be selected once in alternating as per annexure VI of SOP/QAD/0107. © The schedule for performing the media fill will be as follows: anypfand Dae} [oa L_ Sarg” Png i: INTIPSBIALFIOY.021P: ented By ea Kumar; Printed On: 100812020 19:08; Copy Noto: Copy To: Guakty Assurance (Gane) Pte Nare: MCA PRINTER 4245 @% Dive Nae: Canon R-ADY 424514251 UFR IKPD-JTENORAKU} Pst Type: etved Cony Form No. SOP/QAD/0002-0037-002 ‘CONFIDENTIAL,Issuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL. ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LiNE-1) Document No: PSB/ALE/01 REVISION No.: 21 Page 26 of 29 ErectIvE DATE: Periodic Validation Process = 16 month | 26 month | 16 month | 2" 6 month - | | x | x v x Lyophilization V x x x To be executed X: Not to be executed 8.0 ACCEPTANCE CRITERIA The Acceptance criteria will be as per the Aseptic Process Simulation (Media Fill) SOP/QAD/0107. Interpretation of the Test result as) well as Investigation procedur ‘against process simulation failure will also be as per the Aseptic Process Simulation (Media Fill) SOP/QAD/0107, 9.0 DisPosaL Or Mep1A/ MEDIA FILLED VIALS + Following Process simulation incubation and inspection, the vials are to be stored at appropriate place under lock and key condition until their destruction. ‘© The media fill vials will be disposed as per the SOP No. SOP/QAD/0107 10.0 Post CLEANING * After completion of the process simulation tests all equipment or contact parts will be cleaned as per the SOP/CSP/0092. If required additional checks / precautions will be taken, * To confirm the complete removal of media from the vessels, line and contact surfaces following will be done: Form No SOPIQAD/0002-0037-002 CONFIDENTIAL, QA Sigmayyyaine Date Vero | nt NTIPSBIALEI'-021P 1 red By ence Kura Pita On: 1109/2020 12:08, Cpy Ne +o; Copy To: QualtyAssixance (General Pm Nore: MGA PRINTER 4245 Drive Name: Canon IR-ADV 4248/4251 UFR I]KPD-JTENDRAKUs Prt Type eaves CoryIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 wh FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINF-1) DocuMENT No; PSB/ALEO1 REVISION No.: 21 7 of 29 EFFECTIVE DATE: 078 ‘© Swabbing the open surfaces. Collection of rinse water from the vessels. * The swabs and rinses are to be tested for: 4 TOC for rinse water samples, ‘Total Microbial count for swabs and rinses, 4 The acceptance criteria will be as per WFI specifications. 11.0 DocumENTaTION The Media Fill will be performed and documented through a specific media fill batch record, The media fill batch record will contain all the information which is normally included in a batch record, For example? ‘© Media dispensing records ‘* Container closure release and dispensing records * Cleaning Records * Sterilization Records * Names of persons involved in various activities during the media fill ‘Hold times of various components and media solution, * Records of all interventions including type, times and duration ‘© Records of all stoppages including type, times and duration © Identification of boxes and trays of filled vials ‘Record of any unplanned incidents * Yield calculation —- * Batch Reconciliation indicating + Number of units filled + Number of units incubated Form No: SOP/QADV0002-0087-002 CONFIDENTIAL QA Sigmuyygnd Dre 4 yypns OH coh Wes ns yur’ ti WTFOBALF01-22 PP Jordan Pea: OD 19 Cap 1:59 Te: Oye ann Pare MOK PRINTER it Dae Nae Carn NOY eset rh herb aro Pape unconIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh. Kumar Issued On: 10/09/2020 Hh FRESENIUS Fresenius Kabi Oncology Lid. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LiNE-1) Document No: PSBVALP Revision No. 21 e 28 0! Errecrive Dare: OU pw? * Number of units rejected for cause 12.0 OPERATOR QUALIFICATION All personnel required to take part in aseptic filling such as Production, Mictabiolngy 4 one Quality assurance and Maintenance personnel must be included in at satisfactory Media Fill per year. The detailed training of the personnel for-entty and exit procedures as well as aseptic behaviour in critical area will be ensured as a prerequisite for taking part in Media Till activity, Operators may perform non-critical operations, such as pass through of trays of enapty ancl filled containers, prior to” participation in a process simulation providing; they are supervised by a qualified) operator throughout the process. All other operations are considered critical for operator qualification 13.0 ABBREVIATIONS % Percent - 7 {°C __| Degree | cGMP | Current Good Manufacturing Practices [PDA —_ [Parental Drug association PICS ____ [Pharmaceutical Inspection Convention Scheme | BMR | Batch Manufacturing record USFDA. ____| United State Food and Drug Administration HVAC —__| Heating Ventilation Air Cor ig System _ cM Quality Control Micro Hrs | Hours = ‘SOP Standard Operating Procedure | cRAB______| Closed Restricted Access Barrier | LAF [Laminar Air Flow - | Form No,: SOP/QAD/0002-0037.002 CONFIDENTIAL QA Signayyyysnd Date L_ wane” Prin INTIPSEIMLFO- 0214; Poa By: tendra Kum; Pred On 1008/2020 13.08; Copy Nt aft: Copy To Quality Assrarce (Genera, Pinter Nene: MOA PRINTER 4245 @; Oxvr Name: Canon RABY 42454251 UFR IIKPDHITENDRAKU). Pit Type Isuet CopyIssuance Code: INT/PSB/ALF/01-021/001 Issued By: Hitesh.Kumar Issued On: 10/09/2020 Ny FRESENIUS Fresenius Kabi Oncology Ltd. KABI Kishanpura, Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED FILLING PROCESS CYTOTOXIC STERILE INJECTABLE FACILITY (LINE-I) Documenr No: PSB/ALF/01 REVISIONNo.: 21 Page 29 of 29 {CTIVE DATE: O7S¢ oPo IPQA. ___[In-process Quality Assurance ™ a Nitrogen O2 | Oxygen - CQ, | Carbon Dioxide re NA Not Applicable CAPA Corrective and preventive Action ik ___| Out of Specification 7 7 Total Organic Carbon ‘Altemnative Thioglycolate Medium 14.0 ANNEXURES Annexure-Il : Sampling Plan Annexure-IV : Matrix for Media’ Fill Intervention Execution with Validated Frequeney and Tracking Form No: SOP/QAD/0002-0037.002 CONFIDENTIAL pao why aerate ete ad etre ence ac aricreeae e, Se ener tet tampa es ce oteenes a1. INT/PSBIA Issuance 311/001 issued By Hitesh Kumar issued Or’ 09/09/2020 i FRESENIUS s Kabi Oncolog t N kag . wwpara. Baddi PROCESS SIMULATION PROTOCOL ASEPTIC LIQUID AND LYOPHILIZED PILLING PROCESS CYTOTONIC STPRILE INJECTABLE FACILITY (LINE-L) Documenr No: PSB/ALPA Revision No.: Page 1 of 29 EFFECTIVE Dat ASEPTIC PROCESS SIMULATION (MEDIA FILL) PROTOCOL FOR ASEPTIC LIQUID AND LYOPHILIZED MANUFACTURING AND FILLING PROCESS Revision Index Revision | Date Reason for revision Revision as per change control no, CHG-Baddi 2-2014-0211: - 1. Addition of Annexute-V, (List of interventions). 02 |26 Apr. 2014) 2. Revision of Annexure-IMl, (to remove 03 ml pack size from media fill matrix) 3._ Addition of new interventions INFI-21 and INH-22 in Annexure-IV and V. Changes made as per change control no. CHG-BADDI 2-2014-0487 to include 03 | 11Sep.2014 |recommendation of CAPAs (Ref. No, CAPA-Baddi2-2014-0221, CAPA-Baddi2- 2014-0244) Changes made as per change control no. CHG-BADDI 2-2014-0635 to include 04 [27 Nov.2014 |; ecommendation of CAPAs (Ref. No. CAPA-Baddi2-2014-0433) /Revision as per change control CHG-Baddi 2-2015-0498:- 1) Incubation period of media fill vials from 21 days to 14 days that is; Initially 7 days at 20-25°C in upright condition than at 30-35°C in inverted position, for rest of the 7 days. 2)Frequency of inspection of media fill vials from observation on 3rd , 7th, 10th . 14th & 21st to 7th day of incubation & 14th day of incubation 05 |30 July 2015 Revision as per change control CHG-Baddi 2-2015-0859:- 06 Se (Container closure integrity Test removed from the protocol. Annexure-II (Sampling plan) revised to exclude container closure integrity test. ‘Changes made as per Change Control no. 23213 07 29 June 2016 1. Usage of commercial grade PPM in Media fill batches. 2, Usage of Alternative Thioglycollate Medium instead of Normal FTM. 3._Removal of forceful simulation of Power failure and Particle count excursion Form No.: SOP/QAD/0002-0037-002 CONFIDENTIAL Pit kt INTIPSBIALFI04 0111; Ped By ena Kumar; Printed On: 1008120200818, Copy Nao 1: Copy To: Qualty Assurance (Genes PrnterNeme: MOA PRINTER 4245; Orer Name. Canon RADY 42454251 UFR IKPO-ITENDRAKU); Prt Type: sued Copy