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2026년 11월 1주차 규제뉴스

There is a failure to identify a root cause and implement corrective actions to address repeated incidents of alarms, in addition to not following procedures regarding alarms, specifically, a.

According to MLN-RPT-000381: “Summary report for GMP environmental monitoring: (b) (4) (©) (4) effective 07/13/2023, there were a total of 19 non-viable particulate alarms during batch production in the presence ofpersonnel in Gride?™space from ; (b) (4) , and 40 alarms for non-viable particulate in the absence ofpersonnel from (b) (4) . The source ofthese particulates has not been investigated. b. According to MLN-SOP-000188: “Monitoring ofparticles classified area (Bresso)", effective 04/14/2023, in the event of an out of action non-viable particulate result during operation in Grade" “space, any unprotected exposed material in direct contact with the product must be removed, the hood air velocity must be verified, and the hood must be sanitized. It is not clear if the procedure regarding out of action result for non-viable particles was followed since these actions were not verified during the investigation nor documented in the batch record.

Failure to follow procedures, specifically, a.

According to MLN-SOP-000065: “Behavior and Hygiene for Aseptic Areas ofAGC Biologics”, 05/31/2023, operator movement in a Grade” space should be slow and deliberate and GMP manufacturing operators have to sample gloves before replacement. During the sterile filtration and filling of lot (b) (4) batch | (B) (4) , the Grade ™operator working in the BSC was observed executing rapid movements. Additionally, an operator was observed "

Corrective actions and preventive actions (CAPA) implemented are not always being documented per the CAPA SOP COMM-QA-076.

For example, a. Deviation IR-0111 is regarding failures in the sterile packaging of~ (b) (4) © sterilized critical supplies, which resulted in modified packaging configurations as captured in Change Controls GMP-CCR-434. However, no CAPA was initiated. b. Deviation DEV-0602 is regarding personnel monitoring samples being discovered by the contract lab in the sample receipt area (i.e., “garage of disposed materials” per contract lab deviation DEV2018_0042) one week after receipt. As a corrective action, the contract lab tested the samples and found negative growth on any of the plates, including the control plates. No growth promotion testing results, if performed on these plates, was reported. No CAPA was initiated to capture the corrective action taken and no addition corrective and/or preventive action was deemed necessary. c. Deviation DEV-0556 is regarding incorrect lot number of fetal bovine serum (FBS) being recorded on Thymus Organ Medium (TOM) Batch Record due to failure in secondary verification by the operators. The error was not detected during QA review but was discovered 25 days later by the operator who initially reported the incorrect number. As a corrective action,

Report # DEV-0723 019 documented a deviation for GMP lots GMP-™@, Gmp-®4 Gopwhere final product mycoplasma test results provided by contract testing lab were determined by the contract lab to be invalid.

GMP lots Gmp-@ GMpP-@@) GMP-M@ were transplanted into the intended patients on April 12, April 15 and April 19, respectively. Repeat testing on retention samples of all three lots were negative for the presence of Mycoplasma. Root cause was determined to be an error on the part of the contract testing lab.

The environmental monitoring program is deficient in ensuring that the cleanrooms are operating in a state of environmental control.

For example, a. The 2017 EMPQ performed following the modifications to the HVAC system is inadequate as it was limited in the number of samples collected and the type of sampling performed: (6)(@) sampling was limited to per location for both viable and non-viables; however, only non-viable sampling was performed ( for @@) (BAY per location under(H)4)Nconditions. b. The routine environmental monitoring program does not include (6) (4) monitoring for active air viables and non-viables in the ISO7 and ISO8 areas. c. A single viable active air sample ( (b) (4) 5 is collected during the aseptic processing in the BSC aso™ during the manufacturing process, which can take up tol (Bb) (4) . d. Routine surface sampling for viables is not performed for the ISO7 manufacturing area and the associated passthroughs under |(B) (4) conditions. e. There is no surface sampling ( (b) (4) 2) in the biosafety cabinet (ISOM used for the aseptic manufacturing of the product. f. There is no surface sampling, or sampling of the(b) (4) in the incubator after the manufacturing of a lot. The incubator is located in manufacturing room (®)(4)(1SO 7) and used for the in- process incubation ofthe product up

The current cleaning procedures used in the cleanroom have not been qualified.

a. Disinfectant effectiveness studies have not been performed for the sanitizing agents routinely utilized in the manufacturing facility. b. The procedures established and followed for cleaning the facility are inadequate; for example. i. Procedure GMP-SOP-060 is deficient in that it does not describe in detail the process for cleaning the(b) (4) POY) YBSC: specifically, during observation of the simulated manufacturing operations, we noted the following: a) the operators cleaned the whole BSC with one surface ofa disposable sterile (b) (4) pad using an(b) (4) mop. b) the cleaning solution was dry before the {)(O)(4)) set time required in the procedure. c) one wipe was used multiple times for wiping several items before placing them in the BSC. ii. Procedure GMP-SOP-066, includes two different procedures for cleaning the (SYA) incubator even though only one procedure is used at the facility. iii. Procedure GMP-SOP-006 states that(b) (4) cleaning is required for the cleanrooms (floors and surfaces) even though the production room and supportive areas are used(b) (4)for manufacturing product lots. iv. The cleaning ofthe passthroughs is not performed before or after use. It is cleaned

The existing alarm system and its implementation are deficient.

Specifically, a. Temperature probe in freezer(b) (4)used to store released critical reagent, Thymus Organ Media, is not placed in the worst-case location as determined during equipment qualification. b. The firm did not perform IQ/OQ of the alarms and probes installed after 2014, including those installed in freezer ((b) (4). refrigerator incubators (b) (4)and and BacT instrument. The equipment is used for manufacture and release sterility testing of and storage of critical reagents and source material. c. The firm failed to provide records ofpreventive maintenance for any of(b) (4) alarms used for monitoring of differential pressure, temperature, and humidity within the facility, distribution system, as well as the following critical equipment: ®/@) incubators (®)(4) levels and temperature), freezers and refrigerators used for storage of critical reagents, source material, and retention samples, and BacT instrument used for release sterility testing of the product. d. The alarm notification and response are not adequate. Per deviation IR-0114 dated December 5, 2017 and a corresponding (b) (4) log for events #7285 and 7286: On December 3, 2019 temperature within the incubator was o

The Quality Unit oversight of batch record review is deficient.

Specifically, a. A review of the GMPPM batch record, Preparation of Final Product (GMP-SOP-031, FRM" dated April 19, 2019) and the Roomew incubator use log form does not include: 1) verification or periodic recording ofe)) concentration and temperature during this time period, and/or 2) inclusion of the (6) (4) graph printout, which shows continuous monitoring of(4) concentration and temperature over the 17 day time period, 3/26/2019-4/19/2019. The manufacturing process requires (©) 4) concentration to be maintained between(B) (4) and the temperature (6) (4) during the incubation period.

Procedures and process contro] designed to prevent microbiological contamination of drug product are not established with appropriate acceptance criteria.

Specifically, a. GMP-SOP-060, “Operation and Maintenance ofthe! (BY (4) Biosafety Cabinet”, dated July 29, 2019, states certification is performed every |)(b)(4)9 for every BioSafety Cabinet (BSC). Section 8.11.3 of GMP-SOP-060, states the airflow velocity, aerosol leak, airflow smoke pattern, light intensity at work surface, and particle counts are certified using standards traceable to the NIST, but does not include the acceptance criteria. Additionally. the acceptance criteria for airflow uniformity was not specified but was calculated in the most recent Bsc (Dyan certification, dated April 16, 2019. b. The Bsc System Qualification Summary Report (GMP-2019-025-E), dated March 25, 2019, Ongoing Monitoring, did not include acceptance criteria for Airflow Velocity and Airflow Uniformity, which were calculated in the supporting Bsc. (b) (4)Testing Results from October 2018.

The Quality Unit does not have adequate contro] over critical materials.

For example: a. A new container closure was implemented before approval by MC3 Quality Assurance for use in the MC3 facility on July 27, 2019. It was used for the manufacturing ofGMP lots GMP®@@) Gmp.@@) cGMP @@ initiated beginning on April 27, 2019. b. Sterility of critical product-contact equipment sterilized by external vendors (i.e., sterile Starclick specimen final container closure system, tissue slicer, is not being verified through periodic sampling of incoming lots. c. The firm does not have controls in place to ensure that critical product contact supplies, such as— (b) (4)

The inventory control of raw materials is deficient.

Specifically, a. Per deviation DEV-0455 dated August 22, 2016: thymus organ media lot TOM (BY (4) was conditionally released without sterility testing results due to insufficient volume of released TOM available to complete manufacture of lot GMP@@ b. Expired supplies were used in manufacture ofthymus lots GMP PM er deviation DEV-0667 dated February 4, 2019). c. The control system to prevent mix-ups for materials, components, samples, and containers, intended for use in the (b) (4) manufacturing process does not include inventory records that show the current real-time inventory for refrigerator ((6)(4)) and freezers (D) (4) and(6) (4) used for storage of critical reagents, source material, retention and QC samples. d. Materials are not being properly segregated. Freezer (D) (4) used to store(6) 4) retention samples is also used to store retention samples for other products manufactured in the facility, along with research materials. Aside from the /(5)(4)9) mycoplasma retention sample log on the front of the freezer ((B)(4)). there is no log of the contents of the freezer.

A means of assuring data protection has not been established for the following computerized system.

There is failure to maintain a backup file that is assured as secure from alteration, erasure or loss through keeping hard copy or alternate systems. Specifically, the current GMP-EQUIP-021, Operation, Maintenance and Sterility Culture using the BacT/Alert dated September 27, 2018, does not include criteria for back up of data from a (6) based data management software application used for the BacT/ ALERT System, to removable back-up media (DVD, USB) and verification of back up to a networked path.

Performance qualification (PQ) of numerous critical equipment was not completed prior to conducting process performance qualification runs (November 16, 2018 — January 17, 2019) and aseptic processing runs (August 2018).

Specifically, a. PQ ofthe 4) incubators,— (b) (4) and(b) (4) used to incubate the thymus tissue slices, was approved in March 2019. b. PQ ofthe)distribution system, used to maintain ©)@) level inside the incubators, was approved in March 2019. c. PQ of biological safety cabinet, used during the processing of(b) (4). was approved in March 2019.

Critical reagents are not always qualified prior to release for use in the manufacturing ofU.S.

licensed product. SOP-0069233, entitled “General Procedure for Processing and Qualifying Critical Reagents”, v13.0 is not always followed. Specifically,| ... are critical reagents designed by the) mS tst—“‘—s~s~s~s~™CCCCS*@S However, critical are not qualified priortouseinthe) mw ~SSsti<‘<«é‘;é‘s*~SCSCS tO determine iff the oe the genotypic and phenotypic properties of the ila ‘

The bacterial endotoxin procedure is deficient to ensure adequate detection of endotoxin in the samples.

A. Analytical method used to detect bacterial endotoxin in|~ _, LATV Monovalent Bulk (MVB), and LATV Finished Product are inadequate. Specifically, SOP-0067568, entitled “The Endotoxin Testing ofProduct b f= | ’, V40.0 is deficient in that the mixing - requirement for the) .. sample! and subsequent .._| preparations are not described. Without qualified mixing, your firm lacks assurance that endotoxin can be adequately recovered and detected when present in the samples. B.are being used to store - |and MVB samples. Endotoxin can adhere to | ww sé. gitve false negative test results. Your firm conducted a study in 2016 to show, aw |__| Suitability in recovering endotoxin spike at 5 EU/mL. However, this study was deficient, it did not, for example, demonstrate spike recovery at a lower endotoxin level of which is the action limit for MVB.

Your firm did not notify the license holder ofa deviation that may potentially affect the quality of a distributed drug product.

There is a lack ofvalidation to support on assigned expiry.

Specifically, |__ im =eg® currently appliedto| .. _—_|used within the manufacturing and QC areas. In 2017, your firm used data provide by the vendor to support the vo You did not : conduct your own validation to support the assigned expiry. For example, you did not demons tate|- | while ~ being used by your personnel following your manufacturing procedure within your facilities, can remain sterile at thewm XY. ss TF

The batch production and control records are deficient in that they do not include the identity ofmajor equipment used.

Specifically, A. Your firm manufactured and released GAMMAGARD Liquid ® and Cuvitru ® in the (b) (4)_ filling line@ . Filling parameters are embedded in ‘ ” and executed by @@) . The ‘ ” which controls(b) (4) parameters such as fill and filling), are not documented in the batch records. For example, ‘ ” used to manufacture GAMMAGARD Liquid ®, lot no.(b) (4) . manufacture date 7 October 2024 is not documented in the batch record. B. Your firm manufactured and released Glassia ®, used to treat lung problems (emphysema). alarms, such as fill (b) (4) or (b) (4) . generated during filling in filling line@) are not always reviewed/addressed/evaluated during batch record review. For example, alarms such as fill(b) (4) and(BY(4Y) captured by the(b) (4) filling line, during the filling process of Glassia manufacturing batch record no. BE23E022, release date, 4 July 2024, was not evaluated and reviewed.

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not followed.

Specifically, on APR-03-2025, while observing filling operations for delandistrogene moxeparvovec- rokl (ELEVIDYS) drug product batch number| .. | your operator did not follow SOP 05.0105 (titled “Aseptic Techniques andPersonnel Behavior in the Aseptic Filling Suite”, Revision 05, Effective Date: OCT-05-2023) while performing) ..___|checks and an intervention requiring repeated opening of and reaching into the RABS surrounding the filling equipment during filling of product vials in the Grade. area. For example, A. The operator was observed to not perform frequent glove (hand) sanitization. B.The operator was observed to repeatedly perform rapid movements and to not move slowly and deliberately. C.The operator was observed placing their hands, including while holding i to manipulate - vials,| aw -land did not keep their hands at ua times, and did not sanitize their hands oun them ‘om when making an adjustment

Buildings used in the manufacturing of a drug product are not maintained in a good state of repair.

Specifically, on APR-03-2025, while observing filling operations for delandistrogene moxeparvovec- rokl (ELEVIDYS) drug product batch number wna | esas observed on the floor of room |- | a personnel | -. | where operators perform)... and si the Grade. filling area. On APR-08-2025, you clarified that you had determined that the) .. on the floor was due tothe floor) wu the floor of the personnel... during) ... | ‘sik of the|- | Onthe same day, you provided a work order (4MNT-63353-2025) opened on APR-07-2025, to remove the|..__|and adjust the floor... to prevent future) .. from occurring.

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Specifically, Your firm failed to open a deviation for approximately 46 days after observing and failing to adequately document atypical cracks in| glass vialsusedto Shingrix. Yourfirm's supplierrequest for investigation report from dated 3-24-23 revealed a weakness in the bottom of the glass vials that leads to breakage with increased stress fromyour manufacturing process. Your firm utilizedfs of (ea vials produced before 4-24-23 to manufacture approximately/™batches (®)@) vials) of Shingrix released to the US market . For example, Raw Materia Aseptic Period ial ID Batch Inspection {Quantity Date Delivered 2022 30 022 | 2022 l ) 2022 | 2022

Procedures for the cleaning and maintenance of equipment are deficient regarding inspection of the equipment for cleanliness immediately before use.

Specifically, On 07 March 2024 during the walk through ofthe aseptic filling area in Building (6)(4) Lyo Line8 where US licensed Shingrix vaccine is filled, the(b) (4). covering ofthe vial (bY) was observed to have splinter-like cracks. The cracks were observed directly over the location where the vial enters the) (b) (4)

Reserve samples from representative sample lots or batches of drug products selected by acceptable statistical procedures are not examined visually at least once a year for evidence of deterioration.

Specifically, Your firm does not perform an(6) (4) inspection ofyour reserve/retain samples for Shingrix vaccine. Adverse drug experiences which are both serious and unexpected have not been reported to FDA within 15 calenda days of initial receipt of the information by your firm. Specifically, A. A total of eighty-four (84) 15-Day Alert reports were reported late (after 15 days) for Shingrix Vaccine (BLA125614). Example of the 15-Day alert reports submitted late to the FDA include but are not limited tq the following cases: Case ID Initial GSK Receipt [Initial Date Submitted to [Number of Calendar Date FDA Days Late r (by 4) pay 2023 (yay 2024 (6) (4) 2023 b) (4) 2024 ) b) (4)2023 b) (4) 2023 ; (bp) (4 b) (4) 2023 y2023 | b) (4) 2023 a) 2023 bs SSC*d (bya) (8) 4) 2023 )(4) 2024

Inadequate investigation was performed on thehe action level excursions on %(b) (4) of theme) I srom the during Jan 25 —Mar 8, 2023 recorded in the qualification report of the from : a.No deviation was initiated for these consecutive action level excursions on %(b) (4) of the (6) (4)) as per SOP-0067565.

b.The rejected (Bb) (4) were not manually inspected to verify that the(b) (4) were in poor quality prior to concluding that the root cause was due to the malfunction of the light and camera. 4.Your firm’s batch record is not designed to capture critical information in support of 4 which are used in the production of flu vaccine monovalent : Specifically, Master Batch Record, MABR-0009649, entitled (by (4) v10.0, was used to document step. monovalent bulk (Bb) (4). strain serotype H1N1, strain A/Norway/3 1694/2022 V1, is not designed to capture all verification steps performed during

Employees engaged in the manufacture and processing of a drug product lack the training required to perform their assigned functions.

Specifically, training of employees who work in cell therapy manufacturing is not adequate a.On 16 DEC 2024 video recording shows employee dropping paper batch record pages on the floor of a Gradelroom and subsequently returning the paper records to a table work surface and continuing with assisting to place materials into a Grade b.On 1 and 16 DEC 2024 video recording shows employees working with their hands in a Grade wiped their hands and work surfaces with a sterile wipe immediately c.On 1 DEC 2024 video recording shows an employee working in a Grade 'Pass processing suite place on top of paper batch records prior to placing the units in a cell culture d.As of 7 FEB 2025, your Senior QC Manager of Microbiology had not completed job specific training on revised SOPs such as: i.CGM-SOP-00042, Investigation of Environmental Alert Level Excursions, Action Level Excursions, Contamination Recovery Rate Excursions and Adverse Trends (Revision 03) ii.CGM-SOP-00027, Plate , Enumeration and Microbial Identification (Revision 02) iii.CGM-SOP-00241, Operation of the (Revision 01) e.Training status is not adequately monitored to ensure employees are up to date on current training requiremen

Master production and control records lack complete manufacturing and control instructions.

Specifically, as stated by your Senior Manager of Quality Control Analytical, no established procedures exist regarding specific handling or loading patterns (and subsequent removal) of up to 50 (b) (4) from during manufacturing operations occurring in 2024. have a (b) (4) WEI/ on the of the unit and are used in the manufacturing of i cellular therapy products.

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile did not include adequate validation of the aseptic process.

Specifically, batch records for aseptic process simulation do not adequately describe steps to fully simulate manufacturing processes for cell therapy products. APS protocol #QA -00214 rev 6 (b) executed in Januaiy 2024 1 does not include a specific step for placing units (4) as is done for commercial production.

Buildings used in the of a drug product are not maintained in a good state of repair.

Specifically, we observed facility deficiencies related to the manufacturing of cell therapies in cryostorage i rooms and locker/change rooms for personnel, as follows: a.On 3 FEB 2025, we observed visibly dirty and rough floor surfaces in the (b)1,4) fmished product and intermediate product storage room --."

Records fail to include an individual inventory record of each component and drug product container with sufficient information to allow determination of any associated batch or lot of drug product.

Specifically, raw material and finished product inventory is not adequately controlled and/or withheld from use until appropriate in relation to cell therapy manufacturin as follows: a.On 3 FEB 2025, we observed missing (labeled ) inside as compared to electronic inventory of mished product in software. Additionally, the software indicated the (") holding 19 of cryostorage where thee is only b.On 3 FEB 2025, we observed missin labelled among others) inside storage. c.On 3 FEB 2025, we observed C retain stora or the name/identification of those

Your firm’s Quality Unit lacks a procedure/policy that details requirements for the following: An\ is used for receipt of, for example, deliveries ofyour firm’s r here is no procedure or policy in place that addresses the potential for deliveries that may be ) (4) or where possible storage in(b) (4) | may occur.

Lack of oversight of a sterilization firm: * Sterilization of CellTrans equipment is not performed according to the validated process. Specifically, it was found that the ith CellTrans equipment and other hospital equipment based on (b) (4) and available e validation report only describes load items from CellTrans. * Sterilization load can be re-sterilized, however only documented final sterilization information is forwarded to CellTrans, initial failed or incomplete runs are not required to be reported to CellTrans as of this inspection.

The current deviation reporting procedure was found deficient, for example: * During review of the(b) (4) system for monitoring of(6) 4) temperature and humidity, it was found that temperature excursions are not properly documented and reported as deviations.

‘Biers filters were found to have during routin EPA filter certification. However, there is no documentation that a(6) (4)performed whether the percentage ofarea (6) (4) was

Final product lots were released with incomplete batch record or failed lot release specifications.

The batch records for these lots were part ofyour BLA submission. Specifically Lots were released for with incomplete information of purity tests in the batch record. Lot was released for ith failed potency test.

Regarding your firm's current aseptic process observed during inspection we noted the following deficiencies: * Sterile equipment was exposed to Iso(B)(4) before transferring into the (BD) (4) (b) (4) sok for use in your firm’s aseptic process.

* An ver exposed sterile equipment during a process performed within a NS , ° a(b) (4)study was not performed for any ofthe that are used for aseptic processing.(b) (4) study performed for the ISO(1b) (4) tailed to include conditions. + Equipment and other items were observed in the(1B) (4) partiaty blocking the ISO(b) (4) * The ISO(b) (4) contains equipment that are not used for processing that may interfere with room cleaning and impact room quality such as the following: that have not functioned for many years(D4) | no used for processing, an na wall.

Your gowning procedures are deficient.

Specifically, * The SOP, Gowning: Entering and Exiting Procedures for the Islet Isolation Facility, MFG-SOP-201, section 8.1 “Gowning Process: Preparation Step,” requires changing from including the oa: part ofthe preparation. The (6) (4) include and and ere is no assurance that have not been contaminated by the nvironment. The SOP also requires that(b) (4) ve stored in an which is done after ° (b) (4) _gowning is necessary to work in ISOBevirnment to perform aseptic manufacturing steps, as per the , sterile Gowning Technique, MFG-SOP-221. Your firm does not conduct training in, nor have a gowning qualification program for, such sterile gowning of personnel as described by the SOP.

equipment qualification is deticient.

Specifically, the qualification was not performed under the conditions of use and the verification of@ integrity was limited to visual inspection of the

Effectiveness ofthe(b) (4) used for facility and?) caning was not demonstrated.

effectiveness study design did not include acceptance criteria to demonstrate required id not

CellTrans does not require periodic verification of(B) A)cleaning used w(D) (4) No such verification has been performed since 2018 when the initial cleaning validation was completed.

The Quality Unit oversight of(b) (4) is deficient.

Specifically, * Certificates of Analysis from a manufacturer of medi hat are used in the production of the product CMRL 1066 , and who also manufactures (HEPES and CMRL 1066 Transplant Solution). state that these solutions are not sterile erilily Assurance Level (SAL) 0 . All such (6) (4) specifications have been approved by your firm’s Quality Unit and vere released for use in aseptic operations. * Your firm uses the SOP, Material Management Program, QAL—SOP—402, to manage the acceptance of(b) (4) . such “(b)(4) This SOP is linked to specifications that require sterility testing of | Both the material management SOP and specifications are approved by your firm’s Quality Unit. An sterility method is used as part ofacceptance of . The related sterility method validation only addressed edia nd one However, the validation is also used to support the sterility testing of other and media that are used in production or are part of the final product. Establishment ofthe reliability ofthe(EA serptirs report ofanalysis is deficient in that the test results are not appropriately validated at appropriate intervals. Specifically: * Your firm has not established the reliability of suppliers’ Ce

Your firm has not assessed for impurities regarding single(b)(4) parts cs.(b)(4) and sterilize hat are used in manufacturing ofthe product.

* Your firm has not assessed for impurities for your drug product containers: (Specification (Specification Observation | 1 Your firm failed to establish (PY ®ompie program and did not retain samples for drug products for

Carbon dioxide gas used in incubator is not routinely monitored for chemical quality, oil, or particulate levels and no COA is available to describe gas quality.

The responsibilities and procedures applicable to the quality control unit are not fully followed.

Specifically, A. The review and approval process of the qualification of major equipment is deficient. Requalification of the’ ——(b)(4)—————_dused in| (by(a) |Suite, Room performed in March 2023, failed, which led to the initiation of a significant investigation, QN 201091153, on 03May2023. The BCG Vaccine manufacturing process has two (2) Critical Process Parameters (CPP) associated with the b)(4 and b)(4 ). The| (4) |is utilized to cool the (b)(4 — (b)(4) —_ prior to use during the) (b)(4) |Process. ification was performed on 9Jun2023 using the protocol (b)(4) L b)(4 . The associated investigation was closed on 15Jun2023, and equipment was released for manufacturing, without confirming that the generated data were within the acceptance criteria. Quality review and approval of the executed re-qualification protocol was completed only on O8Nov2024. During the review process, the firm identified that the execution performed on 9Jun2023 failed due to | |data points reported outside the acceptance criteria of the protocol. The delay in Quality review process led to utilize the equipment in its failed requalified state

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile did not include adequate validation of the aseptic process.

Specifically, Airflow visualization studies (Smoke studies) were not performed for the following inherent and corrective interventions performed during the aseptic) # process ofBCG Vaccine. A. On 20Nov2024, during the fill line setup ofBCG Vaccine batch (b)(4) using aseptic (b)(4) core | we observed a Grade) |operator using an empty tray for removing the entire vials from the vial! (b)(4) | as a vial storage | | was accidentally slipped and fell over the vials. This intervention was never evaluated in the air flow visualization studies. B. The} (6)(4) |changeout is a corrective intervention during the) (4) process. This was never evaluated through smoke studies. C. On 20Nov2024, during the) (6)(4) |set-up for BCG Vaccine batch | (b)(4) | the had alignment issues. The Grade) 4) |operator entered inside the protective enclosure around the

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed.

Specifically, On 20Nov2024, during the) (b)(4) |process ofBCG Vaccine batch_ (b)(4) using aseptic, (b)(4) we observed the following: A. Grade | (4) (Operators involved in| 4) assembly set-up and ()(4) joperation lacked deliberate b)(4 B. During adjustment of|(b)(4)|, the Grade ®) operator’s arms and upper torso were observed reaching over the b)(4 C. | (b)(4) |used for troubleshooting the non-viable particulate | (b)(4) |alarms were not discarded after touching the) =—(b)(4) ~=——sS: The’ (b)(4) |was placed near other (b)(4) |which were utilized by Grade' |operators for opening the (b)(4) of b)(4 D. (b)(4 inside the Grade’ joperator’s goggles was observed.

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Specifically, a. The firm has initiated about 9 deviation investigations pertaining to exceedance of « (b)(4) | (b)(4) P defects (Critical defect). This is a critical defect with an action limit ofNMT| (b)(4) (NMT

Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use.

Specifically, The (b)(4) used in| (b)(4) |Suite, Room |© |is utilized to |» |the [ (b)(4) for (b)(4 . The firm’s requalification performed in 9Jun2023 using the protocol b)(4 was designed to study the criteria for | (b)(4) , while in production, the time allowed is a b)(4 . The requalification strategy is not designed for the (b)(4) to ensure that the] 4) are cooledto| = (b)(4) of (b)(4) | The firm manufactures about‘© [BCG vaccine batches | (b)(4) utilizing this equipment.

Equipment and utensils are not maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically, From 03/31 to 04/07/2023, during annual requalification of the b)(4 (| (b)(4) }, the equipment underwent maintenance to replace and (b)(4) 4) sed during production. However, | (b)(4) remained in service throughout this period. Sterilized components from the | (b)(4) |were used in the manufacture and release oftBCG batches for distribution.

Manufacturing equipment is not qualified for its intended use.

Specifically, the sterile). ofthe owe drug product bulk requires monitoring ofthe[= fs a critical process parameter. The} .., is assessed and documented based on the display shown on the peristaltic pump. However, there is no routine maintenance, calibration or recertification program established for the peristaltic pumps (Equipment ID used during==... ~S ~—S—Ss=«SY tag produit proces performance qualification batches (#sas . There is no independent confirmation ofthe accuracy ofthis |~ | - |.

Routine environmental monitoring program is deficient.

Specifically, the 4. = on the filling system | are used in an ambidextrous manner during the filling of theow SSS« rg product. However, viable surface sampling of ox isnotperformed.| = gays(asi(atsé‘(isé‘is;ésésS*‘s*S monitored accordingto the Document No. 03.1005 Revision No. 09 Effective date 25 Jul 2024 titled Environmental Monitoring Program-B WI.

Written procedures for records retention, archival, and retrieval of controlled documents and records are not followed.

Specifically, Document No. 02.0066 Revision No. 02 Effective date 08 May 2023 titled Records Retention, Archival and Retrieval requires that Document Control Archivist maintain a log of including the “i database. However, on 22 April 2025, the Document Control . _| staff was unable to provide a log of the win for the physical executed batch records ofthe) sam» ~=~—S——S—~*~™S—«Srg produicett process performaannce qualification batches (#s ws and |

Procedures designed to assure that correct labeling are used for drug products are not followed.

Specifically, according to Section 6.7, “Label Printing” and Section 6.8, “Carton Printing” in SOP QU- OPE-0204067, “BIVV001, Altuviiio, Finished Goods, Labeled Vials, Various Nominal Potency,” version 6.0, effective on 29Oct2024, the “Biological Activity - Assay Activity” or “Lot Potency” value in [U/vial specified in Form QU-FOR-0141268, version 1.0, “Altuvitio Finished Product, 250IU- 4000IU/Vial Nominal Potency, US Specifications, COA” is the potency value to be printed on labels and cartons for Altuviiio Finished Product. However, the potency value for Altuviiio Finished Product 2000IU Lot No. EY0330 was incorrectly transcribed from the Certificate of Analysis, and this incorrect value was printed on the finished product labels and cartons. The potency for Lot No. EY0330 was labeled using the value for “Biological Activity — Specific Activity” (2132 IU/mg) instead of the value for “Biological Activity — Activity” (1811 IU/Vial). Lot No. EY0330 (®)@) vials total) was released by the firm on 09Dec2024, of which (5)(4) vials were shipped to a distribution center in Reno, NV. The error in potency value was not detected by the firm until 11Feb2025 when the batch record for this lot

Examination of packaging and labeling materials for suitability and correctness before packaging operations is not performed.

Written records are not always made of investigations into unexplained discrepancies.

Specifically, protocol 64-0096 [Titled “Protocol for the Real-time Process Validation (PV) for the Transport of BIVV001 Finished Goods via (b) (4) from Sanofi NBO (Northborough, MA) to Sanofi Distribution Center (Reno, NV)] has not been actively executed since 23Aug2024. Specifically, after 23Aug2024, there have been no activities related to the execution of the protocol. No protocols deviations have been opened to investigate the issues that impacted completion of the study. frscila M Pastrana

There is a failure to thoroughly review a batch or any of its components to meet any of its specifications Whether or not the batch has been already distributed.

Change Control PR1257198. opened on 6-Dec-2017 and closed on 21-Sep-2018, did not include a sufficient assessment on a critical material, used for manufacturing of Gammagard Liquid (GGL) and Hy Qvia. (item code (QGP is used in the PABA steps. Specifically. Change Control PR1252801 was opened on 17-Nov-2017 (closed on 23-Jan-2018) to remove the — (b) (4) | code from the Bulk Drug Substance (BDS) Bill of Materials (BOM) and for use of an alternative IUBYRAYH source of(b) (4) (BY 4 After implementation of this corrective action. final container lots were produced withSQM levels of rejects due toISA Change Control Record PR1257198. closed on 21September 2018. documented a decision to use the en (°) hC) as a backup ofthe for the manufacture of Gammagard Liquid and HyQvia. Since early 2019, an increased level ofvisibleSS) was observed again during the (JM) visual inspection for Gammagard Liquid and HyQvia lots manufactured using (YA)trom theAY. The Were identified as A possible root cause was determined to be related to the implementation of the configuration. As a preventive action. the was replaced by the (64) — (b) (4) for manufacture of Gammagard Liquid and HyQvia on April 30, 2019.

Four non-medical broken vial US complaints for Gammagard Liquid were discovered in April.

May 2017 and Were not submitted as BPDRs until February 13, 2018. Specifically. a) PRI194575. dated O3 April2017. reported 3 leaking damaged vials of Gammagard Liquid (10%. 10g. US). b) PR1198237. dated 20April2017. reported customer received one Gammagard Liquid (10%. 10g. US) broken vial. ¢) PR1205477. dated 24May2017, reported one Gammagard Liquid (10%. 30g. US) leaking/broken vial. EMPL AVFRISRHRNATIIRFo— Ss

Quality Investigations were not conducted per SOP-2024-Adverse Event Quality Investigations.

dated March 23. 2018 for the following reported viral transmission and fungal infection events. The causality assessment in each case was assessed as possible by the company ‘manufacturer, and the lot numbers were known. Specifically. a) Suspect Adverse Reaction Report. Case) (b) (4) dated IGN Gammagard Liquid Immunoglobulin, Lot GG. reported fungal infection. The company comment assessed the event of Fungal infection as possibly related to Gammagard Liquid. b) Suspect Adverse Reaction Report. Case(GG dated IGG Gammagard Liquid Immunoglobulin, Lot— (b) (4) reported that patient contracted Hepatitis B trom Gammagard Liquid (was negative 3 years ago). The company causality assessment assessed the event Hepatitis B as possibly related to Gammagard Liquid. c) Suspect Adverse Reaction Report. Case— (b) (4) dated — (b) (4) Gammagard Liquid Immunoglobulin. reported Hepatitis C in a patient. Several Lots but not limitedob)4 DOIG) were used trom 60012016 to 25May2017, The company comment assessed the event Hepatitis C as possibly related to Gammagard Liquid. _

Written procedures are not established for evaluations conducted at least}...

__to review records associated with a representative number of batches, whether approved or rejected. Specifically, your firm does not adequately conduct -.. product reviews ofrs) | to account for evaluating trends of quantitative data for vo batch release. For example, the following data is not trended: (b)(4) Written procedure - instructs that the firm "will continue to monitor the validation status through: ... production and/or product data to monitor trends, demonstrate that the process is in state on[sic] control and can consistently produce product within desired quality attributes."

The establishment oftest procedures including any changes thereto, are not drafted by the appropriate organizational unit.

Specifically, test methods are not adequately established. For example: a. Test Method ‘ii in the finished product i: | vo does not specify the technique by which so should be conducted in| __,,_~=—=————sS|: for quantifying ia . Currently .

Written procedures are not drafted, reviewed and approved by the appropriate organizational units.

Specifically, written procedures for into manufacturing areas for - are not adequate in that there is no requirement for| or | sa by manufacturing employees. Written procedures wx speak to personnel entry to the facility and .. to processing core but lack requirements for

A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary, has not been established.

Specifically, your global procedure, 00000596, Non-Conformance and Recall Management, version 4.0, 31Jan2023, defines the requirements for you firm to assess critical situations and conduct product recalls, as necessary. 00000596 requires your firm to establish an effective system for the recall of non-conforming product to include preparing written procedures and evaluating that system at least either by assessing a real recall or performing a recall. On 26Jun2025, your firm's Quality Site Head stated that you did not have a procedure in place to conduct recall activities, nor have you performed a recall since you began commercial manufacturing of Rebyota. From 02May2022 through your firm has distributed of the finished drug product, Rebyota, into . X

There is no quality control unit.

Specifically, your firm does not have a quality unit with the responsibility and authority to oversee the labeling, storage, and distribution of your umbilical cord tissue product, (b) (4) From September 2023 to December 2025, your firm manufactured and distributed human umbilical cord-derived products including but not limited to approximately lots ((®) @) units) of product marketed as Wharton’s Jelly ( (b) (4) ), lots ((b) (4) units) of product marketed as exosomes ®) 4) E ( (b) (4) ), and® lot (~ units) ofproduct marketed as growth factor ( (1b) (4) ).

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile did not include validation of the aseptic process.

Specifically, a)Your firm did not perform an aseptic process validation for biological products derived from human umbilical cord tissue. b)Your firm has not validated the use the (B) (4) (equipment ID (b) (4)) that is used to sterilize finished product (b) (4) , and processing tools that come into contact with umbilical cord tissue.

Your firm failed to establish written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.

Specifically, your firm has not designed production controls that ensure the human umbilical cord tissue products, (b) (4) , have the identity, strength, quality and purity they purport to possess. The lack ofprocess controls include, but are not limited to, the following: a)You have not validated the manufacturing process for the products listed above. b)You do not have SOPs stating how processing for each product is performed. c)You have not validated the time in which you ()) human umbilical cord tissue in (b) (4) : You®@ human umbilical cord tissue for anywhere from (Bb) (4) with no indication that the process does not affect the product quality or remain asa residual in final finished product. From September 2023 to December 2025, your firm manufactured ~and distributed human umbilical cord-derived products including but not limited to approximately lots (©) @) units) of product marketed as Wharton’s Jelly ( (b) (4) ), ® lots () (4) units) of product marketed as exosomes (b) (4) ), and® lot (units) ofproduct marketed as growth factor ( (b) (4) ).

There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Specifically, your firm did not investigate sterility failures in biological products manufactured from human umbilical cord tissue. : : 7 (b) (4) _ : From September 2023 - December 2025, your firm failed to investigate __ sterility test failures out of ©) manufactured batches of human umbilical cord tissue. Sterility samples are collected (b) (4) from the finished lot, with an average of vials submitted to a (DB) (4) laboratory for sterility testing per batch. ©) 4) of the 11 failed lots were released for distribution. Date of Product olume |Lot# ‘Donor ID iBioburden {Number |Sterility Processing ype esting lof vials jresults | 48) | m)¢4) | )(4) ee ()(4) i _ | || 44) (b) (4), (o) (6), (b) (7C)

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

There is no written testing program designed to assess the stability characteristics of drug products.

Specifically, your firm has not conducted a stability study to determine the expiration dating of rm (b) (4) from time of processing used for human umbilical cord tissue to include (b) (4) (b) (4) | From September 2023 to December 2025, your firm manufactured and distributed human umbilical cord-derived products including but not limited to approximately lots (©) @) units) of product marketed as Wharton’s Jelly ( (BD) (4) ), lots (B) (4) units) of product marketed as exosomes e) ES ( (b) (4) ), and® lot (~ units) ofproduct marketed as growth factor( (b) (4) ).

Procedures describing the handling of all written and oral complaints regarding a drug product are not established.

Specifically, your firm does not have written procedures for the receipt of complaints associated with

Laboratory controls do not include the establishment of scientifically sound and appropriate specifications designed to assure that components conform to appropriate standards of identity, strength, quality and purity.

Specifically, a) You have not validated or established written procedures for the process of manufacturing sterile antibiotic solutions used in the processing of human umbilical cord product. You reconstitute (b) (4) to create what you call an (b) (4) which is made up of (b) (4) designed to be added to a (b) (4) (b) (4). The ™includes (b) (4) to create an’ (6) (4) for incoming human umbilical cord tissue. You have not validated this process. b) You failed to establish a sampling plan that assesses the sterility assurance of your product. c) You failed to validate in house sterility sampling used to determine the sterility assurance of your products. The final sample used to determine the batch release is obtained© the product is (b) (4) From September 2023 to December 2025, your firm manufactured and distributed human umbilical cord-derived products including but not limited to approximately om lots (©) 4) units) of product

Written procedures are not established for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product.

Specifically, your firm has no written procedures for the cleaning and maintenance of equipment used in the processing, packing and holding of (b) (4) Equipment used in the processing, packaging and holding of drug product human umbilical cord tissue product includes: ¢ (b) (4) e Freezers + (b) (4) e Centrifuge e Biologic Safety Cabinet (BSC) e Pipetman e Incubator From September 2023 to December 2025, your firm manufactured jand distributed human umbilical cord-derived products including but not limited to approximately lots (©) @) units) of product marketed as Wharton’s Jelly ( (Db) (4) ), lots (B) (4) units) of product marketed as exosomes ) 4 . ( (b) (4) ), and® lot (— units) ofproduct marketed as growth factor ( (1) (4) ).

Batch production and control records do not include complete information relating to the production and control of each batch.

Specifically, you did not document each significant step in the manufacture, processing, packing, or holding of each batch of product ofhuman umbilical cord tissue. The batch processing record does not include the following: e who conducted the processing step e labeling of finished product e who performed placing product into quarantine, release from quarantine, and placing into available inventory. e The firm’s records do not document final disposition for failed/rejected or otherwise unacceptable vials. From September 2023 to December 2025, your firm manufactured and distributed human umbilical 5 : . a Khitam - (b) (4) : cord-derived products including but not limited to approximately lots ((6) 4) units) of product marketed as Wharton’s Jelly ( (b) (4) ), lots (() (4) units) of product marketed as exosomes ) 4) . ( (b) (4) ), and® lot (units) ofproduct marketed as growth factor ( (B) (4) ).

Written procedures are lacking which describe in sufficient detail the receipt, identification, storage, handling, sampling, testing, approval and rejection of components and drug product containers.

Specifically, your firm has not established written procedures specifying incoming acceptance criteria for receipt, identification, storage, handling, sampling, testing, approval and rejection of human umbilical cord tissue and processing components and finial product containers. | ~ m Lots (BINA) From September 2023 to December 2025, your firm has manufactured approximately |___ lots (

The eligibility of an HCT/P donor was not documented by a responsible person, based on results of donor screening and donor testing.

Specifically, your firm does not document the donor eligibility determination for HCT/P donors whose tissues are used to manufacture (b) (4) . From September 2023 to December 2025, your firm manufacturedwand distributed human umbilical cord-derived products including but not limited to approximately jots )@) units) of product marketed as Wharton’s Jelly ( (b) (4) ), lots (P) (4) units) of product marketed as exosomes ( (b) (4) ), and® lot ( units) ofproduct marketed as growth factor ( (b) (4) ).

Procedures designed to assure that correct labels and labeling are used for drug products are not written.

Specifically, you have no written procedures ensuring the proper labels and labeling is applied to human umbilical cord tissue products to include (b) (4) : e You do not conduct an examination of labels and labeling at any point during the processing of (6) 4) _ e You do not examine each batch of labels prior to labeling (b) (4) (b) (4) __ vials for injection. There is no control over labeling that is issued. From September 2023 to December 2025, your firm manufactured and distributed

Drug products are not quarantined before being released by the quality control unit.

Specifically, on 11/19/2025, we observed umbilical cord tissue product, (1b) (4) , Lot’ (Bb) (4) , being stored in Bello Bio's ® freezer. Lot (b) (4), has not been released for distribution but was not marked as quarantined. Your firm does not have written procedures on how to handle product held in quarantine.

After the completion of the donor-eligibility determination, HCT/Ps were not accompanied with a statement whether the donor has been determined to be eligible or ineligible, based on the results of screening and testing.

Specifically, your firm distributes (b) (4) directly to Regen Suppliers LLC. Your firm provides a Certificate of Analysis (COA) for communicable disease testing to Regen Suppliers LLC. This COA is signed by your Medical Director, however, the certificate lacks: e A statement of whether the donor is eligible or ineligible e A statement of donor eligibility based of donor screening results e A statement that the communicable disease testing was performed by a laboratory certified to

Procedures were not designed to ensure compliance with the donor eligibility requirements.

Specifically, your firm lacks written procedures for donor eligibility determination. From September 2023 to December 2025, your firm manufactured and distributed human umbilical cord-derived products including but not limited to approximately om lots ((6) A) units) of product marketed as Wharton’s Jelly ( (b) (4) ), lots (b) (4) units) of product marketed as exosomes ( (b) (4) ), and ® Jot ( . units) ofproduct marketed as growth factor( (b) (4) i

Written production and process control procedures were not followed in the execution ofthe various production and process control functions during the PPQ runs for RhoGAM S(H)4YW Incidences include, but are not limited to, the following: a.

Deviation 117124 due to operator not following SOP (version 12) “Production ofRhoGAM by incorrectly proceeding with the unnecessary and adding directly into the instead to the resulted in a ofan initiated PPQ Lot(b) (4) ana rejection | (b) (4) due to not being suitable for further processing. b. Deviation 121827, the operator did not follow SOPA), ession 10) securting 1D octorn te and entered non-approved(by (4) results from the QC laboratory resulting in need to perform the adjustments based on the erroneous results which is not part ofthe soP 1(B) 4) (version 10) for PPQ Lot c. Deviation 121766, the operator did not follow SOP (version 10) “Production ofRhoGAM od and added the incorrect quantity o 0 | (6)(4) for PPQ Lot d. Deviation 123472, QA verified the dosage calculation for fill, but did not verify that the(b) (A)valne was transcribed appropriately per SOP GQC-00-025 “Review of Test Data and Release ofTest Kesults.” Therefore, the(by(4)based on the incorrectly transcribed(6) A)value for PPQ Lot64

Deviation investigations are not well documented.

Specifically, a deviation ofan operator not following procedure and incorrectly preparing and using) (1b) (4) instead of(SY) for dilution oflO) (4) — (b) (4) atthe (b) (4) step, which may affect the validity ofthe §(jy(4yy was found during the

Procedures designed to control microbiological contamination are not established.

Specifically, WFI point of use is QC sampled after a(6) (4) fush according to SOP MQC-00-056. However, it was verbally confirmed by RhoGAM Manufacturing Supervisor that operators are not required to flush the WFI prior to use during production; and that there is no written procedure.

Appropriate controls for data integrity were not exercised over computers used during PPQ lots.

Specifically, data integrity remediation project as per Document #//(B) (4) is ongoing as ofthis inspection (December 2-6, 2019); however, PPQ lots were prepared between November 2018 to January 2019. The following systems and equipment used during RhoGAMSEINE production are a part ofthis ongoing project

The following deviations (Events) related to (b) (4) were not initiated in a timely manner or are otherwise inadequate: A.

Deviation Investigation 79659 initiated 18 August 2016was opened due to unknown substance (later identified as plasma) found in the (b) (4) ana(b) (4) centrifuges (b) (4) during a shutdown. The investigation is inadequate in the following: i. Lots of the drug substance manufactured prior to the shutdown was not evaluated as part of product impact. ii. The preventative maintenance of the centrifuges, including the centrifuge (bp) (4) was not evaluated. ili. The last batch manufactured before the shutdown and the discovery ofplasma in the (b) (4) (b) (4) of the centrifuge was not tested to show there was no impact downstream of the centrifugation step; the investigation was closed concluding no impact on product. —. REVERSE : Susan Jackson, CSO OF THIS i i TH AnLAC 4Kio Mihaly Ligmond, CSO March 16,2018 |

The current procedure for CIP of the fails to require the initiation of a deviation when an atypical event is detected during the ) ifically, CAPA 81235 was initiated as part ofEvent Record 79659 to update SO clean.

This procedure does not require the operator who performs the clean ora clean to initiate a deviation when a substance is observed in the ~ (b) (4) |ofthe centrifuge used during the rocess.

The change to the use ofa new at) for the(D) (4), ¢the (BD) (4) was implemented on February 27, 2018 however the associated change control (Change Control 92345) remained open as of March 15, 2018.

As per Documen 4) 0527 entitled “Change Control” * 9) ( rm 1s form was not completed for this change control. | | amet SEE

As per Document(b) (4) 16 entitled “Particle Contamination” a deviation (Event) is not required to be initiated for the detection ofparticles until particle identification is(b) (4) which is allowed to

There is no written justification for the clarifying imits of(b) (4) as stated in Document 2262 / 14.0 entitle 261 — Appendix |: Production File which is a portion ofthe batch record.

The preventative maintenance program for the hich is used to prepare — (b) (4) for the rocess and the used for CIP was not adequately conducted in year 2016 and 2017.

The preventative maintenance program did not ) at a defined frequency. Specifically, A. The executed preventative maintenance records for the year 2016 and 2017 for thefb) (4) fb) (4) and the re ¢°<: not account for all components an | requency of maintenance on each component. SEE

Discoloration resembling®) @was observed on (b) (4) located in the (®) (4)of the Operations Building Room () ()during a walkthrough ofthe area on 3-12-18.

Open operations related the manufacturing of (b) (4) such as the addition of(6) (4)components into _() (4) used in the(b) (4) and(b) (4) process are performed in this room. SEE

The aseptic manufacturing process lacks sufficient controls to ensure sterility of the prademagene zamikeracel final product, specifically: a.

The used in the preparation of media and other components that are used in the aseptic process tested for integrity after use. Therefore, the sterility of these media and components have not been verified. b. The for the LZRSE-Col7A1 retroviral vector (RVV) has not been validated (including not having an established bioburden limit). c. The final DP sterility sample for lot release collected from the final m., does not capture the risk of the final product manipulations, including d. The 0,34/ culture dish which is step involving the of the final assembled cell sheet (placed in a _ ) between two 1.4.) located in MN) _ in the process) is not included in the aseptic process simulation to assess the impact of this on maintaining aseptic conditions of the drug product.

Media and reagents (e.g., are not adequately controlled for quality prior to being used in the aseptic manufacturing process.

a. Media and reagents are not tested for sterility, endotoxin, and identity. Therefore, the safety of these media and reagents has not been determined prior to being in direct contact with the drug substance (DS) and drug product (DP). b. Studies have not been conducted to support the expiry of the media and reagents to (b)( ensure adequate performance.

The inefficient management of deviations by Quality Assurance resulted in delayed investigations for which risk assessments were inadequate and adversely impacted final decisions and actions.

Specifically: a. Numerous deviations were not addressed in a timely manner ( deviations :o be opened, - REVERSE OF THIS PAGE FORM F 483 (9/011) PREviuus hulTIONO%uLe r E

Disinfectant efficacy studies performed to support the disinfectants used in the facility and during the manufacturing processes are deficient.

Specifically, a. OM) which is used as the primary disinfectant (including for use to disinfect materials in the has not been qualified as this 0.4) disinfectant was not included in the disinfectant efficacy studies which were performed in - . b. Facility isolates were not evaluated in the - (and only) disinfectant efficacy studies performed in - c. The efficacy of disinfectants used in the facility do not undergo a periodic review based on environmental monitoring trending to determine if a re-evaluation study is needed.

Written records of investigation of a drug complaint do not include the findings of the investigation and the follow-up.

Specifically, you did not investigate complaint (ID CM 2022-02) received June 21st, 2022 that reported a patient had "pain" and "minor swelling" in their knee after receiving an injection of your product mVASC-lot ws Furthermore, you did not follow your written procedures entitled "Complaint Handling" Document Number - SOP-8001 which states: "For all complaints, the evaluation shall include an assessment of whether there is potential for harm to a patient or end user ofthe device. Should sucha case arise, appropriate customer notification and failure investigation shall commence without delay". Since commercial distribution beganin| , you have distributed approximately) ... | of mVASC (a product described by your Instructions For Use (IFU) as extracellular matrix derived from hypodermis skin).

Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.

Specifically, since your commercial operations began beginning in| wie you have not validated

The identity of each component of a drug product is not verified by conducting at least one test to verify the identity, using specific identity tests ifthey exist.

Specifically, you have not specified any identity test to be performed on components used to manufacture mVASC product. You have established acceptance criteria based off the certificate of analysis for the following, but you have not established criteria for a specific test to verify the identity of the components: a. b é, (b)(4)

There is a failure to thoroughly review the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.

Specifically, your ‘ait h document number - , does not address evaluating batches that fail to meet specifications. Of the| ... batches produced - have failed for reasons to include wwe ws bioburden. Additionally, you did not investigate into the reason of failure for lot ica that failed for - Since commercial distribution began in aw |! you have distributed approximately of mVASC (a product described by your Instructions For Use (IFU) as extracellular matrix derived from hypodermis skin).

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

a) While observing filling operations for Gardasil 9 drug product batch (0.SmL/Dose)) 4. | manufactured for Rest ofWorld (ROW) market within building) = aw sion located near the .. worksite where - of the drug product occur. It was identified that the closest| os | wm | worksite oo . Since the first commercial batch was manufactured on ws total batches of Gardasil 9 have been filled within this. ,,. and released to both US and ROW Markets. b) While observing filling operations for Gardasil 9 drug product batch (0,5mL/Dose am manufactured for ROW market within building wa it was observedthata) ww i not located near the w= _worksitewhere| ss, ~—S—S=s the drug product occur. It was identified that the closest). _|is located ow worksite (from " Since conclusion of the previous inspection, - total batches of biological drug products to includeGardasil 9, Pnuemovax 23, Vaxneuvance, and Capvaxive, have been filled within this, .. and released to both US and ROW Markets.

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Deviation investigation QN 201078686 initiated on 14MAR2023, documents a Grade~_ lenvironmental monitoring (EM) action limit excursion ( ..__) identified for... __|within building) - during the production of Capvaxive drug product Process Performance Qualification (PPQ) batch as (0.5mL/Dose) on soa | The probable root cause for the deviation was identified as sample exposure and contamination outside the Grade | environment during transfer and submission for . This conclusion was made without evidence supporting the sample was contaminated during sample transfer. Your investigation concluded that no sample handling errors occurred during transfer of the|. _| sample. However, additional evidence received during the investigation identified that sample contamination may have occurred during an intervention within the and this was not referenced as the probable root cause within the investigation. Capvaxive PPQ batch) wo was utilized to qualify the Capvaxive commercial manufacturing process within) aw

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established.

Deviations from written production and process control procedures are not recorded and justified.

Specifically, deviations from written procedures and corrective actions for deviations are not always documented and justified. For example: a) Cleaning instructions 4025 and 4065 for the fillingme) for (b) (4) and Octagam and filling room at the department were updated in response to deviation TW #106318 opened on 23 MAY 2019 but no training of operators on the updated instructions was documented. b) Employees setting up and monitoring of temperature alarms in room updated settings after temperature excursions. This room is used for storage of Octagam bulk, bulk, and werfilla. The human error identified in deviation TW #145329 opened 16APR 2021 was not addressed with training. c) Deviation TW #94014 is opened on 1 OCT 2018 for Octaplas(6) (4) machine operations not starting after . Root cause was identified as incorrect assembly of the of the machine and inexperience ofthe . Work instructions were established as part of the CAPA, but no evidence was apparent to demonstrate that firm personnel were trained on these instructions. d) Deviation TW #100586 is opened on 6 FEB 2019 for incorrect amount of PY being added in the (b) (4) for (used for Nuwi operations). The root cause was id

Equipment and(b) (4) are not maintained at appropriate intervals to prevent that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically, you do not always adequately maintain equipment in the manufacturing of plasma derivatives. For example: A. On 12 SEP 2023, we observed tank(b) (4) showed visible on the the tank durin fractionation batch . This creates a for : B. On 12 SEP 2023, we observed showed (Bb) (4) on(b) (4) that creates in the basic fractionation area used for manufacturing of pooled plasma intermediates.

Written procedures are not established and followed that describe the in-process controls to be conducted on appropriate samples of in-process materials of each batch.

Specifically, there is no written procedure for directing recovered for(b) (4) — or po when batches of recovered fail testing to standards. Recovered is a processing aid for manufacturing and Octagam.

Procedures describing the warehousing of drug products are not followed.

Specifically, your written procedure SOP-29727 version « gives instructions to use the(b) (4) " to track storage and movements of materials including those held for dispensing to manufacturing areas and finished product(b) (4) — storage. On 22 SEP 2023, we observed inventory of the dispensing location identified as where inventory did not match the indication in the . For example; differen of were indicated in (b) (4) but only of these items were located in the dispensing area. On 28 SEP 2023, we observed retrieved from(b)(4) location while th showed of product in storage. This batch of finished product was manufactured as batch(b) (4)in 2021.

Procedures designed to prevent microbiological contamination of pi products purporting to be sterile are not established, written, or followed.

Specifically, A. Active non-viable and viable raxticulate sampling is not performed during aseptic processing { (b) (4) (0) (4) in BSc (Grade (4) in Room (6) (4) B. Cleaning of Biological Safety Cabinets (BSCs) as outlined in (b) (4) “Operation, Cleaning, and Maintenance ofthe Biological Safety Cabinets” is inadequate in that: i. The cleaning method for BSCs is not validated to confirm the absence of carryover in the event of a spill or other exposure of product. ii. The cleaning solutions and method specified in your procedure ( (b) (4) were not used during our observation of the cleaning of Biological Safety Cabinet BSC) 4)on 20 JUN 2017. Operators used (b) (4) (which was not specified in the written cleaning procedure) to clean the BSC on this date. iii. | Your procedures for cleaning are ambiguous and do not allow for consistent execution. For example, (b) (4) “Operation, Cleaning, and Maintenance ofthe Biological Safety Cabinets” states "Use of (b) (4) is mandatory in cleaning the BSC" and "Ifusing (b) (4) (b) (4) oo"

Written procedures are not approved by the appropriate organizational units.

Specifically, A. In SOP, (b) (4) , Version 5.0, (b) (4) specific procedures for (b) (4) are not established. B. SOP, (6) (4) Version 7.0, Preventative Maintenance (PM) Program, does not provide instructions for the assessment of equipment that is overdue for PM or calibration. Guat: CDR Donald Ertel, Lead Investigator

Container closure systems do not provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination ofthe (©) @product.

Specifically, you label (b) (4) containing (b) (4) with (b) (4) during (b) (4) steps. Your procedure instructs operators to (b) (4) (b) (4) prior to placing (b) (4) into the BSC. This (0) is then (b) (4) You have not established the compatibility between (b) (4) and (b) (4)

Routine calibration of equipment is not performed according to a written program designed to assure proper performance.

Specifically, probes used to monitor your Liquid Nitrogen Dewars for temperature and LN2 excursions are not regularly calibrated. You use these Dewars to (b) (4)

Establishment ofthe reliability of the component supplier's report of analyses is deficient in that the test results are not appropriately validated at appropriate intervals.

Specifically, you do not periodically validate your suppliers’ certificates of analysis for components or consumables used during (b) (4) b/22/' et

Inadequate controls for inventory of critical starting materials in (6b)(4) used in the manufacture of Flublok Monovalent Drug Substance, which is used to manufacture Flublok recombinant influenza vaccine.

Specifically, During the FDA inspection conducted on March 10, 2026, your firm's system for storage and identification of master cell banks (MCBs), working cell banks (WCBs), master virus banks (MVBs), and working virus banks (WVBs) used in the manufacture of Flublok drug substance was found to be inadequate. Cell and virus banks are considered critical starting material for Flublok Monovalent Drug Substance and are stored in (b) (4) - Your firm’s validated materials inventory tracking system (b) (4) lists master and working cell and virus bank locations as a generic identifier (b) (4) (b) (4) which is not unique toa (b)(4) records do not differentiate between _(b) (4) (b) (4) During inspectional (b) (4) reconciliation of your cell and virus bank inventory on March 11, 2026, discrepancies were observed between your (6) (4) inventory and physical inventory. Examples of discrepancies the (b) (4) system failed to accurately account for the physical inventory are listed in the following table

Computerized systems used for the collection and analysis of quality data have not been validated.

Flow of materials and equipment is not designed to prevent contamination.

Specifically, Room ®® isa Grade (b) (4) with (6) (4) for movement of (b) (4) - (b) (4) the warehouse receiving area - (b) (4) to the (b) (4) warehouse (b) (4) storage area - (b) (4) (Room /@) - (b) (4) the manufacturing (b) (4) (Grade '§ ) for (B) (4) of (b) (4) Your firm’s environmental monitoring data for Room ®® shows consistent mold recoveries (% of all (b) (4) mold recoveries) with rates of 16.19% in 2023, 22.09% in 2024, and 28.10% in 2025. Although the frequency of sporicidal cleaning was increased, no corrective actions have been implemented to address the fundamental deficiency in material flow and segregation.

Written procedures designed to prevent microbiological contamination of drug substance are not established or are not followed.

Equipment and Facilities are not designed to prevent the potential for contamination.

Specifically, On 03/09/2026, _— (b) (4) utilized for holding Flublok drug substance was observed with apparent corrosion, chipping paint, and condensation. (b) (4) was holding drug substance Lot (b) (4) of —_(b) (4) Lot (b)(4) of B/Austria, and Lot (b)(4) of B/Austria at the time ofthe

The Quality Unit has failed to provide adequate oversight and ensure the implementation of effective corrective and preventive actions.

Specifically, Your firm’s own Product Quality Reviews (PQRs) for 2024 and 2025 identified that the root cause category of “Methods” accounted for approximately 41% and 40%, respectively, of critical/major/significant deviations in each review period. Despite this recurring trend being formally documented in two (b) (4) reviews, the Quality Unit has not initiated a Corrective and Preventive Action (CAPA) to systemically address this issue. During the 2025 review period, your firm initiated Significant deviations QE-137857 (Root Cause - Methods) which resulted in rejection of Flublok Drug Substance batch (b)(4) and QE-159034 (Root Cause — Methods) which resulted in rejection of Flublok Drug Substance batch _(b) (4) During the 2024 review period, your firm initiated Major deviation PRLD24E0046 (Root Cause — Manpower/Attention Error with Methods identified as a contributing factor requiring corrective action) which resulted in rejection of Flublok Drug Substance batch (b) (4)

Procedures implemented to prevent cross-contamination of drug substances during product change over (PCO) operations were not followed.

a) Specifically, between 010CT2018 to 2IMAY2025, you routinely failed to change change over between manufacturing ofdifferent drug substances wit in(b)(4) (as identified within deviations DEV-017954 and DEV-017965). This practice does not follow your current and histori = 0161, (ver. 2.0 - 14.0), Maintenance Procedure o ” which requires that the e changed ot. You have manufactured, (B)4)§) an the following drug substances (of which (B)(4)/ are within known expiry/retest dates) for manufacture of drug products (for U.S. and ROW markets) without having changed the(4/0 i Drug Substance Proprietary Name Plant Number Batches Product Code of Drug Product Released and Shipped

The responsibilities and procedures applicable to the quality control unit were not followed.

Procedures and controls utilized within the Quality Control (QC) Laboratory in support of drug substance release and(b) (4)testing are deficient.

The following was observed. a) Your firm failed to adhere to established protocols for drug substance (DS) by not performing sample pulls and associatedai within defined protocol timeframes (SOP-QC-00067). The following issues were noted: e (6) (4) samp pulls were conducted outside the allowable time wi ified

Failure to follow established procedures for reporting and implementing changes to an approved application.

a. Your firm implementeda revised version ofthe assay method - Determination of or the r i drug substance (DS) batches for manu acturing prior to receiving FDA approval for the change completion of the required waiting period following submission of a CBE-30 supplement. The revised assay method was u release testing of S batches (Batch numbers: and for stabili ing of S batches (Batch numbers: . The atches including (6)%4) DS batches were released between 09JAN2024 and , after implementation of the new method on 270CT2023, even though the corresponding CBE-30 supplement(HYP) was not submitted until 20MAR2024 and not approved until 1OSEP2024, b. The approved protocol for qualifying new((b) (4) reference standards was not completely implemented, i.e., change was identified when com aring the information provided in Section 3.2.8.5 ofan Annual Report with(b) (4) to that in the original BLA(b)(4) c. The data to support (5)A) reference standard were not completely reported. eee

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Specifically, a. You initiated deviation DEV23041 on March 28, 2023, when (b) (4) of stoppers with vials was observed during the filling process of Bivigam lot 233798. To address_the (b)(4). you decided to discontinue the fill and initiate repairs. The bulk line was(b) (4). and the bulk was (b)(4) the fill (b) (4) . You stated that the unfilled bulk was returned to refrigerated storage and “was successfully reprocessed as Bivigam Fill Lot 234608 on 03/29/2023.” There was no further investigation into potential impact of (D) (4) on the bulk. In addition, there is no approved procedure for{D) (4) of Bivigam bulk, and the currently approved license includes no provision for reprocessing or reworking of Bivigam. Bivigam fill lot 234608 was released to the US market on 09/05/23. Additional examples of(b)(4) after stopped Bivigam (6) 4) filling operations are presented in the table below. Each Bivigam lot was released to the US market. Deviation ID Date Original Batch ID |Description ew Batch ID / Release date

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

Specifically, a. Particle levels were not adequately monitored or well-controlled in the Grade iasof) (6)I(4)H NNN NNNNN ln(5)IC@)NNNNNNNN in which stevte drug components ae exposed during filling operations. For example: I. Particulates from filling components used during the aseptic filling operation were found in your post filled drug product vials. Since August 2021, you have initiated more than ten deviations for particulates that action limit, and about (b) (4) | events for particulates (b) (4). alert limits for particulates found inside iil filled drug product vials. II. A probe used to measure total non-viable particulates in the Grade}! (Iso) (b) (4)

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written and followed.

Specifically, You currently monitor temperature, humidity, air pressure differential, and non-viable particulates during filling operation in your Grade a (ISOf}) environment. You failed to establish a procedure on how to handle and respond to an excursion when acceptable limits are exceeded during filling operations.

Critical utilitiesr (b) (4) utilized as productL(b) (4) in the manufacture of Shingrix are not adequately qualified or routinely monitored to ensure reproducible quality.

Specifically, [(6) (4L quality control testing is not performed on thef (b) (4) receivedr (b) (4) J and a routine monitoring program has not been established for these utilities that are supplied 1hroughout the facility (b) Further, the utilization of these (b) (4) has continued in the absence ofcompleted qualifications of theȔb) (4) (b)(4)

Quality oversigflt and integrity of electronic data captured to support the manufacturing equipment, environmental monitoring, and manufacturing systems ( e.g., Process Control System) has not been established.

For example: a. For ther (b) (4) J assessments: i. Electronic documentation of the C (b) (4) ofthef (b) (4) , performed on May 8, 2024 is missing. ii. Self-tests for internal diagnostics of equipment were aborted or failed on October 29, 2024, and June 17, 2024, respectively, without explanation or documentation. iii.1 (b)(4) l which is used for the r (b) (4) J instruments, lacks a requirement for quality oversight of the associated testing and metadata. b.For thel (bf(4) _J procedure 9000087546 titled SDOC - Environmental Monitoring, version 04 permits measurements to be interrupted [aborted] and repeated immediately for occurrences such as ISi

Deviation management is inadequate to demonstrate quality oversight of the manufacturing process, and docs not adequately identify, document, or investigate the impact to drug substances.

For example: a. Procedure 9000075940-02, MZP: Alarm Managementand Audit Trail defines critical" alarms (defined as _(b)(4) as (b) (4) critical, (b) (4) Since October 09, 2024, there have been© critical ™alarms that are (b) (4) critical. Despite these (b) (4) critical alarms, (b) (4) has not reviewed, evaluated, or otherwise acknowledged these alarms since October 09, 2024 (as of November 09, 2024). Without (b) (4) of these alarms, the production department continues to issue batch records for the manufacture ofShingrix drug substance per SOP 9000080766 version 4 titled eBR Execution and Review and has initiated manufacture of() 4) batches of Shingrix drug substance without the evaluation of these (b) (4) of alarms. b. High bioburden levels were discovered during a lifetime study of (b) (4) (b) (4) has a (b) (4) which was identified as a source of bioburden contamination to the Shingrix drug substance. Manufacture of Shingrix drug substance continues at risk with (b) (4) (b) (4) Correction of the equipment design is not scheduled until March 2025.

There is inadequate quality oversight to assure that the Shringrix and Measles drug substances have the identity, strength, quality, and purity they purport or are represented to possess.

For example: a. High bioburden levels were discovered during a lifetime study off (b) (4) [()(4) J Quality assurance invalidated this data during the lifetime study, aJbeit the data was considered valid data by quality control. b. There is no quality oversight of unplanned maintenance events to assess the qualification/validation status and product impact. Specifically, procedure GUJ-9000055892-24 General Procedure of Preventive and Corrective Maintenance does not require the quality unit's approval for any unplanned maintenance or repairs to the facility. c. Documentation practices are insufficient. For exampleJ (b)(4) L(b) (4) J in classified Room 1 (b)(4) used to manufacture Measles bulk drng substance lacked supporting documentation. d. Signed and dated original documents pertaining to theL (b) (4) of materials used in the manufacture of Measles drug substance were found in the trash.

There is a lack of data to demonstrate the quality of'Ǖhe (b) (4) J prior to use for vaccine production.

(b) (4) the (6) (4) J have not been inspected and documented for (b)(4) ISi

Laboratory controls do not include the establishment of scientifically sound and appropriate specifications designed to assure that in-process materials conform to appropriate standards of purity.

Specifically, a. ” for the following steps in) the acceptance criteria or specification for the Microbial Purityteston) = . ——_—i isa b. There is insufficient bioburden and endotoxin monitoring throughout the manufacturin processes for the following bulk products:| : ins - , Shringrix, and) ,,., |...|. Forexample, during routine production, Shingrix is tested for bioburden from the si and bioburden and endotoxin samples are taken) .. sterile filtration.

Failure to thoroughly investigate the presence of) _,,, in the Water for Injection (WFI) | os where sterile bukh is manufactured.

The deviation investigations failed to evaluate complaints for[ |, =Sst~*~<C~«~CSC*deecezi edd (ifanny) sincethe| - [ontheWFI| .., jon December 4, 2015, the attributing root cause. a. Deviation 200578478 was initiated on 28 July2017inBuilding, wy SSCs theofthe WFI_| The... |wereidentifiedas| b. Deviation 200654818 initiated on 26 July 2018 in Building in WFI [ml The root cause also attributedtothe04December20155 a’assi‘“‘#(é‘(asti‘(i‘i‘i‘séis

The following corrective actions were found deficient: a.

Thecorrective actions/preventative actions to multiple deviations opened in 2016 which stopped production until November 2016 is deficient in that there was no assessment of the current automated| ...._—_|for equipment to ensure that the cycle was adequate for the ~__oatamination. This equipment includes)mw SEE

Your firm has not performed adequate process validation for!

used in| yy [Which have ranges to include assessing each end ofthe range. For example,

There is a lack of documentation approved by the Quality Unit to support operating outside of your routine operations.

Specifically, a. Deviation 200543472 was opened on 12 FEB 2017 when|- |wasfoundinthe| ,, | after on . The deviation determined that changes needed to be made to SEE

The following equipment maintenance issues were on observed on June 7, 2019 in the) a | ww manufacturing building: a.

son material and a build-up of| ge was observed belowa leaking vom: b. AL —~«zwas observed forthe! jinroom|andi they SCioom. c. was Observed above the in various| ... _|to include the diel d. Apieceofa| ., _|was observed above the as in room) aw G. | wm was observed dripping from a _ for the) .. for i inthe! = wv. += ~—~«room. The ,,, from this|- _was also observed on the (bya) t SEE

Out of Specification Investigation for the Drug Substance is not thoroughly investigated.

(A) Specifically, you initiated an Out-of-Specification (OOS) investigation for SARS-CoV-2rS Drug Batch No. on February 20, 2025, after obtaining a and investigations identified no laboratory or manufacturing errors, respectively, and a on March 18, 2025, confirmed the OOS at ((BY(4y) The investigation timeline and results are summarized below: Investigation Step Result/Finding ‘Specification/Expected The OOS result was invalidated by attributing it to degradation of theUNS) despite inconsistent M(b)(4)l testing where only(PGA data aligned with historical trends. The investigation concluded the reference standard had declined in performance and invalidated the OOS, even though(G4 yyy

Written production and process control procedures are not documented at the time of performance.

Specifically, (A) Pertaining to active air testing used to evaluate the environmental conditions of Grade 8 areas supporting drug product manufacture, the following deficiencies were identified in the concurrence between electronic records (i.¢., instrument history) and official documentation. From February 8, 2025, to October 10, 2025, approximately® active air samples cannot be accounted for based on instrument history. Additionally, there is a lack of correspondence between sample nomenclatures and sampling sites, preventing confirmation that intended samples were procured. Multiple instances were identified where samples retained identical identifiers: Total Samples Taken Samples with Identical Identifier January 8, 2026 | ||

Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination of Drug (Bb)(4) Lots.

Specifically, the product contact surfaces of IQ (E)4Iwyys and systems used in SARS-CoV-2rS Drug (64H manufacturing are not adequately maintained. A) On January 29, 2026, the system displayed These conditions were subsequently identified as system. The equipment had been documented as cleaned on January 28, 2026. (B) Additionally, the resin in system yA) vet the was classified as clean and recorded as being on its use of a lifetime allowance.

Your firm has not validated the cleaning procedures for dedicated equipment used in the manufacture of Aluminum Hydroxide adjuvant to prevent contamination or carry-over.

This adjuvant is a component of your licensed U.S. products including (b) (4) Infanrix, Boostrix, Kinrix, and Pediarix. Specifically, your cleaning validation and monitoring program for the aluminum hydroxide adjuvant production suite( (b)(4) = and (6) (4)) is inadequate. You have introduced unvalidated (b) (4) cleaning steps into routine production, failed to maintain a state of control for your validated (b) (4) cleaning process, and failed to adequately investigate recurring cleaning failures. a) You introduced an unvalidated (6b) (4) workaround into your routine cleaning and manufacturing process. Since May 2023, you have used an unvalidated (b) (4) cleaning procedure with (b) (4) (b) (4) for all batches ofAluminum Hydroxide adjuvant. This procedure was implemented to mitigate a known design flaw where aluminum hydroxide (b) (4) (implemented January 2026) and (b) (4) (implemented May 2023) and is (b) (4) This (6) (4) cleaning step was not validated to demonstrate its effectiveness. Furthermore, this change to your cleaning process was not managed through your firm's change control system.

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has already been distributed.

Specifically, the firm failed to conduct formal investigations, in accordance with SOP-082366, “Deviation Handling,” for failed (6) (4) test results associated with the Aluminum Hydroxide Adjuvant filling equipment. SOP 9000087625, “Requirements for (b) (4)

Equipment and utensils are not maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically, Regarding the cleaning of manufacturing equipment or glassware used in the production of a sterile (b) (4) and a (b) (4) used for a (b) (4) the production of (b) (4) drug product ((b) (4) )in (b) (4) _, includes, but is not limited to, (b) (4) , the SOP titled, Preparation of Equipment, Including Pressure Vessels, Mixing Vessels, Glassware, Tools And Seals For Use In Manufacturing, SOP1367, Ver. 15, states that for post cleaning, ‘ (b) (4) ” The cleaning of each piece of equipment or glassware is documented on (b) (4) In addition, no study could be provided that substantiates the (b) (4) — until drying.

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed.

Specifically, a.On 2/26/2024 during operation of MenA Vaccine batch using (b) (4) unit, and after exchanging located approximately vials, the grade, operators did not reject the(b) (4) product vials located directly below the intervention. As per your SOP instruction# 9000085445-02, before carrying out a change, the line must be (b) (4) so that there are no vials in the . However, the operators did not ensure that the (b) (4) line was to the intervention. In addition, there is not documentation available in the executed batch records to ensure that the operators (b) (4) the (b) (4) lines or reject the product vials the interventions. The firm has used the unit to RabAvert (batch , Expiry(b) (4) ) and MenA Vaccines (batch and Expiry(b) (4) ) for US market. b.On 3/6/2024, during set up operations of(b) (4) unit for MenA batch , | observed the shoulder ofGrade operator touch the Gradey, side of th . No sanitization was performed on the Grade1) side ofthe before closing the .

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Specifically, investigation related to of Aluminum Hydroxide is not adequate. Aluminum Hydroxide is an adjuvant used for Infanrix, , Pediarix, and Boostrix Vaccine products for US market. On 06Apr2023, and were observed on the(b)(4) of , which is used for th of Aluminum Hydroxide bulk material (Deviation # 200991257). The root cause was identified as of(b) (4) due to(b) (4) contact with Aluminum Hydroxide suspension. Based on the investigation, you have identified that a contact time of more than can lead to(b)(4) parts. However, the investigation was not extended to other | surfaces to re-evaluate the established dirty hold times of 72 hours for fixed equipment, such as but not limited to , and for(b) (4) parts, such as not limited to utilized for Aluminum Hydroxid production.

Separate or defined areas to prevent mix-ups are deficient.

Specifically, your firm failed to discard and/or transfer materials to a physical quarantine location to prevent the materials being used beyond dates.(b) (4) materials were observed to be stored in your on 2/27/2024. There was no clear demarcation between materials and or materials in your(b)(4), More than material batches (material lots) had been identified that are currently stored at the

Documents and (6) (4) used for distribution of the(6) (4) drug products are deficient.

Specifically, your firm failed to ensure correct (b) (4) were applied to (b) (4) drug product containers before release. The final (b) (4) on your containers that hold (b) (4) drug products contain incorrect expiration date. The expiration date on thel®) (4) was not based on the associated stability studies. Furthermore, your documentations that accompanied with the (b) (4) drug product shipment, including the packing lists, contain incorrect information. The documents do not bear an expiration date determined by the associated stability studies and do not match with the expiration date on the container (b) (4) that hold ©)@) drug products.

Your firm has not fully investigated or assessed the impact of finding various molds in a (DB) (4) room in which manufacturing materials (used for manufacturing of (b) (4) and (®) (4) ) and stability samples are held.

From March 2023 to April 2024, five quality investigations were initiated to address molds in (b) (4) = (4) (b) (4) room (b) (4) of a (b) (4) and include: ® #70445; #73010; © #73044; DEV-00267; and DEV-00331. These investigations were generated in accordance with procedure (b) (4) -SOP-"-000015, Control of Quality Events and Corrective and Preventive Actions, Ver 21, 23 & 23, which allow for such actions as additional monitoring activities (e.g., (b) (4) ) and requires the use of a root cause investigation (which would allow for the expansion of the scope of investigation). Although your firm initiated various corrective actions (CAPAs), the following was revealed during this inspection: a) Your firm did not initiate investigative environmental monitoring and sampling in manufacturing areas of building to detect for mold contamination beyond routine EM monitoring to address, for example, routes or pathways of supply items which were put at risk by being exposed to molds in (6) (4) room (©) (4). Note that supply items undergo a cleaning/disinfection regimen before going into controlled areas but given the potential for cross contamination and movement of mold spores, routine EM migh

The master production and control records are deficient in that they do not include complete instructions, Specifically, there are no defined (1) (4)time frames and/or instructions for the (Bb) (4) preparation ofthe Concentrated Tetanus Protein (CTP) bulk in the Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) manufacturing process.

A. The CTP bulk requires the (6)I(4)ofthe bulk after the (NN(B)Z)NNN step in Bldg.(4) (Room PU), The ' (DB) (4) © system is rinsed with a (b) (4) solution and collected into ((6)(4) individual 4) (b) (4) that are NN ©)4) intoa (1) (4) container, (6)(4)i the CTP ((b)(4)) process. The CTP bulk is [MB)I@)NM by the technician| (wy@y_ the \(By(AyI container in a (6) (4) ()(@mifor an unknown specified amount oftime under the biosafety cabinet. A bioburden sample is taken at this step at this step, (By(4y the CTP bulk (1) (4) process. B. The production batch record does not include instructions for the (b) (4) steps for the CTP bulk, (b) (4). C. There is no validated mixing time-frame established for the CTP bulk concentration (6) (4) step to ensure (b) (4).

were observed to contain cellulose particles during visual inspection of retain samples related to @ complaint of vial breakage (complaint no.

200255622). This lot had been released and distributed within the US market and was reported to the agency as a Biological Product Deviation Report (BPDR) on 09/15/2022. While reviewing the firm’s CAPA investigation report MLED22A2877 pertaining to deviation MLED22E3775, it was observed that no effectiveness check was conducted to verify the effectiveness ofthe corrective action (updating instruction MLE-1-006038—clarifying the practice of the cutting of bags within filling line 14) implemented in response to the deviation. B. While reviewing | (b) (4) batch number I(b)(4)" | (b) (4) ) for line ?® utilized at the time for sterile (©) (4) ofAct-Hib (US Market), it was observed that the ill(®)(4)iul batch was invalidated due to a reconciliation difference between the quantity ofcrimped vials (11,997) and the quantity ofinspected vials (11,996) prior to being sent for |§(6)(4). Further review into the investigation of the discrepancy (Deviation MLED21£6490) revealed that the discrepancy was likely the result of a lost vial after the crimping step during transfer to visual inspection (b) (4). Due to the vial being lost, it could not be incubated and read for turbidity resulting in a po

Drug products are not stored under appropriate conditions so that their identity, strength, quality, and purity are not affected.

Specifically, While observing warehousing operations within temperature controlled (2-8C) finished product storage room ®@) within the packaging warchouse, it was observed that one shrink wrapped pallet consisting of | (b) (4) boxes ( (b) (4) ) ofWFI diluent batch (6)(4)) were not stored under appropriate

Laboratory controls do not include the establishment of scientifically sound and appropriate standards designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity.

Specifically, reference standards are not included in analytical sequences to verify© (b) (4) |control for the following critical test assays. A. SOP: MLE 1-005714, titled, yyy (by 4yyyyyyyy- A blank is analyzed at the beginning of the ved for nes vs pote method analysis Gia sample analysis. The (6)(4)absorbance sample result is used for the Purified Vi Polysaccharide bulk (Typhoi Vaccine) \(b)(4)icontent final release assay. B. SOP: Qu-WIN-0040813, titled, “V16_J(B)N4)N_Use of(IIE) (4 inRooms 8 and DA blank is analyzed nl (6) (4)NNN ethod analysis individual samples are analyzed. An average of the readings are or the measurement. The| is measured at the steps during the ofthe Vi Polysaccharide ((Typhim Vi Vaccine) manufacturing process to for further processing. These steps are identified as critical processing parameters (CPP) in the manufacturing process.

Procedures designed to prevent microbiological contamination ofdrug products purporting to be sterile are not followed.

Specifically, While observing sterile (6)(4) operations for Imovax Rabies batch X1C16 (US Market) on (6)(4) line P@within OISTRICT

Failure to conduct investigations into unexplained discrepancies.

Specifically, during the review of the calibration certificate for the ), used for the— (b) (4) testing ofthe (b)(4)) for the bulk formulated of Fluad. We observed that the September 2021 Calibration Certificate “As Found” data had not met the acceptance criteria for thePa measurement — (b) (4) © acceptance criteria). Your firm failed to follow procedure as documented in DOC-000134669 v8.0 Execution of Maintenance, in that quality unit was not notified and no investigation was initiated to determine impact on product since September 2020. Between April 23, 2021 - September 15, 2021, your firm manufactured and shipped|" formulated bulk FLUAD Quadrivalent batches to the US.

Lack of corrective action for trends observed during the —(b) (4) | Test of the Monovalent Bulk Drug Substance sample—(b) (4) .

Specifically, There is an ongoing trend of investigations for — (b) (4) observed in the —(b) (4) sample for * (b) (4) of the Fluad Monovalent Bulk Drug Substance for Influenza Vaccine. The investigation into 18 monovalent bulk drug substance batches is investigated under Master Deviation QE000436. Per Doc 000166303 V39 Determination of Sample(by (4). the—(b) (4) Test

The following investigation was inadequate.

Specifically, on April 25, 2022, event 200926036 was opened when the in-process endotoxin test data performed on 4/22/2022 could not be located on the The system administrator was contacted to retrieve a copy of the in order to save the data onto he (BY(4) There was no investigation into why id not retain the endotoxin test data or a determination as to where the data file went. The event was closed after a work order determined no error occurred withthe! (b) (4) _

The following complaint records were found incomplete and/or deficient: a.

Between 10/17/2017 and 12/21/2021, your company has received syringe defect complaints associated with multiple lots of FluLaval in which three separate investigations were opened. The complaints included needle connectivity issues to the luer lock, leaking from luer lock, crack at luer lock, and spinning of luer lock on the syringe. The first investigation concluded “incorrect manipulation ofthe syringe during preparation for injection”; second investigation concluded most probable root cause of “mishandling by the healthcare professional”; and the third was a most probable cause “the defect (LLA crack) was originated in the LLA suppliers process”. No “internal root cause at GSK level”. A crack in the LLA (luer lock adaptor) on the syringe was confirmed by the supplier for multiple lots ofsyringes, one of which was provided to your company. FDA was not notified with regards to the defective devices that were released to the market. b. Complaint files do not always include reply to complainant. For example, the complaint files for complaints 1500115512, 1500093176, and 1500115907 do not contain a reply to complainant.

Procedures designed to prevent microbial contamination ofdrug products purporting to be sterile are inadequate.

Specifically, a. There are styles worn by aseptic operators. The following deficiencies were noted for the orn by the operators working in the aseptic (D) (4) i. There are on the iththe o£ 7 approximately een specifically evaluated by sterility assurance for the impact to the aseptic environment. SEE NIPLOYE! A

Preventative maintenance activities were incomplete.

Specifically, the (b) (4) in the (1) (4) on the are not part of a routine preventative maintenance program to include visual inspection. These wedding (DY)

The sampling ofthe is not representative of use.

Specificall manufacturing d th CLO mentcd On a log. ATT ile QC takes the sample, SEE BLOV NATUR

Deviations from written sampling plans, test procedures and laboratory mechanisms are not justified.

Specifically, There is a failure to thoroughly review any unexplained discrepancy from the firm's contract testing lab used for stability studies of ERVEBO drug product vaccine and related materials. For example, the contract testing lab in is used to perform stability studies for ERVEBO vaccine (recombinant vesicular stomatitis virus-Zaire Ebola live attenuated virus). From 2019-2023, there were 7 out of 18 stability deviations from this contract testing lab for different reasons including missed stability time point; use of expired media for cell potency assay; sample mismanagement; incorrect temperature sample storage during testing; and other reasons. The firm has not fully investigated these deviations to ensure that the contract testing lab is managing the stability samples and performing the stability testing correctly.

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not followed.

Specifically, the following actions/behaviors do not conform to the instructions in your Aseptic Processing procedure (VV-SOP-00953). e During the review of video recording of filling operation of Aplisol (Stabilized Solution) (b) (4) in Suite (Bb) (4) — dated 30" April 2025, we observed an operator repeatedly talking and moving his/her hands in a fast : : : b) (4 : and non-deliberate motion in a Grade ®§ manufacturing area. The employee observed was identified as a Trainer. e During the review of video recording of filling operation of (b) (4) (b) (4) in Suite (b) (4) , dated 13"" January 2025, we observed operators talking and moving hands in a fast and non-deliberate motion in a Grade” manufacturing area.

Good Documentation Practices (GDP) and data integrity practices were deficient.

Specifically, a) Deviation Report No. M26/06/21/03, dated 6/19/2021, - lew reported that the limit ofconductivity for) SS SSSSs«Wass documented a mo instead of,__|_in the following records: 1) Master Formula Record (MFR) for) wwe 0 sie 2) Batch Manufacturing Record(BMR) for; sw Ssés nd or scale for Manufacturing of Lie (BMR no. MBR sg and 3) SOP for Preparation of| me Aree fof] we (SOP No. 101 eet | A typographical error occurred while preparing the SOP, BMR, and MFR where a|] was typed instead ofa b) Deviation Report No. M03/07/21/01lowe sd] reported on 7/3/2021, in the |_| for GMP. __ [cleaning inthe ~ |area, that ‘| > was written on page no.- | of[- | after completion of cleaning on 6/30/2021, for the remaining entry lines. After the operator was accidentally hit by a | | page oii ag of|- |was inadvertently torn from thel w |, resulting in a damage (torn)| a. page. The operator discarded the completed page due to panic and fear of being caught by the supervisor. GMP cleaning was performed on 6/30/2021, but the - —_ cleaning entry on 6/30/2021, which was documented on page ~ |, was not available. c) Deviation Report No. M19/07/21/O1, dated 7/18/2021, wy |was noted during processi

Deficiencies were observed in the detection of ome of the +49 method: a.

No control is included in the initial =e sts=~<CSsSC Step to ensure acceptable quality and quantity of DNA used for the subsequent| .. __ reaction. b. The instructions given for the interpretation of the test results shown in Table | of SOP # 1003-0393-002 are

Reporting of deviations and investigations were deficient as follows; a Inconsistent categorization of recurring deviations: i.

M11/01/22/04 was categorized as major deviation while M30/01/22/01 was categorized as a critical deviation with the same incident of media contamination due to|- clogging. ii, M23/08/21/01 and M15/01/22/01 were both categorized as major with the same incident of unusual peak observed in) ya L b. SOP for the reporting of deviations does not have instruction on the upgrading of the severity of deviation if a similar incident reoccurs. c. A|-_ {throughput study was performed to investigate the root cause ofthe clogged) - _| in deviations M11/01/22/04 and M23/08/21/01. The outcome of the study suggested that the current|- _|configuration is appropriate only for the etn and therefore) .., are recommended (| .. the current number of|- —_|used) forthe! 0 si usedinthe|.. |stepofthe_.. | bioreactor. The same iii study is also applicable to th process because the sam is used forthe)_|usedinthe|...|step; however, the firm did not re-evaluate ifan additional. _|maybeneededinthe| = ~—=S——S—S—Sst mitigate the potential contamination caused by the clogging off | d. Deviation M23/08/21/01 was initiated because an unusual peak was observed duringa | The sii ofthe was substantially different from th

Written procedures for maintenance fail to include schedules for the replacement of HEPA filters prior to failure.

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

Specifically, a) You do not perform) identification each time action level is reached for each[igs b) Your|. (did not consider manufacturing operations when determining sample locations. c) You do not perform complete investigations when an action level is reached to include root cause and corrective action. d) You do not have a system in place that allows for monitoring recurring wa to identify repeated significant organism,

Lots of licensed products were released by the manufacturer prior to completion of tests for conformity with standards applicable to such product.

Specifically, The firm implemented a assay of(b) (4). The following (b) (4) batches (b) (4) and were released for distribution to the ial market, but the firm lacked evidence of whether an application supplement was submitted for review and approval pursuant to the drug product application.

(b) (4) processing areas are deficient regarding the system for monitoring environmental conditions.

Specifically, the following locations of environmental monitoring within line fa , located in room of building ee. are not adequate to monitor environmental during production: used to monitor the environment during filling operations are, (b) (4) ,

The suitability of all testing methods is not verified under actual conditions of use.

Specifically, The QC microbiology review ofenvironmental monitoring(b) (4) is deficient including room design and equipment. During inspection of the lab, it was observed that the room used for environmental monitoring ) is small (about ) with operators and a supervisor to review as many as A system to prevent mix-ups is lacking. °N@) are(A/T ona (b) (4) throughout the room.

GMP training is not conducted on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.

Specifically, The training effectiveness is not systematically monitored, with respect to deviations and CAPA effectiveness. The firm had 25 deviations for training deficiencies in the past 3 years, in (b) (4) classified areas. Corrections and CAPAs to individual traiming deficiencies are not well described in the deviation reports and training on deficiencies are not extended to all relevant operators or production areas. The firm has only recently started to trend and categorize deviations based on root cause and has only recently begun to implement a continuous improvement training but has not taken action to ensure that critical manufacturing steps are carried out effectively.

Backup data is not assured as exact, complete and secure from alteration, erasure or loss through keeping (B)I@)EN LN s9stems Specifically, The firm's Quality Unit including Quality Control Molecular Biology lab manager and IT staff do not perform audits of all GMP lab data inclu...

ding all to ensure adequate controls are in place for all lab systems including the — systems.

Review of laboratory data for drug substance in-process and release testing is not adequate: a)We observed raw data from does not match the analytical packet| lw SStttsti‘<iststsS@S for lot He mw used to document the final results.

This data is generated as part of Final Bulk Drug Substance release testing for residual ik . The analysis packet was reviewed by a QC reviewer on 19 NOV 2024 and did not catch the error. b)On 15 APR 2025, your quality control associate (analyst) who performs the sun testing method for|-_{final bulk drug substance, demonstrated (with typical system access rights) the ability to delete original electronic data from the|_». which saves data files from nel. 6 used for _ test method ( 6 , among others). There is no routine system-level review to ensure the veracity ofelectronic data files submitted. c)On 8 Jun 2016, uw instrument for in-process monitoring of|- |andI~ | bio-reactors in Building- were qualified by testing reference| __,,,, at various concentrations. Along with deviations noted in the protocol, the final report was reviewed and approved in April 2024. One} used in the qualification is the _ which was evaluated by | wa ~~—Ss~té<«éd KO SHOW aeeragee results of The qualification of the instrument has no acceptance criteria for accuracy. These instruments - are still in use today for monitoring bio-reactor cell viability including fo production.

Documentation of critical material inventory is not accurate.

On 14 APR 2025, we observed the inventory system “f > P indicating - | vials ofworking cell bank (WCB| i lot # ) located within liquid nitrogen storage vessel # - _| at Building4 .. | records of the same lot show conflicting inventory of|-vials. Upon observation ofthe storage location, only - |vials were found in cryo-storage. This working cell bank is the starting material for upstream culture that will produce the drug substance - _ under BLA} .. As stated by your Senior Director, Quality Systems and Compliance, no established procedures exist for conducting inventory/cycle counts ofWCB stored in the release and quarantine liquid storage vessels (#-|and#~ | respectively) in Building | Scot T Sallad National Expert XK Dale Sgned Os16.3028 20 39 00

Procedures describing the handling of all written and oral complaints regarding a drug product are not established.

Specifically, since beginning operations in January 2021 your firm has not established or approved your written procedures for handling consumer complaints entitled “Regen Suppliers- Customer Complaint Standard Operating Procedures” that are still in draft form. For example, per these draft procedures under section titled (b) (4) for which your firm defines as any complaint involving (b) (4) (b) (4) . must be investigated by Quality Control and Operations within”? (b) (4), e Your firm does not have a designated Quality Control unit as explained in Observation Number 2. e Your firm received the following two complaints in 2025 that represented a serious adverse event and were not investigated: Adverse Event # 1 On November 9th, 2025, your firm received a compliant which stated three patients had been hospitalized with meningitis after product was administered intrathecally. The administered product was determined to be (b) (4) -lot! (6) (4) _ received by your customer on 10/28/2025 and labeled as“ (DB) (4). Per your customers request your firm provided sterility and communicable disease testing from your Cord Blood supplier (b) (4) . This complaint case was then closed without furth

There is no quality control unit.

Specifically, since beginning operations in January 2021 your firm has not established a quality control unit with the responsibility and authority to oversee the labeling, storage, release, distribution, and complaint investigation of your umbilical cord and umbilical cord blood products. Additionally, on 12/10/2025 your firm signed an agreement for manufacturing and direct distribution to customers with the contract manufacturer (b) (4) without qualifying them as a supplier. Your firm markets and distributes human umbilical cord-derived products that include but are not limited to: Wharton's Jelly and Exosome Products: e Private labels: (b) (4) e Customer private labels: (b) (4) Umbilical Cord Blood Products: e Private label: (1) (4) e Customer private labels: (b) (4)

After the completion of the donor-eligibility determination, HCT/Ps were not accompanied with a statement whether the donor has been determined to be eligible or ineligible, based on the results of screening and testing.

Specifically, a) Your firm provides a Certificate of Analysis (COA) to your customers which includes communicable disease testing results for your private label products (b) (4) . and (b) (4) . These COAs are provided to your firm by your contract manufacturer. (D) (4) This COA is signed by the (1) (4) —-Medical Director, however, the certificate lacks: e A statement of whether the donor is eligible or ineligible e A statement of donor eligibility based of donor screening results e A statement that the communicable disease testing was performed bya laboratory certified to perform such testing on human specimens under the Clinical Laboratory Improvement Act of 1988 or has met equivalent requirements determined by the Centers for Medicare and Medicaid Service. e The address of the establishment reviewing the donor records documents to make a donor eligibility determination. b) Your firm issues Certificates of Analysis (COAs) to customers for the private label product (b) (4) . which include communicable disease testing results. While these COAs bear your contract manufacturer's name (_ (1D) (4) __). they originate from your cord blood manufacturer (b) (4) . The COAs provided to custo

Procedures designed to assure that correct labeling and packaging materials are used for drug products are not written.

Specifically, you have not established written procedures to include the review and approval of labels that are applied to finished product containers or labeling that is sent with product upon final packaging.

Drug product expiration dates do not appear on the labeling in the manner prescribed by regulations.

Specifically, your firm distributes private label cord blood under the brand () (4) that is manufactured by (b) (4) . There is no expiration date on either the primary label or the Certificate of Analysis that accompanies the product. Your firm markets and distributes human umbilical cord blood products under multiple brand labels: Umbilical Cord Blood Products: e Private label: (1D) (4) ¢ Customer private labels: (b) (4)

Complaint procedures are deficient in that written complaint records are not maintained in a file designated for drug product complaints.

Specifically, per your draft written procedures entitled "Regen Suppliers-Customer Complaint Standard Operating Procedure" complaints can be received via (b) (4) . There is no official complaint file to document or track such complaints. Your firm markets and distributes human umbilical cord-derived products that include but are not limited to: Wharton's Jelly and Exosome Products: e Private labels: (b) (4) e Customer private labels: (b) (4) Umbilical Cord Blood Products: e Private label: (1D) (4) e Customer private labels: (b) (4) Respectively, your firm has distributed (©) @) units marketed as Whartons Jelly labeled for (b) (4) (b) (4) units marketed as exosomes labeled for (b) (4) units marked as growth factor labeled for (b) (4) and (©) (4) units marked as cord blood marketed and labeled for (b) (4)

A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary, has not been established.

Specifically, since beginning operations in January 2021 your firm has not established written procedure for recall operations. Your firm markets and distributes human umbilical cord-derived products that include but are not limited to: Wharton's Jelly and Exosome Products: e Private labels: (b) (4) e Customer private labels: (b) (4) Umbilical Cord Blood Products: e Private label: (1) (4) e Customer private labels: (b) (4) Respectively, your firm has distributed (©) 4) units marketed as Whartons Jelly labeled for (b) (4) (b) (4) units marketed as exosomes labeled for (b) (4) units marked as growth factor labeled for (b) (4) and (6) (4) units marked as cord blood marketed and labeled for (b) (4)

The distribution system is deficient in that each lot of drug product cannot be readily determined to facilitate its recall if necessary.

Specifically, during a review of your product transfer logs to customers that are tracked using Microsoft Excel spreadsheets, it was noted that records pertaining to lot distribution could not be reconciled.

Toassist firms inspected in complying with the Acts and regulations enforced by the Food and Drug Administration.

Section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 USC 374(b)) provides: "Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him which, in his judgment, indicate that any food, drug, device, or cosmetic in such establishment (1) consists in whole or in part of any filthy, 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."

SOP for critical steps in shipping is inadequate.

Specifically, BI-RCV SOP 033-AA-VS-01719 “Packing Product " for Shipping” does not describe the duration in which the drug substance final containers need to be loaded in the _In addition, the SOP lacks instructions on the activation ofRCV final container.

Equipment preventive maintenance isnot adequate to prevent frequent malfunction.

Specifically, seal leaks were found.on the final container bottle head tubing ofthree DS batches (Batch # |(b) (4), (4), and (6) (4) after sealing (NNN)I@)NN. FAD! OVEFIS)

Equipment used in the manufacture, (b)(4) of drug products is not of appropriate design to facilitate operations for its intended use.

Specifically, the 4 is not adequately qualified to produce| (b)(4) wa) for = (b)(4) ~—_[ products such as red cell preservation solution and anti-coagulant. a. On 11 SEP 24, we observed unknown white material b)(4 is (b)(4) pieces of equipment producing b)(4 for (64) product formulation. b.| (b)(4) _lis| (b)(4) landusedtoclean’ —=——(B(4)—SSCid equipment. b)( and (b)(4) L CA) equipment create b)(4 long _———(b)(4) ~———sinotused since 4 JUL 2024 d. Equipment connected tothe) ———(b)(4) ~—_—|suchas b)(4 4) |(Open to environment), an (b)(4) connections not represented on approved drawings. e. Approved Drawing for product} (>)(4) module *|does not show product solution! (b)(4) from; = (b)(4) ~~—_—| This module is used for Alyx, Amicus, and Intersol products. Red cell preservation solution and anti-coagulant solutions formulated with are used to manufacture Alyx, Amicus, Intersol, and Blood Pack Units. *This is a repeat observation from the previous inspection in September

Equipment and) (b)(4) |are not maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.

cifically, theenvironment of solution (b)(4) is not adequately controlled with c b)(4 . For example: a. On 12 SEP 2024 and 14 SEP 2024, we observed the showed apparent biological growth on_ (b)(4) |and from) (b)4) | —(b)(4) __ |along with b)(4 distributed through the equipment. This|s—”-—sSO(by(4)——“(«ts*‘“‘;*CS™CSCSSCOtrcOlled AS Grade} | environment. b. On 12 SEP 2024 and 14 SEP 2024, we observed the showed apparent biological growth and (b)(4) on supply | b)(4 . This | (b)(4 controlled as Grade“ environment. c. On 12 SEP 2024, we observed approximately (b)(4) removed from (b)(4) showed apparent biological growth. Fill (b)(4) _|is controlled as Grade» environment. d. On 10 SEP 2024, we observed| b)(4 in (b)(4) showed apparent biological growth. b)(4 is not a classified/controlled environment. e. On 13 SEP 2024, we observed a yellow/brown stain on in | (bya) b)(4 with unknown cause. (b)(4) is controlled as a Grade »™|environment. (b)(4) is used in formulating solutions for Amicus, Alyx, and Intersol solutions.) (b)(4) __|is used in the manufacture of Blood Pack Units.

Buildings used in the of a drug product are not maintained in a good state of repair.

Specifically, manufacturing equipment and facilities showed disrepair that creates difficult to clean surfaces and difficulty in maintaining clean equipment. For example: a. On 10 SEP 2024, we observed a (b)(4) sagging from apparent saturation with rain water. ee b. On 9 SEP 2024, we observed (b)(4) were not covered/closed after cleaning in (b)(4) (b)(4) c. On 10 SEP 2024, we observed peeling paint on (b)(4) d. On 10 SEP 2024 and 13 SEP 2024, we observed cracked and peeling floor surfaces with) (b)(4) b)(4 . Additionally, we observed| (b)(4) \with peeling) (b)(4) near the _ __(b)(4) rn e. On 10 SEP 2024, we observed white crystal formations on (b)(4) iin the (b)(4 ) | b)(4 is used in formulation of fluids for Blood Pack Units. (b)(4) is used in formulation of Alyx, Amicus, and Intersol products. *This is a repeat observation from the previous inspection in September 2022*

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that in-process materials conform to appropriate standards of identity, strength, quality and purity.

Equipment for adequate control over air pressure is not provided when appropriate for the manufacture, (b)(4) of a drug product.

Specifically, your firm does not adequately monitor areas of distinct environmental classification. Environmental air samples are collected] (b)(4) which does not provide adequate data on Grade| rooms where blood pack unit and apheresi products are | (b)(4) _ For example, b)(4) for Alyx, Amicus, and Intersol; as well as ( b)(4) for Blood Pack Units. Additionally, there is no continuous monitoring of differential pressures between rooms. of differing classifications. For example, (Gradei) to (b)(4) (Grade ) where the differential pressure is documented once per day of production.

Washing and toilet facilities lack hot and cold water.

Specifically, your hand washing facilities for employees entering manufacturing and lab areas are deficient as follows: a a. On 10 SEP 2024 and 13 SEP 2024, we observed cold water for hand washing in b)(4 for ( b )( 4) f b. On 10 SEP 2024 and 11 SEP 2024, we observed cold water for hand washingin) —_(b)(4)_—_ for (b)(4) . c. On 10 SEP 2024 and 13 SEP 2024, we observed hand cold air in (b)(4) for.(YA).()(4)int by(4)——iand (YA) /C(b)(4)———~—~—Ss before employees enter production areas. d. We observed no hand washing stations for employees entering the, (b)(4) lab. The firm does not have a procedure instructing employees to wash hands before entering the (b)(4)

Records are not maintained so that data therein can be reviewed at least annually to evaluate the quality standards of each drug product to determine the need for changes in specifications or manufacturing or control procedures.

Specifically, Annual product reviews fail to include data regarding ( b )(4) components used in manufacturing of blood pack units and apheresis components (Alyx, Amicus, and Intersol). For example APRs do not include defect rates, testing summaries, or supplier qualification status. Annual product reviews for BPU, Alyx, Amicus, and Intersol products for the calendar year 2023 were significantly delayed until being signed and approved on 12 SEP 2024.

The validation ofthe(b) (4) used during the (6) (4) manufacture ofthe AUCATZYL (Obecabtagene autoleucel) drug product is not complete.

Therefore, the validation does not ensure assurance. Specificall a. have not been completed on(ob) (4) which is used to prepare the (6)(4) lentiviral vector and which is used to prepare b. In the , the validation of he(DA demonstrate growth of(b) (4) iin every validation run.

Critical utilities (b) (4) 0 are not adequately validated or routinely monitored to ensure reproducible quality.

Specifically, the validation testing of(0) (4) 0 ets performed by collecting a from each(b) (4) and routine monitoring is not performed. Ls Disiafectant tcc are inadequate to mitigate cross-contamination. Specifically, the disinfectant study does not include data to support the effectiveness against viral contaminants. EMPL OYFF(S) SIGNATURF

Quality oversight is inadequate.

Specifically, a. There is a lack of a separate and independent quality assurance unit needed to perform objective review. b. Internal audits are not performed at the defined frequency according to the Quality Manual. c. No independent review of final test reports and associated test data is performed. d. An administrative staff member was identified as acting Quality Assurance Manager, and no evidence was found that this individual performs any quality assurance activities as defined by Quality Manual and confirmed per employee. e. SOP ADMIN006, How to Write a Standard Operating Procedure, does not require review and approval of any technical or QA procedures. No evidence was found of any QA review of any controlled SOPs. f. Per the Clongen Quality Manual, (b) (4) review is required to be conducted by the Laboratory Director and the Quality Assurance Manager to assess current policies, practices and procedures to determine effective changes. Clongen stated that (b) (4) review has not been performed since 2023. However, that is no evidence of any reviews being performed.

Written procedures are not established for critical laboratory tasks.

Specifically, for: a. Sample receiving and (b) (4) when receiving sample shipments from (b) (4)

Equipment is not qualified or monitored for its intended use.

Specifically, a. Technician was observed using out of calibration equipment (pipette and thermomixer) during the extraction step for mycoplasma testing on June 16, 2025. (©) @) of® pipettes on a rack were discovered to be out of calibration. b. Preventive maintenance (PM) and calibrations requirements are not established and routinely performed on critical equipment including the (b) (4) PCR System (ID#(®)(4)), (b) (4) Thermomixers# (6) (4) (b) (4) gel imaging system (ID #(6)@4)), Electropheresis (b) (4) (ID #H(b) (4), and ©) @) (ID # ®)@)), c. Qualification studies were not initially performed on the (b) (4) and (b) (4) freezers prior to use.

Quality control documentation and practices are inadequate.

Specifically, a. Test runs are not documented during performance including (b) (4) of electrophoresis gels, critical test parameter checks, and reagents lot numbers and expirations. b. Quality control of positive controls is recorded on an (b) (4) with no record of (b) (4) (b) (4)

Employee training and qualification is inadequate.

Specifically, administrative staffmember performs essential tasks such as (b) (4) with no evidence of training on updated procedures or non-existing procedures.

A quality agreement defining the roles and responsibilities of each involved party is not established.

Specifically, there is no quality agreement established with (b) (4) regarding mycoplasma release testing.

Quality oversight is inadequate to ensure (b)(4) drug substance (DS) has the | 7 (b)(4) it purports or is represented to possess.

For example, a. Your quality unit does not review production records adequately to ensure there are no errors that have occurred. Master Batch Records (MBRs) have!(b)(4)lndergone complete review and sign-off by Quality Assurance followed by re-review after additional issues are identified that require corrections and notations. b. Lots (b)(4) and (b)(4) have been re-dispositioned three times after the initial batch release due to identification of additional deviations subsequent to batch disposition. c. Deviation management is inadequate to demonstrate quality oversight of the manufacturing process and does not adequately identify, document, or investigate the impact to ( b )( 4) DS. For example, i. Deviations from written production procedures are not identified as deviations, and procedures governing deviations are not followed. For example, 1. During performanceofMBR. (b)(4) /for lot (b)(4) Me was noted that the (b)(4) [did not have the appropriate| «) connector to connect to the)(b)(4)| Holly Brevig, CSO, Lead Inspector 05/30/2025 OF THIS PAGE SUSAN BUTLER -S Smyanesm xcsinrum Susan S. Butler, Staff Fellow Jacob LBterman jean Jacob L. Bitterman, Biological Reviewer DISTRICT

Environmental monitoringprogram is deficient to ensure environments are classified and controlled to manufacture (b)(4) DS.

For example, a. Validation of the environmental monitoring (EM) sampling for viables has not been conducted. For example, EM samples for viables are transported to an off-site testing facility; however, no studies have been conducted to assess the impact of this process on microbial recovery. b. There was no non-viable particulate monitoring of the ISO) (b)(4) during the manufacturing activities for the processing of (b)(4) DS PPQ lots. OF THIS PAGE SUSAN BUTLER-s —o Susan S. Butler, Staff Fellow Jacob L. Qty sore ac Jacob L. Bitterman, Biological Reviewer Bitterman -S Didte:2025.08.200042:03 400" DISTRICT

Qualification of areas used to manufacture (b)(4) DS is not adequate.

Specifically, a. Cleanroom recovery tests do not support‘your dela for differential pressure alarms contained in the building management system (BMS) (b)(4) | Specifically, you retain a delay setting for differential pressure alarms of |__(b)(4) _despite the cleanroom installation and operational qualification (IOQ) demonstrating a much more rapid room recovery time (e.g., the IOQ for clean room suite, (4) recovers in less than or equal to (b)(4) |). Thus, the differential pressures failures in areas used to manufacture (b)(4) | drug substance are not investigated. b. The Air Handling Unit (AHU) | covers the Grade (b)(4) and the Grade) (b)(4) |(b)(4) | However, the qualification failed to evaluate all rooms supplied by «| For example, Rooms and | ©) |were not included in the cleanroom qualification. Therefore, there is insufficient data to demonstrate that these rooms are ina state of control. c. Diagrams supporting airflow into cleanrooms are deficient. For example, document H-01-000- 621 in support of airflow of cleanroom suite} 4) does not demonstrate a scientifically founded air balance. Thus, the documentation does not support adequate airflow suitable for supporting the respe

Monitoring of utilities is deficient.

For example, a. Critical product contact (b)(4) [used in the manufacture of (b)(4) |DS is not adequately qualified or| (b)(4) |monitored. Specifically, incoming quality control testing is not performed on the (b)(4) |received from the vendor, and |_(b)(4)_|monitoring program has not 2

Disinfectant efficacy studies are inadequate to mitigate contamination and cross-contamination.

For example, a. The disinfection efficacy study does not demonstrate effectiveness against viral contaminants. b. The disinfection efficacy study does not demonstrate effectiveness against microbial agents for all representative surfaces in areas used to manufacture) (b)(4) DS. For example, the _(b)(4) __ that are used to transport material into and out of cleanrooms and store | (b)(4) lwere excluded from the study.

Procedures regarding out of specification results described in sop, tby(4) Laboratory Investigation Management, are inadequate.

The procedures have insufficient detail regarding when expanded investigational activities will be required, how hypothesis testing or retesting investigations will be designed, or how results of the expanded investigational activities will be used to make decisions.

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.

Specifically, your firm's environmental monitoring (EM) program for cross-contamination detection has significant limitations in scope and coverage. (b) (4) (b) (4) , are manufactured at your facilities. However, there are no analytical methods for detection of (b) (4) from (b) (4) samples taken from (b) (4) areas. The current test method utilized only detects (Bb) (4) and fails to include (b) (4) manufactured in the same facility. From January 1, 2025, to November 20, 2025, alone, your firm tested at least © EM samples, but only for the presence of (b)(4) . Results for these were found to be false positives for the presence of (6) (4) , and were then subjected to confirmatory testing, (b) (4) (6) 4) (Procedure RD-02-01-020, Document No. 1138932, Revision H) with a concentration limit of© © for (b) (4) detection.

The responsibilities and procedures applicable to the quality control unit are not fully followed.

Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel.

Employees engaged in the manufacture and processing of a drug product lack the training required to perform their assigned functions.

Specifically, QC analysts responsible for testing of environmental samples (EM) for the absence of (b) (4) are not trained by the quality team, resulting in inadequate oversight of personnel qualifications. For example, per the firm’s training procedure No. RD-03-01-019, Revision W, each analyst is required to complete, including but not limited to, (b) (4) containment training (Training Code: (b) (4) containment training (Training Code: (b) (4) ), and good documentation training. QC analysts performing (b) (4) testing have not completed mandatory training requirements per the firm's training procedure (Document No. RD-03-01-019, Revision W).

Laboratory records do not include a description of the sample received for testing, the quantity of the sample and the date the sample was received for testing.

Specifically, your firm does not maintain adequate sample logs for environmental monitoring (EM) samples that failed the absence of (b) (4) test per (b) (4) for Determining the Absence of (b) (4) in Environmental Samples (Document no. RD-02-01-020, Revision S). For example, between January 1 and November 20, 2025, a total of®@) EM samples failed the (6) (4) test for absence of (b) (4) However, there is no record of the receipt and tracking of these samples, which were subjected to (b) (4) Test Method (Procedure RD-02-01-020, Document No. 1138932, Revision H).

The quality control unit lacks authority to review production records to assure that no errors have occurred and fully investigate errors that have occurred.

Specifically, Your firm failed to document and investigate the use of an out-of-calibration thermometer during the filling of (b) (4) cylinders. On 04/27/2026, an out-of-calibration thermometer (Serial #(b) (4)) hat had exceeded its calibration due date by approximately four months was observed being used during the filling of Lot (b) (4). The thermometer was used to determine cylinder fill pressure based on temperature during filling operations. No documentation, deviation, investigation, or product impact assessment was initiated to determine the effect of the out-of-calibration thermometer on product quality. Approximately lots have been released since Dec 2025.

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Specifically, The Quality Unit failed to maintain adequate oversight of the Quality Management System (QMS), including the following: a) Qualification Protocols Failure to review and approve execution data, and associated documentation to confirm that acceptance criteria and all required activities were completed before implementation, as documented througha final report or formal authorization, including but not limited to: e LD7047: (b) (4) Method created on Dec/01/2025, to support chemical assay testing of approximately ©samples, with the final report approved on April 29, 2026. e DV1049: (©)(4) Media Validation/ Expiration to support the (6) (4) expiration dates of (©) @ media used for microbial testing of approximately "® samples (lot (b) (4) ) with the final report approved on April 28, 2026. b) Out-of-Specification (OOS) Investigations Failure of scientific rationale and evidence to support identification of root causes, and implementation of actions for OOS investigations, including but not limited to: e 20251100SC002 (completed Nov/26/2025): No root cause identified; no rationale provided for

Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.

Specifically, a. The intermediate precision studies documented in the Method Verification Report for (b) (4) by HPLC (Method ID: LD7045, Effective date: 02/09/2026) and the Method Verification Report for (0) (4) by (b) (4) (Method ID: LD7023, Effective date: 12/30/2025) are deficient in that the results presented for Analyst II were performed on two separate dates and combined as a single dataset without adequate justification. Furthermore, a laboratory error was identified in each of the two analyses. These errors were not documented, investigated, or disclosed in the corresponding Method Verification Reports. b. The Intermediate Precision study for Method Validation Report for (b) (4) by HPLC (Appendix I) (Method ID: LD7045, Effective date: 01/30/2026) had results which failed the specification. The test specification was changed, and a second test was performed. The results for the second preparation, passed the initial specification and were documented in the final report. The original failing results and the specification change were not included in the final

Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.

Specifically, A. You have not performed product specific Filling Validation Studies for (b) (4) (b) (4) and (b) (4) (b) (4) drug products at your firm. B. You have not completed equipment cleaning validation studies to validate equipment cleaning SOP #10, Cleaning and Sanitization Procedure Packaging Room and Equipment, effective date 02/01/2024 which is used for the cleaning of shared equipment used in the packaging of the drug products (b) (4) (b) (4) and (b) (4) (b) (4) as well as several (Db) (4) products.

Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use.

Specifically, your firm failed to complete protocol driven Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) studies for the following packaging machines

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.

Equipment and utensils are not cleaned and maintained at appropriate intervals to prevent malfunctions, contamination, that would alter the safety, identity, strength, quality or purity of the drug product.

Specifically, On 04/16/2026, I observed presence of unknown “Reddish and Whitish” residue inside the product loaders/elevators and inside the product filling ©@ (®) on the (b) (4) Machine Model (b) (4) . You did not document when the equipment was last used, the products packaged, lot number, and cleaning records performed for the equipment. The (b) (4) Machine Model (b) (4) is utilized for packaging capsules and (b) (4) and (b) (4) drug products at your firm.

The batch production and control records are deficient in that they do not include a statement of the actual yield and percentage of theoretical yield.

Specifically, Your Packaging Batch Records for () (4) and (b) (4) drug products do not include a statement of the actual yield and percentage of theoretical yield for packaging, the identity of individual major equipment used, the identification of the persons performing, and checking each significant step in the operation for each batch of drug product packaged (not all-inclusive).

Drug products are not stored under appropriate conditions oftemperature, humidity, and light so that their identity, strength, quality, and purity are not affected.

OF THIS PAGE | DISTRICT ADDRESS AND PHONE NUMBER ., 3rd Fl 04/14/2026-04/20/2026* Parsippany, NJ 07054 een (973) 331-4900 Fax:(973)331-4969 3030238141 [email protected] SUED Mr. Dhaval A. Shah, President Paxeuticals LLC 333 New Rd, Suite 3 CITY, STATE, ZIP CODE, COUNTRY TYPE ESTABLISHMENT INSPECTED Parsippany, NJ 07054-4212 Contract Packager Specifically, your firm failed to complete a summer warehouse temperature mapping study in the warehouse where you store finished (b) (4) which has a labeled storage condition of merc.

(b) (4) identified on equipment product contact surfaces is not characterized nor its potential impact to drug substance quality assessed.

Specifically, Procedure SOP-105027 (“SOPQ: Visual Inspection ofProcess Equipmentfor Cleanliness”, Version 2.0, Effective on 02/14/2019, and Version 3.0, Effective on 02/01/2024) lists (b) (4) types of (b) (4) as Type (b) (4) , and instructs for a work order initiation upon identification of surface quality and integrity issues, if a work order does not exist. In addition, the procedure the procedure states that “(B) (4) and to (b) (4) ” However, (b) (4) identified during (b) (4) cleaning audits performed for Prothrombin Area Equipment, and during (b) (4) cleaning audits performed on Bulk Thrombin Area Equipment, was not characterized to determine the type of (b) (4) , hor was a risk/impact assessment for the identified (BD) (4) performed. The (b) (4) for (b) (4) inspected as part to the (6) (4) visual inspection of process equipment on| (1) (4) do not provide information about the type of (b) (4) identified nor about the size of (b) (4) or surface area covered to compare with (b) (4) from the previous years. (DB) (4) inspection in (5) 4) found that (b) (4) exhibited (Db) (4), including (b) (4) and (b) (4). (b) (4) inspection in (©)(4) found that (b) (4) exhibited (D) (4). including

Microbiological recovery studies used to validate the swab testing method used in cleaning validation are inadequate.

Training and qualification related to laboratory operations are not adequately documented or implemented and associated corrective actions are not demonstrated to be effective.

Specifically, A.Your firm lacks formal written instructions and training provided to analysts on proper pipette usage. Specifically, an analyst “oe was observed on 07/23/2025 using improper pipetting technique (bubbles were observed in the pipette tip) during sample preparation for bioburden testing of batch (b) (4) of the PROTHROMBIN intermediate. On that same date, another analyst (°) was observed using improper pipetting technique (bubbles were observed in the pipette tips) during sample preparation for potency testing ofbatch (b) (4) of the PROTHROMBIN intermediate using the “ (b) (4) " pipette with the (b) (4) —. This ©0 O}MO) ad previously been the subject of CAPA-162998 initiated on 04/27/2025 as a result of deviation QE- 173372 initiated due to an Out of Limit result for the potency test caused by inconsistent pipetting volumes. The CAPA required a senior analyst to observe ™”” use of the pipette ( (b) (4) and provide retraining if needed. The CAPA also restricted” from the pipette ( (b) (4) ) for volumes of 1 mL or less with the (b) (4) until this evaluation was completed. There is no documentation demonstrating that has been observed, retrained, and reassessed by the seni

Procedures regarding segregation of duties are inadequately defined or not always followed in the Quality Unit.

Specifically, A. (b) (4) does not adequately define roles and responsibilities for individuals regarding use of accounts for individuals having dual system access privileges for (b) (4) used in potency testing. For example: i.On 5/20/2025, (b) (4) ii.On 5/12/2025, (b) (4)

Investigations (nonconformance reports) are not initiated in a timely manner after detection of a deviation according to (4) ‘SOP-32984, Nonconformance and CAPA Pharm Segment.

Specifically, the SOP requires nonconformance reports to be created within fter detection/identification. Since January 2024, creation of 19 nonconformance reports exceeded the requirement with at least three reports exceeding 21 days or more after detection. / /

Procedures describing the handling of written and oral complaints related to drug products are deficiently written or followed.

Specifically, SOP IG_MSP-000532_ING version 20.0 describes the process for receipt, management, and investigation of customer product quality complaints. Your firm’s handling of customer product quality complaints investigation is deficient in that it does not require practice of testing retention samples of respective lots for most frequent complaints. Since 2021, your firm has received US customer product quality complaints for Fibrin Sealant [VistaSeal] categorized as biologics thawing issue as follows: 2021, 46 complaints; 2022, 31 complaints; and 2023 (Q3), 14 complaints. For example, review of selected biologics thawing issue complaint investigations 800010433, 800010845, 800010963, 800011603, and 800011859 revealed that none of the complaints investigated were supported by testing the retention samples. There is no documented evidence that your firm retention samples were tested as part of the complaint investigation for biologics thawing issue.

There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed.

Deviations from written production and process control procedures are not justified.

Specifically, Your firm’s SOP IG_MSP.000577 Investigation Protocol of Analytical Deviation in the Quality Control Laboratories describes the procedure for investigating any deviation from approved procedure or specification. Analytical deviation investigation record is required, and a_ predefined testing plan is required to isolate and confirm OOS results. Flebogamma batch*(b) (4) was initially tested as QC sample — (b) (4) © on 31 January 2020 and retested as QC sample “"(b) (4) on 07 February 2020. There is no documented evidence of a laboratory OOS investigation opened for the initial test result. The initial test result met the Method specification. No predefined test plan was approved for retesting Flebogamma batch . There was no justification documented for conducting a retest on Flebogamma batch . Consequently, there is no justification for the average ofPee within specification test values reported in (0) (4) for Flebogamma batch— (b) (4) the assay results should be reported as single test value result for the batch.

Your firm failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.

The written stability testing program is not followed.

Specifically, The Protocol # BIG-RD-SOP-000282, titled “Deviations General Procedure for Stability Studies ( (b) (4) | Barcelona, Scientific Innovation Office)” (Version 2.0, Effective from 6-Oct-2023; Section 7.2.1 Notification) is inadequate because it permits you to not open out of specification (OOS) investigations for reoccurring OOS at different time-points and different batches, if “the notification has been created” for the first OOS result (“i.e analytical incidents under accelerated conditions that have expected results due to previous studies”). Specifically, only one OOS investigation was opened for Fibrin Sealant Batch A04G03174 as Deviation # 300116307 for the 4 ml produced at (b) (4) with OOS result 3.6% fores (°) h C.) ee However, the reoccurring OOS results from the following batches and time-points from the same Stability Study at (b) (4). 0 hours were not investigated. All results were out of specification limit (b) (4) fores (2) C9 (document # IG_ESP-00030-ING): Batch #Time PointResult,% ee A0AGO3I7AI AOAGOSITAI 6 ADAGOSET2I _

The final study report did not include a description of all circumstances that may have affected the quality or integrity of the data.

Specifically, (b) (4) as well as any instruments used to monitor temperature during (b) (4) and (b) (4) were not identified in the source records for any of the subjects for the (b) (4) study.

The study director failed to assure that the protocol, including any change, was approved and was followed.

Specifically,(0) (4) clinical observations related to alopecia were documented in the source records for) (4) ut of i ® subjects but were not included in the (b) (4) Report of the (b) (4) Final Report as required by the protocol. For example, Subject ID Abnormal Finding Recorded Dates ©) (b) (4) (b) (4) - at (b) (4) (b) (4) “— (b) (4) (b) (4) al (b) (4) (b) (4) | | (b) (4) b) (4 b) (4 ‘e) ( (b) (4)

Standard operating procedures have not been established for test system observations and handling of (b) (4) (b) (4) or (®) (4) during study.

Specifically, for the (6) (4), (10) (4) , and () (4) studies, the firm completed test system observations and took actions for (b) (4) or (6) (4) However, no standard operating procedures were established that describe these processes.

The quality assurance unit failed to maintain a copy of a master schedule sheet that contained all required elements for all nonclinical laboratory studies conducted by the testing facility.

Specifically) (4) procedures including(®) (4) preparation, (b) (4) , test system observations (©) (4) (6) (4) data collection, and sample collection were performed by the firm for the ( (4) © @ ang () (4) studies. However, no master schedule was maintained listing these ©) studies.

The study director failed to assure that all raw data, documentation, protocols, specimens, and final reports were transferred to the archives during or at the close of the study.

Specifically, (b) (4) and the (b) (4) signed Amendment” of the protocol for the (1) (4) study were not transferred to the archives after the study was completed on (1) (4) . A copy of (b) (4) (b) (4) was not (b) (4) as reported in the Compliance section of the (b) (4) Final Report, until (10) (4)

A quality program which addresses all of the core CGTP requirements, appropriate for the HCT/Ps manufactured and the manufacturing steps performed, has not been defined and followed.

Specifically, your firm’s quality program has not been defined or followed for the following: 1.The following temperature/humidity excursions occurred in the refrigerators or FDA Testing areas below: 5 (b) (4) a. Fridge (Sample Storage) b. Fridge one (Sample Storage) . (b) (4) c. Fridge 1 (Reagents Storage) d. (b) (4) Room e. (b) (4) Room Nonconformances were not documented or investigated addressing the excursions above. According to procedure entitled, “Temperature Log Procedure, Version 1.0, Effective Date: 04/01/2024” Section 6.4 states: “Normal refrigerator temperature range for refrigerators is 7 (4 . considered between is | °C)/).” Sections 6.6 — 6.6.3 state: “6.6. IMPORTANT: If the temperature is out of range, proceed to the following steps: 6.6.1. Close the fridge/freezer s ” S (b) (4) door and tag the instrument as “Do Not Open”. 6.6.2. Leave the instrument closed for at least . 6.6.3. After (b) (4) , recheck the temperature, if the temperature is still abnormal,

Procedures appropriate to meet core CGTP requirements for all steps that you perform in the manufacture of HCT/Ps were not defined and followed.

Specifically, Your firm has not defined in your procedure entitled, “Procedure for repeating and reporting (B) (4) samples ( (b) (4) ), Version 1.0, Effective Date: 07/31/2023” the following manufacturing steps regarding review, sign-off, and release of final test results to a client are captured. For example, data entry and/or transfer into your (D) (4) system was not described. The (b) (4) review and documentation of the performed reviewed were also not described.

Records were not detailed as necessary to provide a complete history of work performed.

Specifically, during the inspection when I reviewed quality control and preventative maintenance records from August 2023 — December 2024 for the equipment and areas below, the following were missing documentation of review by signature and date: a. (b) (4) b. (b) (4) Oe we) d. e. (b) (4) f(b) (4) Qc (b) (4) Log g.Refrigerator (b) hRefrigerator (4) i.Refrigerator jf) (4) Room k(b) (4) Room

Records were not retained for the appropriate length of time, 10 years after their creation.

Specifically, your firm’s _(b) (4) is programmed to store test results for (b) (4). Your firm does not have the original testing data prior to (BD) (4) , THIS IS A REPEAT OBSERVATION.

A records management system relating to core CGTP requirements was not maintained and documented.

Specifically, during the inspection I reviewed quality control records regarding refrigerator temperature, room temperature, and humidity, however your firm was unable to provide quality control records for the following: a.Refrigerator"(Sample Storage) b.Refrigerator' (Sample Storage) : (b)(4) c.Refrigerator (Reagent Storage) d(b) (4) Room e(b) (4) Room

There are no individual reject rates established for each defect category that is classified as(D)(4) The reject rate established is cumulative for all (b)(4) defects.

Change Control 219756 dated June 11, 2012 was implementedto change the cumulative reject rate for (b)(4) _ defects, such as associated with Microbial contamination” from oO a cumulative reject rate of or the WinRho (liquid formulation), HepGamB (Liquid), and Vaccinia Immune Globulin (VIG) products. A. are categorized as defects as opposed to “ is categorized as a Defect.

Not all lots ofproduct that fail the Acceptable Quality Limit (AQL) after the initial (B)(4) inspection is performed are reinspected under tightened limits for both the additional (6)(4) reinspection performed by production or the AQL performed by Quality.

For example: Deviation 212555 was initiated on May 29, 2012 for HepaGamB lot (b)(4) using 3mL Vial Lot"on having an atypical number of(6)(4) defects (classified as a (6)(4) defect), detected during the initial (6)(4) inspection process. The Acceptable Quality Limit for this inspection also failed the acceptance criteria as a vial with the(AVE) defect was detected. The lot was 100% reinspected for this defect. There were noreject limits established for this 2nd reinspection and there was no AOL performed for this reinspection. This lot was reinspected a third time under a tightened limit of (MAY dy land failed to meet this criteria with additional defects being found. Additional lots ofproduct that were affected by this deviation were also reinspected and failed either the reinspection and/or the AQL for the(b)(4) defect of here are no procedures in place which address the criteria for the reinspection of lots that fail the initia nspection or an AQL. Additionally, there are no procedures in place which address the limit for the number ofreinspections that can be performed on any given lot. .

There is a lack of assurance that there is adequate control over critical documents including, but not limited to, Policies, Standard Operating Procedures (SOPs), Work Instructions (WIs) Forms, Electronic Templates (ETs) Drawingsand Manuals.

The firm’s Record and Information Denartment (R41) dictribntac aantentlos documents}, »|, inwhich documents are to be returned is not always effective in that numerous incidences were o bserved where obsolete documents have been used by operators and technicians and have resulted in deviation investigations. Examples include, but are not limited to: [ - EMPEDYEE(S) SIGNATGRE on

SOP 25.026.0002.01.00 defines a On Oiled JO Ment A The printing, and circulation of such documents are not always controlled: A.

The firm uses(b)(4) software as a system for maintenance ofcontrolled documents. This allows for documents to be(0)(4) te use in various departments. There is a lack ofassurance that there is adequate control over controlled documents available to operators on(b)(4) Users who have access to the system are allowed to print offany of the effective controlled forms and procedures without accountability for these documents.

The firm’s deviation control system is inadequate in that it fails to adequately assess the classification of .

deviations that may affect product quality. Specifically, during manufacture of Liquid WinRho lot (b)(4) and HepaGamB lot(BVAYo ithe was exceeded. There is a lackofassurance that the product impact for these lots was adequately addressed in that iati i Deviations” that are use Per SOP 10.060.0023.20.19, QA Batch Record Revi eviations require

Deviation 109218 was initiated on June 7, 2010 for HepaGamB Finished Goods lot (b)(4) having been EMPEYEE(S) SIGHATURE——Z

Written procedures are not always followed.

The(D)(4 treatment module of the batch record (Document number 24.5002.08, step 17,

There is no defined change out period for product contact flexible hoses used in manufacturing.

The SOP for Growth Promotion of media used for’environmental monitoring is incomplete in that it does not specify the length oftime test articles should be incubated.