글로벌 규제 모니터
2026년 7월 4주차 규제뉴스

Complaint records are deficient in that they do not include the findings ofthe investigation and follow-up.

Specifically, A. Your firm failed to adequately investigate customer complaints that were received as Adverse Events. The following adverse events were reviewed and deemed inadequate; this is not an exhaustive listing: i. Complaint# 1406005 opened on 08/03/2025 as an Adverse Event and critical complaint. Customer found a shard of metal in the ointment that was on their®®. The product was(b) (4) (6)(4) NNN Ointment 149, Lov! (BYKAYI Expiration (b) (4) ii. Complaint# 1285238 opened on 12/20/2023 as an Adverse Event. Customer stated they immediately felt a burning, intense itching, and what felt like "shards of glass," resulting in their (4) becoming (BAYT NEE: This product was (E)IC4) lll iilllllllllll = (4) Solution USP (694), Lov! (6) (4). Expiration (ON). iii. Complaint# 1269630 opened on 11/15/2023 as an Adverse Event. Customer had a severe reaction to the (8%) utilized. The product was (O)(4) (b)(4), Lot# (6)(4) Manufacturer Lot# (6) (4), Expiration ©)@). B. Additionally, your firm failed to file a Field Alert Report (FAR) for Complaint# 1329875 opened on 08/07/2024 as an Adverse Event (AE). Customer stated they noticed a "black" substance inside the (b)(4) and on the inside of

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

Specifically, A. Your operators are not following appropriate aseptic practices during active manufacturing activities. The following is not an exhaustive listing of the inadequate aseptic practices observed during the commercial manufacturing of(b) (4) Solution (6) (4) (Lot# (6) (4)) on Filling Line "*: | i. Brisk movements and walking swiftly throughout the Grade B room near the (6) (4) Filling Line (Grade A). | ii. Donning a) pair of sterile gloves and moving away from the glove donning station. We also | observed some instances where they put on one glove and held the second one as they walked away from the station and utilizing the sterile © @ pair to throw away trash. y P y | iii, While changing the environmental monitoring plates within the Grade A area of Filling Line# ™®, the operator was seen moving quickly and reaching over areas where open and exposed empty | bottles were located. iv. During an intervention ofremoving a stuck empty bottle, we observed the operator manipulate the forceps at the end that comes in contact with the open container. Additionally, the operator abruptly manipulated ajammed bottle in a matter that the bottle was flicked into the(b) (4) ()(4) ste

Written procedures are not followed for the receipt, storage and handling of.

Specifically, A. Your firm failed to document and complete the Purchasing Notification of Missing Documents Form (SOP21-076 Form B) in your locked Quarantined cage for the following incoming shipments: i. (G4) Material (GAY. Lov# (BPAY) received on 16-FEB-2026 ii. (6) (4) (Material# (b)(4) _) received on 1 1-MAR-2026 iii, = (BY) materials (Lot# (6)(4) received on 11-MAR-2026 These items have not been issued the SOP21-076 Form B. This issue was not resolved within the required time or escalated to the Warehouse and Quality Management Team as required by SOP21-076, Receiving Process, Rev. 32, Effective Date: 24- NOV-2025 section 5.5.1. which states, “If the shipment is missing the proper documentation or is incorrect or incomplete, immediately email the Sourcing and Procurement, Materials Management and Incoming Quality departments a complete copy of SOP21-076 Form B (Purchasing Notification of Missing Documents). If the issue is not resolved within(6) (4) 7 escalate the issue to the Warehouse and Quality Management team.” Your Quality Assurance Manager stated that FormB has not been filled out for all materials missing documents upon receipt and the procedure has not been followed.

Personnel were observed conducting aseptic manipulations where the movement of "first air" in the ISO 5 area is blocked or disrupted.

Specifically, On 5/27/2026, the operator was observed conducting aseptic manipulations in which the movement of first air in the ISO 5 LAFH <Redacted B4> was blocked during the aseptic production of the following sterile drug products: • Sodium Phosphate 15mmgm in Dextrose 5% 100mL, Order ID: naphos052726, BUD 06/06/2026 • Cefepime 2g, Order ID: cefepime2052726, BUD: 06/11/2026 The operator's hand placement was observed blocking the bag port and needle, and vial stopper and needle. The operator's hands were positioned in a manner that obstructed the unidirectional "first air" between the HEPA filter and the critical work surface. On 5/28/2026, the operator was observed conducting aseptic manipulations in which the movement of first air in the ISO 5 LAFH <Redacted B4> was blocked during the aseptic production of the following sterile drug products: • Daptomycin (Cubicin) 750 mg/NS 50 mL, Order ID: 84305997, BUD: 05/30/2026

Personnel performed aseptic manipulations with exposed hair or skin.

Specifically, On 5/27/2026, during the aseptic production of the following drug product: • Ondansetron 8 mg, Dexamethasone 12 mg in Sodium Chloride 0.9% 50mL Order ID: 83618268, BUD 5/2712026 I observed your operator's head and face enter the ISO 5 LAFH located in the non-hazardous Oncology suite without adequate protective gowning. The skin surrounding the operator's forehead and eyes was visibly exposed and unprotected by appropriate gowning at the time of the aseptic manipulation. On 05/29/2026 during the aseptic production of the following drug products: • Roiniplostim 500 mcg/3 mL Syringe, Order ID: 83919777, BUD 5/29/2026 • Ipilimumab (Ye/voy) 50 mg in Sodium Chloride 0.9% 100 mL, Order ID: 84304960, BUD 5/29/2026 • Nivolumab 180 mg in Sodium Chloride 0.9% 82 mL, Order ID: 84304861, BUD 5/29/2026

Personnel were observed moving quickly in a critical area or in an area immediately adjacent to a critical area likely causing disruption of unidirectional airflow.

Specifically, On 06/02/2026, during aseptic production operations, an operator was observed moving quickly within ISO 5 LAFH <Redacted B4> while performing aseptic manipulations. At the time of the observation, the operator had an exposed, filled syringe of sterile drug product in hand. Rapid personnel movement within the ISO 5 critical zone is likely to disrupt unidirectional (first air) airflow, thereby compromising the sterile air barrier protecting exposed drug products and critical sites from potential inicrobial and particulate contamination. The following drug products were being aseptically produced at the time of this observation: • Daptomycin 750 mg in Sodium Chloride 0.9% 50 mL, BUD 06/04/2026, Order ID: 84305998 • Sodium Bicarbonate 8.4 % 150 mEq in Dextrose 5% 1000 mL, BUD: 06/03/2026, Order ID: 84327268

Lack of disinfection of supplies at each transition from areas of lower quality air to areas of higher quality air.

Smoke studies were inadequately performed under dynamic conditions.

Specifically, your firm failed to adequately perform smoke studies under dynamic conditions to demonstrate unidirectional airflow, simulate aseptic production, simulate worst-case conditions including all components, materials, and equipment present during actual or routine aseptic operations, and an adequate air quality environment within your ISO 5 critical areas.

Failure to appropriately and regularly clean and disinfect or sterilize equipment located in the ISO 5 area.

Specifically, your operator failed to disinfect the <Redacted B4> machine between aseptic production operations. For example: On 5/27/2026 during the aseptic production of the following drug products, the operator failed to disinfect the <Redacted B4> machine between aseptic production operations: • Sodium Phosphate 15mmol in Dextrose 5% 100mL, Order ID: naphos052726, BUD06/06/2026 • Cefepime 2g, Order ID: cefepime2052726, BUD: 06/11/2026 On 5/28/2026, during the aseptic production of the following drug products, the operator failed to disinfect the <Redacted B4> machine between aseptic production operations: • Daptomycin (Cubicin) 750 mg in Sodium Chloride 0.9% 50 mL, Order ID: 84305997, BUD:05/30/2026

Production areas have difficult to clean or contain porous, particle generating, or visibly duty equipment or surfaces.

Specifically, observations include, but are not limited to, the following: • Peeling and Chipped Paint -Non-Hazardous Oncology Pharmacy SCA-Peeling and chipped paint was observed on both side of the door frame and surrounding walls of the non-hazardous Oncology Pharmacy Segregated Compounding Area (SCA). This room contains an ISO 5 classified LAFH used to produce sterile drug products. • Protruding Sprinkler Head -In-Patient Pharmacy ISO 7 Classified Cleanroom (Hazardous)-A protruding sprinkler head was observed in the ceiling of the In-Patient Pharmacy ISO 7 classified cleanroom used to produce sterile hazardous drugs. The sprinkler head is located directly above the ISO 5 classified LAFH. The sprinkler head is not on a routine cleaning schedule and the date of last cleaning is unknown.

Failure to conduct media fills that closely simulate aseptic production operations under the worst-case, most-challenging, and stressful conditions.

Specifically, your firm's media fill protocol does not closely simulate the manipulations, container/closure configurations, or fill volumes used during actual production operations. For example, • During actual production, operators use syringe(s) to admix drug product into prefilled bags, sometimes changing the <Redacted B4> between each product addition. However, during media fill simulations, the operator aliquot <Redacted B4> of media and transfer it between <Redacted B4> bags <Redacted B4> dispensing into <Redacted B4> vials for incubation. • During media fill simulations, operators dispense approximately <Redacted B4> of media into <Redacted B4> vials for incubation which does not represent final fill volume of your firm's sterile drug products. However, during actual production operations, operators fill prefilled bags (ranging from <Redacted B4>) or syringes.

Materials were exposed to lower than ISO 5 quality air.

Specifically, on 5/28/2026, I observed sterile wipes stored on a counter across from ISO 5 LAFH <Redacted B4> within the ISO 7 classified cleanroom. The wipes were opened and exposed to ISO 7 air quality and were subsequently used to clean and disinfect the surfaces of the ISO 5 LAFH. According to staff, the wipes are stored in the ISO 7 environment until contents are fully depleted. Drug products aseptically produced on 5/28/2026 include but are not limited to • Daptomycin (Cubicin) 750 mg/NS 50 mL, Order ID: 84305997, BUD: 05/30/2026 • Cefepime/Sodium Chloride 0.9% 50 mL, Batch: 052826FS1, BUD: 06/12/2026 • Bumetanide 3 mg in Dextrose 5% 50 mL, Order ID: 84299952, BUD: 05/29/2026 • Acyclovir 600 mg in Sodium Chloride 0.9% 250 mL, Order ID: 84301319, BUD: 05/29/2026 • Iron Dextran 975 mg in Sodium Chloride 0.9%, Order ID: 84301224, BUD: 05/28/2026 On 5/29/2026, I observed sterile wipes stored in a cart adjacent to the ISO 5 LAFH in segregated compounding area (SCA) in the Oncology Pharmacy Suite. The wipes were opened and exposed to unclassified air and were subsequently used to clean and disinfect the surfaces of the ISO 5 LAFH. According to staff, the wipes are stored in the SCA

Written records of investigations into unexplained discrepancies do not always include the conclusion and follow- up.

Specifically, Investigations initiated and performed by your Quality Unit in response to laboratory investigation reports (OOS) and Quality Incident Reports (QIR) for drug products, are not always comprehensive to determine all potential root causes. Additionally, Corrective and Preventive Actions (CAPAs) as a result of investigations are not always comprehensive to address root causes or adequately documented to have been performed. For Example, A. The firm's out-of-specification (OOS) investigations forg@ system failures consistently lack adequate documentation of definitive conclusions and systematic follow-up actions. For example: -OOS 2025-032 (TAMC failure: ID Microbacterium phyllosphaerae), opened April 22, 2025: Investigation closed

Document control procedures under Quality Unit oversight are inadequate.

Specifically, During our walkthrough on September 15, 2025, we observed discarded cGMP records in your outside trash bins, QC laboratory waste bins, and QA office shred bins which appear to be cGMP-controlled records. Your document control procedures do not detail record discard and/or shredding operations and which records are permitted to be discarded. The firm's current document control procedures fail to establish adequate protocols for the proper disposal ofcGMP records, including criteria for determining which records may be discarded and appropriate disposal methods for different types of controlled records. Examples of these improperly discarded records observed during our walkthrough are listed below. A. Records found in outside trash bins are as follows: -Finished Product Specification (FPS) form for batcho@ printed in error and discarded without proper documentation. -Master Manufacturing Record for ® ml w@ campaign, signed by QA but listing incorrect product (should have beenw@ ml), discarded without proper documentation. -Refractive index test form, printed in error and discarded without proper documentation. -Finished Product Specification (FPS) forms for O@ duplicate

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. During our inspection, we observed that your firm has on numerous occasions extended product shelf life without supporting stability data. For example, your firm extended the shelf life for homeopathic drug product US o@ nl batch number ®@® originally expiring @@ This batch was manufactured around August 2024 and shipped to the US market. Due to excess unsold inventory at the distributor, your firm initiated Planned Process Deviation (PPD)®@ dated m@ to extend the shelf life from )(4) tom@ Your firm completed relabeling with a new batch number ®@ _ and new expiration date ofm@ with the repackaged batch awaiting QA review atthe time of our inspection. We observed similar shelf-life extension practices during our review of QIR-177. dated®@ for@@ batch number @ and QIR-229, dated @@ for O@ batch number @@ B. Your firm packagesa variety ofo@ homeopathic drug products after receiving bulk product from contract manufacturers. While your firm performed a risk assessment dated May 12, 2025, to identify potential risks associated with qualification, packaging processes, and their impact on product quality, patient safety, and regulatory compliance, your firm has not perform

Complaint investigations under Quality Unit oversight are inadequate.

Specifically, A. Your firm failed to conduct adequate investigations for complaints involving the same product and similar adverse events. Three complaints were received for @@ reporting similar burning sensations: -CCPF-41394, dated 08/26/2024, foro@ batch number @@ with a complaint that "o@ elt like burning sensation." -CCPF-41415, dated 10/04/2024, forme batch number @@ with a complaint that the product "madeg@ burn." -CCPF-41432, dated 11/01/2024, for m@ with a complaint that the product "burned@@ ra Despite having batch numbers available for two of the complaints, the firm did not perform any testing on retain samples. The firm's conclusion that there was "no trend for this issue" was inaccurate, as all three complaints involved the same product and similar burning sensations in them@ area, with the pattern established since the first complaint on 08/26/2024.

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

Specifically, A. During the review of video footage of your Process Performance Qualification (PPQ) batchm4) (filing batches), manufacturing date 08 Jul 2022, I observed the manufacturing activities documented in Batch Manufacturing Record (BMR) are not contemporaneous and reflective of the actual activities performed. For example, 1)Fora - Step no. “Record the time at (0 ofcompounding” is documented in the BMR as 13:38. Whereas according to the video footage, this activity was completed on 13:48 2)For Bioburden and—_ Sampling — Step no. i Specification section for “Record time of sampling” is documented in the BMR as 13:48. ereas according to the video footage, this activity was completed on 13:56. B. During the review of video footages of batch a. I observed four (4) production operators working inside a small Grade B and Grade C rooms and two (2) production operators working inside a very small Grade A area (separated by 4) from Grade B) moving rapidly from one area to other areas within the room potentially creating a lot of air turbulence. Additionally, these operators were observed bending down, moving objects from one comer to another inside Grade B and Grade C areas

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

Specifically, Your Quality Unit lacks an adequate oversight on the control and management of GMP documents that are critical to ensure the sterile drug products manufactured at the site for the US market are safe and effective. For example, but not limited to: A. On 06/08/2023, I inspected one (1) out of four (4) lock and key access controlled Shred-it bins maintained by your firm. I observed your manufacturing department employees destroyed ““GMP documents” pertaining to original records and raw data by disposing inside an access controlled “Shred- it” bin located in your manufacturing area’s write-up and printing section. This section is used by your production operators to print controlled GMP documents and complete documentation activities related to manufacturing and sampling. Many of the documents recovered from this Shred-it bin were signed under “Reviewed by” and “Quality Approved by” sections and dated. The following are some examples of the original controlled GMP documents found inside the Shred-it bin

The written stability program does not assure testing of the drug product in the same container-closure system as that in which the drug product is marketed.

Specifically, (b) (4) samples charged on stability at a contractor are not “labeled and packaged” (L&P) and are not stored inside materials that are consistent with the product L&P. Based on the pictures of stability samples stored inside chambers, I observed aboutba vials charged on stability were inside a closed thick

The retention period for drug product reserve samples (except those described in 211.170(b)(2) and (3)) is deficient in that they are not retained for one year after the expiration date of the drug product.

Specifically, Your procedures Q-27 (Reference and Retention samples) and Q-40 (Commercial Product Quality Review) are deficient in that there is no mention of storing retention samples at conditions that is consistent with the product labeling. There is no mention of examining retention samples visually at least once a year for the evidence of deterioration. Additionally, your Quality Agreement withwe) holder is deficient in that there is no mention of responsibilities pertaining to the handling and annual verification of retention samples. During the current inspection, I observed that no retention samples are stored and that your firm has no dedicated area, or a room maintained at required conditions consistent with the product labeling conditions for the storage and handling of retention samples.

There is a failure to thoroughly review any unexplained discrepancy and 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.

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

Specifically, A. On 06-Jun-2023, I observed two (2) brown color objects (about 1.5 to 2 cm in length) inside a transparent ceiling light cover from the viewing window of Grade B room of conventional suite that has Grade A area separated byet andoa LAFoe controlled at Grade A. On 12-Jun-2023 upon my requests, your firm unscrewed the light cover that revealed the following issues: 1. Two (2) dead inspects resembling butterflies along with a gap of about 1 to 1.5 cm on interior of the

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

Specifically, During the inspection, we observed the following equipment cleaning deficiencies for equipment identified as having been cleaned: A. On 03/16/2026, we observed (b) (4) was being stored directly on the (b) (4) _ floor of (b) (4) while manufacturing (b) (4) Tablets USP (b) (4) Batch #(b) (4) _—_—. The (b) (4) is utilized for unloading materials from (b) (4) . B. On 03/16/2026, presence of white caked residue was observed in Capsule Machine ID #(®) (4) (Non- dedicated) product contact surfaces including cavities for encapsulation and Capsule (b) (4) ID A(b) (4) The equipment is located in Room 4° (Capsule Machine Room) and was cleaned for type “<-> cleaning (Major cleaning) on (b) (4) after manufacturing (b) (4) Capsules USP, (b) (4) Batch #(b) (4) on (b) (4) , and the equipment was issued a “Cleaned" status. C. On 03/18/2026, presence ofunknown white powder was observed inside the validation (b) (4) locations inside (b) (4) ID #(6) 4) located inside Room #”" Block & (non-dedicated equipment). The equipment was last used for manufacturing (b) (4) and (b) (4)

Established lab control mechanisms are not followed.

Specifically, During our lab walkthrough on 3/16/2026, we observed ® volumetric flasks in the volumetric flask cabinet, containing expired stock standards for both impurities and the active compound, along with their

There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any ofits components to meet any ofits specifications whether or not the batch has been already distiibuted.

1. Failing sterility tests occU1Ted when returned complaint samples of~)(4> !from the US market were tested. The sterility tests evaluated the remaining liquid inside samples retlllned for reports ofvisual contamination including mold, black specks, and discoloration on the~><4> IThe ~_c42 J container closure system is designed with a'~c4 I to protect the product remaining inside the bottle during use. Without identifying any deficiencies m the Cb> c4> I the sterility failures were attributed to inadequate handling by customers. Investigations were not timely. They were closed with no action to address the product on the market or extend the investigation to other batches ofthis product and other products made in the same environment, dilling the same time period. The investigations did not consider the manufactllling environment where these aseptic products were manufactlll·ed, which was subjected to repeated water incursion events into the aseptic manufactlll·ing areas and persistent recovery ofmold organisms. Failure to thoroughly investigate complaints and consider the environmental conditions at the time of manufactlll·ing is a repeat observation from the May 2025 warning lett

Aseptic processing ai·eas are deficient in that floors, walls and ceilings ai·e not smooth and/or hard swfaces that ai·e easily cleanable.

4 CbH 4 > Jand )(4) Jai·e used in the constrnction ofthe 1 <bX >----, \Uf\_,,J ~ Iaseptic manufacturmg ai·eas m builclin~ The(b><4> Remediation before project swnmaiy documentb 4 ____J identifies this mate1ial has a nsk of acce erated deterioration ofswfaces in contact with moisture and a:isinfectants, an inability to ensure complete decontamination, and a growing problem of maintaining sterile conditions in preparation areas. The document identifies the~> c41 ] mate1ial is not wate1proof. It is located in ai·eas that have been subject to water incursions from ramwater or utility leaks and 6 r sistent mold recoveries. No specific remediation plan to fully replace the material throughout the r < ><4>----i <bR4>7 manufacturing ai·ea has been established as commercial manufacturing continues using these areas. For example, this matedal is located in: a. The Grade B ceilings o~CbH4> Iaseptic filling rooms~H4> I (b)(4) b. The Grade CI Ipreparation (compounding) ai·eas. (b)(4) c. The Grade Cwashing ai·ea for machine paits used to suppo1t I Imanufacturing. d. The Grade Cmate1ial weighing and dispensing ai·ea for ~H4>

Procedures designed to prevent microbiological contamination ofdmg products purp01ting to be sterile did not include adequate validation of the aseptic process.

Inadequate smoke studies is a repeat observation from the May 2025 Warning Letter. 1. For r <bR4r7 aseptic filling line lbR4> smoke studies were approved by the Quality Department that showed first air was dismpted above sterile surfaces and sterile components during interventions, such as: a. During installation ofthe r-----<bR4>~ the operator's hands dismpt the airflow to the exposed r-<bR4>-----i_ appeared to be turbulent and flowing upward during b. The airflow in the area around the'ct,><4>

Procedures designed to prevent microbiological contamination ofdmg products purp01ting to be sterile are not established.

Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

1. Equipment surfaces that directly contact ste1ile tb) (4) ~> <4> I equipment including the [ packa~g are not ste1ilized. ~ (b)(4) 4 X > filling line I machme contact parts ke-1eft in place between batches and cfisinfected. Failure to sterilize c1itical equipment surfaces is a repeat obse1vation from the May 2025 warning letter. 2. During cleaning of the aseptic filling line ~bX4>Jon Janua1y 13, 2026: (b)(~) a. The operator used a single wipe to clean the I I underneath the bowl, and bowl instead of getting a new wipe for each area as reqmred bySOP. The bowl was never rotated as required by the SOP to ensure all outer areas are disinfected. b. During cleaning ofthe 6H4> I, the operator failed to pull the component toward themselves to clean all areas ofthe h,><4> I c. An operator was obse1ved picking up a wipe offthe floor, throwing it away, and placing their hands into Grade A area without disinfection of their hands. d. The operators did not wipe smfaces in a unidirectional manner. e. The~>sLJ machine was not adequately cleaned, and not adequately disinfected. Due to the machine's size and height, operators were unable to reach and clean all surfaces ofthe equipment.

Written procedures are not established that describe the in-process controls and examinations to be conducted on approp1iate samples ofin-process materials ofeach batch.

1. For thect,><4> I ste1il~(bH4>1products: a. There is no 100% visual inspection process for ~! I bottles to detect visible particulates, container defects, or other quality issues at coulcl affect product safety and efficacy. b. There is no destrnctive testing to detect c1itical defects in a statistically significant number ofsamples filled into~H4> !bottles. 2. For th~ 4> I sterilQ products, destrnctive testing is used to b 4> I units for visual inspection: a. The visual inspectors were unable to consistently detect pruticles smaller than~H4>Jmicrometers (µm). No alternative approaches were used to enhance the ability to pe1fo1m the inspection an the smaller particles were eliminated from the challenge kit. b. The defect kit does not include intiinsic pa1ticles, such as b > IpruticleskH4> Ipruticles, or extiinsic pruticles such as fibers or threads for the qualification for visuaf inspectors. c. No sub-visible testing has been perfo1med as pa1t ofthe destrnctive testing.

Aseptic processing ai·eas are deficient regarding the system for monitoring environmental conditions.

There is no surface monito1ing of Grade A surfaces in the~> c41 Imachine.

Approp1iate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records ai·e instituted only by authorized personnel.

Approp1iate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records ai·e instituted only by authorized personnel. The software used to operate the ~H4> d Machine does not have individual usemame and passwords. Operators can make changes to pai·ameters like 11ling times (volume) and ~H4> I There is no audit trail to document what settings were used and any changes made.

Records ai·e not kept for the maintenance and inspection ofequipment.

Written procedures ai·e not followed for evaluations conducted at least aimually to review records associated with a representative number ofbatches, whether approved or rejected.

Your furn failed to conduct annual product reviews in a timely maimer to ensure that appropriate conective actions ai·e taken when necessaiy. XLV-PQR-RAP-0046, APR for~H4> Iremains in draft status at.the time of the inspection, approximately seven months after the review peliod ended. The draft review covers tl batches that were discai·ded during the review pe1iod. ~ out ofl(bH4> 2025 aimual product reviews were late or ai·e not yet completed for US products. *DATES OF INSPECTION l/12/2026(Mon), 1/13/2026(Tue), 1/l 4/2026(W ed), l/l 5/2026(Thu), 1/16/2026(Fri), 1/19/2026(Mon), 1/20/2026(Tue), 1/21/2026(Wed), 1/22/2026(Thu)

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

Specifically, A. Aseptic techniques aimed at maintaining sterility ofsterile items and surfaces are not used at all times. 1) Sterile materials are not always handled with sterile tools. For instance, • • f, j (b)(4J,fill' • I :) i. Durmg equipment setup or1 J I ml operation (b)( 4~ a!~~ #c (b)( 4j0l/09/2025), non-sterile (b)(A~were used to remove! (b 4~covers for the ( oprr bowl and stopper chute. 4 ii. During equipment setups for (b)( ' nd vial filling operations L fl (h) (4) Batch #I (b' 14~01/09/2025 and! (b)(4~drug producfl (bH4i ial Batch # (b)( 4IO 1/10/2025), sterile scissors were placed on the non-sterile surfaces in the RABS. The scissors were subsequently used to cut open~ bags containing sterile parts such as stoppers and I (h)(4) In addition, this was observed during review ofdynamic air flow visualization study videos (VR-EV-A-0 l 0) ofthe vial filling line. 2) While reviewing approved dynamic air flow visualization study videos (VR-EV-A-150, version 4 02) ofthef (bH !filling line, the following deficiencies were noted: i. Operator was observed to block first air to the ex~sed sterileI (b)(} ith non­ ·1 r MOO h'I rfi • r (b) 4 d' • • sten e: •w I e pe onnmg: 1a ~ustme

Written procedures for production and process controls designed to assure that the drug product has the identity, strength, purity, and quality that they are purported or represented to possess are not fully established or followed.

Specifically, ' 0 A. I (b)(j are perfonned forl "•:ct~g__11roduct manufacturing. According the PPQ batch records, for example, size~ (b)(~and ~ g~(b><4J,m L, Batch size: (b)(4) C (b)(4), d . I L -~ (liJ ~ere taken 10 ......,_-,-__,,.......'an testing samp es were taKen rrom th\ ___ 1 4 Cb>< >stages of the batch productions. The current[ (b)( 4) ampling plan including tfle .,_n_u_m_b-er...ofsamples do not provide a statistically sound representation ofthe C ~ filled in the batch productions. B. Appropriate visual inspection (VI) procedures designed to assure batches otj CbH4Jproduct meet appropriate specifications and statistical quality control criteria are not established. I) 100% visual inspection of! (b}(4]~nd the acceptance testing (AQL testing) are performed in the packaging room next to packaging and labeling machinery equipment with loud background noise, and without dimmed ambient lighting. During~ filling operation for 4 L ~ atch #..._ ____, 01/14/2025, it was observed that in addition to the I CbH 4 visual inspection inspectors and..._,--_,t QL inspector,! (&)< ~roduction and QC personnel were also present in close proximity pertonning packaging, labeling, and QC sampling

Adequate procedural controls were not established to protect the electronic data acquisition and process control systems used for the manufacturing ofj (b)(4ps and DP in your manufacturing facility.

Specifically, A. Reviews ofelectronic data including audit trail information are not performed by the Quality Assurance (QA}unit for manufacturing equipment prior to the final approval ofmanufacturing_ batch

The responsibilities and procedures applicable to the Quality Unit are inadequate: A.

The Quality Unit failed to follow the deviation management SOP, 2-SMP-L (b><4}oso (5.0), by not including the recordable event RE202401 I in media fill report VR-PV-A-009 (03). B. The Alert Limit and Action Limit Management Procedure SOP, 2-SMP{ (b)(4}015 (8.0), allows alert limits to be adjusted with a CAPA that does not require a risk assessment. CAPA 2-SMP~ F,o77-R02 (4.0) was approved for loosening the requirement to investigate mold from(m:;FUE} ] (b)(4J covery to greater tha~ FUf (bH 4Jecovery in Grade C and D areas. C. The deviation management procedure, 2-SMP-~ 080 (5.0), is inadequate: 1) lt does not require a CAPA for excursions for which "the cause is clear". For example, a CAPA was not opened for recordable event RE2024011 when the particle counter exceeded the acceptance criteria inside the filling machine for vials during media fill run VR-PV-A-009 (03). 2) Abnormal events and abnormal material events are not required to be listed in validation reports. For example, I. In the! (b)(◄~drug substance batch record for preparation for! ('oH4J r~the failure ofthel (b)( 4p,achine was classified as an abnormal event and was not included in the drug substance process validatio

Laboratory controls do not include the establishment ofscientifically sound and appropriate standards designed to assure that components and in-process materials confonn to appropriate standards of identity, strength, quality, and purity: e),f)LO'fEE1S) s,:;;N,\ Tl.RE ~j -1/J, };...

There is a failure to submit a field alert report (FAR) to FDA within 3 working days of receiving information concerning bacteriological contamination in the distributed drug product.

Specifically, No FAR was submitted regarding bacteriological contamination observed in the aseptic process simulation (APS) Batch #(b) (4) !. On 25 Sep 2024, APS Batch #0C~f(4) Iwas conducted on the Kb) (4) ]filling line. On 30 Sept 2024, positive growth was observed in multiple filled units. Deviation investigation IR/DR/PD/24/049 was initiated on 30 Sep 2024 and closed on 09 Dec 2024. From 29 May 41 2024 (lasJ)(~uccessful APS) to 25 Sep 2024,r >< batches of aseptically filled[(b) (4) Jinjection USP an batches of~~ b 4 Inj~ction were manufactured on theOC~>:(4)] filling line. In addition, lbH•> batches o (b) (4) 1sterilized drug products were manufactured. These batches are currently in the U.S. market and within expiry . OBSERVATION2 There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications w hether or not the batch has been already distributed. Specifically,

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

Sp ecifically, The airfl ow visualization partial studies (smoke studies) performed on the (b) (4)1 and [(b) (4) 1 filling lines show the following deficiencies. The above filling lines are used to manufacture products for the U.S. market. A. I (EL) watc~ed video ofsmoke study ofth~'[6f(4) filling line[Ilij]4) LAF for b) (4) stoppers transfer performed on 13 Nov 2023. I (EL) noted ingress of Grade Bair into the Grade A (b) (4L during transfer. I also observed the operator's deficient aseptic technique ofquick movement during transfer created disruption to the unidirectional airflow. B. I (EL) watched video of the dynamic smoke studies of th((b) (4)1 anc{6f(4) (I>~ filling line interventions performed on 04 Apr 2024. I (EL) noted the studies were 11ot conducted under dynamic conditions. Although various interventions were performed, th6(1>)(• S filling lines remained static and did not simulate the commercial manufacturing conditions.

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

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Specifically, On 11 Feb 2025, during the aseptic filling of U.S. product (b) (4) njection, USP Cb) <4lmg/mL lb><•, mL), Batch #I b 4 on the b 4 filling line. The following were noted. A. Investigator Piechocki noted materials came off loose along the(D) (~) frames in th ~ BS Grade A filling room ceiling. You confirmed they are tapes used to additionally secure the (b) (4) to its frames. These tapes are approximately 2 cm in width and 135.5 cm in length. They were observed

Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

Specifically, 4 You conduct l b) (4) Ifor al lb> < > filling lines Grade B areas to control microbiological contamination. A ll(b) (4~11ing lines are used to manufacture drug products for the U.S. market. However, your(b) (4) efficacy study is inadequate in that the biological indicator (BI) and chemical indicator (CD locations were not justified. No risk assessment was performed to determine appropriate indicator locations. Instead of placing them in most difficult to reach places, Bis and Cis were placed in the open areas of the Grade B cleanrooms during validation.

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

Specifically, ......_____,,__ Your viable environmental monitoring (EM) results are not always reliable because the 6 4 (b) (4) plates incubation condition at 1b>(◄>(b><◄> 0c is not supported by the growth promotion test (GPT). For example, section 4.10.2 ofSOP QCB-091, entitled "Environmental Monitoring Programme fo1(b) (4) Line<b><◄> requires to incubate all E (b) (4) plates a~b><◄>(b><◄> 0c for NL111 b 4 followed by~b>(◄>(b><◄ > 0c forNLT b 4 However, during GPTthe(6 4 plates are only • ' (I>)(•) ' incubated a1!b>(◄>!b> 1•> 0c for s____ You do not have growth promotion data to demonstrate the capability o~(b) (4) media to support microorganism growth a~> 1◄><b> 1•> 0c. .

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

Specifically, A. There is no assurance that all active air sample data obtained using (b) (4) air samplers are reviewed and complete as part ofthe batch production record. Active air samples are obtained throughout the filling area within the filling line (fixed equipment) and the filling area (portable equipment) following QCB-050, "Environmental Monitoring Programme" and QCB-091, "Environmental Monitoring Programme for (b) (4) ______ Line!b>l 4>. However, upon review ofthe electronic data associated with It>><•>of the (b) (4) air samplers, 17 aborted runs were observed, including air samples collected within the (b) (4) areas and corridors. According to your microbiology personnel, these aborted runs are associated with samples which were collected, however the person collecting these samples did not visually ensure that the air sample was completed for the entire b 4 collection time, and these electronic data logs are not reviewed as part of the batch record.

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

Specifically, drug substance used for the manufacture of(D) (4) (b) (4) [njection, USP (b) (4) is tested for related compounds following method RM­ I 100478-LC-RC. According to version 00 of the method used to release drug substance batches

Laboratory records do not include complete data derived from all tests, examination and assay necessary to assure compliance with established specifications and standards.

Specifically, A. Laboratory results within the LIMS system are not adequately verified to ensure that data obtained from the chromatography system are appropriately reported. For example, the total impurities related to EMPI.O f/S/ SIGNATVRE

Your multi-product manufacturing areas are not adequately controlled to prevent potential cross-contamination.

Specifically, a. There are no physical or procedural segregation controls for materials, equipment, and personnel movements between upstream and downstream manufacturing areas. b. The clean room grade (CRG) areas lack s[pecified pressure differentials between upstream and downstream manufacturing suites for ~ intermediate, and parameters for air exchange rates for the CRG manufacturing suites have not been defined. c. There are no established standard operating procedures (SOPs) for managing shared processing areas for concurrent multi-product manufacturing operations. d. During inspection, it was observed that operators in the CRG and Grade C manufacturing suites frequently left~ ---- (bH-Of , pen for extended periods with_out covers. This . d I . ~ - . f • (b)<-O~ r----(6)1:l issue occurre mu tip e times ctunng me connection o aseptic .----1LOL___ ______(b_~ ... <41on .,..,...___,,,.......,.,.--=-___,,,_...,""' (b>< 4 and ~•H 4 Additionally, opera ors were seen working in the Grade c (bH - rea without 1 masks while performing these open operations. Operators were also o served spraying f "'"ltoj •1, sanitization near ope!f ""1posing risk o(::contamination 1o l ~e .. L___,...,.___

Your QC laboratory controls used for in-process, release, and stability testing ofj (b)(4J intermediate do not include appropriate test procedures that assure conformanc_e_t.&n" appropriate standards of QUalitv and 4c,urity.

Specifically, the' -=:.,jmethod for in-process testing of Cb>< ;in.termedi,rr te (b)<"~is not adequately verified or validated (b)(4J ~ CbT(41 -w for its intended use. You reported that_ l and ~ 1/o LJut between iJ (b)(4} (b)(~ . . . ­ ofl}ests) ofl ....Jtests were mvahdated mainly ue o a1lecl system suitability criteria resulting from low% recovery of the lowest standard concentration. The lowest standard concentration for this method is also the limit of quantitation (LOQ) for the method, and is therefore, expected to have sufficient recovery. The recurring system suitability failures indicate that there is no assurance that the method is adequately validated and capable of consistently meeting system suitability criteria.

The stability program SOP "FDBT-SOP-0405 (revision 10)" is not being followed.

The SOP requires that stability testing for internal tests be initiated within the te_s_t_initiatio_o windows (b)(41 indicated in Table 2 of Section 4.4.5.5. However, review of historical ]intermediate r stability sample pulling and testing schedules from January 2024 to l'vlarcn to·2~5 showed that the following stability tests were performed outside of the testing initiation windows specified in the SOP: CEX-HPLC analysis of,Jn1 Cb><4~:~(-20°C, 24-month time-point) performed 78 days past the testing window, lot (-20°C, 24-month time-point) performed 92 days past the testing window, lo (b~~4~-20°C, 24-month time-point) performed 107 days past the testing window, lot ..(-20°C and 5"C , 6-month time-point) performed 57 days past the testin1(Wm~crow1 CbJH4l(-20°C and 5°C, 9-month time- point) performed 24 days past the testing w1naow; and-S- - PLC analysis of lot [ Cb><4J (-20°C and 5°C, 6-month time-point) performed 29 days past the testing window.

Your cleaning and sanitization program is deficient in preventing potential contamination in the controlled drug substance manufacturing areas.

Specifically, a. The SOPs (FDBT-SO~r-0_682_re\lisio~><1?; FDBT-Wl-0040, revision 12; FDBT-Wl-0347, revision 3) for Grade A; pperation and cleaning are inadequate in providing ex~licit instructions on post-use cleaning. It was observed that only the outer surfaces of 41 the~ (b)( 4:used to hold WCB vials and the cell viaar ilit sample cups were cleaned wit (b)( fwipes. However, the areas inside the (b)( 4~which had direct contact with vials and cups, were not cleaned post-use. b. Your cleaning and sanitization procedure for the manufacturing areas in th~L t"Rj facility (SOP-0322, revision 21 .0) does not require documentation and verification m the cleaning logbooks during the facility cleaning and sanitization that the treated surfaces are wetted and remain wetted for the contact time validated in the disinfectant efficacy studies. C. Your disinfectant efficacy study (Report# 22-137DET, approved 24 Jan 2023) does not adequately support the sanitization procedure for the antimicrobial and sporicidal effectiveness 'flthe..d~~~fectants and sporicidal agents on all re12resentative ma_o_ufa.cJu1~g s~urt~c~es in thE\_ jfacility. For example, materials used tor (b)( ·j 1 LJcomputer keyboa

_Envlmnmeptal monitoring (EM) of classified processing areas in your[ (b><j acility for the (b)( >jntermediate manufacturing operations is deficient.

Specif1car 1y, . a. During the routine EM monitoring of the solution preparation activity room t n March 06, 20~5, a QC analyst was obs~rved using inadeq_uate sa~pling techniqu~ er (b)( 41 plate did not make full contact with the surfaces while the viable samples were colle-cnm. b. There is no EM sampling for th~ operation.

Your fir~ faited to exercise appropriate controls for the electronic data acquisition systems used forl Cb>< 4~intermediate manufacturing.

Specifically, r (b)(4l ~m a. There is a lack of documented evidence that the,_____~-- ~ystems and the [ CbTC~system have been validated to pr~ ect onginalefectronic records an rerevar lCmetaaata (e.g., audiLtrails) J hese svste.rns are uJilized to collect and process data 4 from data loggers during theL__ Cb>< jvalidation of critical process ~ .uipm?r:,t and systems at your faciliiy,Trici'uclTng ,- -~---.---- Cb>1 4 ) L :Jin addition, audit trail review-is not performecrtor eacfiaatasetouring the valicfat1on review. During data review, only final printouts of the measurement results are reviewed, and they are not verified against the original electronic records. b. Your firm lacks an adequate program for comprehensive evaluation of the,..[---.(6,~ ~..§.tern audit trails to identify and address any aberrant trends associated with user-aborted L Cb><j sequences/injections/sample-sets events. Specifically, your firm's dataset auaiftrai1•-r-e-v,-e-w...s failed to include in-process testing_r~sults and "Trial Injections" datasets. System audit trail reviews are only performed I Cb>< 41In addition, user privilege settings in r Cb>14'allow your QC analysts to pertmm-oa1cn processing or ma

SOPs or work instructions are not followed or are inadequate.

Specifically, a. The instructions in the QC release and stability test methods are deficient to ensure conformance to appropriate standards of quality and purity. For example, 1. c::: ::.M 022-6.J Cb><1,Analysis of Cb>< 4i(revision 7). The! Cb>< 4;method is used for in-process, release, and y ing.'"there are specific sections of FDBT-TM-0226 that provide instructions (_C--0 -;,r Yanyan Cao, Ph.D., Pharmaceutical Scientist

Aseptic processing areas are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

Specifically, J (6)(4 . A. an<\_ are being used to clean the' (b)141Gr.ade..e. ctHljng machine 1 ~ces. However, you do not have a validation study to show that theI lis effective against mold species. B. Workinstruction (WI)! (b)14l oes not contain sufficient details on how to clean 4 the (b)( filling machine surfaces. For example, the bottle bowl comes into contact with sterile bottles used to fill the sterile! (b,<, drug products. r o ;ve_ye.r the only inJ~truction written in the above WI is to "Clean the inside ofthe bottle bowl". (bH ;ctoes not have adequate cleaning details to prevent microbial contaminkhon orclrug products purporting to be sterile.

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Laboratory records do not include the initials or signature ofa second person showing that the original records have been reviewed for accuracy, completeness, compliance with established standards.

Specifically, On 11/13/2024, I (EL) reviewed the! <6TT4 ~ 1l lines Grade D ~gowning room) viable (bT<4!air and surface monitoring records.[ (b,c4 p ut ofthe total! (b) ro: !ates reviewed showed maccurate colony enumerations. The discrepancy was confirmed by the QC Microbiology supervisor. Your environmental monitoring data is not subject to second-person review to make certain that all test results and associated information are appropriately reported.

The information provided by the firm does not conform to the{b)(4) ~cifically, in the H4> the(b)(4) drug substance (DS) shelflife iS(bH4> at :$(b><4> C.

However, the shelflife applied to DS Process Performance Qualification (PPQ) batches (Batch(b)(4) and post- PPQ batches (Batch(b)(4) waS(b)(4)

The(b)(4) (b)(4) integrity test procedure used for thc(b)(4) does not follow the vendor recommendations (documenC ,n versio~ or SOP CHVI-346656 v2.0 '~H4> IOperation of(b><4> and Integrity Test of(b><4> ~(4) {,'.

For example: a. (b)(4) lversio11:(b><4> indicates to.__ _ __, <6H4> for test set-up. However thelbH4> or test set-u is in(b><4> per SOP CHVI-346656 v2.0 Figure<bH4) 'he according to the guidance shown in \U)\~, the(b)(4) Manufacturing Executing System (MES) guidance for the operators. b. (bH4> 1versioij(bH4> "indicates that the(b><4> should be (bH4> ____________(b>_c4_>______, _________This step is not inc.Jnde.dj n SOP CHVI-346656 v2.0 or in th1(b)(4) ¥ES guidance for the ope~ators. c. (b)(4) version(b)(4) indicates to observe and disregarofilill 7 that occur in the(bH4> 2 (b)C4> (waiting time), and to observe the.._(b-)(4~>____] __ for:ci,>_m .-----(observation time). i. The(b)(4) lMES instructions indicate to start the timer immediately after the(b)(4) is (b)c4> ruicl.conduct the test for~ c4> 1£ohc:;er_vatio.n..time) witbou\ r entioning any . . . (MES . . ~ h (b) o wa1tmg time mstruct1on patus1

Process Parameters (PPs) are not adequately controlled within established ranges iDCb><4> DS manufacturing process.

Specifically, PP deviations occurred duringr,><4> post-PPQ Batch(b)(4) and BatchCbH4>manufacturing, including deviations for Critical Process Parameters (CPPs). In addition, Batch H4> and BatchCbH4> ad out-of-specification (OOS) and borderline results, respectively, fol1"p,><4> I assay at release. The CPP deviations observed include: a. ~_<4> ---=---c-_batcfl(b)(4) outside proven acce table range on )(4) Stage): duringCb> <4> of productiorr>(4) ,step for Batch Cb> (4) (a CPP) waS(b> <4> f chwas e PAR ofn,)(4) ~ nd NO~ ofr,><4> for:ci,>~> hCbH4>andCbH4> exceedance forCb> c4> -------=~ ;-------­ as per CHVI-626612): during(b><4> manufacturing for Batch atc%u4> _Jiad )(4) ~ Cb>~4> espectively which limit, andr)(4) halo,)(4) which exceeded the :'.SCb)(4) o ff(b)(4) limit. CbH4> fo~lbH4)___, and(bH4> are CPPs. C. (b)(4) Batch(b)C4> Excursion o:Ji(b><4> during'Cb><4> during the(b)(4) ste for Batchb><4> the (b)(4) was....r-ep_o_rt_e_d_ru_,Q(b)(4) the acceptable range iS(b)(4} Cb 4 ._____....;.-------­

Critical material used to manufacture(b)(4) is-not tracked, maintained, or replaced throughout their lifetime.

SRer.i:6r.::iJ1v._·______..., a. The(b><4> ~ grity Tester used fo~(b)(4) r------, including ther,><4> (b)(4) DSCb><4> Cb/\ 4 ) (SAP No: CbH4> installed 4 "6etweeli1£e_,_____,_____-,...,Cb>< > to avojd,..". o~the product(b)(4) entering and damaging the instrument. The(b)(4) is not tracked or maintained and is replaced only when damaged. During the FDA inspection oftheCb><4> internty_te~t execution on October 24, 2025, a'(bH4> __________..., coming from the(b)(4) through the(bH4> r~hm~ approx1mately(bH4> Impact ofthe(b><4> in the results ofthe(b)(4) ,.------ ~ntegritY. test c_aruiot be discarded. .....,. b. The(b)(4) .---- instrument used to sea\(b)(4) ____,drug substance bags does not have a unique tracking number, and is not maintained or calibrated. c. The /h)/4) used for the CbH4 >'~------1or for the_(b_> <~4>~_. 1 !b> C4> do not have a preventative mamtenance program. The product contact part ofthe (b)(4) and replacedb c4> ] however, maintenance ofthe_(b>...;.<4""'">--:-:" ~ t th is "failure-based" (they are used until they fail, and then they are replaced by a working(b)(4) The facility has a single spare(b><4> to be used as replacement for the,_~>_<4>___. ""'4' used forI!>>m a

Donors were not screened by a review of relevant medical records for risk factors of communicable disease agents and diseases.

Specifically, From June 2022 to January 2025, your firm failed to adequately screen directed donors of semen and oocytes based on your donor medical history interview titled, F-DNE-253"FDA Screening Questionnaire for Risk Factors and Conditions" revision 6 effective 6/20/2022 through revision 9 effective 1/29/25. Your questionnaire failed to screen risk factors for Creutzfeldt-Jakob Disease (CJD), a relevant communicable disease agents or diseases (RCDAD). The initial question, Question #24, asks " , but does not include time spent in the and if answered no by the donor, the questionnaire instructs the donor to skip questions #24a, b, and c, which are: x Question #24a. "

You did not establish and maintain procedures for screening of HCT/P donors.

Specifically, Your procedure titled P-AE-2025 "PROCEDURE FDA regulations" revision 8 effective 1/10/2024, does not address all steps in performing donor screening. For example: 1. The procedure does not address what RCDADs must be screened during review of a donor's relevant medical records. For example, see OBSERVATION 1 for deficient screening questionnaires. 2. The procedure does not address what clinical evidence to look for when screening a donor for RCDADs. 3. The procedure does not address making inquiries into records and other information when the circumstances indicate that follow-up information might be relevant for screening a potential cell or tissue donor.

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.

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

Specifically, I) The following deficiencies were identified during the review of the Smoke Visualization studies conducted in October 2025 for the <Redacted B4> ISO 5 Laminar Air Flow Hood (LAFH) (Equipment 10: 00167) in which sterile 2 GM Magnesium Sulfate in 5% Dextrose 50 ml Bag Injection is produced: a. Processes which occur during routine operations, such as sanitizing the Magnesium Sulfate vial stoppers and drawing 4 mL from the vial using a syringe, sanitizing each 5% Dextrose Bag Injection Port, injecting the contents of the syringe into the Dextrose bag, and placing an IV seal on each IV port injected, were not simulated during the Dynamic Smoke Study. b. During the Dynamic Smoke Study, the smoke was positioned away from the technician and the area where the technician was performing operations within the LAFH; as a result, the airflow pattern over the operations could not be visualized. C. The set-up of environmental monitoring (EM) plates and units within the LAFH were not simulated during the smoke study and the units were not turned on during the smoke study to demonstrate the air flow pattern. 2) The following deficiencies were identified during the review of the Smok

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

Specifically, The following deficiencies were identified during the facility walkthrough on 05/ 18/2026 within the <Redacted B4> ISO 5 Laminar Air Flow Hood (LAFH) (Equipment ID: 00167) which is used for producing sterile drug product 2 GM Magnesium Sulfate in 5% Dextrose 50 m L Bag Injection: 1) Scratches were observed on the HEPA filter grate, and the grate was observed to be curved inward (indented) on the left side of the ISO 5 LAFH. Additionally, similar inward curve/ indentation of the HEPA filter grate was observed in the Dynamic Smoke Study video which was conducted in Ocrober 2025; 2 GM Magnesium Sulfate in 5% Dextrose 50 mL Bag Injection Lots 74946 (BUD: 08JAN26) and 75101 (BUD: 24JAN26) were compounded in the ISO 5 LAFH on <Redacted B4> and <Redacted B4>, respectively. 2) Cracks were observed on the interior of the plexiglass side panel on the right side of the ISO 5 LAFH. Additionally, similar cracks were observed on the plexiglass in the Static Smoke Study video conducted in October 2025; 2 GM Magnesium Sulfate in 5% Dextrose 50 mL Bag Injection Lots 74946 and 7510 I were compounded in the ISO 5 LAFH on <Redacted B4> and <Redacted B4>, respectively. 3) Yellow stains th

Acceptance criteria for the sampling and testing conducted by the quality control unit is not adequate to assure that batches of drug products meet appropriate statistical quality control criteria as a condition for their approval and release.

Specifically, The firm's Quality Unit does not perform independent Acceptable Quality Limit (AQL) sampling and testing of finished sterile drug products following 100% manual visual inspection. The firm's procedure # SC-03 ·•Final Visual Inspection of Compounded Sterile Preparations (CSPs)" does not include instructions for Quality Unit AQL sampling and testing. Without independent AQL testing by the Quality Unit, there is no objective, statistically sound evaluation of whether released product is essentially free of visible defects. Specifically, Sterile Drug Product 2 GM Magnesium Sulfate in 5% Dextrose 50 mL Bag Injection Lot 74946 (Compounding Date: <Redacted B4> BUD: 08JAN2026; Batch Size: '( <Redacted B4> Units) and Lot 75101 (Compounding Date: <Redacted B4>; BUD: 24.IAN2026; Batch Size <Redacted Units) were each released following 100% visual inspection performed solely by the same compounding technician who produced the respective lots, without any independent AQL sampling or testing performed by the Quality Unit prior to release for distribution.

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, The firm's procedure# SC-03 "Final Visual Inspection of Compounded Sterile Preparations (CSPs)" does not include instructions for creation and characterization of the defects to be used, including the range of sizes to be used in, and instructions for the qualification of the Visual Inspection Qualification (defect) <Redacted B4>. Specifically, the defect <Redacted B4> designed on O5NOV2025 and used to qualify manual visual inspectors is inadequate in that the particulates contained in the defect <Redacted B4> are of unknown size. No threshold studies (e.g., probability of detection studies) have been performed to determine whether the particulates in the <Redacted B4> represent the range of defect sizes likely to be encountered in the finished sterile drug product, and whether trained personnel can reproducibly detect them. As a result, there is no scientific basis for concluding that the compounding technician, who was qualified on the <Redacted B4> on 06NOV2025, and who conducted the 100% visual inspection of Sterile Drug Product 2 GM Magnesium Sulfate in 5% Dextrose 50 mL Bag Injection Lot 74946 (Compounding Date; <Redacted B4> and Lot 7510 I (Compounding Date: <R

Written procedures are not established and followed for the cleaning and maintenance of equipment, including, utensils, used in the manufacture.

processing, packing or holding of a drug product. Specifically, The contact times maintained during the cleaning and disinfecting of the Cleanroom Suite and the ISO 5 LAFH, used for producing sterile drug product 2 GM Magnesium Sulfate in 5% Dextrose 50 mL Bag Injection Lot 74946 (Compounding Date: <Redacted B4>) and Lot 7510 (Compounding Date: <Redacted B4> are not documented. The firm's procedure# SC-I7 '·Sterile Compounding Area Cleaning and Disinfecting" specifies a required minimum contact time of <Redacted B4> for <Redacted B4> and <Redacted B4> and a minimum of <Redacted B4> for <Redacted B4> <Redacted B4> however.the contact times are not recorded in the compounding batch records or cleaning logs and the firm 's procedure SC-17 does not require documentation of the contact time.

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

Specifically. 1) No assessment of retain samples, batch records, and laboratory testing data were conducted at the time of receipt of the below listed complaints, as required by the firms procedure# QA-IO ··customer Complaints Management" Steps 7.6.1 and 7.6.3 which states that Quality investigates the complaint to determine if the compounded product may have resulted in a Quality Non-Adverse Event, Adverse Event, or Serious Adverse Event and Quality checks retain samples, batch record, and laboratory testing data for the reported lots, respectively. a. Complaint# CR25-540 (SKU: 03 1098; Product: Holixia Solution (Minoxidil 7%/Progesterone 0.1 %; Lot# 71065): Patient Complaint Description: Getting severe migraines and causing scalp to burn/itch. b. Complaint# CR25-389 (SKU: 031098, Product: Holixia Solution, Lot# 71065): Patient Complaint Description: Patient experienced itchiness and redness on the skin/itchy scalp. c. Complaint# CR25-365 (SKU: 031098; Product: Holixia Solution (Minoxidil ?%/Progesterone 0.1 %; Lot# 71065): Patient Complaint Description: Burning scalp and she felt .. bumps" on her scalp. d. Complaint# CR25-538 (SKU: 141057; Product: Melidu Emulsion; Lot #7 1466)

Procedures designed to prevent objectionable microorganisms in drug products not required to be sterile are not established, written or followed.

Specifically, The firm's non-sterile topical drug products and <Redacted B4> Water, used in producing the non-sterile drug products, are not routinely tested for objectionable microorganisms such as Burkholderia cepacia complex (BCC) . <Redacted B4> Water is used as an ingredient in the formulation of topical drug products including, but not limited to, Clobetasol Propionate 0.05%/Niacinamide 4% Solution and Hydrocortisone 0.5%/ Hydroquinone 8%/Tretinoin 0.025% Emulsion. Additionally, the firm 's procedure# TM-47 "Microbial Analysis of <Redacted B4> Water at SKNV FL" does not require testing of the <Redacted B4> Water for BCC.

Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.

Specifically, your firm failed to ensure that the laminar airflow hoods used for the production of sterile and non-sterile drug products were maintained in a state of adequate control. During the <Redacted B4> cleanroom certification conducted on January 28, 2026, a <Redacted B4> laminar airflow hoods at your facility were found to be operating outside the acceptable airflow velocity range at the time of certification, as documented by the as-found FAIL designation in Certification Report #02647-20260128RTO1 : <Redacted B4> Your firm did not initiate an investigation or quality related event in response to these findings and did not conduct a product impact assessment for sterile and non-sterile drug products produced in these laminar airflow hoods since the previous <Redacted B4> certification in July 2025. feUe1.i,iiR~

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, your firm has not conducted annual product reviews for any drug product in your portfolio. Your Quality Assurance Manager confirmed that no annual product reviews have been completed and that the standard operating procedure governing the conduct of annual product reviews has not been approved and remains in draft form. The following drug products have been in commercial production for more than one year without an annual product review being conducted: • Lorazepam 0.25 mg/0.125 mL Oral Solution -commercially produced since November 28, 2023 <Redacted B4> batches to date) • Lorazepam 0.5 mg/0.25 mL Oral Solution -commercially produced since November 28, 2023 <Redacted B4> batches to date) • Phenylephrine Hydrochloride Injection 0.1 mg/mL -commercially produced since January 29, 2024, <Redacted B4> batches to date) *DATES OF INSPECTION 5/27/2026 (Wed), 5/28/2026 (Thu), 5/29/2026 (Fri), 6/01/2026 (Mon), 6/02/2026 (Tue), 6/03/2026 (Wed) AMEN DMENT 1

Facilities and equipment used in the manufacture of Fibrinogen are not in a state of good repair or are in a state of uncleanliness.

Specifically, a. On June 12, 2025, paint chipping was observed in the in, Production Site ® Manufacturing Suite while was being pertormed via . b. On June 12, 2025, in Production Site ( Manufacturing Suite0) (4) dry residue was observed underneath where ine PA) we hung, c. On June 12, 2025, in Production Site @ Manufacturing Suite ©) @) rust and residue were observed on the of the Grade area. d. On June 12, 2025, in Production Site Room (Grade™cracks were observed on the floors. e. During observation of of the DS manufacturing process at Production Site — Manufacturing Suit Grade on June 12, 2025, visible residue was observed on the lid ofan The addition of |) (6)(4Y is performed via an step during Fibrinogen (Human) (BT524) DS manufacturing. f. Centrifuges used for the purification of Fibrinogen DS intermediates by (B) (4) treatment, located in Manufacturing Suite(B)4)(Grade™, showed visible spots on various surfaces. g. Additionally, documentation ofequipment cleaning in (b) (4) suite(YA) Grade is not performed.

‘The design ofthe Fibrinogen activity assay is deficient.

Specifically, the in-house Fibrinogen (Human) reference material that has not been calibrated against a current International Standard for Fibrinogen. Dates of inspection: June 12, 2025 (Thursday), June 13, 2025 (Friday), June 16, 2025 (Monday). June 17, 2025 (Tuesday), June 18, 2025 (Wednesday), June 19, 2025 (Thursday) and June 20, 2025 (Friday). ! a Mae

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

Specifically, written procedures do no include sufficient details to ensure consistent implementation and written procedures are not always followed in that: i) your procedure for good documentation practices, SOP No: QA-013-01, titled Procedure for Maintaining Good Documentation Practice, Effective January 1, 2024 states, "All documents should have the signature and date of the person who prepared the document, review of the documents and approve the document." However, during a review of your log books the following was found: a) Logbook for 2023 Stability Sample Location Chart, Register Reference No: QC-042:A11, the date and signature of the employee performing the action is not documented. b) Logbook for 2025 Entry Log Card for Sample Reconciliation, Register Reference No: QC-042, the date and signature of the employee performing the reconciliation is not documented.

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

Specifically, A) Your quality unit failed to ensure that appropriate controls are in place to isolate the technical services laboratory from ongoing construction (start date 03/02/2026) in the adjoining room. Endotoxin sample preparation and testing is ongoing during construction. Change Control Plan CCP 26-001, approved by Quality Assurance on 02/09/2026, states that construction is not expected to impact laboratory operations. (b) (4) sheeting is currently hung between the lab and construction area but is unsealed with gaps between the sheeting and laboratory walls. Additionally, on 03/24/2026 we observed construction personnel temporarily removing the (b) (4) barrier, exposing the construction area to the laboratory. Dust is present on the laboratory side of the sheeting and on the laboratory floor near the construction area. Air purifiers have been installed on laboratory benches to mitigate the impact of airborne particles during construction, use of which was not evaluated in CCP 26-001. Your Associate Director of Technical Services indicated they are unaware of the potential impact of airborne dust on sample integrity or endotoxin test results. CC 26-001 did not include an e

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

A. Your firm failed to complete Analytical Method Verification Studies for the following USP methods used to test (b) (4) : 1. Assay: (b) (4) 2. Impurities ((b) (4) ): Impurities Testing in (b) (4) (b) (4) 3. Example: (b) (4) USP (b) (4) Loté(b) (4) B. Your firm failed to complete Analytical Method Verification Studies for the following USP methods used to test (b) (4) : 1. Assay: (b) (4) 2. Impurities ((b) (4) (b) (4) , and (b) (4) ): Impurities Testing in(b) (4) 3. Example: () (4) USP (b) (4) BN#(b) (4) C. Your firm failed to complete Analytical Method Verification Studies for the following compendial methods used to test (D) (4) ((b) (4) ) 1. Assay: Chromatography <621> 2. Example: (b) (4) Tank# (b) (4), QC# (b) (4)

Specific identification tests are not conducted on components that have been accepted based on the supplier's report of analysis.

Specifically, 1. Your firm does not perform specific identity testing on each container of each shipment of each lot of(b) (4) used in the manufacture of OTC drug products, such as (b) (4) suppositories. The following lots were released without appropriate identification testing e § lots of various count sizes of (b) (4) suppositories in 2025, totaling approximately (b) (4) doses distributed 2. Your firm does not perform all required identification and compendial tests for(b) (4) . Testing for these components has been reduced despite their classification as high-risk materials. Full compendial testing is not conducted to ensure the quality, purity, strength, and suitability of these components prior to use in drug product manufacturing. The following lots were released without appropriate identification testing e § lots of various count sizes of (b) (4) suppositories in 2025, totaling approximately (b) (4) doses distributed

Equipment for adequate control over humidity and temperature is not provided when appropriate for the manufacture, processing, packing or holding of a drug product.

Specifically, During the inspection, a walkthrough of the (b) (4) stability chamber set to operate at "°C + °C /™% RH +8% RH revealed the use of an (b) (4) , unqualified device to assist with temperature control while OTC drug products were on stability. The () (4) device had not been qualified, validated, or approved for use in maintaining required stability conditions.

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

Specifically, Your firm’s written procedure titled “Annual Product Review” requires the preparation and maintenance of APRs for all OTC drug products. During the inspection, APRs for calendar years 2024 and 2025 were requested for all OTC drug products manufactured at this facility. Your Quality Unit was only able to provide one (1) APR for (b) (4) for 2024. Your firm currently manufactures over” different OTC drug products; however, APRs have not been completed for the majority of these products, indicating that APRs were not conducted in accordance with your established procedure.

Time limits are not established when appropriate for the completion of each production phase to assure the quality of the drug product.

Specifically, During the inspection, the manufacturing process for (b) (4) suppositories was observed. Your firm compounded (b) (4) in a designated compounding tank, and the compounded material was held in the tank for multiple days without proceeding to the next step of production. Your Quality personnel confirmed that your firm does not have data or studies to support this hold time for compounded material in the compounding tank.

Laboratory records do not include complete records of any testing and standardization of laboratory reference standards.

Specifically, your firm has not adequately qualified the DNA plasmid reference standard’ (b) (4) used in the test method TM-0059 Determination of Lentiviral Vector Titer by (b) (4) (6) (4) in Quality Control. This test method relates to the viral vector Anti-BCMA02 CAR aLVV used in manufacturing drug product ABECMA. Three testing reports speak to the structure of the DNA Plasmid (lot ®) (4)) expected to be (6) (4) bp in length but give conflicting data: 1.Report (b) (4) dated (Bb) (4) _— for (b) (4) with size of(6) (4) bp 2.BioInformatics Report dated) (DB) (4) — shows (b) (4) total size of (b) (4) bp 3.Report #RPT-2265 dated _(b) (4) shows (b) (4) plasmid with size greater than or equal to (b) (4) bp. This plasmid reference standard lot has been used in all testing of viral vector batches with TM-0059 since prior to 2021.

Your HACCP plan does not include control measures that will consistently produce a 5 log reduction in the most resistant microorganism of public health significance that is likely to occur in the juice, for a period at least as long as the shelf life of the product.

Specifically, Your (6) (4) entitled "(b) (4) (b) (4) "and dated 11/27/24 does not ensure a 5 log reduction in the pertinent microorganism for all juice products that you manufacture, throughout their shelf life. 1.) The following products are not included in the validation study: Detoxifier, Tropical Blend Juice, Aloe Vera Juice, Turmeric Juice, Peach Juice, Raspberry Lemonade, Strawberry Juice, Watermelon Beet Mint, Pear Juice, Prickly Pear Juice, Lychee Juice, Apple Cloudy, Celery Juice, Kale Juice, Spinach Juice, Kale Spinach Apple, Carrot Ginger, Carrot Beet Ginger, Carrot Apple Beet Orange, Citrus Pomegranate, Calamansi, Meyer Lemon Juice, Key Lime Juice, Lemonade Ginger Turmeric Mango, Mango Go Go Smoothie, and Strawberry Orange Mango Ginger Juice. 2.) The validation study does not address all pertinent microorganisms for products included, such as Hepatitis A Virus and Norovirus for Strawberry Lemonade and Strawberry Smoothie. 3.) The validation study did not assess pathogen recovery or growth under normal and moderate abuse conditions over product shelf life.

You are not monitoring the sanitation conditions and practices with sufficient frequency to assure conformance with current good manufacturing practice including safety of water that comes into contact with food or food contact surfaces, including water used to manufacture ice, condition and cleanliness of food contact surfaces, prevention of cross-contamination from insanitary objects and exclusion of pests.

Specifically, 1.) Apparent rust and missing pieces of metal were observed on the blade of your (6)(4) blender. In addition, apparent black grime was observed to be embedded around the inside rim of the blender lid. This blender was used in production of Cucumber Juice, lot (6) (4) . 2.) Cutting boards were observed to be heavily nicked, with two boards exhibiting black stains. Workers were observed chopping cucumbers on these cutting boards on 8/12/25 and 8/13/25. 3.) One cockroach-like insect was observed scurrying out from underneath a pallet holding cases of cucumbers on 8/12/25. One live cockroach was observed on crates being used to hold (6) (4) of cucumber juice during (6) (4) on 8/13/25. One live cockroach was observed by the door leading from your break area to the production room on 8/13/25. One dead cockroach was observed by the door leading from the hallway to the production room on both 8/13/25 and 8/20/25. And one live cockroach was observed in your office area near (6)(4)" on 8/28/25.

Your review of critical control point monitoring records does not ensure that the records are complete.

You did not fully implement the verification and recordkeeping procedures listed in your HACCP plan.

Specifically, 1.) You did not maintain an (6)(4) Log for the (6) (4) Report dated 8/14/25, for Lot ID (6) (4) (contaiming Cucumber Juice, lot (6) (4) ). 2.) You did not review your Product Temperature Monitoring Forms for the time periods 5/21/25, 6/03- 06/25, and 7/03/25. 3.) You did not review your (6) (4) Bag Inspection Logs for the time periods 6/02-04/25, 6/05- 06/25, 6/09-12/25, and 6/16-19/25. This is a repeat observation from the previous inspections conducted in March 2024 (written observation), October-November 2022 (written observation), and June 2019 (written observation).

You did not review all of your calibration records within a reasonable time after the records were made.

Specifically, You did not review your pH Calibration Logs for the time periods 6/03-05/25, 6/06/25, and 6/11-12/25. *DATES OF INSPECTION 8/12/2025(Tue), 8/13/2025(Wed), 8/20/2025(Wed), 8/28/2025(Thu), 9/03/2025(Wed), 9/04/2025(Thu), 9/08/2025(Mon)

Records fail to show test results so as to provide a complete history of the work performed.

Specifically, During review of donor test records, serum protein electrophoresis records failed to include a quantitative Total Protein result to provide a complete history of the work performed. You fail to receive quantitative results from the contract laboratory for Total Protein and instead accept the interpretive value as your result. You currently receive these results as interpretations of results that are listed as N, ABN-L, and ABN-H. Additionally, Center Medical Specialists do not review protein values that are reported. A review includes ensuring a hold is placed on the donor and 14-day medical screening is failed. Donor holds are reviewed to ensure the donor has not had (BD) (4) consecutive unacceptable results. These results are utilized in donor eligibility determination.

Written standard operating procedures including all steps to be followed in the collection of blood and blood components for further manufacturing purposes were not always followed.

Specifically, During observation of donor arm preparation and venipuncture, I observed three collections where your

The standard operating procedure fails to include a written description of the procedures for investigating adverse donor and recipient reactions.

Specifically, During review of Donor Adverse Event Reports, donor ™""""° had a donor adverse event (DAE) on 10/12/2025, which resulted in emergency services transporting the donor to the hospital. The DAE resulted from improper set up by Phlebotomist an , which cause a centrifuge spill. The centrifuge spill resulted in a red blood cell loss for the donor. Deviation record 2711266 does not include discussion with employees involved, investigation into improper set-up, or immediate actions with the employees involved.

Written procedures have not been developed for the of post marketing adverse drug experiences.

Specifically, procedures for vendor qualification and auditing have not been followed concerning the PV vendor, initially contracted in 11/2021, with no initial qualification, annual reassessment, or contract- required audit each 2 years. ͘ ͘ ͘ ͘ ͘ ͘ ͘

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) Inadequate Cleaning Validation Your cleaning validation (Disinfectant Efficacy Study) does not evaluate whether your cunent cleaning agents and procedures effectively remove hazardous drug products to prevent cross -contamination or product carryover . The cleaning agent manufacturer study provided as evidence for hazardous drug removal is inadequate for the following reasons: Your firms pellet press and metal detector are used during the manufacturing process of all hazardous drug products such as Testosterone, Estradiol, and Progesterone. For example, your firm used the <Redacted B4> Tablet Press and <Redacted B4> Metal Detector during the production of Testosterone 50mg Cholesterol, Lot 02242026TN2, expiration date 02/11/2027 and Estradiol 6mg, Lot 11202025TN2 expiration date 11/20/2026. Both sterile finished drug products were approved and released for distribution. • It only evaluated Estradiol and Progesterone not all hazardous dmg products manufactlued at your facility. • It only tested <Redacted 4> surfaces, not other product contact materials such as the plastic components of your firm's metal detector. [(6) (4) I • It is not representative of your current

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

Specifically, Your firm has failed to establish hardness specifications to demonstrate that these drug products conform to appropriate quality standards. Your hardness analyses demonstrate wide ranges of intra-batch results. For example, such variability was observed in the following lots: Drug Product Lot Hardness Test Results Low (kgF) Hardness Test Results High (kgF' Qty Made Qty Distributed Testosterone 50mg Cholesterol 02242026TN2 4.4 20.9 <Redacted B4> Testosterone/ Anastrozole 10014mg 08262025TN2 5.4 13.6 Estradiol 10mg 10212025TN3 8.3 12.7 Testosterone 100mg SA 01232026TN4 4.7 15.0 Testosterone 200mg SA 01222026TN3 13.1 20.7 Progesterone 100mg 04262024TN2 1.02 2.63 Testosterone 200mg SA 03272024TN3 4.76 11.86

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

Specifically, Your procedures do not require investigation when Acceptable Quality Limit (AQL) sampling fails after 100% visual inspection. On July 10, 2025, during visual inspection of Ascorbic Acid Preservative Free Injection batch SP2500050, (batch size: <Redacted B4> units), your initial 100% visual inspection rejected 80 critical, 49 major, and 12 minor defects. Subsequent AQL sampling identified 5 major defects, exceeding your acceptance criterion of <Redacted B4> major defects, and the AQL failed. Your Quality Unit approved proceeding to <Redacted B4> visual inspection without initiating an investigation to determine why the initial 100% visual inspection failed to detect the 5 major defects found during AQL sampling, without documenting the rationale for this decision, and without evaluating whether other batches may be similarly affected. After <Redacted B4> visual inspection and tightened AQL sampling (which passed), the batch was released. Your procedure PRD07 "Visual Inspection", Revision 00, Effective Date 09/09/2025, does not require investigation of AQL failure before proceeding to <Redacted B4> re-inspection.

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

Specifically, Your firm lacks adequate controls to ensure the integrity and reliability of analytical data generated by High-Performance Liquid Chromatography (HPLC) systems used for release testing of sterile drug products.

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

Specific ally, A. Non-Viable Particle Monitoring Probe Orientation On February 12, 2026, during the production of Glutathione (Preserved), Batch SP26012, the orientation of the non-viable particle counter probe was not directed into the flow of air in the monitored location. The probe was positioned <Redacted B4> rather than in­line with the <Redacted B4> laminar airflow, preventing representative sampling of the ISO 5 environment where aseptic manipulations occur. Your firm cannot demonstrate that the orientation and placement of the probe provides a meaningful sample of the critical aseptic processing area. B. Environmental Monitoring Equipment Obstructing First-Pass Air Your firm's procedures for environmental monitoring during production operations do not ensure that monitoring equipment is positioned to avoid compromising unidirectional airflow in the ISO 5 critical zone. Specifically, your procedure MIC0l "Viable Environmental and Personnel Monitoring", Revision 00, Effective Date 10/ 17/2025, does not provide specific instructions for the placement of settle plates and non-viable particle monitoring equipment within the ISO 5 <Redacted B4> laminar airflow hoods to ensure the

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

Specifically, Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established and followed. Specifically, A Your firm has initiated approximately 46 Excursion (EXC), representing <Redacted B4> batches of product, reports for microorganisms recovered from the ISO-5 critical zone in the Laminar Flow Hoods where sterile drug products are compounded. Since December 2024 organisms recovered included Staphylococcus species (epidermidis, hominis, capitis, haemolyticus), Bacillus simplex (clausii, infantis, circulans), Corynebacterium tuberculostearicum, Microcococcus luteus, and other organisms such as Kocuria, Peribacillus, Paenibacillus, Fictibacillus, Streptomyces, Cladosporium, Sphigmonas and Penicillium citrinum. These organisms have been characterized as either spore forming, or non-spore forming organisms recovered from either gloved fingertip, sleeve monitoring, active air, and/or passive air samples. Of the approximate 46 excursions initiated affecting multiple products batches including Phenylephrine HCL 100mcg, Oxytocin, Sucinylchlorine Chloride, Fentanyl Citrate, Labetalol, Rocuronium Bromide, Hydromorphone HCL, Diltia

There is a failure to thoroughly review any unexplained discrepancy and 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 failed to identify the root cause of particulate contamination in your drug products intended to be sterile and failed to implement effective corrective and preventive actions to prevent recurrence. These deviation investigations have been described as, Investigation Major Particulate Matter DRL Threshold Exceedance, 100% Visual Inspection Particulate Matter Threshold Exceedance, AQL Failure, and Major DRL Particulate Matter Threshold Exceedance. Since December 2024, your firm has initiated approximately 110 deviation investigations due to visual inspection failures for particulates. The majority of the deviation reports have been initiated due to contaminates observed that presents as material found on the plunger, floating particulate, or adhered to the stopper barrel. Despite this recurring pattern of particulate contamination, your firm has not

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

Your firm's VAL-24-076-FR, Disinfectant Efficacy Study for <Redacted B4> against EM Isolates from the Connecticut Facility Located at 755 Rainbow Road, Windsor, CT 06095, Rev.1 established a <Redacted B4> dwell time when cleaning with <Redacted B4>. Your firm uses <Redacted B4> to clean and disinfect all classified areas. The following deficiencies were noted in V AL-24-076-FR executed in December 2024. i. No evaluation of other organisms other than Bacillus subtilis (spizizenii) and the mixed culture of Bacillus altitudinis/pumilus/safensis. The firm has recovered other spore forming organisms from the ISO-5 sterile compounding core including: Penicillium citrinum, Streptomyces, Cladosporium and related organisms Peribacillus and Paenibacillus.

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

Specifically, 1. Environmental and personnel monitoring within the Lin~><4> j LAF are not ap5 priately established. The aseptic connection for connecting the ~><4> Ivessel to (b)(4> vessel for L (b><4> Img/ml drug product is performed within t e LAF on ( ine(b><4> ~ was reclassified as Grade A-Air in July 2025 with bacterial alert and action limits of r> cfu/plate and (b> cfu/plate, respectively. The area is not held to Grade A classification during this critical operation with a specification of No Growth. In addition, there is no immediate personnel monitoring conducted for the individual after completing the aseptic connection. 2. The ~><4> Ion the sterile filling lines in the ~><4> blocks are 4 installed oythe operate~) (b>< > the Grade A filling area then \UJW n rom within the Grade A filling areaci,><4> .f Tne operators garment (bwJ <4> was observed to touch the G"raae A exposed portion of the ~><4> ·7These (b)(4> are not further sanitized.

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

Specifically, There has been no asee!_Lc process simulation (media fill) conducted since July 2022 for I Cb>< 4 > mg/ml intended for the US market, which requires (b><4> =:] sing Line (b)(4) reguires an aseptic connectiol1ct,><4> and is usedwfien (b)(4) cannot be (b)(4) ~erformed on tne filing line. Since March 2024, at least m]6atches of1 I (b)(4) -7 mg/ml have been shipped to the US market.

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, Eme,!9yees engaged in visual inspection of sterile finished pharmaceutical products work u:30 1(b)(4) ] however, the qualification of the employee is only performed after ~><4> of visual 1nspect1on the first time the employee is qualified to perform visual inspection and is not performed again at subsequent requalifications. Of the (b)(4) employees qualified for visual inspection, ~><4> , ere first qualified in ~><4> Jwere first qualified irl(b~-;-i an~(b><4>l were first qualified in(b><4> with the remainder first qualified more recently, and none were challenged after ~><4> since their first qualification.

There is a failure to thoroughly review any unexplained discrepancy and 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, Investigations into issues requiring the filing of Field Alert Reports are not always complete. For example, 1. Investigation MC-EP1 -24-0107 was opened on 06/06/2024 due to a consumer complaint of an 18 mm glass t ece found in a dispensed vial of~><4> ii lnjection, USP(b)(4) mg per (b)(4) ml batch ~(b)(4) I The investigation could not fina he source of thk glass; however the roo cause was attributed to vials breaking in the ~><4> ] and leaving glass in intact vials. Corrective actions to the investIgat1on included adding new preventative maintenance to the ~><4> I 4 r Cbx >7 , adding a review of(b)(4) Irejected vials, and adaing a new visual inspection challenge vial for larger glass pieces, and requalification of the visual inspection employees; however, there is no discussion of whether or not the glass vials used for the product are still acceptable or why the visual inspection was unable to see the glass in the time and conditions of the visual inspection operations, which were not changed. 2. Investigation MC-EP1 -24-0197 was opened on 10/30/2024 due to a consumer complaint of a 15 mm glass piece found in a dispensed vial of~><4> IInjection,

Not all quarterly periodic adverse drug experience reports have been submitted within 30 days of the close of the quarter.

Specifically, quarterly Periodic Adverse Drug Experience Reports (PADERS) for Fenoprofen (ANDA 215548) were not submitted. These PADERS should have been reported on a quarterly basis since the ANDA approval date on 5/16/2023. This resulted in 10 quarterly reports that were not submitted.

Not all annual periodic adverse drug experience reports have been submitted within 60 days of the anniversary date of the approval of the application.

Specifically, Ketoprofen (ANDA 074014) Periodic Adverse Drug Experience Report (PADER) e 2023: PADER was due on 3/30/2023 and was submitted on 6/20/2023.

An annual report was not submitted within 60 days of the anniversary date of U.S.

approval of the application to the FDA division responsible for reviewing the application.

Written procedures have not been developed for the reporting to FDA of post marketing adverse drug experiences.

Specifically, your firm has not developed written procedures for the reporting of postmarketing adverse drug experiences to FDA. For example, standard operating procedure, 'SOP No. QLT-001-0, Handling Customer Complaints and Inquiries,’ Section 4.0, describes how it is the responsibility of the Chief Scientific Officer or regulatory agent designee to file 15-Day Alert and Periodic ADE Reports. However, the SOP does not describe the procedure for filing the Postmarketing Adverse Drug Experience Reports or Annual Reports with the FDA.

Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Zhejiang Medicine Co., Ltd – Xinchang Pharmaceutical Factory -Changhai site located at 188-1 Mid Zhiyuan Avenue, Lihai Sub-district, Yuecheng District, Shaoxing City, Zhejiang Province, 312366, P.R.China was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for three years, provided that the outcome of any inspection conducted during this period is positive.

Quality management for the manufacturing site Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory – Changhai site listed to manufacture the Rifampicin API was limited to only production related activities with QA activities and QC testing overseen by Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory. Pharmaceutical Quality system: Organization and Responsibilities The SOP addressed responsibilities of different site positions was available. Quality Assurance of Xinchang Pharma: Divided in three different sections, API, Finished Drug Product and Quality Management office. …

Number of personnel involved with the manufacturing of API products at the Xinchang Pharmaceutical Factory – Changhai site, according to the presentation by the company accounted for 123 staff. Following from the June 2025 WHO PQT inspection the company introduced a new organization chart showing responsibilities and reporting lines in quality and production units. The organization chart was found acceptable. Job descriptions Adequate number of qualified trained and experienced personnel were available. Responsibilities (job descriptions) were specified in writing. …

The buildings and facilities used for manufacturing intermediates and APIs were situated, designed, and constructed to allow for appropriate cleaning, maintenance, and operations based on the type and stage of manufacture. The flow of materials and personnel through the building or facilities was designed to prevent mix- ups or contamination. Production At the Xinchang Pharmaceutical Factory – Changhai site, workshops were designated to the production of Rifampicin. There was a clean zone of Class D for final crystallization, drying and packaging. …

Equipment in the workshops was dedicated to produce Rifampicin API. The equipment was designed to be of appropriate size and location for use, cleaning, sanitization, and maintenance. Equipment construction ensured that surfaces contacting raw materials, intermediates, or APIs maintained the quality of these substances. The equipment in the workshops was check. Contamination controls were discussed.

Documents were managed manually in a paper-based system. Documentation for the manufacture of APIs was prepared, reviewed, approved, and distributed as per established procedures. The issuance, revision, replacement, and withdrawal of all documents were regulated, with revision histories kept. The procedures set retention periods for archived documents based on document importance. Quality documents were reviewed periodically. If unchanged after review, it was stamped “REVIEWED” and the review date became the new valid date. …

Written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials were available. Raw materials were accepted upon receipt of the supplier's delivery notice and COA, then checked for appearance and weight. After cleaning, samples were tested. Materials were labelled "quarantine" pending analysis. If approved, QA replaced the label with "qualified." Supplier Qualification A list of qualified suppliers was established. Suppliers of raw materials were periodical audited and annual quality reviewed. …

Raw materials for manufacturing were weighed and measured under appropriate conditions to ensure their suitability for use. The weighing and measuring devices employed were of suitable accuracy for the intended purpose. The two workshops were dedicated to the manufacturing of Rifampicin API. The production of Rifampicin was in operation at the time of inspection. The production workshops were briefly inspected.

Rifampicin was initially packed in accordance with its BPR. Each bag was labelled with the product name and batch number. The outer product label indicated the storage conditions together with the product name and batch number. The newly introduced packaging line was in operation at the time of inspection and was observed from the window. This semi-automated packaging machine largely reduced the powder contamination in the room. During the packaging process, product samples for QC testing were collected.

Facilities were available for the storage of materials under appropriate conditions. Records were maintained of these conditions. Separate storage areas were provided for quarantine, rejected, returned or recalled products. The factory was equipped with dedicated warehouses for raw materials of drug products, finished dosage forms, chemical raw materials and APIs. The area and space of the warehouse, which had an individual material sampling area and sufficient space for materials, quarantined and finished products and met corresponding storage conditions. …

QC testing is conducted across three different sites as per the following: IPQC testing laboratory at Changhai site, ZMC Xinchang Pharmaceutical Factory was briefly inspected. The testing of environment monitoring was performed by the contract QC at laboratory of Changhai Pharma. and change has been made after last inspection. The environment monitoring testing was performed in IPQC laboratory. The IPQC laboratory onsite was responsible for the testing of incoming materials and intermediate products. QC laboratory at Xinchang site, ZMC-Xinchang Pharmaceutical Factory was inspected. …

During the most recent WHO PQT inspection conducted in June 2025, major observations were noted pertaining to VMP, PV, and analytical method validation. The corresponding CAPAs addressing these observations were reviewed and found to be satisfactory. Validation master plan (VMP) Validation Master Plan for Xinchang Pharma has been updated. Process validation Process validation (PV) utilizing Rifamycin S Sodium, supplied and manufactured by Keming Biopharma, has been conducted since the previous inspection. …

The SOP addressing CC “Procedure of change control” SOP-QAP000024-17 effective on 30/09/2025 was verified. Changes were classified as minor, medium and major, and a CC register was kept. Since the last WHO PQT inspection in June 2025, the SOP addressing CC was updated and Change Control related to Rifampicin were introduced. Examples of changes related to Rifampicin’s manufacturing and testing were verified.

Reprocessing and Reworks, Returns Rejections This section was not reinspected. Recovery of Solvents Solvents were recovered following manufacturing process of Rifampicin. No mother liquor was recycled.

A complaints procedure was available which specified that the complaint-receiving personnel should inform QA on the complaint with QA responsible for logging, classifying and investigating complaints and preparing the reports. Complaints were categorized as critical, major or minor based on the severity and effect on public health. Based on the investigation, preventive and corrective actions are taken when necessary. A complaints register was kept by each site with corporate overseeing implementation. Following from the last WHO PQT inspection of June 2025 this section was not reinspected. …

The production for Rifampicin in the inspection scope was not contracted. The contract labs are used for water and genotoxic impurity testing. The qualification requirements for contract laboratory service were checked.

Final conclusion – Inspection outcome Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Tianjin Tianyao Pharmaceuticals Co., Ltd, located at No.19 Xin Ye 9th street, Tianjin 300462 China; was considered to be operating at an acceptable level of the WHO guideline on Good Manufacturing Practices (GMP) for active pharmaceutical ingredients. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

Principles, quality manual (QM) and quality policy (QP) An overall pharmaceutical quality system (PQS) was established at the site, apart from an overarching quality management system of the corporate company. A quality policy was available and focused on continuous improvement and customer focus towards people’s access to high quality, safe and effective medical products. …

Production activities The batch production and analytical records of a couple of batches were spot-checked.. Validation policy The SOP for validation master plan (VMP) was in place. A VMP for 2026 was established including workshop 105 comprising blocks 28 and 15 related to Dexamethasone Sodium Phosphate. Validation documentation Validation activities were well documented as per validation protocols and reports. …

Design and layout Documented layouts of the site were available. The site comprised several buildings and workshops; two production buildings were covered by this inspection being relevant to the inspection scope and at which production operations of Dexamethasone Sodium Phosphate took place.

• 1. Building no. 28 (Chemical area) which comprised of two floors; a. First floors for centrifuges.
• b. Second floor for reactors.
• 2. Building no. 15 including a. Chemical area for the final steps before the final crystallization.
• b. Clean area no. …

General controls The quality control laboratory being a part of the quality unit was independent from the production department. Laboratory facilities were also independent from the production facilities and, in general, adequate in terms of design, space and equipment. The laboratory was responsible for physical, chemical, microbiological, and stability testing of incoming raw and starting materials; intermediates; finished APIs; packaging and labelling materials; purified water and other utilities along with environmental monitoring; and stability programme. …

General controls The receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials were carried out in accordance with a written procedure. There was system in place for evaluating the suppliers of critical materials and materials were purchased against an agreed specification, from suppliers approved by the quality unit. Receipt and quarantine Materials were received in the receiving bay and checked according to the purchase order, including verification of whether the material came from an approved supplier. …

Packaging materials A written procedures were established for describing the receipt, identification, quarantine, sampling, examination and/or testing and release and handling of packaging and labelling materials. Label issuance and control Access to the label storage area was limited to authorized personnel. Procedures were used to reconcile the quantities of labels issued, used and returned and records were maintained. …

Summary of the last WHO inspection Date and conclusion of most recent WHO inspection The most recent WHO onsite inspection was performed from 14 to 18 November 2022 and was closed as compliant. Before this, the site was inspected by WHO 18-21 April 2016 and was also closed as compliant. Summary of key information about the site According to the site master file: Senador Laboratories Private Limited, Ahmedabad, is engaged in the manufacture of medicinal products, including solid oral dosage forms (hormonal and non-hormonal tablets) and injectable hormonal formulations (terminally sterilised suspensions). It is located in a so called “Pharma zone”, surrounded by other pharmaceutical companies. The Ahmedabad facility was commissioned in 2009 as part of Famy Care Limited. In May 2015, Famy Care demerged its female contraceptive business into a separate entity, Jai Pharma Limited. In November 2015, Mylan Laboratories Limited (a Viatris Company) acquired Famy Care’s female contraceptive business. On 20 November 2015, Jai Pharma Limited formally became part of Mylan Laboratories Limited. …

Dutch Health and Youth Care Inspectorate (IGJ) — 4-7 October 2023

USDFA — 17-24 November 2025

Final conclusion – Inspection outcome Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, MSN Pharmachem Private Limited located at Plot No. 182 to 186, 192-A, 193 to 197 & 212/A, B, C, D, Phase-II, IDA Pashamylaram, Pashamylaram (Village), Patancheru (Mandal), Sangareddy District, Telangana, 502 307 India, was considered to be operating at an acceptable level of the WHO guideline on Good Manufacturing Practices (GMP) for active pharmaceutical ingredients. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

A documented system for quality assurance was established, with procedures covering key quality elements in place. The Quality Department was divided into QA and QC and was separate from the Production Department. Operations were specified in written form and critical GMP requirements were essentially met. Quality manual AQM-001/02, effective date: 28/4/2025, was reviewed. Senior management commitment was in place to ensure implementation of PQS as per objectives, roles and responsibilities. …

There were approximately 1028 staff working on site. In general, personnel had the necessary qualification and practical experience. Personnel interviewed during the inspection had sufficient knowledge of GMP standards. Responsibilities of staff and their duties were well documented. Personnel qualification There was an adequate number of personnel qualified by appropriate education, training and experience to perform and supervise the manufacture of intermediates and APIs. …

Production In general, buildings and facilities used in the manufacture of intermediates and APIs were located, designed, and constructed to facilitate cleaning, maintenance and operations as appropriate to the type and stage of manufacture. Buildings and facilities had adequate space for the orderly placement of equipment and materials to prevent mix-ups and contamination. Facilities were designed to minimize potential contamination. Cleanrooms were utilized for final processing of the finished APIs. …

Design and construction Production equipment was of good standard and appeared to be well maintained. Spot-checks on differential pressure gauges indicated that equipment and devices were timely calibrated. The workflow in the facility was appropriately designed, and the equipment appeared to be installed to facilitate production and reduce the risk of contamination and mix ups. All production equipment reviewed was identified as to its content or purpose with cleanliness status identified by appropriate labels. …

Documentation system and specifications In general documents were designed, prepared, reviewed, and distributed properly. Documents were approved, signed, and dated by the appropriate responsible persons. Records were made or completed when any action was taken. The documentation reviewed during the inspection indicated that there were two types of SOPs (corporate and site specific). An eDMS was in place for the issuance, revision and monitoring of SOPs. Specifications were established and documented for raw materials, intermediates, and APIs as well as labelling and packaging materials. …

Receipt and quarantine The SOP for raw material receipt, inspection and handling at warehouse was reviewed. Handling of receiving, storage and reconciliation of key starting material (KSM) batches was done manually through bin cards. Labels for quarantine were generated by warehouse, while labels for approved and released RM were generated by QC. Example from received shipment of materials was checked as per procedure and found satisfactory for key starting material for Oseltamivir received from MSN life science Unit II. …

In general, different production and in-process control activities were well controlled and documented in the respective batch records. Weighing and other critical operations (excluding printing and attaching finished API labels) were performed by production and witnessed by QA. Prior to use, production personnel verified that the materials were those specified in the batch record for the intended intermediate or API. Actual yields should be compared with expected yields at designated steps in the production process. Expected yields with appropriate ranges were established and verified. …

There were written procedures describing the receipt, identification, quarantine, sampling, examination, testing and release and handling of packaging and labelling materials. Packaging and labelling facilities were inspected immediately before use to ensure that all materials not needed for the next packaging operation had been removed. This examination (line clearance) was documented in the batch packaging records as well as the room/equipment logbooks. Labelling operations were designed and performed in such a way to prevent mix-ups. …

Warehousing procedures SOP for handling and storage of intermediates was in place. The procedure included steps for sampling, dispensing, packaging, and labelling. Oseltamivir intermediate ORT-1 was stored at 2C – 8C. Intermediates were packed using triple laminated bag sealer. Storage of finished API and intermediate was done in areas with controlled temperature in the range of 15C – 25C. Daily Temperature monitoring was conducted. Logbooks for monitoring temperature were checked. …

Adequate laboratory facilities, along with adequate equipment and instruments, were available at the disposal of the QC team. Different QC activities were performed at the QC unit or outsourced to qualified third parties (contracted laboratories) as per established procedures. The performed QC activities were documented in analytical sheets, whether in paper or in electronic format using an established LIMS. Physicochemical Laboratory The SOP for analytical data review and SOP for good chromatographic practices were established. …

The master validation plan was reviewed. A plan was in place on quarterly basis for different validation and qualification activities. In Q1/2026, PV and CV for Oseltamivir were planned considering the additional process equipment (addition of new blocks to meet the product demand). Validation documentation There was an established requirement for documentation of the validation and qualification activities, including through protocol and related reports. The template of the qualification and validation reports included dedicated sections for approval, conclusion and deviations (if any). …

A procedure for change management was available. CC Classification according to specified matrix and timelines of CC management were in place and extension of time was allowed for only 3 times after then CC should be cancelled. Trending of CC was performed as per SOP. Trending report for 2024 was available and 2025 was under draft. CC Trends were done per product.

Rejection The SOP for handling of rejected materials was in place and was applied to raw and packaging materials. Rejected material register for 2025 was checked and no rejection for raw and packaging material took placed in 2025. Rejected materials were stored in segregated and secured areas. Reprocessing & Reworking The SOP for reprocessing and reworking was in place. As per the mentioned procedure, quality failed returned batches, recalled batches and OOT batches can be reprocessed/reworked based on investigation, recommendation and approval by QA head. …

Complaint: The SOP for market complaint management was in place. Repeated complaints were considered if repeated within 12 months period of receiving complaints. Register for complaints 2023, 2024 and 2025 were checked. No complaint for Moxifloxacin HCL monohydrate in 2023, 2024 and 2025. Annual trend analysis for market complaints for Jan-Dec 2025 was checked. Several complaints were spot-checked. Recall: The SOP for recall was in place. Mock recall was done every 3 years +/- 3 months. In general, no recalls were conducted by the manufacturer. Register for recall for 2025 was checked.

No contract manufacturing was implemented by MSN Pharmachem for the production of Moxifloxacin HCL monohydrate or Oseltamivir (phosphate). The SOP for qualification of contract service providers was in place. The QC laboratory agreement between MSN Pharmachem private LTD. and MSN central analytical laboratories located in MSN laboratories private limited manufacturing site in Rudraram. An audit report was reviewed. As per the quality agreement, API, intermediate, raw materials and working reference standards were in scope for testing. …

Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, TMDA Quality Control Laboratory, located at Off-Mandela Road, Mabibo-External, 16106 Dar es Salaam; Tanzania was considered to be operating at an acceptable level of compliance with WHO Good Practices for Pharmaceutical Quality Control Laboratories guidelines. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the laboratory to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

1.1. Structural and general requirements The TMDA Quality Control Laboratory located at the Sub-Head Office in Dar es Salaam was organized into 3 sections:  Medicines Chemical Analysis  Microbiological Analysis  Medical Devices and In-Vitro Diagnostics (IVDs) Testing The organizational structure of the laboratory, including responsibility, authority and interrelationship of the personnel, were indicated in the organizational chart. 1.2. Quality management system (QMS) A documented QMS was established, implemented, and maintained with procedures covering key quality elements. …

2.1. Externally provided services and supplies The laboratory documented its process for selecting and purchasing required products and services. including measurement materials (e.g., Reference and Certified Reference Materials, chemical and biological reference substances, equipment, reagents), and external services (e.g., calibration, qualification, sampling, testing, maintenance, proficiency testing, assessment, and auditing). …

3.1. Personnel The laboratory employed qualified personnel with documented education, training, and experience. Chemistry testing was performed and supervised by qualified personnel with experience in pharmaceutical analysis or equivalent. Microbiological testing was performed and supervised by qualified personnel with experience in microbiology or equivalent. Job descriptions and records Job descriptions were available for personnel involved in laboratory activities. …

4.1. Sampling The laboratory was not involved in physical sampling. In the case of internally submitted samples, sampling was performed by inspectors. Externally submitted samples were sampled by the customers. Internally submitted samples were:  Registration samples  Port of Entry (PoE) samples  Routine Surveillance (inspection) samples  Post-Market Surveillance (PMS) program samples Externally submitted samples were samples obtained from:  International organizations e.g., WHO  Foreign nations through MRA  Government institutions in Tanzania and other domestic organizations and indivi …

SOP on laboratory safety was reviewed and discussed. Environmental health and safety policies were implemented to safeguard staff, the public, and the environment. A documented laboratory safety policy, outlining general and risk-based instructions, was made available to all staff and actively enforced. A designated staff member oversaw its implementation and monitored compliance. …

Based on the areas inspected, the people met, and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Bliss GVS Pharma Limited, located at Survey No. 43-44, Vevoor Village, Palghar, Maharashtra, 401404, India, was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer to a satisfactory level, prior to the publication of the WHOPIR This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

The site had a quality management system (QMS) that incorporated Good Manufacturing Practices (GMP) across all areas of the facility, including manufacturing, packaging, laboratories, warehouses, and other departments. The QA, QC, and production departments reported independently to the Chief Executive Officer (CEO), and both QA and QC Site Heads reported independently to Corporate QA and Corporate QC, respectively. The CQA controls and governs the implementation and operation of the quality system. Some elements of the QMS were assisted by computerized systems such as SAP ECC version 6.0. …

Bliss GVS Pharma Limited has a multi-product manufacturing facility that produces finished pharmaceutical products of various therapeutic categories and dosage forms. In general, the manufacturing facility was well-maintained and adequately equipped with sophisticated equipment. In a number of manufacturing areas, equipment were connected with a vacuum transfer system to transfer in- process materials from one stage to another under closed conditions. The deficiencies raised in this section have been adequately addressed and will be verified during future PQ inspections.

The facility observed a high level of sanitation. There were adequate change-room facilities for gowning, handwashing, drying, and disinfection. The training curriculum provided specific training for each employee on adhering to personal hygiene and clothing requirements outlined in the standard operating procedure, as well as to the pictorial entry and exit procedures displayed in the respective change rooms.

The Validation Master Plan (VMP) was prepared for 2 years, covering 2025-2026, and included activities such as process validation, computerized system validation, qualification/requalification, and other areas. The requalification frequency was described in the VMP. Equipment requalification was performed every 3 years for critical equipment; AHUs were requalified annually and biannually. Temperature mapping covering three seasons was completed for various storage areas. The contracted services were used for the qualification and requalification of equipment and areas. …

SOP for complaints was reviewed. The site QA manager was responsible for recording complaints received. Complaints can be received by a complainant (any regulatory agency, distributor, logistics agent, retailer, stockist, field staff, customer, doctor, or patient) through letters, emails, faxes, or telephone calls. Acknowledgment of receipt of a complaint was specified to be within 3 days. Complaints were categorized as critical, major, and minor. The preliminary investigation report was expected within 3 days. The investigation team comprised the QA team and the concerned department. …

The product recall SOP stated that the site QA Head was responsible for initiating the product recall proposal and for reviewing classification, recall depth, and CQA approval. The recalls were classified as Class I, Class II, and Class III. Depth of recalls included up to the consumer or user levels. Recalls could be triggered by any regulatory agency (statutory recalls) or by the manufacturer (voluntary recalls). No statutory recalls ever happened. One voluntary recall (initiated by Bliss GVS) took place in 2025

No manufacturing processes or steps for the finished products were performed off-site. Some analytical testing was outsourced to competent laboratories. The Analytical Research and the QC departments were responsible for identifying and evaluating new external testing laboratories. These laboratories were required to have the necessary infrastructure, facilities, and equipment to carry out the required activities. A facility audit was required to qualify external testing laboratories. Quality agreements were then established between Bliss GVS Pharma Ltd. …

The self-inspection SOP was reviewed. A self-inspection checklist was used. The self-inspection schedule for 2025 indicated that each department was to be audited twice. A list of qualified internal auditors included 18 self-inspection auditors. Classification of nonconformances as critical, major, or minor was used. The deficiencies raised in this section have been adequately addressed and will be verified during future PQ inspections.

A current organizational structure had been approved by the Plant (Site) Head. There were adequate number of personnel with the necessary qualifications and practical experience. According to the company presentation, there was a total of 466 employees, of which 169 were in OSD production, 50 in semi-solid production, 46 in QA, 100 projected in QC, 29 in the warehouse, 48 in engineering, 5 in IT+SAP, 5 in technical transfer, learning and development, 3 in human resources, and others. Duties and responsibilities were documented in up-to-date, controlled job descriptions (JDs). …

Implementation of the SOP for training of personnel was primarily the responsibility of the Learning and Development (L&D) Team, which was part of the HR department. The SOP provided for induction training, on-the-job training, technical and functional skill assessment, evaluation of training, and training effectiveness check. Training records were kept for each individual employee. Post-training questionnaires were used, with a pass mark of 80%. Effectiveness checks were conducted randomly, not for each individual training course/program. …

Personnel hygiene procedure provided for grooming, illness, cuts and burns, smoking, eating and chewing, and frisking. Each employee was trained in these areas. Employees with open lesions or exposed body surfaces, cuts, abrasion or burns were not allowed in the manufacturing areas. It was stated that the face biometrics access system did not allow an employee to enter a changeroom if their body temperature exceeded 38°C, which could be due to flu-like symptoms or infectious diseases. Those with diarrhea and vomiting were also prohibited from entering controlled areas (cleanrooms). …

The layout of the manufacturing facility was discussed. The manufacturing facility spanned two floors, with all manufacturing activities carried out across small-, medium-, and large-scale facilities. The ground floor (GF) houses small-, medium-, and large-scale manufacturing areas, a warehouse, and a packaging area for medium- and large-scale products. A lift was used to transfer materials from GF to FF. The first floor (FF) houses QC, QA, documentation storage, the stability section, control samples, BMS, the secondary water system, and the ointment manufacturing area. …

The manufacturing facility was equipped with sophisticated equipment and instruments. The equipment were located, designed, constructed, and maintained to suit the operations to be carried out. Equipment found inside the granulation area were installed and operated to minimize the risk of contamination. The granules were charged to the compression machine via the vacuum transfer system, whereas the compressed tablets were manually charged for blister packing. …

The warehousing areas were inspected. Access to the warehouse was through a limited-access biometric system, via a change room where wearing appropriate protective gowning was required. There were two separate receiving bays, one for starting materials and the other for packaging materials. Starting materials were passed through a dedusting tunnel and were then placed on plastic pallets. …

Documents such as change control management, SOP management, retention sample management, stability management, vendor qualification, specifications, standard testing procedures (STPs), QRM, OOS, OOT, deviations, incidents, CAPA, artwork management, and preventive maintenance were handled in the SAP system. QC recorded finished product results in the SAP system, and QA finally released the batch. Paper-based files, mainly containing records, were kept by QA in portable mobile racks with a computer-controlled filing-tracking system. …

The inspector visited the production areas, including small-, medium-, and large-scale areas. Adequate gowning instructions were provided before entering the manufacturing areas. Personnel-specific gowning was provided, each labeled with the person's name. The shoe cover, 2-piece gowning, beard mask, and hairnet were available. 70% IPA was used to sanitize hands before entering the clean corridor. In general, the facility was well-maintained, with adequate lighting and cleanliness. Face recognition and biometric access were provided for the personnel working in the manufacturing areas. …

The inspectors visited the QC laboratory. The laboratory had 82 staff members working across sections, including physical, chemical, instrumentation, stability, microbiology, and good laboratory practices. The laboratory was equipped with 20 HPLCs, 1 UPLC, 2 GCs, 5 dissolution testers, 1 Malvern Mastersizer, and others. Samples of raw materials, semi-finished products, finished products, and for the ongoing stability program were received into the laboratory through a static passbox and stored in separate lockable stainless steel cabins. …

Initial conclusion – Inspection outcome Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Kaygee Laboratories Private Limited, located at Plot No. 06, Phase II, New Industrial Area Mandideep, District Raisen, 462046 Madhya Pradesh, India, was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines. The deficiencies observed during the inspection, as listed in the full report, were addressed by the manufacturer to a satisfactory level before the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

A detailed presentation was provided at the opening meeting. The company had an established Quality Policy committed to meeting stakeholder expectations. The Quality Policy was approved by the Director and was included in the SMF (Annexure‑04). The organization was structured with clear reporting lines from corporate leadership to site‑level operations. Overall governance was provided at the corporate level, supported by senior executive roles overseeing quality, operations, and R&D. Independent Corporate QA oversight was in place, separate from manufacturing. …

Personnel qualification The site personnel overview indicated that staffing levels and organisational structure were established to support manufacturing, engineering, quality, warehouse, administrative, and information technology functions. The distribution of personnel across these functions demonstrated adequate resourcing to support GMP operations and quality system requirements. Records of training were maintained, and training was periodically assessed. The observation related to training was adequately addressed in the respective CAPA plan. …

Design and construction During the inspection, Block III, dedicated to the production of Isoniazid and Pyrazinamide, was visited. The buildings and facilities used for the manufacture of intermediates and APIs were appropriately located, designed, and constructed to facilitate cleaning, maintenance, and operations in accordance with the type and stage of manufacture. The facilities were designed to minimize the potential for contamination. …

Design and construction Equipment used in the manufacture of APIs was of appropriate design, adequate size, and suitably located to allow for intended operation, cleaning, sanitization, where applicable, and maintenance. Equipment surfaces in contact with raw materials, intermediates, or APIs were constructed of materials that did not adversely affect product quality beyond established specifications. Production equipment was operated only within its qualified operating range. …

All documents related to the manufacture of APIs were prepared, reviewed, approved, and distributed in accordance with the SOP for documentation and control. Manufacturing and quality documents were maintained in paper format at the time of inspection. It was noted that the site was in the process of implementing electronic systems. The issuance, revision, superseding, and withdrawal of all documents were controlled in accordance with the applicable SOP. Revision histories were maintained for controlled documents. …

Receipt, identification, quarantine, storage, handling, sampling, testing, and release or rejection of materials were performed in accordance with the applicable SOP. Sampling activities were conducted in the designated sampling/dispensing room. When up to five containers were received, 100% sampling was performed. For consignments containing more than five containers, sampling was conducted in accordance with the √n+1 sampling plan. For bags received in quantities of up to ten, 100% sampling was applied, while consignments exceeding ten bags were sampled according to the √n+1 approach. …

Production operation Process flow charts for Isoniazid and Pyrazinamide were provided and reviewed. The facility was inspected to verify the actual workflow against the documented process. The inspection commenced on the 2nd floor of Block III, where reactors were installed, including reactors used for hydrolysis and condensation steps. Crystallization activities, including cooling and chilling, were performed on the 1st floor, which was classified as a Class D clean room. Product transfer was carried out through closed lines, and equipment was opened only during batch-to-batch cleaning. …

General: SOP for Labelling System and Its Control in Manufacturing Area (effective 6 March 2026) was established and implemented. The SOP described the labelling system and associated controls applicable to the manufacturing area and defined the status labels used, including those for finished products, in-process samples, rinse samples, intermediates, and accessories. The approved label formats were provided in Annex 1 of the SOP. Packaging and labelling materials complied with established specifications. …

Warehousing procedures Facilities were available for the storage of all materials under appropriate conditions. SOP for Temperature and Humidity (effective March 2026) was reviewed. The specified storage temperature for finished APIs was NMT 30 °C. Key starting materials were stored under ambient conditions in line with MSDS requirements. Sampling and dispensing of solid raw materials were performed in a controlled booth under RLAF, with appropriate gowning and balance controls in place. …

An independent QC department was established and headed by the Head-QC. The QC department was responsible for conducting analytical and support activities, including raw material analysis, water testing, packing material analysis, in-process testing, microbiological analysis, finished product analysis and stability testing. The department also performed laboratory equipment and instrument calibration and verification, environmental monitoring, and provided analytical support for validation activities. …

Validation documentation A VMP, effective 26 Feb 2026, was available at the site and was reviewed during the inspection. The VMP described the overall approach to qualification and validation activities. It defined the responsibilities of the relevant functional groups involved in validation activities and outlined the general principles, stepwise execution, and defined frequency for re-qualification and re-validation. The VMP addressed project-related validation activities and included installation, operation, and performance qualification of equipment. …

All system, process, equipment, and material changes were managed through the change control system in accordance with the applicable SOP. Changes were evaluated by the Technical Committee, approved by QA, and subjected to documented impact assessments to ensure that validated systems remained in a compliant state. The scope of the procedure covered all prospective changes affecting product quality and the quality system within the API manufacturing facilities. …

Rejection Rejected materials were stored in a designated rejected area that was secured and physically segregated in accordance with the applicable SOP. The warehouse ensured that rejected materials were either returned to the manufacturer or supplier at the earliest opportunity or destroyed, as applicable. The Quality Control Department affixed a red sticker marked REJECTED to rejected materials. The sticker contained the material name, analytical report number, date of rejection, and initials of the QC chemist. …

Complaints SOP on customer complaints (effective July 2025) was reviewed. The SOP defined the procedures for receipt, investigation, classification, and closure of customer complaints. Roles and responsibilities were clearly assigned across relevant departments. Complaints were classified as Critical, Major, or Other, with defined timelines for investigation and response. Critical complaints required investigation within 12 calendar days, while non-critical complaints required investigation within 40 calendar days. …

A list of approved contract laboratories was available. QC testing was outsourced to laboratories that were authorized to perform testing of all QC samples. The SOP on technical agreements for contract laboratories (effective September 2025) was reviewed. Valid technical agreements were in place for both laboratories, with a defined validity period of three years, and are currently effective. No contract manufacturing activities were reported. Miscellaneous Samples taken Not applicable Assessment of the site master file Site Master File effective 2 February 2026 was provided and reviewed. …

Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Pharco B International (2) for Chemicals (PBIC) located at New Borg El Arab City, Second Industrial Zone No. 5, Block 22 Alexandria, 21934 Egypt, was considered to be operating at an acceptable level of compliance with WHO good manufacturing practices guidelines. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive.

A documented system for quality assurance was established, with procedures covering key quality elements in place. The Quality Department was divided into QA and QC and was separate from the Production Department. Operations were specified in written form and critical GMP requirements were essentially met. The procedures reviewed and discussed during the inspection were generally of an acceptable standard; however, in some cases, improvements appear to be necessary. Product Quality Review (PQR) PQRs were performed according to an established SOP for “Annual product quality review”. …

An organogram was presented at the opening meeting with clear separation between production/operations and quality-related activities. The quality assurance and quality control activities at the site were assigned to two different appointed managers. The managers reported functionally to the Corporate Quality Unit. Personnel qualification Personnel met during the inspection were adequately qualified based on education, experience and training. …

Production There was one production block on the site. Sofosbuvir was manufactured in the non-dedicated production facility and lines. Both chemical and clean area in the production block were inspected. QC laboratories Laboratory areas were separated from production areas. Nevertheless, laboratory areas, in particular microbiological laboratory were located within the same block of the production areas with separate access doors. Utilities In general, all utilities impacting the product quality of the products (e.g. …

Design and construction Equipment used in the manufacture of intermediates and the API was non-dedicated. Generally, the equipment was appropriately identified for its intended use and maintenance. Equipment maintenance and cleaning Written procedures were established for the cleaning of equipment and its subsequent release for use in the manufacture of intermediates and APIs. The SOP related to “Sofosbuvir equipment cleaning” was checked. Equipment was divided into three groups for cleaning. …

Documentation system and specifications Documents related to the manufacture of intermediates or APIs were prepared, reviewed, approved, and distributed according to written procedures. The issuance, revision, superseding and withdrawal of documents were controlled with maintenance of revision histories. The site used a manual record system while a computerized system limited to the material management and QC-laboratory activities, i.e., HPLC, GC, etc. The risk assessment study for data management and data integrity implementation was spot-checked. …

Receipt and quarantine Incoming starting materials and finished API products were quarantined after receipt until released for use or distribution. The “Material supplier list” was in place. The status of raw material was indicated, with respect to material under quarantine or approved. The material label and status were checked. Sampling and testing of starting materials and finished APIs Both starting materials and finished Sofosbuvir API were sampled in the warehouses. Sampling rooms located in the warehouses were equipped with LAF and access control was in place. …

Written procedures were established to monitor the progress and control the critical and major process parameters that may cause variability in the quality characteristics of intermediates and APIs. In-process controls and their acceptance criteria were defined. Raw materials were weighed and measured using appropriately accurate devices. Three quality grades of Sofosbuvir APIs were produced, distinguished by coding, each with distinct process and specifications. …

The SOP for activities in the production finishing areas was in place. The SOP provided for line clearance prior to operation and a template for finishing area cleaning and clearance checklist was utilized. The checklist was issued by QA along with the BMR issued for each individual batch. Packaging operations were not in operation at the time of inspection. Packaging and labelling were not inspected in detail due to time constraints.

Warehousing procedures Adequate facilities were available for the storage of materials under appropriate conditions. Records of these conditions were maintained. Distribution procedures APIs were released for distribution to third parties only after approval by the Quality Unit. WHO grade Sofosbuvir API batches were solely distributed to European Egyptian Pharmaceutical Industries (EEPI) upon the agreement between the two companies.

Physicochemical Laboratory Written procedures were established for the sampling, testing, approval or rejection of materials and finished API products. Specifications, sampling plans, schedules, and test methods under the responsibility of QC were in place. Separate rooms or areas for receiving samples, GC, HPLC, Karl Fischer Titration, reference standards and retention samples were available. Several sampling and testing procedures were checked. …

Validation documentation There was an established requirement for documentation of the validation and qualification activities, including through protocol and related reports. The template of the qualification and validation reports included dedicated sections for approval, conclusion and deviations (if any). Qualification The SOP for equipment qualification was reviewed. The procedure provided for lifecycle management of equipment qualification, including DQ, IQ, OQ and PQ. Process Validation (PV) The SOP for PV was in place. …

A change management procedure was available. Several changes were documented in the APQR.

Rejection Intermediates and APIs failing to meet established specifications were identified as such and quarantined. These intermediates or APIs could possibly be reprocessed or reworked as described below. Reprocessing The SOP for reprocessing and reworking was in place. The Procedure allowed reprocessing and reworking of batches not meeting preset specifications. Reworked batches were required to be validated (concurrent approach) and declared to regulatory authorities along with stability data prior to sale. The list of reprocessed batches was provided. …

Customer complaint and product recalls were managed according to written procedures. No complaints and recall on Sofosbuvir were reported as there were no commercial batches of WHO grade Sofosbuvir have been distributed since last inspection.

PBIC did not outsource any production activities. On the other hand, several QC activities were outsourced by PBIC to third parties. All outsourced laboratory activities were controlled through quality agreements as guided by the supplier qualification procedure.

Summary of the last WHO inspection Date and conclusion of most recent WHO inspection No onsite WHO inspection has been conducted at this manufacturing site. In the absence of recent WHO onsite inspection data, reliance was placed on the January 2024 GMP inspection performed by a stringent regulatory authority (AEMPS), together with the associated GMP certificate and the follow‑up CAPA documentation and also with other supporting documents. Summary of key information about the site Laboratorios León Farma S.A. is a pharmaceutical manufacturing site located at Polígono Industrial Navatejera, C/ La Vallina s/n, 24193 Villaquilambre, León, Spain, operating under AEMPS registration number 4208‑E. The site belongs to the CHEMO / INSUD PHARMA Group, with corporate headquarters located in Madrid, Spain. The facility has been operating under a validated and continuously updated Site Master File, with the current version SMF‑MT‑53 dated March 2026. The site is authorized for the manufacture of human medicinal products, including investigational medicinal products (IMPs), and for importation of intermediates followed by further processing for export to third countries. …

Korean Ministry of Food and Drug Safety (MFDS Korea) — 21 to 23 October 2025

AEMPS (Spain) — 15–17 January 2024

Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, Zhejiang Medicine Co., Ltd – Xinchang Pharmaceutical Factory -Changhai site located at 188-1 Mid Zhiyuan Avenue, Lihai Sub-district, Yuecheng District, Shaoxing City, Zhejiang Province, 312366, P.R.China was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the manufacturer, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for three years, provided that the outcome of any inspection conducted during this period is positive.

Quality management for the manufacturing site Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory – Changhai site listed to manufacture the Rifampicin API was limited to only production related activities with QA activities and QC testing overseen by Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory. Pharmaceutical Quality system: Organization and Responsibilities The SOP addressed responsibilities of different site positions was available. Quality Assurance of Xinchang Pharma: Divided in three different sections, API, Finished Drug Product and Quality Management office. …

Number of personnel involved with the manufacturing of API products at the Xinchang Pharmaceutical Factory – Changhai site, according to the presentation by the company accounted for 123 staff. Following from the June 2025 WHO PQT inspection the company introduced a new organization chart showing responsibilities and reporting lines in quality and production units. The organization chart was found acceptable. Job descriptions Adequate number of qualified trained and experienced personnel were available. Responsibilities (job descriptions) were specified in writing. …

The buildings and facilities used for manufacturing intermediates and APIs were situated, designed, and constructed to allow for appropriate cleaning, maintenance, and operations based on the type and stage of manufacture. The flow of materials and personnel through the building or facilities was designed to prevent mix- ups or contamination. Production At the Xinchang Pharmaceutical Factory – Changhai site, workshops were designated to the production of Rifampicin. There was a clean zone of Class D for final crystallization, drying and packaging. …

Equipment in the workshops was dedicated to produce Rifampicin API. The equipment was designed to be of appropriate size and location for use, cleaning, sanitization, and maintenance. Equipment construction ensured that surfaces contacting raw materials, intermediates, or APIs maintained the quality of these substances. The equipment in the workshops was check. Contamination controls were discussed.

Documents were managed manually in a paper-based system. Documentation for the manufacture of APIs was prepared, reviewed, approved, and distributed as per established procedures. The issuance, revision, replacement, and withdrawal of all documents were regulated, with revision histories kept. The procedures set retention periods for archived documents based on document importance. Quality documents were reviewed periodically. If unchanged after review, it was stamped “REVIEWED” and the review date became the new valid date. …

Written procedures describing the receipt, identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials were available. Raw materials were accepted upon receipt of the supplier's delivery notice and COA, then checked for appearance and weight. After cleaning, samples were tested. Materials were labelled "quarantine" pending analysis. If approved, QA replaced the label with "qualified." Supplier Qualification A list of qualified suppliers was established. Suppliers of raw materials were periodical audited and annual quality reviewed. …

Raw materials for manufacturing were weighed and measured under appropriate conditions to ensure their suitability for use. The weighing and measuring devices employed were of suitable accuracy for the intended purpose. The two workshops were dedicated to the manufacturing of Rifampicin API. The production of Rifampicin was in operation at the time of inspection. The production workshops were briefly inspected.

Rifampicin was initially packed in accordance with its BPR. Each bag was labelled with the product name and batch number. The outer product label indicated the storage conditions together with the product name and batch number. The newly introduced packaging line was in operation at the time of inspection and was observed from the window. This semi-automated packaging machine largely reduced the powder contamination in the room. During the packaging process, product samples for QC testing were collected.

Facilities were available for the storage of materials under appropriate conditions. Records were maintained of these conditions. Separate storage areas were provided for quarantine, rejected, returned or recalled products. The factory was equipped with dedicated warehouses for raw materials of drug products, finished dosage forms, chemical raw materials and APIs. The area and space of the warehouse, which had an individual material sampling area and sufficient space for materials, quarantined and finished products and met corresponding storage conditions. …

QC testing is conducted across three different sites as per the following: IPQC testing laboratory at Changhai site, ZMC Xinchang Pharmaceutical Factory was briefly inspected. The testing of environment monitoring was performed by the contract QC at laboratory of Changhai Pharma. and change has been made after last inspection. The environment monitoring testing was performed in IPQC laboratory. The IPQC laboratory onsite was responsible for the testing of incoming materials and intermediate products. QC laboratory at Xinchang site, ZMC-Xinchang Pharmaceutical Factory was inspected. …

During the most recent WHO PQT inspection conducted in June 2025, major observations were noted pertaining to VMP, PV, and analytical method validation. The corresponding CAPAs addressing these observations were reviewed and found to be satisfactory. Validation master plan (VMP) Validation Master Plan for Xinchang Pharma has been updated. Process validation Process validation (PV) utilizing Rifamycin S Sodium, supplied and manufactured by Keming Biopharma, has been conducted since the previous inspection. …

The SOP addressing CC “Procedure of change control” SOP-QAP000024-17 effective on 30/09/2025 was verified. Changes were classified as minor, medium and major, and a CC register was kept. Since the last WHO PQT inspection in June 2025, the SOP addressing CC was updated and Change Control related to Rifampicin were introduced. Examples of changes related to Rifampicin’s manufacturing and testing were verified.

Reprocessing and Reworks, Returns Rejections This section was not reinspected. Recovery of Solvents Solvents were recovered following manufacturing process of Rifampicin. No mother liquor was recycled.

A complaints procedure was available which specified that the complaint-receiving personnel should inform QA on the complaint with QA responsible for logging, classifying and investigating complaints and preparing the reports. Complaints were categorized as critical, major or minor based on the severity and effect on public health. Based on the investigation, preventive and corrective actions are taken when necessary. A complaints register was kept by each site with corporate overseeing implementation. Following from the last WHO PQT inspection of June 2025 this section was not reinspected. …

The production for Rifampicin in the inspection scope was not contracted. The contract labs are used for water and genotoxic impurity testing. The qualification requirements for contract laboratory service were checked.

Based on the areas inspected, the personnel interviewed, and the documents reviewed, and taking into consideration the findings of the inspection, including the observations listed in the Inspection Report Ecron Acunova Limited, (Navitas Life Sciences) located at No.52- 2, Near Kasturba Hospital OPD Block, Manipal, 576 104; India was considered to be operating at an acceptable level of compliance with WHO GCP and BE study guidelines. The deficiencies observed during the inspection, as listed in the full report, were addressed by Ecron Acunova Limited to a satisfactory level before the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive

A summary of the CRO’s Phase I and bioequivalence capabilities, facilities, regulatory track record, and end-to-end clinical, bioanalytical, and regulatory services for generics and early-phase drug development was presented during the opening meeting. An organizational chart depicting key positions and the names of responsible persons was available at the CRO. The organizational chart for clinical and bioanalytical functions was dated 16 January 2026, authorized, and kept up to date. A job description, including defined responsibilities, was available for each employee. …

An inventory of all computerized systems connected to the network was available as an Excel sheet, with clear identification of GxP-regulated systems. Any changes to the network were documented. Procedures for Computer System Validation (and for changes to the CSV) were established to ensure that computerized systems were suitable for their intended purpose and were validated, operated, and maintained in accordance with GCP and GLP principles, as applicable. Access to software systems containing trial-related information was controlled. …

Appropriate QA and QC systems with written SOPs were in place to ensure that trials were conducted and that data were generated, documented, and reported in compliance with the protocol, GCP, GLP, and applicable regulatory requirements. A designated software was used to upload, approve, and authorize SOPs. On the first day of the inspection, relevant SOPs related to study activities were provided to the inspection team and were uploaded to the shared folder. The Quality Manual, Ecron Acunova Limited, was provided, and it was verified to be in accordance with WHO guidelines. …

The archival facility was visited during the inspection. Access to the archive was restricted to the designated archivist through an access card system, and an entry logbook was maintained. Different categories of documents were retained in the internal archive for defined minimum retention periods, ranging from immediate transfer to a minimum of three years, before being transferred to the external archive. Third-party archival services were provided. The service agreement with the service provider was available. …

During the inspection, a tour of the facility was conducted. The facilities were maintained in a clean condition and were provided with adequate lighting, ventilation, and environmental controls. Floors, walls, and workbench surfaces were designed to allow easy cleaning and decontamination. Clinical trials were conducted under conditions that ensured the safety of subjects. The site was appropriate to the level of potential risk involved. The CRO had sufficient space to accommodate the personnel and activities required to conduct the studies. …

A sufficient number of qualified medical, paramedical, technical, and clerical staff were available at the Manipal facilities to support trial conduct and to respond effectively to foreseeable emergencies. The total workforce comprised 99 employees, including 41 personnel in Clinical, 38 in Bioanalytical, 8 in Quality Assurance, 6 in Project Management and Regulatory, and 6 in the Clinical Laboratory. …

The clinical phase of the studies was conducted on the premises of the CRO. A tour of the facilities was conducted. The CPU comprised five wards located on the second and third floors, with a total capacity of 148 beds; one ward was visited during the inspection. A sample processing room was available, equipped with a −70°C deep freezer monitored by a monitoring system (with probe placement based on temperature mapping) and a centrifuge. In the housing areas, bedside, toilet, and bathroom alarms were installed, tested, and found functional. …

The inspectors visited the in-house clinical laboratory, which was used for analyzing samples. The clinical laboratory was found to be suitable. The clinical laboratory held a valid NABL accreditation in accordance with ISO 15189 requirements for medical laboratories. During the study, accreditation under ISO 15189:2012 was valid from 18 May 2022 to 17 May 2024. This was subsequently renewed from 26 July 2024 to 25 July 2026, followed by recertification to ISO 15189:2022, issued on 13 August 2025 and valid until 25 July 2026. …

Both studies were approved by the independent Ethics Committee before initiation. The committee’s independence from the sponsor, investigator, and CRO was verified, and adequate documentation of IEC review and approvals, including meeting minutes, approved protocols, informed consent forms in relevant languages, and valid subject insurance, was available for each study. Informed consent form Information was provided to study participants both orally and in writing, in vernacular languages, at an appropriate level of complexity. …

The studies were monitored by qualified sponsor representatives to ensure compliance with the protocol, GCP, GLP, and applicable regulatory and ethical requirements, including verification of CRF completion and data accuracy. Pre-study, during-study, and post-study monitoring visits were conducted, and written monitoring reports were prepared following each visit. Observations were communicated promptly to the CRO and Sponsor, and corresponding responses and corrective actions were documented.

The Principal Investigator was responsible for the overall clinical conduct of the study, including the clinical aspects of study design, the administration of investigational products, liaison with local authorities and the ethics committee, and the signing of the protocol and the final study report. Curricula vitae of all three PIs were available and were also reviewed. Annual GCP training records for 2025 were available through the system and were reviewed without issue. Relevant contracts were also available.

Information on the receipt, storage, handling, and accountability of investigational products at all stages of the trial was recorded. Information on shipment, delivery, receipt, description, storage (including storage conditions), dispensing, administration, and reconciliation of remaining pharmaceutical products was verified. Details of the investigational products, including dosage form and strength, lot number, and expiry date, were documented. Randomization was performed in accordance with SOP for Randomization for BA/BE Studies. …

Randomly selected CRFs from the studies within the scope of the inspection were reviewed. For the inspected studies, CRFs were maintained on paper. The CRO had implemented a new electronic database, initially for screening activities starting in December 2023 and for full clinical phase activities starting in August 2024. Data collected for each volunteer were specified in the trial protocol. Copies of clinical laboratory reports and ECGs were included in the respective subject CRFs, and all relevant study information was appropriately documented.

Volunteer recruitment procedures were defined in SOP for Mode of Advertisement. Permissible recruitment methods included print, radio, television, newspaper, personal or telephonic contact, email, posters, and letters. Access to the database was password- controlled to protect confidential information. Recruitment materials, including display advertisements in English and Kannada, had prior approval from the ethics committee. At the time of inspection, no active advertisements were issued, as recruitment was primarily supported by an existing volunteer pool and word-of-mouth referrals. …

Meals were standardized, controlled, and scheduled during the study days. The CRO arranged standardized meals, snacks, and beverages for study subjects in accordance with the clinical trial protocol and the catering service agreement. The timing, duration, and quantity of food and fluids consumed were recorded. Standardized meals were designed by a dietitian with appropriate qualifications, training, and experience. The qualifications, training, and experience of the two dietitians were reviewed and found acceptable.

The study was planned, organized, performed, and monitored to ensure an acceptable safety profile for volunteers. A medical doctor was responsible for medical decisions in the event of adverse events and for notifying relevant health authorities, the Sponsor, and, where applicable, the ethics committee, particularly in cases of serious adverse events. First-aid equipment and appropriate rescue medication were available in the ICU and were ready for emergency use at the study site. …

Human plasma samples from the study related to the WHO application no. MA199, containing K2EDTA as anticoagulant, was analyzed for Artemether and its metabolite Dihydroartemisinin, and for Lumefantrine, in accordance with the respective standard test procedures and SOP for Study Sample Analysis. Three separate high-performance liquid chromatographic methods with mass spectrometric detection for the determination of Artemether and its metabolite Dihydroartemisinin, and of Lumefantrine in human K2EDTA plasma, were developed and validated by the CRO. …