Global Regulatory Monitor
Regulatory News, Week 2 · 2026/11

Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information.

Specifically, On 13 Jun 2025, the firm received a spontaneous consumer report (case—— ()(6)) describing hospitalization following Yorvipath use. The firm's own triage, completed 16 Jun 2025, identified the case as serious (hospitalization), unexpected, and expedited. The firm subsequently classified case ©) ©); non-valid on the basis that no patient identifier was available. The firm's own case narrative documenteda single patient's sequential 12-day clinical course including laboratory values, emergency care at a hospital, and inpatient treatment — meeting the threshold for an identifiable patient. No 15-day expedited report was submitted to FDA forcase) Furthermore, internal firm correspondence dated 18 Jun 2025 confirms that the firm applied the same non-valid classification collectively to three additional adverse event reports from the same social media source, each previously identified by the firm's own operations team as individual patient adverse event reports, on the basis of absent reporter email address and patient details — without individual medical review of each case.

There are no written procedures for the surveillance, receipt, evaluation and reporting of post-marketing adverse experiences to FDA.

Specifically, No written procedures to ensure systematic surveillance, receipt, and reporting of post-marketing adverse experiences identified through social media monitoring to FDA for SKYTROFA and YORVIPATH.

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

Specifically, for Study Number (b)¢ not all Group 1 specimens were retained in the archives at the close of the study. Additionally, the study director failed to document an exception from the regulations in the compliance statement of the final report.

The study director failed to assure that unforeseen circumstances that might affect the quality and integrity of the nonclinical laboratory study were noted when they occurred and corrective action was taken and documented.

Specifically, A. For study— (b) 4), test article ; (b) contamination was detected in pre-dose baseline samples from 5 animals (201, 254, 454, 305, and 405). No corrective actions were documented. B. For study(BY A), conducted by the same Study Director, test article (2) (4)) contamination was detected in vehicle control samples from all 16 Group 1 animals (23 of 72 samples). No corrective actions were documented. C. For study 9 @)@), the same freeze-thaw error occurred on three occasions within 47 days (June 1, July 15, and July 18, 2023), affecting animals in Groups 2, 3, and 4. No corrective actions were documented. Furthermore, the Quality Assurance Manager signed Quality Assurance Statements certifying study compliance for the above studies, despite corrective actions not having been documented for the circumstances identified above.

Not all method validation activities were documented in source records from studyPe.

For instance, stability of|) in whole blood was evaluated after 1-hour, 2-hour, and 4-hour incubation periods at room temperature. However, source records have no time stamps to support the incubation time points. A similar finding was observed in the shipping and short-term stability experiments.

Existing standard operating procedures (SOPs) were not always followed during the conduct ofmethod validation experiments.

For instance, 2a. SOP Q053698, Section 9.8.2, states that only failed stability QCs should be included in subsequent confirmatory runs. Yet, confirmatory run 8 included a new full set of stability QCs instead of including only failing stability QCs from run 7. 2b. SOP Q053698, Section 5.1, states that an average percent relative error (“%RE) should be calculated for each concentration (QC) level and used to accept or reject precision and accuracy (P&A) runs. Additionally, a P&A run should be rejected if the average %RE value exceeds 25% at LLOQ and ULOQ levels and 20% at all other QC levels. Yet, P&A run 9 was rejected based on visual assessment instead of a calculated average %RE value. At my request, average %RE values were calculated during the 1 ction, and it was discovered that run 9 was incorrectly rejected because the average %RE value waspe. all QC levels.

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, you failed to properly maintain the equipment inside the ISO 5 classified areas of your <Redacted B4> Compounding Systems. During the inspection of the <Redacted B4> systems located in <Redacted B4> Room Suite <Redacted B4> Room Number <Redacted B4> the following conditions were observed: 1. On 09/09/2026, what appeared to be rust and chipping paint was observed at the fixed base of the <Redacted B4> inside the ISO 5 classified area of <Redacted B4>, and at the junction between the fixed base and rotating section of the <Redacted B4>. In addition, on 09/10/2026, a reddish-colored seal at the base of the <Redacted B4> appeared to have been coated with paint after the base was repainted. 2. On 09/09/2026, what appeared to be extensive rust and chipping paint was observed at the fixed base of the <Redacted B4> inside the ISO 5 classified area of <Redacted B4>, including significant deterioration and corrosion at the junction where the <Redacted B4>. In addition, on 09/10/2026, a reddish-colored seal at the base of the <Redacted B4> appeared to have been coated with paint after the base was repainted. On 09/09/2026, you were observed manufacturing Oxytocin 30U into 500mL

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

Specifically, your firm's environmental monitoring (EM) program does not adequately address the identification, evaluation and corrective actions that should be taken for microorganisms recovered in your facility. For example, A. As per SOP 6.22 rev 04 Environmental Monitoring Program, you have established microbial contamination alert and action limits for air and surface sampling performed in your classified areas and personnel monitoring that are not appropriate for ISO 5 classified areas. Surface sample alert <Redacted B4> CFU) and action <Redacted B4> CFU) levels permit recovery of microorganisms in critical ISO 5 areas, including the <Redacted B4> containment cells and vestibules, without warranting a formal investigation, corrective action, or preventive measure. Samples from ISO 5 environments should yield no microbiological contaminants, and any recovery in these critical areas should prompt a formal investigation and corrective action. B. Your firm has not conducted a risk assessment of your facility to justify the sampling locations of your environmental monitoring nor have you identified microorganisms that may be considered objectionable. C. Your firm has failed to ade

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

Specifically, A. Your firm's Quality Unit (QU) failed to exercise adequate oversight and did not implement appropriate corrective and preventive actions in response to microbial contamination recovered within the <Redacted B4> ISO 5 containment cell. On 10/25/2025, surface sample <Redacted B4> from <Redacted B4> yielded 1 CFU identified as Serratia marcescens, a gram-negative opportunistic pathogen with known clinical significance. This recovery was documented under deviation UDR 2025-10 and classified as an out-of-trend (OOT) statistical outlier, within established EM alert and action limits. The QU classified this event as major yet assessed the risk as minimal. The QU approved the investigation's conclusion that the probable root cause was "contaminated material introduced during compounding," despite the investigation explicitly noting that these materials were "discarded prior to deviation detection and unavailable for testing." The QU approved the conclusion that the event was a "sporadic environmental contamination" and that "no further corrective actions are required at this time." The QU failed to ensure systemic actions were implemented to prevent recurrence; the only act

Drug products do not bear an expiration date determined by appropriate stability data to assure they meet applicable standards of identity, strength, quality and purity at the time of use.

Specifically, your firm has established the Beyond-Use-Dates for repackaging finished drug product Dexmedetomidine HCI 20 mcg/5 mL into 10mL syringes based on assay specifications outside the defined manufacturer's specifications. Your firm has assigned BUDs of <Redacted B4> days at Controlled Room Temperature (CRT) andE} days under refrigerated conditions for this repackaged product but do not have data to support these timeframes. For example, the following technical study lots failed potency testing as per the manufacturer's specifications: • Room temperature Lot <Redacted B4> compounded 02/08/2026, reported assay result of 89.7% on Day <Redacted B4> b)(4) • Room temperature Lot <Redacted B4> compounded 02/09/2026, reported assay result of 92.6% on Day <Redacted B4> • Refrigerated Lot <Redacted B4>, compounded 04/15/2026, reported assay result of 93.4.% on Day <Redacted B4> • Refrigerated Lot: <Redacted B4> compounded 04/16/2026, reported assay result of 88.4% on Day <Redacted B4> ______ Furthermore, the commercially distributed Lot #DEXM2020260204 compounded on 02/04/2026, reported an assay result of 93.4% on Day <Redacted B4> outside the manufacturer's defined specification of

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, A. Your firm established a pH specification of <Redacted B4> as of 08/19/2022 for finished compounded drug product Azithromycin 500mg in a 250mL Dextrose 5% IV Bag but expanded the specification to <Redacted B4> on 12/03/2025 without adequate scientific justification or any supporting data.

The accuracy, sensitivity, specificity, reproducibility of test methods have not been established and documented.

Specifically, A. The assay method used to test the repackaged drug product Dexmedetomidine HCL 20 mcg/5 mL has not been validated. Documentation, QUF-414-VJ Certificate of Analysis dated 08/07/2026, obtained from your contract testing laboratory indicates that the potency method used met system suitability requirements under a non-cGMP analysis protocol, and that product-specific method validation was not performed for the sample. The contract laboratory further noted that the reported specifications were provided for informational purposes only, and that your firm bears responsibility for verifying that the specification and analyzed reported are appropriate for the product being tested. Your firm was unable to provide any evidence demonstrating that the method used to test this product has been appropriately validated. B. Your firm outsources your finished drug product sterility testing to a third-party laboratory who performs an ATP-bioluminescent method. Since August 2025, an established method USP <73> has been implemented but you do not have evidence to demonstrate that the laboratory's ATP-bioluminescent method is equivalent to USP <73> ATP bioluminescence-based microbiologi

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

Specifically, A. You, <Redacted B4> cleaning procedures are deficient since they fail to define the use of a sporicidal agent to clean and disinfect the ISO 5 vestibule areas of your <Redacted B4> Compounding Systems which operators use to clean components, containers and closures prior to loading them into each <Redacted B4> System. Your cleaning procedure only includes a cleaning log which states'~ the vestibules with <Redacted B4>. Your procedure does not require operators to use a sporicidal cleaning agent as part of your cleaning process for the ISO 5 vestibules. During environmental monitoring activities on 05/15/2026, you recovered the endospore-forming microorganism Bacillus spp in the ISO 5 <Redacted B4> vestibule and the ISO 5 <Redacted B4> vestibule. Your procedures do not require the use of sporicidal agents to ensure the ISO 5 vestibules are free from endospore-forming microorganisms. B. Your <Redacted B4> cleaning procedures are deficient since they fail to define the process operators are required to follow when cleaning and disinfecting the ISO 5 vestibule areas of you <Redacted B4> Compounding <Redacted B4> Systems which operators use to clean components, container

The persons double-checking the cleaning and maintenance are not dating, signing or initialing the equipment cleaning and use log.

SpecificaJly, you failed to verify that the cleaning operations for you <Redacted B4> and <Redacted B4> cleanrooms were performed at the time cleaning operations were conducted. Your Good Documentation Practices procedure requires critical steps or operations to be verified by a second person, and for the second person to sign/initial and date when the operation is performed indicating the second person observed/witnessed the entire step or operation. Your <Redacted B4> cleaning records, and <Redacted B4> Room cleaning records require operators who perform cleaning operations to complete, sign/initial and date each form. The forms also require QA to verify each cleaning operation was performed by also signing/initialing and dating each form. Multiple instances were observed on your cleaning records where the QA verifier initialed and dated the cleaning records days after the cleaning operations were performed. The QA verifier failed to initial and date the forms at the time cleaning operations were conducted. For example, • On 08/25/2026, operators cleaned <Redacted B4> and <Redacted B4> as well as <Redacted B4> Room <Redacted B4> and <Redacted B4> Room <Redacted B4> where the <Red

Samples of representative units were not visually examined for correct labeling at the completion of finishing operations.

Specifically, you failed to visually inspect representative samples of your finished drug products to ensure they contain the correct labeling. Your Visual Inspection Program requires 100% visual inspection of your syringe and IV bag drug products for defects such as leaks, particles, metal, fiber and hair. Inspectors document the results of their inspection on Visual Inspection Worksheets which are included with each product's batch manufacturing record. Your procedure does not require inspectors to perform a visual inspection of finished drug products for the correct labeling. Your Visual Inspection Worksheets also do not show finished product labeling is visually examined, including the worksheets for Heparin Sodium 500U into 500mL 0.9% NaCl IV Bags, Lot# HEPA500020260824, and Phenylephrine HCL 40mg into 250ml 0.9% NaCl IV Bags, Lot #s PHEN4020260824, PHEN4020260825 and PHEN4020260826.

Stability studies do not support the labeled retest date.

Specifically, Your firm does not perform microbial testing during stability studies to establish the risk of microbial : : (4) : (4) contamination throughout the? shelf life or retest date of API. (b) (4) (b) (4) — - thi “oc 4 batches of API were released for the US market within the last three years since November 2022.

Your firm failed to establish adequate written procedures for cleaning and maintenance of equipment used in the manufacture, processing, or holding of drug substances, and failed to validate cleaning procedures to ensure that equipment is routinely cleaned to prevent contamination.

Specifically, Your firm has not validated cleaning procedures for major manufacturing and processing equipment used in. the nroduction of activepharmaceutical ingredient (API) m@ and API intermediates for The equipment that lacks validated cleaning procedures include, but are not limited to the following: API/Intermediate Process | Equipment Name Equipment ID SEE TAMIL Digitally signed REVERSE OF Tamil Arasu, Investigator by TAMIL THIS PAGE ARASU-arasu-s 02/13/2026 Date: 2026.02.13 S 13:54:26 +09'00'

Your firm failed to establish and follow appropriate written procedures for equipment qualification.

Specifically, Your firm has failed to establish and follow appropriate written procedures designed to ensure that equipment used in the manufacture of active pharmaceutical ingredients (APIs) and API intermediates is qualified for its intended use. The equipment that lacks adequate qualification or requalification include, but are not limited to, the following: i Digitally signed SEE | | TAMIL pyran REVERSE OF | Tamil Arasu, Investigator ARASU -S THIS PAGE ARASU - 5.6. 02/13/2026 S 2026.02.13 13:56:11 +09'00'

Your process validations are inadequate.

Specifically, You have performed a process validation for the manufacturing of the API m@ (DMF# w@ using production equipment that have not been qualified. For example, the process verification protocols, oe have used major production equipment that have not been adequately qualified. we The lack of equipment qualification undermines the validity of the process validation study, as there is no documented evidence that the equipment performs consistently and reliably within its intended operating ranges. Digitally signed SEE TAMIL yytawne REVERSE OF Tamil Arasu, Investigator ARASU -S 57127909 THIS PAGE ARASU -p5.te. 02/13/2026 S 2026.02.13 13:58:27 +09'00'

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 complaint investigations were deficient. For example, A. Complaint Investigation 2024-39 was initiated on 10/31/2024 when your customer informed of an incident involving anaphylactic reaction followed by death of?® o) © . : . Ow : after using drug products This @@ drug was manufactured using API supplied by your firm (Lot# m@ Though this non-sterile API is used in m@ drug, the investigation did not extend to raw materials used in the manufacturing process including »@ water for potential endotoxin contamination. No retain samples were tested and no risk assessment was performed to the current testing frequency ofm@ ©) for thea water used in the production. Similar complaint was filed again on 2/19/2025 (Complaint# 2025-05) for another batch (Lot# m@ and the investigation is still SEE Digitally signed THIS PAGE . 2/06/202 ARASU -S Date: 2026.02.06 16:21:17 +09'00'

Procedures designed to prevent objectionable microorganisms in drug substance not required to be sterile are not effective.

Specifically, You have not established a written procedure for testing of objectionable organisms ing@ water that is used in the production process of APIs that are used for the manufacturing ofm@ drug products. For example, »@ APT is used inw@ drug products.

Your supplier qualifications are deficient.

SEE Digitally signed REVERSE OF Tamil Arasu, Investigator TAM |L by TAMIL ARASU THIS PAGE ARASU --s 02/06/2026 Date: 2026.02.06 S 16:23:33 +09'00'

Cleaning Validation Program is deficient, Specifically The firm manufactured and shipped 8 ari products for the US market in the past three years each with a different particle size as listed below: Product Name Product Type | == NDC The firm performed three cleaning validations to establish successful product change over cleaning as detailed below for and product changeovers: i a completion A washing amount of or more is required.

: CL-001 | 9/22/2014 aaA ea @ products —~NPproductsy | Validated A washing amount o or more is required. CL-001-4 | 6/5/2018 products, products products) peso product product) . 10/27/2023

Out of Specification investigation (OOS) is deficient and further no CAPA is initiated to prevent recurrence.

Specifically, 1. investigation OOS21001 was initiated on 3/3/2021 to probe the failure of ssay %) in (IM API batch |M@against a specification of to % using Ion chromatograph. The root cause of failure was attributed to error in the first standard preparation without any scientific justification or comparison with historical area response obtained for standard.

Reports of analysis from component suppliers are accepted without establishing the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.

Specifically, Raw material suppliers o the raw material utilized in the manufacturing ofearl foree were qualified without establishing complete reliability of supplier’s certificates of analysis (COA) through confirmatory testing. Results of vendor and firm were not comparable for multiple quality attributes. Your written procedure for supplier qualification process, SOP GMP-SOP-S-017, revision 2 on Purchasing / subcontractor management

The roles and responsibilities ofthe quality unit is not fully followed.

Specifically, 1. During the review ofOOS investigations, it was observed that about ten confirmed OOS was reported for failure of specific surface area (SSA-BET) in API batches and the root cause was attributed to fluctuation inf EEOofraw material owever, no CAPA was initiated. 2. During the review ofOOS investigations, it was observed that about 13 confirmed OOS was reported for failure of specific surface area (SSA-BET) in API batches and the root cause was attributed to insufficient cleaning of lines after product changeover cleaning. However, no CAPA was initiated. 3. The BET method validated in 2014 (VDR-A-001) for testing of specific surface area.i PI shipped for US failed to meet the acceptance criteria. The firms QA Manager (from ite) stated that the method was not revalidated (validation report- A-001) until August of2023 because the

Review of audit trail for analytical data generated by your firm is inadequate.

Specifically, Review of the electronic audit trails from the Specific surface area measuring machine (BET)- Macsorb HM-model 1201 (ID-RK062 for API samples and ID-RK 131 for raw material samples) indicated repeated events of ‘Measurement error’, ‘Measurement interruption’, ‘Measurement warning’ and ‘File delete’. For example, during the test runs, the following incidents were observed between September 2022 and September 2023:ecm | at | ws |Measurementerror | J [Measurementinterruption | 6 | [Measurement warning | 4 P File delete . iii Filemove Cir [Filerename—C~SC—~SS File save with different name a )=—S18 However, your quality unit did not initiate deviation for these instances to assess what may have caused these events. You also failed to investigate what those interruptions are and why the files were deleted. Your Audit Trail Review -SOP GMP-SOP-S-046 is deficient in that it does not cover system errors such as the ones listed in the table above. This limits your ability to review, document, and investigate all electronic data and is a gap in your Data Integrity Program.

Laboratory Controls are inadequate.

Specifically, a) The working standards used during release testing of for assay and volatile analogues not always elude peaks for the corresponding volatile analogues . During qualification ofyour working standards one of the requirements is to verify the presence of all peaks. However, injection ofstandard lo during analysis ofcommercial XANGAPT lotsOF aces not contain peaks for all volatile analogues at their respective retention time. b)Access control to samples that have not been assigned and those for which testing has been completed is not restricted. In addition on 9/11/23 completed samples of releasedVAY NNW batches were observed on theMM%noor ofthe QC laboratory stored next to samples that were in process of lo Your firm noted verbally that the completed samples were not discarded because they will be used to qualify analysts, however there was no documentation to support this. c) Your site does not conduct growth promotion of media used to perform environmental monitoring of the filling room used for A Pr. d)On 9/11/23 I observed a filled GC vial labeled as "extra" unattended in the laboratory near to GC 23 stand alone equipment, when requested for the origin of the vial

Specifications of Water used in the manufacture of APIs do not demonstrate the water is suitable for its intended use.

Specifically. specifications or water — used for cleaning and processing afteri do not include testing to confirm the absence of B. Cepacia from your water system.

Your cleaning procedures are not validated.

Specifically, a)Your firm has not performed validation of the cleaning procedures used to clean equipment that is used for filling Api into containers. b)Procedure #MSE18-33 requires cleaning of manufacturing equipmen however the number of consecutive batches manufactured on the equipment i varies. For example the campaign executed to asses the cleaning re-validation study of 10/15/20 consisted offft |batches, however the previous manufacturing campaign consisted of(Mi lots. c) Cleaning validation studies for bulk containers including clean hold time do not include samples to determine appropriate microbial levels. d) Removal o usedurine - verified using this method is not sensitive to indicate 1 is reduced to levels that indicate it has been removed. e)Your test method used from 2015-2020 to evaluate cleaning validation samples had an LOQ of pm but your specifications for residue were(bpm. This test was not suitable for the evaluation of cleaning validation samples during this time.

Changes that could affect the production and control of the intermediate or API are not always handled using the formal change control system.

Specifically, a) The following changes were not handled using the change control system (list is not exhaustive): Change ofAC system inPPM fitting room, your firm noted that the reason to not execute a change control for this change was because the AC was being replaced with a unit that met the same specifications. However at the time of the change the comparison between the old and new unit was not documented to justify the lack of change control. On 8/6/23 UQSE20-19 test method used to evaluate rinse samples from cleaning validation was changed to obtain a lower LOD and LOQ the residue limit on equipment was also changed from bpm tofbpm. The reason for not performing this change using the change control program was not documented. b) Change control CCQ22-17 enacted to address change in storage of PB nedium used by QC from refrigeration to room temperature states that the firm will verify if the storage conditions change has any impact on tests. However there were no steps, protocol or instructions on how your firm would perform the noted verification. In addition on 9/15/23 I observed that there is no calibrated device to monitor the temperature of the room where the media is sto

Your validation protocols for the execution ofrevalidation studies do not specify critical process steps.

Your process validation studies for PUM do not show the critical process parameters that were going to be studied, review of batch records shows that the validation study did not include variation of parameters within the established ranges. In addition parameters such as the timer used to control the flow inhl: not defined as critical process parameters.

Your receiving procedures for raw materials are inadequate.

The firm's Production Unit utilizes critical raw materials within the manufacturing process prior to the completion of identification testing and release of the raw materials by the firm's Quality Control Unit.

For example: (b) (4) lot#(D) (4) was received and sampled on 07/12/2023. Identification testing was conducted from 08/03/2023 - 08/08/2023 and the lot of(b) (4) was released by Quality Control on 08/09/2023; however, the raw material was utilized in the manufacturing of(b) (4) \PI (b) (4) lot#(b) (@)on 07/31/2023. (b) (4) iot#(P) (4)was received and sampled on 07/28/2023. Identification testing was conducted on 08/03/2023 and the lot oi/(B) (4) was released by Quality Control onpep however, the raw material was utilized in the manufacturing of (b) (4) API (b) (4) lot# (>) 4)on 07/31/2023. (b) (4) lot4#(b) (4) was received and sampled on 06/13/2022. Identification testing was conducted on 06/18/2022 and the lot of(D) (4) was released by Quality Control on 0/20/2020 Fa (4) however, the raw material was utilized in the manufacturing of(D) (4) aPI(D) (4) lot# yn 06/19/2022.

The firm’s stability program was inadequate in that the firm’s QC Laboratory failed to utilize a stability indicating method for assay testing of(b) (4) The QC Laboratory utilizes a titration method for assay testing of (b) (4) for all stability testing that the firm has conducted on their(B) (4) API products including the following US marketed API:(B) (4) For example, the firm utilized the titration assay method for the accelerated stability studies of(D) (4) API (lot#s(b) (4) The data from the accelerated stability studies was later utilized to determine the shelf life of the product.

The firm has no data to support the use of the titration assay method as a stability indicating method or that it has the ability to detect impurities or degradants over the shelf life of the API.

Verification testing of the raw material supplier COA is inadequate as the firm has failed to conduct all of the analyses listed on the respective supplier COA.

For example: The(b) (4) tot#(B) (4)c0A from(b) (4) lists the following analyses: appearance, specific gravity.(D) (4) (b) (4) The firm's verification testing of the aforementioned supplier COA only included the following: specitic gravity,(1D) (4) The(D) (4) jotX(D) (4)coa fron(b) (4) lists the following analyses: purity, ignition on residue, moisture (DB) (4) foreign matter. The firm's verification testing of the aforementioned supplier COA only included the following: purity and ignition on residue,

Equipment and utensils utilized in the production of API for the US Market are not cleaned or maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, purity and quality of the drug substance.

For example: Reddish-brown discoloration was observed on the interior of the water hose to holding vessel (RT-8). The aforementioned hose is utilized in the pumping of water into the ceiling of the vessel to prevent(b) (4) from escaping. The holding vessel is utilized in the manufacturing of(b) (4) API (b) (4) Reddish-brown discoloration was observed on the interior ofthe water hoses to(b) (4) 'GM-5). The aforementioned hoses are utilized in the pumping ofwater to cool the interior of the vessel. The(b) (4) is utilized in the manufacturing oi(B) (4) API(b) (4) White powder residues were observed on the exterior of the Kubota scale within the Line @).ompling room. The aforementioned scale is utilized in the weighing of critical raw materials used for the manufacturing of(b) (4) (b) (4) API. According to the management team, the scale was reported to have been cleaned; however, the tirm does not document any cleaning activities within the sampling room. The firm utilizes a(D) (4) sampling tool during the() (4) apt (b) (4) manufacturing process. The sampling tool is utilized at various points ofthe initial process including(b) (4) (b) (4) According to the management team, the sampling

Your firm failed to test samples of each component for identity and conformity with all appropriate written specifications for purity, strength, and quality (21 CFR 211.84(d)(1) and 211.84(d)(2)).

Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Your firm also failed to conduct appropriate laboratory testing, as necessary, for each batch of drug product required to be free of objectionable microorganisms (21 CFR 211.165(a) and 211.165(b)).

Your firm’s quality unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to validate and establish the reliability of your component supplier’s test analyses at appropriate intervals (21 CFR 211.84(d)(1) and 211.84(d)(2)).

Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

Your firm failed to have, for each batch of medical gas, appropriate laboratory determination of satisfactory conformance to final specifications for the medical gas, including the identity and strength of each active ingredient, prior to release (21 CFR 213.165(a)).

Your firm failed to test samples of each incoming designated medical gas for identity and conformity with all appropriate written specifications for purity, strength, and quality. Your firm also failed to validate and establish the reliability of your incoming designated medical gas supplier’s test analyses at appropriate intervals (21 CFR 213.82(a) and 213.82(b)).

Your firm failed to establish and follow adequate written procedures describing the handling of all written and oral complaints regarding a medical gas, including provisions for review by the quality control unit of any complaint involving the possible failure of a medical gas to meet any of its specifications and, for such medical gas, a determination as to the need for an investigation in accordance with 21 CFR 213.192 (21 CFR 213.198(a)).

Your firm’s quality unit failed to exercise its responsibility to ensure medical gases are manufactured in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 213.22).

Results of stability testing are not used in determining expiration dates.

Specifically, Procedure QP-20-17, “Stability Test” requires long term stability studies for establishment and confirmation of thenny expiration date applied to OTC drug products. 44 drug product lots had stability studies initiated between 2018 and 2019, however all ofthese studies were cancelled approximately three months after the stability studies were initiated. To date, there has been no stability studies completed to confirm thegsay expiration date established for any drug products manufactured at the firm. In addition, according to the reporting worksheets for drug products, informal results were recorded for 9- month and 12-month timepoints for attributes such as pH and viscosity in which several lots did not meet the established criteria. There was no investigation conducted to determine the impact of these out of specification results on those drug products which had been distributed to the US market. Furthermore, i unique drug products were manufactured in the year 2019, however only,,, of these drug products were placed on stability.

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

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

Specifically, A. There are no written procedures which outline the process for verification by the Quality Unit of the paper and electronic analytical data to ensure that the data and the calculated test results are complete and accurate for all chemical and microbial tests performed. B. There is no written procedure which outlines the issuance, use, and reconciliation of logbooks and worksheets used within the manufacturing area (including, but not limited to batch production records for bulk manufacturing, filling, and packaging and labeling, and equipment logbooks), and the laboratory (including but not limited to analytical raw data worksheets, equipment usage logs, reference standard logs used for documenting weight, and laboratory inventory logs). C. According to QP-20-18, Product Review”, |... _ product reviews are required to be performed and documented for drug products manufactured withing,a productreviews were not conducted for the approximately), 45 drug products manufactured within §) 4 wa 28 required per procedure.

Established sampling plans are not followed and documented at the time of performance.

Specifically, Sampling ofthe 4) system is not adequately documented, established, or justified. For example: ERMPLOYEE(S)

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

Specifically, A. Ancillary containers used for the dispensing ofraw materials for manufacturing are not maintained in a clean state. For example, during the walkthrough ofthe drying room for ancillary containers on 18Nov2024, I observed containers which contained various amounts ofwater remaining at the bottom of the equipment, including containers that had already been labeled as fully cleaned. B. The preparation of the detergent used for the cleaning ofmanufacturing and ancillary equipment used in manufacturing is not adequately documented. Your quality personnel described that the detergent used for cleaning is prepared by | lll INN 1 2000 MlNINN This preparation is not described in any procedure, nor is the preparation documented, including lot number of detergent used and expiration date ofthe prepared solution.