FDA Warning Letter to Simtra BioPharma Solutions

Delivery Method: VIA UPS Reference #: 320-26-49 Product: Drugs Recipient: Recipient Name Franco Negron Recipient Title Chief Executive Officer Simtra BioPharma Solutions Building C, Suite 270, 2nd Floor
400 Interpace Parkway
Parsippany, NJ 07054
United States

frnegron@simtra.com Issuing Office: Center for Drug Evaluation and Research (CDER) United States

Warning Letter 320-26-49

March 3, 2026

Dear Mr. Negron:

The United States Food and Drug Administration (FDA) conducted an unannounced inspection of your drug manufacturing facility, Simtra Deutschland GmbH, formerly Baxter Oncology GmbH, FEI 3002806419, at Kantstr. 2, 33790 Halle/Westphalia, Germany, from September 18 to 26, 2025.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your October 20, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

Significant deficiencies were identified with aseptic processing controls in your (b)(4) and restricted access barrier system (RABS) processing lines used to aseptically manufacture sterile drug products for the U.S. market.

Cleaning and Disinfection

You used (b)(4) extensively to rinse critical, interior surfaces and aseptic processing equipment in your (b)(4) and RABS lines after production. This (b)(4) was fed from (b)(4) cleaning use points inside your (b)(4) and RABS through excessively long (up to approximately (b)(4)) deadlegs from your (b)(4) loop. Deadlegs in (b)(4) systems are known to cause stagnation of (b)(4) and excessive microbial growth.

Between June 2023 and September 2025, routine testing of (b)(4) cleaning use points in your ISO 5 (b)(4) and RABS resulted in at least 47 microbial recoveries, including 14 that exceeded your action limit. Your routine monitoring samples repeatedly recovered gram-negative, biofilm-forming, (b)(4) organisms including Sphingomonas, Methylobacterium, Bradyrhizobium, and Ralstonia species. Investigations for at least two incidents associated with microbial recoveries identified the design of your (b)(4) cleaning use point piping as the most likely root cause. However, your corrective action and preventive action (CAPA) plans have failed to comprehensively address the identified deficiencies in your (b)(4) system design.

Furthermore, post-production environmental monitoring (EM) samples taken within your ISO 5 (b)(4) and RABS between June 2023 and September 2025 have resulted in repeated recoveries of gram-negative (b)(4) organisms including Sphingomonas, Methylobacterium, and Cupriavidus species.

This sampling identified a worrisome adverse trend in your RABS in late 2023 in which (b)(4) gaskets and (b)(4) were found to be contaminated with gram negative microbes. Significantly, too-numerous-to-count (TNTC) levels were present on RABS (b)(4) gaskets in multiple instances during this period. Your investigations acknowledged that equipment design (including (b)(4) gaskets) and maintenance, in combination with cleaning (e.g., residual (b)(4) from cleaning), caused the deviation.

You failed to sufficiently address the underlying cause of residual (b)(4) in a timely manner, instead relying on personnel to (b)(4) dry any observed moisture.

In your response, you commit to corrective actions including (b)(4) sanitization of (b)(4) cleaning use point piping and (b)(4) of the (b)(4) used in ISO 5 cleaning. Additionally, you explain your process of (b)(4) -drying your (b)(4) and RABS with (b)(4) drying of residual (b)(4) during visual inspection by operators. You also commit to implementing (b)(4) disinfection of the (b)(4) in your (b)(4) and RABS.

Your response is inadequate because your corrective actions fail to address the fundamental, self-identified design flaw in your (b)(4) supply lines” that lead to each of your (b)(4) and RABS processing lines for cleaning. You also fail to holistically address residual (b)(4) from cleaning your (b)(4) and RABS units across your site. The residual (b)(4) issue poses a significant risk to barrier/ (b)(4) system control (e.g., interference with decontamination cycle efficacy) and can potentially lead to drug product contamination.

**(b)(4)* Integrity Testing*

You failed to adequately maintain equipment to assure aseptic conditions. Your (b)(4) integrity testing program for (b)(4) was found to be deficient. For example:

• Your (b)(4) integrity testing program for (b)(4) permitted (b)(4) to fail acceptance criteria during pressure decay testing (b)(4) times before requiring replacement. Your translated procedure states, “All (b)(4) that fail the leak test (pressure drop test) may be retested. If the (b)(4) fails more than (b)(4) times, it must be replaced.”
• When (b)(4) failed leak testing, retesting was often not performed the same day but at a later date. As a result, you manufactured drug products using (b)(4) that had failed leak testing without confirming their integrity. For example, (b)(4) on line (b)(4) failed to meet acceptance criteria on July 1, 2025, and did not pass testing until July 19, 2025. In the 18-day period between these tests, your production schedule indicated you manufactured at least (b)(4) batches of drug products.
• You lacked raw (b)(4) testing data. During the inspection, you were unable to locate raw (b)(4) integrity testing data from (b)(4) for line (b)(4).
• Instead of reviewing raw (b)(4) testing data, your quality assurance unit relied on forms containing transcribed information. In your response, you commit to enhancing your (b)(4) integrity testing program through procedural updates requiring additional quality oversight, defining actions following test failures including not permitting production to proceed “following an invalid or failed test,” and implementing quality review of visual and (b)(4) testing results.

You indicate that inappropriate acceptance criteria programmed into your (b)(4) integrity testing device caused many of the failures. You also assert, “[T]here has been no impact to any released batches or the overall control of sterility assurance at the site.”

Furthermore, your response states that in your operators’ experience, pressure decay failures are generally not indicative of non-integral (b)(4), and they instead relied upon visual inspection.

Your response calls into question the reliability of your (b)(4) integrity testing program. Visual inspections, on their own, are insufficient to monitor (b)(4) integrity. Visual (b)(4) examinations provide far lower detectability than, and cannot be substituted for, (b)(4) integrity testing devices. It is essential that your firm use (b)(4) integrity testing devices that are capable of reliably detecting sub-visible breaches in (b)(4) integrity.

You also failed to perform retrospective evaluation of potentially impacted products and processes. In response to the uninvestigated (b)(4) integrity failures, you concluded there was no quality impact to released batches or overall contamination risk at the site. However, you appear to have limited your review only to examples cited during the inspection.

Additionally, you failed to assess equipment management across your site to identify other potentially impacted critical equipment that may affect aseptic conditions. You should give continual attention to the integrity of critical equipment. This includes comprehensive maintenance procedures that establish adequate integrity testing and proactive replacement before breakdown.

Protective Equipment Materials

You failed to implement other adequate equipment control systems to prevent contamination during aseptic processing. Our investigators observed particles shedding from (b)(4) material in aseptic areas. For example, loose, visible fibers were observed on and dislodging from (b)(4) covers during (b)(4) installation within critical aseptic filling areas. Fibers also were observed on tubing in two locations in line (b)(4). Subsequently, unused (b)(4) covers were inspected and observed to have loose fibers indicating the material itself was the source of contamination. You use the material is used to protect (b)(4) and the end of sterile tubing.

Furthermore, this is an ongoing issue. Your customer reported your previous non-pharmaceutical grade (b)(4) material as a source of particulate contamination. In response, you introduced your current (b)(4) material across your (b)(4) and RABS processing lines without evaluating its particle generating characteristics.

In your response, you explain the (b)(4) seams on the (b)(4) are the apparent source of visible fibers and they appear to be statically charged. You also indicate you are working with your supplier to address this issue while taking interim controls including awareness training, visual checks of equipment at risk of fibers, removal of observed fibers with sterile lint-free wipes, and the exchange of equipment when fibers are observed attached to product contact surfaces.

Your response is inadequate. You limited your retrospective batch review to only the two batches observed to be exposed to loose fibers during the inspection. Your response also fails to assess the particles generated by the (b)(4) material to determine their characteristics (e.g., size). Additionally, your response fails to support the adequacy of visual inspection as an interim control or to review quality indicators for particle related issues (e.g., complaints, deviations). Finally, your response did not address your failure to evaluate particle generation in the replacement material when you implemented a change control for (b)(4) in response to a particle generation complaint. This is a quality oversight failure.

Aseptic processing operations should be designed and executed to minimize exposure of sterile articles to potential contamination hazards in the manufacturing operation. Flaws in the design of cleanrooms and aseptic processing lines or improper execution of aseptic operations can enable entry of contaminants into the critical (ISO 5) processing area and lead to product contamination.

(b)(4) technology represents a significant advance over traditional operational designs. However, all technologies have failure modes that require ongoing, vigilant monitoring and maintenance to ensure a state of control, including (b)(4). A strong quality system is essential to oversee design and construction of aseptic processing lines and supporting utilities, and to ensure ongoing proper operational control to safeguard against contamination hazards throughout the facility lifecycle.

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

In response to this letter, provide the following:

• A comprehensive assessment of your (b)(4) system design, control, and maintenance including, but not limited to: o Identification of deadlegs and any other insanitary elements of your (b)(4) system. o A comprehensive remediation plan and detailed CAPA timeline for improving design, control, and maintenance of your (b)(4) system. Include re-piping and modifications to eliminate deadlegs, removal of insanitary fittings, assurance of appropriately designed recirculating loops, and completion of all other needed remediations to ensure sanitary systems. Place special emphasis on identifying and eliminating any deadlegs that feed (b)(4), RABS, or other sterile production equipment. o The validation report for the (b)(4) system after all identified design issues have been fully corrected and any maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report. Include the summary of all improvements made to system design, as well as the program for ongoing control and maintenance.
• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of potential contamination from residual moisture after cleaning. For each production line, assess (b)(4) cleaning and (b)(4) drying cycles, identify specific equipment parts which remain within the (b)(4) and RABS after cleaning, and address the potential for (b)(4) to remain stagnant within equipment between production operations. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture products intended to be sterile.
• Based upon the cleaning effectiveness assessment, provide a CAPA detailing improvements to your cleaning and disinfection program including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning and disinfection execution for all products and equipment, and all other needed remediations.
• A comprehensive assessment of the design and control of your firm’s manufacturing operations with a detailed and thorough review of all microbiological hazards.
• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
• A comprehensive evaluation of your ongoing (b)(4) maintenance program. o Address elements including, but not limited to, frequency of integrity tests (e.g., at least (b)(4)), (b)(4) testing procedure and methodology, and appropriate practices to reduce the occurrence of invalid tests. o Conduct an analysis of the various failure scenarios that have occurred during your (b)(4) leak testing (e.g., device set-up problems, failure to meet initial pressure, employee interference). Also include further clarity on whether supervisors will be notified immediately, prior to initiation of a retest, of any instance of a (b)(4) integrity test failure. o Include a product impact assessment. o Provide associated CAPA.
• A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
• A risk assessment addressing the use of shedding material within your critical ISO 5 production areas. Include a detailed summary of how you determined that your interim controls are adequate to prevent the contamination of products. Include details of your investigation such as evaluation of particle generation, particle size distribution, and the likelihood of detection by visual inspection. Discuss your investigation into potentially impacted lots of product including your evaluation of quality indicators such as complaints and deviations. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls. 2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

Your (b)(4) cycles were inadequately validated to ensure that they were capable of consistently decontaminating all interior surfaces of your (b)(4) and multiple RABS lines in preparation for aseptic production.

Biological Indicator Recoveries

Inadequacies in your (b)(4) process were demonstrated through a trend of routine recoveries of biological indicator (BI) growth at completion of validation cycles executed in your (b)(4) since 2022.

Notably, your acceptance criteria were inappropriate in that they allowed routine recovery of multiple BI survivors. For example, positive BIs (upwards of 8 recoveries) were identified in nearly all validation cycles ((b)(4) of (b)(4)) between 2022 and 2025 on your lines (b)(4) lines. These positive BIs occurred at various locations within each line. However, based upon your inappropriate acceptance criteria, only two of the (b)(4) validation cycles were found to be unacceptable.

Furthermore, you attributed recent validation failures in 2025 to “rogue” phenomenon in a BI lot, but this fails to recognize the multiple positive BIs that occurred with other BI lots in the same year. You also failed to acknowledge your long-term trend of routine BI positives in most of your (b)(4) validation studies.

Inadequate *(b)(4)** Validation*

Your (b)(4) validation did not demonstrate reliable decontamination cycle capability. For example:

• (b)(4) were not (b)(4) during the (b)(4) validation cycles such that (b)(4) were present in the (b)(4). Your validation instruction, PPVA VA 48074e/03, appears to permit (b)(4) to rest on the bottom of (b)(4), creating an occluded surface which undermines the ability of (b)(4) to decontaminate this critical location.
• You did not document or adequately specify each location of BI placement. You also lacked scientific evidence to support the triplicate BIs being representative of each location.
• You allowed repetition of validation cycles without proper investigation in each instance of observed BI growth. Your (b)(4) validation cycle was repeated in your (b)(4) after initially failing to meet its acceptance criteria for positive BIs ((b)(4) out of (b)(4)). In your response, you committed to assessing your (b)(4) for surface exposure and implementing remediations based on your findings where possible, increasing BIs in (b)(4) with (b)(4) for (b)(4) decontamination process validation, updating your procedures to address failed validation cycles, reducing the allowable BI growth, implementing investigational requirements for any BI growth, and optimizing the (b)(4) cycle in your (b)(4).

Your response is inadequate. You failed to address multiple years of consistent recoveries of positive BIs across multiple locations within your (b)(4) during previous validation cycles. Recurrent failures are indicative of poor cycle robustness and require further investigation. Furthermore, your commitment to increase the number of BIs in (b)(4) does not address setup and configuration adaptations that can ensure consistent exposure of all interior surfaces to (b)(4).

Incomplete exposure of interior surfaces to (b)(4) compromises decontamination effectiveness and places the (b)(4) and RABS environment at risk. Furthermore, as discussed above, the inconsistent removal of residual moisture prior to (b)(4) treatment of your (b)(4) and RABS could further compromise (b)(4) decontamination efficacy.

In response to this letter, provide:

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification and ongoing monitoring of variation to ensure a continuing state of control.
• A comprehensive, independent review of the adequacy of (b)(4) cycles. Place special attention on (b)(4) cycle stages including (b)(4). Provide a timeline for a detailed report on the findings of the independent review and associated CAPA activities (e.g., cycle parameter changes such as an increased decontamination phase duration; optimized airflow; improved surface exposure).
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your decontamination cycles that includes vigilant monitoring to ensure an ongoing state of control. Also, include your program for assuring ongoing state of control throughout your facility and equipment infrastructure.
• Procedures to ensure residual (b)(4) is appropriately removed from RABS and (b)(4) units before execution of (b)(4) cycles. Request for a Meeting with FDA

After you submit your response to this warning letter, we recommend you reach out to this office to arrange for a teleconference to discuss your corrective actions and preventive actions in detail. Please direct your request to Patricia Warren at patricia.warren@fda.hhs.gov and cc: CDER-OC-OMQ-Communications@fda.hhs.gov.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Simtra Deutschland GmbH located at Kantstr. 2, 33790 Halle/Westphalia, Germany, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority that appear to be adulterated may be detained or refused admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days 1. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3002806419 and ATTN: Samantha Bradley.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research

CC:
Rémi Helmig
Site Director
Simtra Deutschland GmbH
Kantstr. 2
33790 Halle/Westphalia
Germany
rhelmig@simtra.com

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1 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.

• ## Content current as of:

03/10/2026

• Regulated Product(s)

  • Drugs