Delivery Method: VIA EMAIL WITH READ RECEIPT Reference #: 320-25-68 Product: Drugs Recipient:
Recipient Name
Mr. Roland Holmqvist
Recipient Title
Chief Executive Officer
Rechon Life Science AB
Soldattorpsvagen 5
Limhamn
216 13 Skane Lan
Sweden
Issuing Office: Center for Drug Evaluation and Research (CDER)
United States
Warning Letter 320-25-68
April 30, 2025
Dear Mr. Holmqvist:
The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Rechon Life Sciences AB, FEI 3002806978, at Soldattorpsvagen 5, Limhamn, Skane Lan, 216 13, Sweden, from August 26 to September 6, 2024.
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 September 27, 2024 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 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)).
You failed to ensure adequate aseptic behavior and establish appropriate written procedures designed to prevent microbiological contamination risks during the manufacture of drug products purported to be sterile. On August 26, 2024, our investigators observed an operator touching the (b)(4) of the (b)(4) with their gloved hand during the set up and assembly of the aseptic processing line.
This unacceptable practice of touching the (b)(4) with gloved hands was permitted in your standard operating procedure (SOP-0870-3.0) for filling and sealing on the ampoule line. For example, your procedure allowed the operator to adjust the (b)(4), “with the fingertip” of a sanitized gloved hand.
Your smoke studies simulated multiple adjustments of the (b)(4) with gloved hands during interventions and assembly. In one smoke study video, the operator made contact with the (b)(4) of the ampoule line (b)(4) during the “Assembly” phase.
In your response, you provide corrective actions and preventative actions (CAPAs), including awareness training for all operators, a deviation investigation that examined 2 years of (b)(4) swab samples, a procedure revision, and the rejection of the affected batch.
Your response is inadequate. You state that there was no intentional or accidental contact of the gloved hand with the (b)(4) during inspection. You also state the SOP for filling and sealing on the ampoule line “specifically stated that operators are not allowed to touch the (b)(4).” However, this assertion conflicts with your procedure and operator practices demonstrated in your smoke study videos. You did not provide environmental monitoring trend data for the (b)(4) swab samples. Furthermore, your revised procedure still allows for (b)(4) adjustments with sanitized, gloved fingertips, instructing operators to touch the (b)(4) as “(b)(4)” and to not “touch the (b)(4).” It is important that personnel avoid direct contact of critical surfaces with any part of their gown or gloves. Only sterile instruments should be used for manipulations and interventions on the aseptic processing line when handling sterilized materials. These sterile instruments should be stored in ISO 5 conditions when not in use to prevent contamination.
For additional guidance on aseptic processing 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:
- A comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
o All human interactions within the ISO 5 area
o Equipment placement and ergonomics
o Air quality in the ISO 5 area and surrounding room
o Facility layout
o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations) - 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.
- Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to better assure routine and effective supervisory oversight for all production batches. Also, describe the frequency of quality assurance oversight (e.g., audit) during aseptic processing and other operations.
- A thorough risk assessment that evaluates how poor aseptic technique and cleanroom behavior, such as those observed during the inspection, may have affected quality and sterility of your drugs.
2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your investigations into environmental monitoring (EM) excursion results and out-of- specification (OOS) assay results were inadequate.
A. Your CAPAs to the persistent contamination of objectionable microorganisms were not robust, as evidenced by the continued recovery of gram-negative organisms and spore formers in the ISO 5 and 7 areas and on personnel since 2022. This deficiency was also cited during the previous inspection when an adverse trend of gram-negative rods (Moraxella osloensis) were recovered from operators’ clothing.
For example, your investigation into the trend of eight occurrences of gram-negative organisms recovered from either operators’ gowning or from an ISO 7 air sample, was inadequate. You concluded that the adverse trend was due to operators talking in the ISO 7 areas and an increase of staff illness. Your CAPA included awareness training for operators and a procedural update for persons who perform sampling in (b)(4). However, your investigation did not provide a holistic evaluation of all potential contamination sources and personnel practices in the facility contributing to the adverse trend.
In your response, you state you will implement additional immediate actions, including the requirement for mouth covers in ISO 8 areas and having operators apply a second layer of shoe covers as they pass through the (b)(4).
Your response is inadequate. Although you state you do not have a “current issue related to objectionable microorganisms, i.e. spore formers and gram-negative bacteria,” you fail to provide sufficient evidence to support this statement. In addition, you do not address ill operators working in aseptic areas as noted in your deviation as the identified root cause for the trend.
B. Your investigations into OOS results were inadequate because they lacked scientific rationale for root cause determinations. For example, you initiated an OOS investigation for (b)(4) assay content for (b)(4) Injection, (b)(4) mg/mL, batch (b)(4). The specification for (b)(4) content was (b)(4) mg/mL. The sample was injected (b)(4), and your initial test yielded an (b)(4) result of (b)(4) mg/mL (b)(4). Your investigation concluded, without adequate scientific justification, that a non-functional injector syringe was the probable root cause. You invalidated the original results without an obvious laboratory error and no manufacturing assessment was performed. A new analysis was performed and the passing results were recorded.
In your response, you acknowledge that the laboratory investigations “contain gaps” and your procedure for conducting OOS investigations can be improved. You revised your procedures to include hypothesis testing during the laboratory investigations.
Your response is inadequate. Your revised procedures do not require a manufacturing investigation to be conducted prior to invalidating data unless it is an obvious laboratory error. In addition, your company did not conduct a retrospective review of invalidated laboratory data for drug products marketed in the United States to ensure the drug meets the identity, strength, quality and purity it purports.
In response to this letter, provide:
- A comprehensive independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.
- A comprehensive independent review of your personnel and environmental monitoring program, including but not limited to:
o A plan to fully remediate these programs. For example, describe changes to equipment, procedures and practices that will ensure meaningful ongoing data is collected to promptly detect and respond to emerging microbial trends from your classified areas. Provide an updated timeline for implementation of your program, including procedural changes. - A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products currently in the U.S. market and within expiry as of the date of this letter and a report summarizing the findings of the analysis, including the following for each OOS:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
o A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include, but not be limited to, addressing the following:
o Quality unit oversight of laboratory investigations.
o Identification of adverse laboratory control trends.
o Resolution of causes of laboratory variation.
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified.
o Adequately scoping of each investigation and its CAPA.
o Revised OOS investigation procedures with these and other remediations.
3. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
A. Your firm failed to validate and assess the effectiveness, distribution, and reproducibility of (b)(4) decontamination to ensure it can safely achieve a state of control in aseptic rooms against objectionable microorganisms.
For example, your firm utilized (b)(4) as an (b)(4) decontamination of aseptic filling lines (b)(4). Your investigation reported several instances of spore-forming bacteria during (b)(4), in ISO 7 areas. The identified bacteria included species such as Paenibacillus provencensis/shunpengii/urinalis, Bacillus infantis, Niallia circulans complex, Metabacillus halosaccharovorans, Peribacillus simplex, Bacillus subtilis group and Bacillus cereus group. The root cause was identified as an “inadequate process for (b)(4) sanitization,” which was “unclear and may be causing the growth of spore forming bacteria in Grade B.” Additionally, the same (b)(4) decontamination cycle showed positive biological indicators (BIs) on aseptic lines (b)(4) during (b)(4) periods ((b)(4)). The results indicate the (b)(4) decontamination process is ineffective.
In your response, you state the BIs were used for informational purposes only and not as an evaluation of the (b)(4) decontamination process. You acknowledge the title of the SOP “(b)(4) Sanitization – Decontamination of rooms at Bulk Production” is misleading and the use of (b)(4) is not implemented as a routine decontamination process. You corrected the title to be “Disinfection of grade A and B areas within Bulk Production with (b)(4).” You state that you will collaborate with your vendor to perform a mapping study to verify the effectiveness of the disinfection process.
Your response is inadequate. You do not provide evidence the (b)(4) decontamination process provides adequate surface coverage of all areas on the aseptic line, is compatible with materials, and ensures that residual (b)(4) that may remain on equipment does not affect product quality. Critical cleaning and sanitization agents must be validated. A mapping study is not validation of the disinfectant. Validation requires documented evidence that the disinfection process consistently removes or inactivates known or possible pathogens.
B. Our investigators observed walls and floors of numerous ISO 8 production rooms were sticky and left visible (b)(4) residue when wiped by the hand. The investigators additionally noted fibers from disposable coveralls stuck to the walls in one of the production rooms. Such residual contamination can compromise product sterility and safety potentially resulting in patient harm.
In your response, you state that your Quality Control Microbiology (QCM) group discovered the sticky floors and walls (b)(4). Your deviation investigation concluded that the probable root causes were a build-up of new cleaning disinfectants and a possible interaction with materials in the facility. Your CAPA included wiping surfaces with (b)(4) after cleaning.
Your response is inadequate. You did not provide the deviation investigation for the evaluation and identification of the (b)(4) residue and a risk assessment of contamination to the drug product. Furthermore, you did not provide an assessment of your cleaning validation with regard to the new cleaning agents.
In response to this letter, provide:
- A CAPA plan, based on the retrospective assessment of your cleaning and disinfection program, that includes appropriate remediations to your cleaning and disinfection processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning and disinfection. Describe 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.
- Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include, but not be limited to, identification and evaluation of all worst-case:
o Drugs with higher toxicities
o Drugs with higher drug potencies
o Drugs of lower solubility in their cleaning solvents
o Drugs with characteristics that make them difficult to clean
o Swabbing locations for areas that are most difficult to clean
o Maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product. - A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
4. Your firm failed to maintain buildings used in the manufacture, processing, packing, or holding of drug products in a good state of repair (21 CFR 211.58).
Your firm did not properly maintain classified areas and cleanrooms used in the manufacture of drug products. Our investigators observed peeling paint on the ceiling as well as bubbled paint and rust at the bottom of the door in ISO 7 room (b)(4). Room (b)(4) provides access into aseptic filling line (b)(4).
These deficiencies were discussed with your management at the time of the walk-through of the aseptic areas. Management stated the peeling paint surfaces above the (b)(4) door may be caused by the surface material being incompatible with the cleaning agent used to clean the production facility. It is critical that the building is maintained to prevent exposure of sterile articles to potential contamination hazards in the manufacturing operation.
In response to this letter, provide 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.
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 Rechon Life Science AB at Soldattorpsvagen 5, Limhamn, 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 days1. 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 3002806978 and ATTN: Erika V. Butler.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
___________________
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.
