- Delivery Method:
- VIA UPS
Recipient NameMr. Barry Scott
Recipient TitleChief Executive Officer
- PETNET Solutions Inc.
810 Innovation Drive
Knoxville, TN 37932
- Issuing Office:
- Division of Pharmaceutical Quality Operations I
10 Waterview Blvd, 3rd Floor
Parsippany, NJ 07054
CMS # 584016
October 17, 2019
Dear Mr. Scott:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, PETNET Solutions Inc., FEI 3006577728, at 350 Washington Street, Unit 268, Woburn, Massachusetts, from March 19 to April 5, 2019.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for positron emission tomography (PET) drugs. See 21 CFR, part 212.
Because your methods, facilities, or controls for compounding, processing, packing, or holding do not conform to CGMP, your PET 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 April 26, 2019, 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’s facilities are not adequate to ensure the prevention of contamination of equipment or product by environmental conditions that could reasonably be expected to have an adverse effect on product quality (21 CFR 212.30(a)).
During the inspection, our investigator observed a state of disrepair and lack of cleanliness in your facility that commercially manufactures sterile injectable PET drugs. For example, rusted screws were observed holding up a light fixture in the ISO 5 area of the (b)(4) where you aseptically fill PET drug products. Furthermore, our investigator observed a hole in the top of your (b)(4) enclosure, approximately three inches in diameter, open to the surrounding room. The top of the (b)(4) surrounding the open hole was visibly dirty. Also, our investigator observed filth and damaged floor tiles in the immediately surrounding area of the room directly in front of the (b)(4).
Your response stated that the (b)(4) is negatively pressured to protect the operator and draws air from the surrounding environment. The presence of a negatively pressured area adjacent to an ISO 5 area requires careful facility and equipment design, as well as attentiveness to ongoing control, maintenance, cleaning, and disinfection activities to ensure appropriate air quality for your aseptic filling environment.
Between March 2016 and March 2019, adverse trends were identified in environmental and personnel monitoring samples taken from the ISO 5 areas where you conduct aseptic manipulations. Isolates from these samples frequently included Bacillus, spp., and related bacterial sporeforming species. Also, during the (b)(4) certifications conducted by a third party between July 2017 and January 2019, sporeforming fungi were repeatedly identified in the ISO 8 area of your (b)(4) immediately adjacent to your ISO 5 area.
In 2017, your firm also had a sterility test failure for a batch of Fludeoxyglucose (FDG) F18 injection. You identified the microbial contaminant as the sporeforming bacteria, Brevibacillus limnophilus.
Sporeforming organisms can pose a significant challenge to disinfection processes. We note you implemented a (b)(4) disinfection regimen. However, significant trends of sporeforming organisms continue in your facility. For example, in January and February 2019, your environmental monitoring identified Bacillus species in multiple surface samples for the ISO 5 Biological Safety Cabinet (BSC) you use to aseptically prepare final product vial assemblies. Over approximately three years, you failed to adequately respond to data indicating insufficient microbial control in the areas where you conduct aseptic manipulations, as well as adjacent areas.
Excursions and trends in environmental monitoring results should be monitored and promptly reviewed. Adverse trends should trigger a comprehensive evaluation of the state of control of your manufacturing operation.
In your response, you stated that your facility is being remodeled. However, your risk assessment for facility remediation lacked sufficient details. Your response also did not include a plan for ensuring that your facility is adequately maintained, and environmental conditions are appropriate, to ensure product quality.
In response to this letter, provide:
• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide 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)
o Adequacy of procedures to ensure ongoing maintenance and control of your facility
• Your results for all environmental and personnel monitoring conducted from April 2019 to present. Describe each interim measure implemented to ensure risk mitigation and provide all testing and all monitoring results obtained during remodeling. Also include facility monitoring trends and any excursions (e.g., differential pressure, humidity, non-viable particles, viable particles) during this period. List the date of production, name of product, lot number, and equipment used. Describe in detail when the overall remodeling work began and ended, and what construction was performed each day and the location.
• Your Planned Variance (PV00000182) document and Enhanced Environmental Monitoring protocols (D0013699 and D0013698) referenced in your risk assessment.
• Your facility qualifications, media fills, and most recent static and dynamic smoke studies performed for both the BSC and (b)(4) during and since completion of the facility remodeling.
• Your investigations for any failed (b)(4) tests since the FDA’s March 2016 inspection of your facility.
2. Your firm’s laboratory failed to develop and follow adequate written procedures for testing components, in-process materials, and finished PET drug products to ensure conformance with appropriate standards, including established standards of identity, strength, quality, and purity (21 CFR 212.60(a) and (b)).
You failed to establish adequate testing procedures for environmental monitoring for your aseptic manufacturing operations. For example, the action levels in your standard operating procedure (SOP D0012118) for environmental monitoring are not appropriate. For surface samples taken from the ISO 5 area of your (b)(4), your procedure does not require an investigation unless (b)(4) colony-forming units (CFU) are recovered from a single sample or there are (b)(4) occurrences of growth (not exceeding the single sample action limit) in a (b)(4).
These action levels in your environmental monitoring SOP are not appropriate, are of particular concern when considering the repeated recoveries of sporeforming microorganisms in your ISO 5 areas.
An ongoing goal for environmental control of ISO 5 areas is to remain free of microbial contamination. Action levels should be set appropriately. PET drug manufacturing requires vigilant environmental control, which requires prompt, appropriate attention to microbial recovery in ISO 5 areas.
We note you committed to identify any microbial contamination in both the ISO 5 BSC and the ISO 5 area of the (b)(4) for (b)(4) after the remodeling of the facility is completed. However, you did not include a justification for limiting this identification to a (b)(4). Environmental monitoring in ISO 5 areas should include routine identification of any microorganism.
You also failed to follow your established sterility testing procedure (SOP D0001993) and your procedure lacks details on disinfecting and material flow. For example, your operator omitted the (b)(4) for sterility testing of (b)(4) of your PET drug product Fludeoxyglucose F-18 Injection, USP. During another sterility test, your operator omitted the (b)(4) media tube for sterility testing for (b)(4) of Amyvid, Florbetapir F-18 Injection. Additionally, on a separate occasion, your operator incubated the sterility test tubes for both the (b)(4) and (b)(4) media at the wrong temperature for sterility testing of your PET drug product F-18 Florbetapir.
Testing is a critical control that provides assurance that your PET drug products are sterile and therefore suitable for intended use. It is important that you follow established, appropriate procedures to ensure your sterility testing is able to detect the presence of microorganisms.
Your response did not address whether you will have additional quality oversight for sterility testing, given the issues were attributed to operator error. Additionally, we note your procedure (SOP D0001993) for sterility testing lacks details on disinfecting and flow of testing supplies between unclassified and ISO 5 areas.
In response to this letter, provide:
• A comprehensive assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.
• Your investigations for any microorganisms recovered in ISO 5 areas or on operator gloves, as well as any trending data you have regarding detection of 1 CFU or more since January 2019. Include all organism identifications and the locations where organisms were recovered.
• Your process for qualification of the media used for sterility testing and whether the media is prepared off site or supplied by a vendor.
• A comprehensive assessment of your sterility testing program, including, but not limited to, disinfection of material, material flow, and environmental monitoring.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.
We note that this facility is part of a larger corporation, with PETNET facilities throughout the United States that share corporate quality oversight and procedures.
You should comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to CGMP requirements for PET drug products.
Quality Assurance Program Audits
In your response, you stated that you identified the need for facility improvements through “internal audits.” FDA reminds you of your responsibility to correct CGMP deficiencies found during quality assurance program audits, also referred to as “internal audits” in your correspondence with the FDA.
Guidance on Positron Emission Tomography (PET) Drugs
See FDA’s guidance document, PET Drugs—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing.
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 these 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 firstname.lastname@example.org, 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 the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.
We request you email Kent Bui, Kent.Bui@fda.hhs.gov, within five days of receipt of this letter to schedule a regulatory meeting.
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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 and ORAPharm1_responses@fda.hhs.gov. Please identify your response with FEI: 3006577728 and CMS # 584016.
Craig Swanson for Diana Amador-Toro
Program Division Director/District Director
U.S. Food and Drug Administration
OPQO Division I / New Jersey District
Cc: Craig Sawyer, Pharm.D.
Woburn Facility Site Manager
350 Washington Street, Unit 268
Woburn, MA 01801