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  5. Iso-Tex Diagnostics, Inc. - 655666 - 07/20/2023
  1. Warning Letters


Iso-Tex Diagnostics, Inc. MARCS-CMS 655666 —

Delivery Method:
Via Electronic Mail Return Confirmation Requested

Recipient Name
Megan M. Maloney
Recipient Title
President/Quality Assurance/Regulatory Affairs
Iso-Tex Diagnostics, Inc.

1511 County Road 129
Alvin, TX 77511
United States

Issuing Office:
Division of Pharmaceutical Quality Operations II

United States

DATE: 7/20/2023

Case #: 655666


Dear Ms. Maloney:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Iso-Tex Diagnostics, Inc., FEI 1626310, at 1511 County Road 129 Alvin, TX, from January 30, 2023, to February 10, 2023.

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 March 2, 2023, 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 have buildings used in the manufacture, processing, packing, or holding of drug products of a suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations (21 CFR 211.42(a)). Your firm also failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas, and an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(iv) & (v)).

Your deficient facility design, equipment suitability, and environmental conditions significantly increased contamination risk to drugs intended to be sterile.

Inadequate Design and Control of Facility Conditions

You failed to ensure that cleanrooms are properly designed and constructed of materials that allow for the ease of cleaning and disinfection. For example, our investigators observed:

  • The door of your (b)(4) connection to your aseptic processing cleanroom and gowning room was in disrepair and unable to fully close.
  • Foreign particulates hanging from two ceiling HEPA Filters within your aseptic processing cleanroom.
  • Inadequately sealed fluorescent light fixtures in aseptic processing cleanrooms.
  • Exposed electrical lightbulb sockets and an emergency light within aseptic processing cleanroom without a cover.

Inadequate Monitoring and Control of Environmental Conditions

You failed to ensure that your facility is designed, controlled, and maintained to prevent lower quality air from entering and contaminating your aseptic processing cleanrooms, resulting in departures from your established limits throughout your clean rooms. For example:

  • Since at least December 1, 2022, negative differential pressure was frequently documented between your sterile drug processing cleanroom containing aseptic processing hoods and the adjacent gowning room, that allows for lower quality of air to move into your aseptic processing cleanroom. You lacked investigations into these recurring excursions.
  • From at least August 10, 2022, you failed to maintain the relative humidity below (b)(4) as established in your “Environmental Quality and Control Program” procedure. Your relative humidity data reveals repetitive and extended excursions. For example, in aseptic processing cleanroom (b)(4), from January 15, 2023, starting at 7:40pm, and ending January 18, 2023, at 7:10pm, the relative humidity ranged from 60.1 to 94.8%, and averaged 73.5%. Upon request for additional information on April 26, 2023, you did not provide any investigations into the excursions. You were also unable to provide procedures, use logs, or qualification documentation for a (b)(4) dehumidifier operating in gowning cleanroom, suite (b)(4), used to control relative humidity. Your use of a (b)(4) dehumidifier in a cleanroom indicates a poorly designed HVAC system.

Aseptic processes should be designed to minimize exposure of sterile articles to potential contamination hazards, including, but not limited to, variation in environmental conditions. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. A suitable facility monitoring system is critical to maintain appropriate environmental conditions throughout all of your cleanrooms. All deviations from established limits should be appropriately investigated to rapidly detect atypical changes that can compromise the facility’s environment. Prompt detection of an emerging problem is essential to preventing contamination of your aseptic production operations.

Your response is inadequate because you fail to address systemic issues to ensure your facility is suitable for the aseptic processing for sterile drugs. You also do not provide meaningful evidence that your manufacturing environment is under an ongoing state of control.

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.
  • A thorough, independent assessment, and corrective action and preventive action (CAPA) for your pressure differential system and environmental temperature and humidity conditions. Include a comprehensive evaluation of monitoring, recording, alarm documentation, deviation investigation, data retention and overall system control in your assessment. Provide a CAPA that includes, but is not limited to:

    o The state of control of air balance between clean areas and adequacy of integration of each of the HVAC systems
    o Documentation for all alarms, irrespective of the length or location of the event, and retention of this data
    o Remediated procedures for investigating deviations from established limits, including but not limited to specific provisions for handling instances in which a pressure reversal occurs
    o Remediated facility monitoring systems that will rapidly detect atypical changes of pressure, temperature, and humidity, in your cleanrooms simultaneously

  • A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
  • A detailed risk assessment addressing the hazards posed by distributing drug products with potential contamination. Specify actions you will take in response to the risk assessment, such as customer notifications and product recalls.
  • Complete investigations into all batches with potential microbial contamination. The investigations should detail your findings regarding the root causes of the contamination.
  • All microbial test methods and specifications used to analyze each of your drug products.
  • 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.
  • Your complete investigation into failed cleanroom certification study data relating to air changes. Include all original and corrected calculations regarding air changes, the location of all air inlets and exhaust outlets in the room, and a detailed description of the BSC design (e.g., intake of air) and its position in the room. You should also provide an independent assessment of the investigation, and the adequacy of air changes in all of your cleanrooms, by a qualified consult.
  • Smoke studies that evaluate the suitability of your biological safety cabinets (BSC) used for the aseptic manufacturing of your drug products.

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 firm manufactures sterile radiopharmaceutical drug products that are aseptically filled. You failed to have appropriate gowning for aseptic production of sterile injectable drug products. For example, investigators observed your production personnel:

  • With exposed facial skin and hair entering your ISO 5 production environment while performing aseptic manual filling of Volumex I-131, Lot # V230102-1107.
  • On multiple instances, failing to disinfect their sterile gloves before returning to the ISO 5 area.
  • Use poor sterile gowning behavior and practices (e.g., sterile gown touched the floor while donning the gowning).
  • Gowning without using suitable sterile gloves.

Your firm’s failure to ensure that personnel gown appropriately and strictly adhere to acceptable aseptic procedures significantly increases the risk of drug product contamination.

In addition, your production staff and equipment (e.g., active air monitor, analytical balance printer) blocked the path of unidirectional airflow in your ISO 5 production environment during filling operations of Volumex I-131, Lot # V230102-1107.
Unidirectional airflow design is used to protect sterile equipment surfaces, container- closures, and drug product, and should not be obstructed by personnel or equipment. Disruption of unidirectional air in the critical area poses a significant risk to product sterility.

Your response is inadequate because you do not commit to conducting a retrospective review of drug product manufactured under these conditions for potential quality and safety impact. Additionally, your response does not include supporting documentation of CAPA activities.

In response to this letter, provide:

  • Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also, describe the frequency of quality unit oversight (e.g., audit) during aseptic processing and supporting operations.
  • A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
  • A gowning qualification program that establishes, both initially and on a periodic basis, the capability of an individual to adequately don the complete sterile gown in an aseptic manner.
  • Details regarding how you will establish adequate gowning, training, gowning qualification, and supervision on an ongoing basis.

3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

Our investigators observed inadequately controlled laboratory reagents (i.e., inadequate labeling), as well as expired testing materials. The use of uncontrolled and expired testing materials may impact the validity of your testing results used to support the release of your drug products.

Your response is inadequate because you do not conduct or commit to conducting an investigation to determine product impact nor do you commit to determining whether your corrective actions require extension to other related procedures.

In response to this letter, provide a comprehensive, independent 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.

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.

Repeat Violations and Observations at Facility

In a previous warning letter, 2011-DAL-WL-03, issued on December 3, 2010, and previous inspections ending on January 31, 2018, July 10, 2015, and September 12, 2011, FDA cited similar CGMP violations and observations. You proposed specific remediation for these violations and observations in your responses. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive six-system audit of your entire operation for CGMP compliance and evaluate the completion and efficacy of all CAPAs before you pursue resolution of your firm’s compliance status (i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System).


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 all violations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved violations may also prevent other Federal agencies from awarding contracts.

Failure to address violations may also cause FDA to withhold issuance of Export Certificates. 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 address any violations.

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. 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.

Your written notification should refer to case # 655666.

Please electronically submit your reply, on company letterhead, to Rebecca Asente, Compliance Officer, at ORAPHARM2_RESPONSES@fda.hhs.gov, and copy Ronda Loyd-Jones, Director, Compliance Branch, at ronda.loyd-jones@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Rebecca Asente via phone at (504) 846-6104 or email at Rebecca.asente@fda.hhs.gov.


Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II

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