VALIDATION OF A GLOVEBOX WORKSTATION

Clinical researchers are creating ADC’s (antibody drug conjugates) that consist of an antibody, a linker, and a cytotoxic drug. By combining the unique targeting of monoclonal antibodies with the cancer killing ability of cytotoxic drugs, the use of this type of ADC allows sensitive discrimination between healthy and diseased tissue. These anti-cancer drugs use high potency active pharmaceutical ingredients (HPAPI’s) to achieve targeted therapy for treatment of people with cancer. Many of the HPAPI’s are novel compounds of unknown potency and toxicity. Some cytotoxic agents are made of a combination of nanoparticles. The establishment of limits of operator and patient exposure for nanoparticles are only recently being investigated. However, nanoparticles less than 10nm (nanometers) may be absorbed through the skin. The greatest risk to the operator is the inhalation of the HPAPI’s. The occupational exposure limit (OEL) is based on the toxicity of the drug. The OEL is measured by the potency of the drug, the frequency of contact with the drug, the duration of contact with the drug, and the quantity of the drug. Unfortunately, much of this is unknown when researchers are working with nanoparticles and ADC’s. Therefore, during the risk assessment personnel protection must predict protection in a worst-case environment. The recommended containment solution specified is typically Occupational Exposure Band (OEB) 4 or 5. This is a system for grouping compounds of similar toxicity and potency to guide the assessment of the engineering controls required to achieve safe manufacturing of ADC’s in research, development, and manufacturing work environments.

Many existing research labs, pharmaceutical and biopharmaceutical manufacturers, and contract manufacturing organizations (CMO’s) are not designed nor are they equipped with the engineering controls to safely handle the manufacture of ADC’s. The safe manufacture of ADC’s requires more modern facilities, equipment, and engineering controls as well as programs, practices, and procedures to adequately protect the operators and the work environment.

The FDA mandates that any substance manufactured for human consumption must strictly comply with current good manufacturing practices (GMP). Flow Sciences, Inc. (FSI) provides verified containment and control solutions per current GMP requirements for manufacturing ADC’s for clinical trials with the glovebox workstation to maintain exposures below acceptable limits. Therefore, the Flow Sciences, Inc. Glovebox Workstations used for the manufacture of ADC’s are fully validated. A master device record (MDR) documents the entire validation process of the glovebox workstation from design, construction, quality control, and facility acceptance testing. The ISO 9001 based quality management system and lean manufacturing concepts allow the rapid construction of glovebox work stations.

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DESIGN QUALIFICATION

During a meeting with a Flow Sciences containment expert, details of the user requirement specifications (URS) are documented. In the manufacture of ADC’s both personnel and product protection must be addressed. A risk assessment is performed to verify the degree of containment and other engineering controls that must exist to assure compliance with the specific OEL of the drug.

The purpose of the Glovebox Workstation is to provide negative pressure containment for applications using toxic HPAPI’s requiring isolation that meet or exceed ISO Class 5 clean processing. The ISO Class 5 environment is created by the movement of air thru the HEPA filter inlet, which is 99.97% efficient at 0.3 micrometers, across the inside work surface of the glovebox in a horizontal, unidirectional flow and into the return bag-in/bag-out HEPA filter exhaust. Airflow and containment is predicted using computational fluid dynamics. Computational Fluid Dynamics (CFD) is the study of fluid dynamics using sophisticated computing technology. URS may require changes in the design of the glovebox. FSI uses CFD in the design process to study the effects of changes in airflow in the enclosure design. This assures the change in the design will maintain stable airflow that improves containments while also providing a low turbulent atmosphere that allows sensitive equipment to perform properly and minimize potential product loss.

The ADC’s may be sensitive to fluctuations of temperature or humidity. Therefore, stabilization of temperature and humidity may be engineered into the design. LED lighting provides the precise amount of light to perform the most detailed procedure. The glove ports provide additional protection to the operator. Additionally, pass through or waste chute attachments may be engineered per the user requirement specifications. The FSI Glovebox Workstation has been evaluated by third-party testing facilities that have confirmed containment levels less than or equal to 50ng/m3 and a balance stability to the 7th decimal place which exceeds the industry norm.

The design engineers at Flow Sciences, Inc. create a 3D animated model and can also build a full-scale mock-up. When the URS documents are signed by representatives of the customer and Flow Sciences, Inc. the installation qualification and construction of the Glovebox Workstation begins. Many companies elect to have several “copy exact” gloveboxes shipped to various locations. This standardizes processes and procedures to assure reproducibility of product from more than one research or manufacturing site.

INSTALLATION QUALIFICATION

During the installation qualification, supply chain management assures the high quality and integrity of the product. QC (quality control) verification of materials used in the manufacture of the glovebox are documented in the MDR. All materials used in the assembly of the Glovebox Workstation are in stock at Flow Sciences, assuring on-time delivery of every unit. Assembly of the Glovebox Workstation is per FSI standard operating procedures that include several quality checkpoints before progressing to the next step. Each unit is assigned a unique serial number to provide traceability to all materials used in the manufacture of the glovebox. When the assembly of the Glovebox Workstation is completed and all quality checks compliant with the user requirement specifications, the operation qualification begins.

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The general enclosure performance is measured using standard ASHRAE 110 and SEFA 9-2010 testing protocols. Flow visualization testing is performed to visualize airflow into the glovebox and determine the effectiveness in drawing air away from the operator. The large volume smoke test evaluates the containment capacity of the glovebox and the time required to clear the glovebox of contaminants. The tracer gas test evaluates the effectiveness of the glovebox in containment of contaminants. This confirms that the airflow inside the glovebox is as was designed using the computational fluid dynamics.

The HEPA Filter Efficiency Evaluation determines the efficiency of the HEPA filters and their housing to remove particles from the air. The performance of the inlet HEPA and bag-in/bag-out (BIBO) primary HEPA filters and housing are tested using the Institute of Environmental Sciences and Technology recommended practice IEST-RP-CC001, HEPA and ULPA Filters. This test confirms the HEPA filter integrity and efficiency is as was determined by the supplier of the HEPA filters. The air particle cleanliness level is determined per ISO 14644-1 Cleanrooms and Associated Controlled Environments – Classification of air cleanliness by particle concentration. This test determines the cleanliness of the air inside the glovebox by measuring the number of particles (0.3µm and greater) per cubic meter of air. This test confirms the particle cleanliness inside the glovebox.

OPERATION QUALIFICATION

The operation qualification consists of the Factory Acceptance Testing that is performed on the Glovebox Workstation to measure the performance, interior cleanliness and to determine the containment effectiveness during simulated operations. The testing is performed in the Flow Sciences laboratory under the direction of Lab Manager Allan Goodman, Ph.D. The laboratory meets ISO Class 7 particle requirements and maintains positive pressure while allowing ten air changes per hour.

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The Surrogate Powder Testing simulates the containment expected for compounds during typical work practices. This test provides documented evidence that the containment system design and manufacturing of the glovebox meets the contracted Occupational Exposure Levels (OEL) as defined by client/facility protocol and/or user requirement specifications. At FSI, this test is digitally recorded to provide documented evidence of correct execution of the test or to evaluate out of specification results.All validation documentation includes serialized documentation including a Certificate of Calibration for all instrumentation used and Certificate of Analysis for all surrogate products used. Validation documentation, maintenance manuals and recommended usage guidelines are shipped with the glovebox from North Carolina to facilities around the world.

PERFORMANCE QUALIFICATION

When the client receives the glovebox, all documentation should be reviewed and filed for future reference. The external packaging is removed and the glovebox is thoroughly cleaned in place per industry recommended practices. Cleaning solutions should be compatible with the components used in the manufacture of the glovebox. It is recommended that Site Acceptance Testing (SAT) be performed before any manufacture of ADC’s by any operators. This testing is the same test protocols and standards as used in the Factory Acceptance Testing at FSI. It is recommended that the facility occupational health and safety team is included in the execution of the SAT and operators wear sufficient personnel protective equipment (PPE). FSI recommends that the glovebox is serviced and certified annually by a third party certifying company.

The safe handling of ADC’s can be performed in the FSI Glovebox Workstation. Ray Ryan, Founder and President of FSI states, “Flow Sciences is a solution based company. Sometimes we have the solution on our shelves, but most of the time we have to develop a solution to fulfill that industry need.” The expertise and experience at FSI enables rapid manufacture of high quality containment solutions for the manufacturers of ADC’s per current FDA GMP’s.

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JAN EUDYCleanroom/Contamination Control Consultant, ISO 9000/cGMP auditor, HACCP/Food Safety Auditor