HPAPI

Non-Sterile Hybrid Isolator

Abstract 

In 2011, Flow Sciences, Inc. was commissioned with providing an isolator for a large pharmaceutical company that was capable of protecting its employees by reducing their exposure below the occupational exposure level (OEL) of highly potent active pharmaceutical ingredients (APIs) in an isolator. Here we describe the unit designed and constructed and the in-house testing results. 

Background 

In the ongoing search for new therapeutic treatments, pharmaceutical companies are developing a new class of active ingredients known as High Performance Active Pharmaceutical Ingredients (HPAPI). As the name suggests, these compounds are highly potent and therefore it is critical that exposure to the pure material is minimal. More commonly associated with oncology drugs, an ‘explosion’ of HPAPIs is predicted over the next 5 years due to the high levels of research currently being conducted in this area. 

Clearly, with the advent of this phenomenon, containment of these compounds from the scientists tasked with working with them is of major concern. One reason for this is the high expense often associated with new equipment designed to handle the task. In order to combat these potentially high capital outlays, many companies are looking at alternative methods of containment, including modification of existing equipment. The Non-Sterile Hybrid Isolator, offered by Flow Sciences, Inc., is one such method of reducing the cost of containment (Figure 1). 

Figure 1. Non-Sterile Hybrid Isolator with bag in/bag out and main chamber. 

The isolator is designed to protect personnel from exposure to chemicals including HPAPIs by fully encompassing equipment used by scientists during processes such as weighing, crushing and bag in/bag out procedures. The isolator has been developed using Flow Sciences’ expertise in fluid dynamics and can be designed and manufactured to fit the customer’s needs. 

Case Study 

In 2011, Flow Sciences, Inc. was tasked by a major pharmaceutical company with the design, construction and installation of a non-sterile hybrid isolator for use by its employees during powder handling operations. The design of the isolator included a bag in/bag out (BIBO) annex and a main enclosure. 

After installation of the isolator, a third party industrial hygiene consulting company, IES engineers, was contracted to perform Site Acceptance Testing (SAT) and determine the effectiveness of the isolator. Using industry accepted testing methods; IES performed sampling of the air, surface and the testing area environment to evaluate the containment performance of the isolator using a surrogate powder (naproxen sodium) during typical operator procedures. The design containment performance target (CPT) for the VBE air samples was set at 75 nanograms of surrogate powder per cubic meter (ng/m3) of air. This value was chosen to provide an additional margin of safety compared to the OEL for an API of 150 ng/m3. Surface samples were collected and used for reference purposes. All of the containment verification testing activities were performed using industry accepted practices.1-3 

Procedure 

Prior to the containment verification assessment, the sampling strategy developed by IES was approved by the client and included typical and maximum use scenarios. The procedures, using naproxen sodium as an API surrogate, were: (1) reference standard development, comprising of: (a) dispensing approximately 500 mg of naproxen sodium into volumetric flasks; (b) development of a buffer capacity, which included dispensing of approximately 1 g of naproxen sodium into 50 mL water, followed by 5 minutes of mixing; (2) minor cleaning procedures of the VBE interior, including a wipe down of the floor surfaces and gloves with methanol and removal of equipment and materials used during the procedures. Each procedure was performed three times establish a greater level of confidence in the containment verification data. 

Airborne samples were collected from personal, source, and area locations. Personal samples were collected within the breathing zones of the operators. Source samples were collected at 200 mm from the potential emission source and area samples were collected at distances no closer than 1.5 m from the process or equipment and at a height of 1.5 m. These samples were then analyzed and exposures quantified. 

Baseline samples were collected for all locations prior to performing the operations. 

As can be seen from the table above, all samples collected for the various zones were well below the CPT of 75 ng/m3 air 3

Summary 

In summary, FlowSciences designed, constructed, and installed a non-sterile hybrid isolator for a large pharmaceutical company to limit exposure of employees to APIs during powder handling operations. Containment Verification Testing of the isolator, using a surrogate powder, was performed at the pharmaceutical company by IES, a third party industrial hygiene consulting company. The test results demonstrated that the isolator provided effective containment of powders to the CPT of 75 ng/m3 for the tasks performed. 

References 

1) American Society of Heating, Refrigerating and Air-Conditioning Engineers, “Method of Testing Performance of 

Laboratory Fume Hoods, ANSI/ASHRAE 110-1995” Atlanta, GA, 1995. 

2) International Society for Pharmaceutical Engineering, “ISPE Good Practice Guide: Assessing the Particulate 

Containment Performance of Pharmaceutical Equipment,” Second Edition, 2012. 

3) Section II: Sampling Measurements and Instruments of the OSHA Technical Manual 

 

Contributing Authors: 

• Steve Janz, Flow Sciences, Inc. 

• Allan Goodman, Ph.D., University of North Carolina, Wilmington; 

• George Petroka, Director BioPharma/EHS Services CIH, CSP, RBP, IES Engineers 

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For a PDF of this Press Release or for questions or comments, please contact us below:

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About Flow Sciences, Inc.

Flow Sciences is the world’s leading developer of containment solutions for research and development laboratories, pilot plants, automation equipment and robotics, manufacturing and production facilities where toxic or noxious potent powders, fluids, or gases require safe handling while weighing, mixing, processing, or manufacturing. Since its start in the 1980s and with the introduction of the Vented Balance Safety Enclosure (VBSE™) in the 1990s, Flow Sciences has gone on to develop a comprehensive line of over 500 enclosures, including industry standards like the Vented Balance Safety Enclosure (VBSE™), the Contained Vented Bulk Powder Enclosure, and innovative laboratory technologies like the FS1501 Nitrogen Controller and the Bag-In/Bag-Out HEPA Filtration System. For its accomplishments, Flow Sciences received an Expert Achievement Award from the U.S. Department of Commerce for accomplishments in the global marketplace, the Deloitte and Touche North Carolina Technology Fast 50 Award, the UIBS R&D and Technology Collaboration Award, along with many others. During the 1990s, Flow Sciences pioneered the Vented Balance Safety Enclosure Series (VBSE™) which introduced the first independent fan exhaust system to isolate vibrations for balance accuracy, swiftly becoming the world leader in laboratory safety equipment. Flow Sciences technologies are now used to improve safety and containment in virtually every industrial sector around the globe, from pharmaceutical, food processing, robotics, chemical, forensics, agriculture, academia, infectious diseases, asbestos, tires, biotechnology, batteries, and nanotechnology. Flow Sciences has over 30 years of expertise in the development of containment solutions that deliver superior engineering quality and service at each level of controlled airflow containment systems. Flow Sciences offers the incorporation of Computational Fluid Dynamics (CFD), further refining the process of presenting personnel and product protection through framed enclosure solutions. The company’s Flow Sciences China division serves as a market leader in mainland China, spearheading the development of solutions throughout Asia. Under its Flow Sciences brand, Flow Sciences offers the best in laboratory containment, and is committed to finding containment solutions that meet your needs.

 

All other product names and trademarks are the property of their respective owners, which are in no way associated or affiliated with Flow Sciences.

 

Headquarters: Leland, NC USA:

Flow Sciences, Inc., 2025 Mercantile Drive, Leland, NC 28451;

Tel: 1-800-849-3429, Fax: 1-910-763-1220, Email: information@flowsciences.com,

Web: http://www.flowsciences.com/

 

Flow Sciences, Inc. Public Relations:

Jonathan Mann 2025 Mercantile Drive, Leland, NC 28451;

Tel: 1-910-332-4846 direct, Email: jmann@flowsciences.com,

Web: http://www.flowsciences.com


Isolator Containment Levels for a Fraction of the Cost

PRESS RELEASE

Contact: Flow Sciences, Inc.

Tel: (800) 849-3429

Fax: (910) 763-1220

 

 

 

 FOR IMMEDIATE RELEASE

Flow Sciences’ Hybrid Isolator Contains to Less Than 50 ng/mwith Bulk Powders 

LELAND, NC, June 26, 2018 — Flow Sciences, a leading provider of containment systems for laboratory, pilot plant, and manufacturing facilities, now offers a Bulk Powder Hybrid Isolator glovebox that is proven by third-party acceptance testing to facilitate an interior concentration of less than 50 nanograms per cubic meter (50 ng/m3).

 

The system maintains all of the engineering controls of the standard Hybrid Isolator, but is now designed to include a 20” cutout and a membrane set which can accommodate 3 bulk powder drum diameter sizes. The membrane set also prevents powder from spilling over the lip of the drum during pouring operations. In addition, it can be shipped with a hydraulic lifting jack which allows the customer to lift a drum through the base of the enclosure into its interior to work with the bulk powders in a contained environment.

Flow Sciences’ consultation process breeds innovative solutions, which drives the evolution of our standard products. This adaption of our Hybrid Isolator Series is a perfect example of who we are as a company. Every interaction with end users and engineers adds to our growing enclosure repertoire, which continues our corporate vision of providing the best containment solution for numerous applications. Using our TaskMatch application search tool, we combine today’s consumer-oriented market with our own expert consultation to create a product of optimal performance.

In the constantly connected landscape of today, the ever increasing toxicity of active pharmaceutical ingredients (APIs) presents the ever increasing need for personnel and/or product protection. At Flow Sciences, we consistently strive to ensure the safety of the whole process by engineering and manufacturing optimal enclosure. Flow Sciences creates engineering controls for hazards that cannot be eliminated or substituted.

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For a PDF of this Press Release or for questions or comments, please contact us below:

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About Flow Sciences, Inc.

Flow Sciences is the world’s leading developer of containment solutions for research and development laboratories, pilot plants, automation equipment and robotics, manufacturing and production facilities where toxic or noxious potent powders, fluids, or gases require safe handling while weighing, mixing, processing, or manufacturing. Since its start in the 1980s and with the introduction of the Vented Balance Safety Enclosure (VBSE™) in the 1990s, Flow Sciences has gone on to develop a comprehensive line of over 500 enclosures, including industry standards like the Vented Balance Safety Enclosure (VBSE™), the Contained Vented Bulk Powder Enclosure, and innovative laboratory technologies like the FS1501 Nitrogen Controller and the Bag-In/Bag-Out HEPA Filtration System. For its accomplishments, Flow Sciences received an Expert Achievement Award from the U.S. Department of Commerce for accomplishments in the global marketplace, the Deloitte and Touche North Carolina Technology Fast 50 Award, the UIBS R&D and Technology Collaboration Award, along with many others. During the 1990s, Flow Sciences pioneered the Vented Balance Safety Enclosure Series (VBSE™) which introduced the first independent fan exhaust system to isolate vibrations for balance accuracy, swiftly becoming the world leader in laboratory safety equipment. Flow Sciences technologies are now used to improve safety and containment in virtually every industrial sector around the globe, from pharmaceutical, food processing, robotics, chemical, forensics, agriculture, academia, infectious diseases, asbestos, tires, biotechnology, batteries, and nanotechnology. Flow Sciences has over 30 years of expertise in the development of containment solutions that deliver superior engineering quality and service at each level of controlled airflow containment systems. Flow Sciences offers the incorporation of Computational Fluid Dynamics (CFD), further refining the process of presenting personnel and product protection through framed enclosure solutions. The company’s Flow Sciences China division serves as a market leader in mainland China, spearheading the development of solutions throughout Asia. Under its Flow Sciences brand, Flow Sciences offers the best in laboratory containment, and is committed to finding containment solutions that meet your needs.

 

All other product names and trademarks are the property of their respective owners, which are in no way associated or affiliated with Flow Sciences.

 

Headquarters: Leland, NC USA:

Flow Sciences, Inc., 2025 Mercantile Drive, Leland, NC 28451;

Tel: 1-800-849-3429, Fax: 1-910-763-1220, Email: information@flowsciences.com,

Web: https://www.flowsciences.com/

 

Flow Sciences, Inc. Public Relations:

Jonathan Mann 2025 Mercantile Drive, Leland, NC 28451;

Tel: 1-910-332-4846 direct, Email: jmann@flowsciences.com,

Web: https://www.flowsciences.com


Designing and Testing Containment Systems for High Potency Active Pharmaceutical Ingredients (HPAPIs)

Designing and Testing Containment Systems for High Potency Active Pharmaceutical Ingredients (HPAPIs)

Dr. Robert K. Haugen, Director of Product and Technology Development

Flow Sciences, Inc. 

2025 Mercantile Drive

Leland, North Carolina 28451

V 1.4; 2/7/2018

Background:

Flow Sciences (FSI) designs, tests, and manufactures laboratory containment devices.

In the ongoing search for new therapeutic treatments, pharmaceutical companies are developing a new class of active ingredients known as High Potency Active Pharmaceutical Ingredients (HPAPI’s).  As the name suggests, these compounds are highly potent, requiring “solid dilution” into therapeutic doses. It is therefore critical to maintain very minimal exposure to such ingredients during compounding and other operations. Commonly associated with oncology and cardiology drugs, an increasing demand for HPAPI’s is predicted over the next five years. 1

Unlike better-known typical reactive chemicals, these Pharmaceutical Ingredients are designed to be biologically active in low concentrations. HPAPI’s can therefore harm researchers with adverse symptoms at very small exposure levels! Warfarin, for example, shares its chemical roots with rat poison! 2

CMOs (contract manufacturing organizations) are the key stakeholders in this market as a good proportion of HPAPI manufacturing and compounding is understandably outsourced due to stringent manufacturing protocols and safety requirements. During research on the US market, Flow Sciences identified 96 CMOs (with over 130 production facilities worldwide) that are focused in this area; approximately 40% of these facilities are dedicated to the manufacture of both HPAPI’s and cytotoxic drugs.

A Containment Testing Program Geared for HPAPI’s

In 2011, Flow Sciences, Inc. was tasked by a major pharmaceutical company with designing and constructing a hybrid isolator for the protection of its employees during tablet crushing operations.  The design of the isolator included a bag in / bag out (BIBO) assembly and a containment glove box enclosure.

After design and construction of the isolator, it was factory tested using a variety of recognized testing methods, including flow visualization, tracer gas testing, and surrogate powder testing.  In each of these tests the detectable levels for the agents used was far below the client’s exposure standards, and often below quantitative levels of detection.3   Examples of such devices are shown below.

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To test such devices for effective containment of the materials used within them, Flow Sciences uses a series of specific tests detailed below:

 1) ASHRAE 110-2016 Test 4

Sulfur hexafluoride gas (SF6) gas is released at a flow rate of 4L per minute inside the containment area using a diffuser. The presence of escaping sulfur hexafluoride, a tracer gas, is monitored in the mannequin breathing zone located at right, center, and left positions in front of the device’s sash opening.  An as-manufactured acceptance level of 0.05 ppm in the mannequin breathing zone is set as the maximum acceptable level (AIHA Z9.5). Results of this test found that the concentrations of sulfur hexafluoride outside of the hybrid isolator is typically far below this level.

 2) Human as Mannequin (HAM) test 5

A modified, non-standard, HAM test (Human as Mannequin) uses the ASHRAE 110 diffuser described above in the vicinity of manipulated small lab objects on the containment device’s work top. The formally published version of this test was commissioned by Lawrence Berkeley National Laboratory 5.

 

Results of this modified test generally show the concentrations of sulfur hexafluoride outside of the hybrid isolator is at or below 0.050 ppm.

3) Surrogate Powder Test 6

Generally speaking, these tests are highly specific to the types of operations and procedures used by the customer. Flow Sciences designs a custom enclosure, based on customer input and requirements, and performs a containment evaluation based on ergonomic parameters, safety requirements, and customer containment requirements.

 

Below, is an actual custom unit undergoing surrogate powder testing.   The enclosure design and processes carried out inside the unit dictated the sampling strategy.  For this study, two operations were performed – tablet crushing within the isolator and a procedure where powder was transferred.  Using ISPE guidelines, air samples were collected from twelve locations around the isolator focusing on key areas including operator breathing spaces and other areas, such as joints, where leakage can be experienced. The samples were collected on a suitable sample media, and the analysis for surrogate powder performed by a third party.  In such a setup, the customer defines an acceptance level, often in the nanogram per cubic meter level, which is then used as a pass-fail criterion for Flow Sciences’ tests.

 4) Other Tests at the Customer’s Discretion:

Many pharma labs have specific applications, operations, or logistics challenges requiring special test arrangements. For these situations, Flow Sciences individualizes custom procedures which may include any or all of the following:

a) Incorporating actual devices used by the CMO into Flow Sciences’ factory containment tests. (Grinders, shakers, etc.)

b) Building medium density fiberboard (MDF) aerodynamic models of equipment to simulate air flow challenges inside the containment area.

Multi-Disciplinary Containment Solutions

 

Testing equipment to scrupulously contain HPAPI’s is important.  As you might imagine, the high standards and diverse applications of these pharma customers leads to an overwhelming number of different containment products whose performance must be evaluated.

 

The need for hybrid isolators, bulk powder isolators, stainless steel enclosures, sieve enclosures, balance enclosures, nitrogen enclosures, etc. has given Flow Sciences an opportunity to showcase its unique design diversity on their company website. Flow Sciences has therefore operationally designated several respective markets and developed an online resource for each market.

 

For example, Flow Sciences has recently published an electronic booklet for the Contract Pharmaceutical Manufacturer, detailing containment technologies developed for this industry. 7

TaskMatch: Matching Containment to Your Application

 

Researching containment solutions has, historically, been an arduous adventure. This cumbersome search process has now been redefined to empower end users to optimize their containment solutions with ease.

 

TaskMatch is an intelligent search tool that combines containment categories, application specific enclosures, and uses key containment concepts to aid researchers in discovering products and solutions for tasks identified as key to their process using the full capabilities of the online search tool. Customers can access this search tool on the Flow Sciences website: www.flowsciences.com/taskmatch/ .

 

When I enter HPAPI into the application search box, data and photos for many existing products immediately come up:

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Notice this is a sophisticated search.  Search results reveal relevant products, even though some do not mention the term HPAPI in their descriptionThere are hundreds of enclosure types represented in this reference; scores of categories available to differentiate. Additionally, TaskMatch provides details about the specific enclosure, containment category information, videos, and a contact form to request a containment consultant to work with you on the details of your process and containment requirements.

 

Flow Sciences highly recommends customers contact them directly for guidance before choosing the best Flow Sciences product for their application. Remember, Flow Sciences containment products can be tested to existing test Standards or to customer-defined criteria which can be organized at Flow Sciences’ facility in Leland, North Carolina.

Summary

In the ongoing search for new therapeutic treatments, pharmaceutical companies are developing High Potency Active Pharmaceutical Ingredients (HPAPI’s) into completed products. For worker safety, it is critical to maintain very minimal exposure to such ingredients during compounding and other operations.

Flow Sciences designs such products and then rigorously tests them in their test facility to document their effectiveness and containment. This testing always involves input from customers to validate the safety of the overall containment strategy. Flow Sciences has experience in producing hundreds of different varieties of containment devices to achieve this purpose. Research labs, CMO’s, and government testing agencies who use such products may find product matches by using the Flow Sciences website which facilitates matching applications with appropriate Flow Sciences containment products.

Contact Flow Sciences

Footnotes:

  1. https://www.giiresearch.com/report/root310060-hpapis-cytotoxic-drugs-manufacturing-market.html
  2. https://en.wikipedia.org/wiki/4-Hydroxycoumarins
  3. Flow Sciences can share test results with any interested party.
  4. ASHRAE 110-2016, ASHRAE Standard Project Committee 110 Cognizant TC: 9.10, Laboratory Systems SPLS
  5. “Human as Mannequin” (HAM) Test Methodology, ECT, Inc. & Lawrence Berkeley National Laboratory (LBNL), 2005
  6. http://www.flowsciences.com/solutions/services/
  7. http://www.flowsciences.com/contract-manufacturing-contract-research-solutions-booklet/


Validation of a Glovebox Workstation


VIEW / DOWNLOAD THE WHITE PAPER

 

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.

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.

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.

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.

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.

 


Resources


Toxic Treatments - Controlling Exposure Risks in ADC Manufacturing

This year marks the 80th Anniversary of the National Cancer Institute, established by President Franklin D. Roosevelt to support research on the causes, diagnosis, and treatment of cancer. Since the 1940s, cancer researchers have produced nothing short of astonishing science.

 

The development of antibody drug conjugates (ADCs) ranks among one of the most important advancements in cancer treatments in recent history. The ability to precisely target abnormal cells throughout the body and deliver highly toxic drugs to the center of tumors significantly improves upon the negative side effects of traditional chemotherapies that employ a total war approach to defeating cancer.

 

Anticancer drug development has not come without challenges for pharmaceutical companies that manufacture ADCs. The potency and effectiveness of ADCs are dependent upon engineered nanoparticles (ENPs) — the cytotoxic payload that destroys cancer cells — but little is known about the environmental and human health hazards posed by ENPs. Yet, the promise ENPs hold for patients is why we continue to wield them in the quest for a cure even without a full understanding of their key physical characteristics, chemical properties, and associated hazards.

 

The National Institute of Occupational Safety and Health (NIOSH) has been a primary champion of safe nanotechnology. Their research suggests that nanoparticle exposure can happen through skin contact or ingestion, but the risk is greatest when the material is airborn and potentially inhaled. As a result, NIOSH recommends that laboratories use high-efficiency particulate (HEPA) filters along with a well-designed exhaust ventilation system to reduce the risk of exposure.

 

A BRIEF HISTORY of ANTICANCER TREATMENTS

 

Traditional chemotherapies have always posed serious side effects for patients because they cannot specifically target cancer cells. In the 1960s, “poison” was the general term used for chemical anticancer therapies. The label reflected scientists’ skepticism of the “chemical cure” hypothesis first imagined by Paul Ehrlich at the turn of the century.

 

The advancement of cancer therapies has benefitted greatly from the early pioneers like Ehrlich. The development of cancer drug screening models by Murray Shear was the first to test an array of compounds for their effectiveness in treating specific cancers. The discovery of hormone therapy in the 1930s by Charles Huggins also expanded treatment options that are still used today in combination with other therapies.

 

These early contributions to cancer treatments were largely individual accomplishments because there was no general public support for research. That changed in the 1950s with the inauguration of the Cancer Chemotherapy National Service Center (CCNSC). Widely recognized as a turning point in anticancer drug development, the CCNSC was the precursor to the multi-billion dollar cancer pharmaceutical industry. Up until the 1990s, all new cancer therapies were developed by the CCNSC.

 

It wasn’t until the 1960s that scientists began to conceptualize a cure for cancer, which greatly advanced after Howard Skipper introduced the “Cell Kill” hypothesis. Skipper hypothesized that a given dose of medicine would only kill a consistent fraction of cancer cells, which encouraged a more aggressive use of chemotherapy and dramatically increased remission rates. Through the 1970s and 80s, scientists made even more incredible advancements in the fight against cancer and were officially recognized in 1973 with the establishment of medical oncology.

 

It is a testament to the dedication of oncologists that, starting in 1990, cancer mortality rates have consistently declined. In 2007, the decline doubled largely as a result of prevention, diagnosis, and advances in cancer treatment.

CHEMOTHERAPY and the ADVENT of ADCs

 

Chemotherapy is an imperfect treatment that has historically been combined with surgery and radiotherapy along with immune-, hormone, and biological therapies to achieve remission in patients. Of all the available cancer treatments, chemotherapy is the most toxic to cancerous and healthy cells alike causing acute side effects for patients and limited therapeutic results. The limitation of chemotherapy as a treatment option is directly related to the systemic nature of disease.

 

Cancer spreads throughout the body based on changes in the molecular biology of tumor cells. While advances in research have allowed us to track and anticipate the spread of cancer, traditional chemotherapy cannot precisely target systemic cancers. The chemical composition and size of chemotherapy drugs also make them insoluble and incapable of overcoming biological barriers to reach cancer cells in sufficient concentrations. As a result, chemotherapy can damage a patient’s immune system and other organs, which is compounded by the fact that many patients also experience drug resistance, resulting in reduced dosage and low survival rates.

 

The history of anticancer drug development has only recently included nanomaterials, but they have quickly shown promise for combating some of the most serious side effects of chemotherapy treatments. This new class of highly potent biopharmaceutical drugs are gaining weight with oncologists in the fight to defeat cancer for their demonstrated ability to target cancer cells, bypass biological barriers, and combat drug resistance.

 

The success of ADCs is a function of their unique structure that combines the selectivity of immunotherapy with the potency of chemotherapy to create a novel class of anticancer treatments. ADCs are made by connecting an antibody to a cytotoxic agent through a linker that controls the pharmacokinetics, therapeutic index, and efficacy of the drug. Without these three elements, ADCs would not be able to target and kill specific cancer cells. While it may sound simple, manufacturing ADCs is a tricky science. Cytotoxins and antibodies have to be combined in exact ratios, and linkers have to release drugs at precise times in order to achieve their desired results.

 

Developing targeted anticancer therapies that overcome the characteristic downfalls of traditional chemotherapies has been a main goal of pharmaceutical and biopharmaceutical manufacturers since the discovery of monoclonal antibody technologies in the 1970s. Though these ADCs have experienced their own clinical hurdles—low delivery efficiency, the omnipresence of target antigens, and tumor antigen heterogeneity—they largely hold more promise for eventually realizing Ehrlich’s goal of a chemical cure, which probably wouldn’t be possible without the advent of nanotechnology.

 

NEW TECH on a NANO SCALE

 

Nanotechnology is a science of the small. Nanoparticles are defined as materials that have at least one dimension measuring between 1 and 100 nanometers. The size, shape, and surface area of nanoparticles distinguish them from their macro-cousins and contribute to their high potency. The size of nanoparticles also influences their chemical properties. When combined, the size, toxicity, and solubility of nanoparticles represent the evolution of anticancer drug development.

 

Nanoscience research combines advancements in engineering and medicine to produce targeted therapies that can more effectively deliver drugs to patients suffering from intractable forms of cancer. Three ADCs have received market approval from the U.S. Food and Drug Administration (FDA). The first ADC to be approved in 2000, Mylotarg® was withdrawn from the market in 2010 after clinical studies had shown that it did not outperform traditional therapies. The initial setback in the development of Mylotarg® may have been more of a premature judgment than proven analysis. More recent studies have shown that using Mylotarg® in combination with other anticancer therapies significantly improves event-free and relapse-free survival in adults suffering from acute myeloid leukemia.

 

Adcentris® and Kadcyla® have also been approved by the FDA for treatment of two forms of blood cancer and HER-2+ metastatic breast cancer, respectively. Both drugs have demonstrated ability to positively affect survival and remission rates in cancer patients, leading oncologists and drug manufacturers alike to boast a new era of cancer treatment. In addition to targeted ADCs, scientists have also recently advanced bioaffinity nanoparticle probes for imaging and even nanodevices for early detection and screening.

 

EXPOSURE RISK

 

Nanoparticles are more effective at fighting tumors primarily because of their toxicity. The smaller-sized particles have more surface area than their larger, macro-cousins. When these potent cytotoxins are introduced into cancer cells, they are capable of delivering higher dos amounts because toxicity is inversely proportional to particle size. It is precisely their size makes them capable of fighting formerly untreatable cancers, but their size alters more than their potency. Nanoparticles also act differently than larger molecules with similar chemical compositions, which further expands the range of uncertainty and increases occupational exposure risks.

 

Nanotechnology is an emerging field. The side effects of exposure to nanoparticles has only been measured in animal studies; while these studies are not directly applicable to cases of human occupational exposure, they have proven that nanoparticles are more potent than their macro-cousins. We still do not know, and therefore cannot fully anticipate, all the risks associated with the production of engineered nanoparticles (ENPs) like those used in ADC manufacturing. However, we do know that exposure to hazardous materials is calculated based on dose size, which is expressed as particle surface area. This means that an equal weight of nanoparticles is potentially more harmful than larger, chemically similar molecules due to the increased surface area exposure alone. Taking into account that the size of nanoparticles alters their chemical characteristics, the near-atomic size of the particles could also pose more adverse health risks.

The small size of ENPs makes inhalation exposure the biggest threat to scientists and technicians who work with and develop ADCs. In addition to their heightened toxicity, nanomaterials can agglomerate into larger particles or longer fiber chains, affecting their properties, behavior, and the exposure risk for humans. Skin can also be exposed to nanoparticles. Our outer layer of skin is only 10 µm thick. While it is difficult for particles and compounds to pass through the outer layer of skin, contact with anthropomorphic substances during nanomaterial manufacturing is a risk that is not fully understood and, therefore, should be managed.

As the production of ENPs continues to grow in response to their successful use in cancer treatments, they will continue to pose hazards for the people who make them. It is acutely ironic that the characteristics of ENPs for which they are so useful—small dimension, large surface area, and high toxicity—also increase the occupational risks associated with their development. As researchers continue to learn more about the risks of occupational exposure to ENPs, we will be able to fine-tune our risk-based assessment guideline and regulatory decision-making. In the meantime, we can still minimize risks by applying the precautionary principle.

 

More research is needed to determine the key physical and chemical characteristics of nanoparticles and their associated hazards, but this lack of information is precisely why taking measures to minimize worker exposure is prudent. At the very least, when working with nanoparticles, employers must establish workplace-engineering controls and include effective source ventilation and capture protocol to minimize exposure risk. The National Institute for Occupational Safety and Health (NIOSH) recommends the use of local exhaust ventilation systems and high-efficiency particulate (HEPA) filtration for any workplace task that would increase risk of exposure to nanoparticles.

 

CONTAINMENT MATTERS™

 

ADC production requires a laboratory that can provide both product and personnel protection during the initial familiarization phase as well as conjugation, verification, purification, and scale-up. Flow Sciences has designed a comprehensive containment solution that covers the entire scope of ADC development and simplifies laboratory setup.

 

The Glovebox Workstation was designed specifically for ADC development with a HEPA filtration inlet and Bag-In/Bag-Out technology offering both product and personnel protection for antibody-drug development and conjugation. Our engineers have analyzed all phases of the manufacturing process and designed the Glovebox Workstation to specifically address all of the containment and exposure risks. They have also submitted the Glovebox Workstation to rigorous engineering and performance testing to ensure effective containment.

 

Manufacturing ADCs requires specialized equipment and careful handling. One of the largest challenge pharmaceutical companies face is the need to balance conflicting requirements for handling antibodies alongside highly potent active pharmaceutical ingredients—HPAPIs or cytotoxins. Maintaining a clean environment is absolutely necessary for successful antibody-drug conjugation just as reducing occupational risk is necessary for a successful laboratory. The Glovebox Workstation guarantees product protection by applying isolator design principles to prevent contamination. Personnel protection is also vital while weighing cytotoxins because they are designed to disrupt cell reproduction and damage DNA, posing significant risks to operators. The Glovebox Workstation provides personnel protection for working with HPAPIs by operating under negative pressure.

 

In order to meet the requirements for product and personnel protection while accommodating the unique process of ADC development, laboratories typically have to invest in both positive- and negative-pressure enclosures. The cost of equipping a laboratory for ADC production is oftentimes cost-prohibitive, leading some laboratories to shop out ADC production and cede process control to contract manufacturers. Instead of bearing the cost of purchasing multiple enclosures to encompass the complex process of ADC production, the Glovebox Workstation can be used for weighing HPAPIs as well as conjugation, purification, and filling.

 

Successful ADC manufacturing depends upon thorough control and tracking of molecular-level characteristics, including: drug-to-antibody ratio (DAR), monomer content, drug distribution, and cell killing activity or antigen recognition. It also depends upon designing a process that controls for successful experimental parameters within selected ranges so that the manufacturing of ADCs can be scaled up to grams. Purification techniques that are crucial in the manufacture of ADCs can only be performed on process solution volumes at the gram scale. As production continues to be scaled up for early clinical phases, the manufacturing process ultimately depends upon careful analysis and control during the earlier experimental phases. Turning over this process to contract manufacturers forces pharmaceutical companies to turn over control. The Glovebox Workstation allows companies to save money and keep ADC processing in house.

 

GLOVEBOX WORKSTATION

 

The Glovebox Workstation provides negative-pressure containment for toxic applications using HPAPIs requiring isolation that meets or exceeds ISO 5 clean processing. The Glovebox Workstation comes standard with a HEPA inlet that creates a clean environment ensuring product protection; it also uses horizontal laminar flow to reduce turbulent airflow and reproduce consistent, performance-based results. Laminar, or unidirectional, airflow systems direct filtered air in a constant stream, reducing turbulence. Consistent airflow is necessary for limiting exposure risk and ensuring reproducibility.

 

  • Designed to offer both product and personnel protection for an all-in-one approach to safe ADC manufacturing.
  • HEPA inlet exceeds ISO 5 requirements for cleanroom classification.
  • Bag-In/Bag-Out HEPA exhaust ensures safe recirculation of air in the room.
  • Laminar airflow reduces turbulence and allows for consistent, performance-based results.
  • Balance stability to the 7th decimal place makes the Glovebox Workstation ideal for weighing HPAPIs like those used in ADC manufacturing.

 

The Glovebox Workstation has been evaluated by third-party testing facilities that have confirmed containment levels at or below 50 ng/m3 with balance stability to the 7th decimal place. This makes the Glovebox Workstation ideal for antibody-drug conjugation that requires accurate methods and precise measuring.

 


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ENGINEERING and ADMINISTRATIVE CONTROLS

 

The foundation of any effective workplace safety program is establishing risk management programs that include the use of good work practices and appropriate personal protective equipment. Flow Sciences, Inc. has partnered with pharmaceutical companies and laboratories that manufacture ENPs and ADCs to design task-specific containment enclosures that minimize product loss and exposure to nanoparticles.

 

In addition to the applying the patented engineering controls developed by Flow Sciences engineers, both national and international experts on the risks of occupational nanoparticle exposure agree that laboratories can limit exposure levels by implementing a thorough risk management program. By using good work practices and appropriate personal protective equipment, laboratories can limit exposure to nanoparticles and reduce the risks associated with these hazardous materials.

 

Flow Sciences is committed to partnering with our customers to ensure that they have access to the most effective occupational risk assessments, education and training, and personal protective equipment (PPE).

 

There are no specific limits for airborne exposure to ENPs. While occupational exposure limits (OELs) have been set for micro- and macroparticles of similar chemical composition, these limits may be insufficient for recommending protection against exposure to nanoparticles. Applying the precautionary principle, there are a number of additional measures that employers and workers can take to reduce potential exposure to nanoparticles: good work practices like cleaning using HEPA vaccums and wet wiping method; preventing food consumption in the workplace; setting up hand-washing facilities for showering and changing clothes; and proper PPE.

 

THE FLOW SCIENCES ADVANTAGE

 

We are now closer than ever before to realizing a chemical cure for cancer, with engineered nanoparticles and targeted delivery systems that do not cause the same side effects as traditional chemotherapies. The advancements in anticancer drug research enabled by nanoscience raise exciting opportunities for personalized oncology. Scientists are already beginning to imagine using biomarkers to diagnose patients and develop individualized treatments. As researchers continue to bridge the data gap, it’s important to stay abreast of risk assessments and incorporate those into environmental and occupational health and safety plans.

Nanomaterials present new options for cancer patients who once had little hope, but they also bring with them new challenges that need to be addressed in order to fully realize their potential. Partnering with a company that understands the process and risks of ADC development is crucial for drug developers who are leveraging new technologies and need to manage exposure risks. Responsible development of any new material requires that laboratories managed risks to health and the environment. The engineers at Flow Sciences are experts in containment technology and have worked closely with companies that produce ADCs. You can rest assured that we understand the manufacturing process and the risks involved. We can help you overcome any challenge that stands in the way of developing life-saving new technology.

 

 

FLOW SCIENCES: WHO ARE WE?

 

Flow Sciences’ team of industrial engineers design workstations and enclosures that reduce product contamination and maximize protection for professionals who work with toxic substances and uncertain risks. All of our products are engineered and manufactured at our corporate headquarters in Leland, NC and are backed by our sophisticated design process and award-winning excellence in engineering, including 11 U.S. Government patents. We have worked with pharmaceutical companies, research and development laboratories, manufacturing, and production facilities for 30 years. Our task-specific designs are dynamic solutions that are adaptable to our clients’ workflow and specific needs.

 

Flow Sciences was one of the first companies in the U.S. to use computational fluid dynamics (CFD) in drafting our enclosures to ensure optimum airflow. Our engineers use CFD algorithms to simulate fluid flows and interactions within contained spaces. This enables us to predict and control airflow through design, which we then test in our state-of-the-art laboratory. Working closely with our clients to mimic real-world applications, we develop testing protocols based on the intended use of our enclosures and measure them against industry-accepted standards to ensure proper containment. We have designed, manufactured, and tested over 13,000 enclosures, generating a wealth of data on situational flow dynamics, which allows us to control for consistency, safety, efficacy, and overall quality.



Containing ADC Development

80 Years Later: The Fight Against Cancer Continues

 

This year marks the 80th Anniversary of the National Cancer Institute, established by President Franklin D. Roosevelt to support research on the causes, diagnosis, and treatment of cancer. Since the 1940s, cancer researchers have produced nothing short of astonishing science.

 

The development of antibody drug conjugates (ADCs) ranks among one of the most important advancements in cancer treatments in recent history. The ability to precisely target abnormal cells throughout the body and deliver highly toxic drugs to the center of tumors significantly improves upon the negative side effects of traditional chemotherapies that employ a total war approach to defeating cancer.

 

Anti-cancer drug development has not come without challenges for pharmaceutical companies that manufacture ADCs. The potency and effectiveness of ADCs are dependent upon engineered nanoparticles (ENPs) — the cytotoxic payload that destroys cancer cells — but little is known about the environmental and human health hazards posed by ENPs. The promise ENPs hold for patients is why we continue to wield them in the quest for a cure despite a full understanding of their key physical characteristics, chemical properties, and associated hazards.

 

Yet, we can still minimize occupational exposure by applying the precautionary principle. When working with nanoparticles, employers must evaluate workplace-engineering controls and include effective source ventilation and capture protocol to minimize exposure risk. According to the National Institute for Occupational Safety and Health (NIOSH), “A well-designed exhaust ventilation system with a high-efficiency particulate (HEPA) filter should effectively remove nanomaterials.”

 

Flow Sciences, Inc. has partnered with pharmaceutical companies and laboratories that work with hazardous chemicals like those used in manufacturing ADCs. We specialize in designing task-specific containment enclosures that minimize product loss and exposure to nanoparticles during the complex and sensitive manufacturing processes that characterize ADC production.

 

The Glovebox Workstation series of enclosures provide containment for toxic applications using highly potent APIs requiring isolation that meets or exceeds ISO 5 clean processing. The Glovebox Workstation comes standard with a HEPA inlet that creates a clean environment ensuring product protection; it also uses horizontal laminar flow to reduce turbulent airflow and reproduce consistent, performance-based results. We have submitted the Glovebox Workstation to third-party testing and confirmed containment levels at or below 50 ng/m3 with balance stability to the 7th decimal place. This makes the Glovebox Workstation ideal for the initial phases of conjugation process development that require accurate methods and precise data with minimal scattering.

 

ADC development depends upon thorough control and tracking of molecular-level characteristics, including: drug-to-antibody ratio (DAR), monomer content, drug distribution, and cell killing activity or antigen recognition. It also depends upon designing a process that controls for successful experimental parameters within selected ranges so that the manufacturing of ADCs can be scaled up to grams. Certain purification techniques that are crucial in the manufacture of ADCs can only be performed on process solution volumes at the gram scale. As ADC production continues to be scaled up for early clinical phases, the success of the manufacturing process will ultimately depend upon careful analysis and control during the earlier experimental phases.

 

ADC production requires a laboratory that can handle the initial familiarization phase as well as further investigation, observation, verification, purification, and scale-up. Flow Sciences has designed several containment options that cover the entire scope of ADC development. We offer a Hybrid Isolator for working with highly toxic APIs and the LEV III (local exhaust ventilation) enclosure that is built for scale-up operations. All of our enclosures designed for ADC development have undergone rigorous engineering and performance testing so that you can work confidently as you explore new cancer treatments.

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