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
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.
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:
Notice this is a sophisticated search. Search results reveal relevant products, even though some do not mention the term HPAPI in their description. There 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.
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
- Flow Sciences can share test results with any interested party.
- ASHRAE 110-2016, ASHRAE Standard Project Committee 110 Cognizant TC: 9.10, Laboratory Systems SPLS
- “Human as Mannequin” (HAM) Test Methodology, ECT, Inc. & Lawrence Berkeley National Laboratory (LBNL), 2005