Engineering Controls and Physical Facilities

[Transcript of Video]

John Petrich (0:00):

Gene therapies should not be prepared on an open bench but should follow the established US Pharmacopeia’s aseptic technique guidelines and utilize a Class II biosafety cabinet.

Class II biosafety cabinets ensure product sterility and personnel safety by providing four levels of protection: first, by protecting the operator from airborne biological products; second, by protecting the laboratory and the environment from hazards; third, by protecting the gene therapy from airborne contamination in the laboratory with a downward flow of filtered air; and, finally, by preventing cross contamination within the biosafety cabinet work area through the use of a flowing, uniform, downward flow onto the work area.

The three main types of Class II biosafety cabinets that an institution may have are Type A2, B1, and B2. In the US, most of the cabinets are Type A2, especially if the institution does not handle hazardous compounds. These cabinets use motor-driven blowers to draw directional airflow around a user and into the air grill, which protects the operator. The air is then drawn beneath the work surface and back up to the top of the cabinet, where it passes through a high-efficiency filter. A column of high-efficiency particulate air (HEPA)-filtered, sterile air is blown downward over the products to prevent product contamination. Air is also exhausted through a HEPA filter and, depending on the type of biosafety cabinet, is either recirculated back into the room or pulled by an exhaust fan through ductwork, where it is expelled from the building. A Type A2 biosafety cabinet exhausts 30% of the air to the outside, and 70% of the air is circulated through the cabinet.

Inversely, a Type B1 cabinet exhausts 70% of HEPA-filtered air, while 30% is recirculated inside the cabinet. Importantly, for Biosafety Level 2 (BSL-2) containment of hazardous drugs, which would include most gene therapies, a Type B2 cabinet should be used, as it exhausts all of the air, with no recirculation inside the workspace.

Jeff Wagner (02:24):

So, the National Institute for Occupational Safety and Health or NIOSH recommendations are relevant here, based on the viral vector. It is important to note that the current modified viral vectors that are available and approved by the Food and Drug Administration are limited primarily to Biosafety Level 1 or BSL-1, but some are BSL-2. And it is the BSL-2 procedures for NIOSH that do include the use of a biological safety cabinet.

The primary recommendations from the US Pharmacopeia’s Chapter 800 or USP 800 is that externally vented hoods are required for the manipulation of sterile hazardous drugs. And these include Class II biological safety cabinet Type A2, B1, or B2, which are all acceptable. Most institutions are well prepared or are down the path of preparing for implementation of USP 800.

And there are some facility-related implications to these standards. An example might be that, if the hood is not externally vented today and recirculates air into the cleanroom via high-efficiency particulate air or HEPA filter, running an exhaust to the roof may not be possible, based on the location of the current pharmacy, if there are rooms or other facilities above that cannot run a chase through the roof. But other than that, most institutions are well on the path of aligning with USP 800 and should have the appropriate facilities to handle hazardous drugs.

[Transcript of Video]

Brian Yarberry (00:00):

As of right now, I think you definitely would need to be able to do it with a hazardous drug preparation area. In the future, you will be looking at many more of these products on the market, and there will be probably a need for a dedicated space for the preparation, handling, and storage of these medications.

Right now, if you do not have that space, your hazardous drug preparation area will suffice fine for the preparation of any gene therapy medication that is currently available. The thing you will need to put in place and in process is how you are going to handle these medications, along with the other medications you prepare in those areas. For example, how is your hood cleaned before and after any gene therapies are prepared, the cleaning products you use, and how those products will make you more efficiently clean the hood.

Jeff Wagner (00:51):

If a facility has one hood, that indicates that the hood may have downtime in between handling or preparing hazardous drugs, and it could be possible in that scenario to adjust schedules or other therapies and their preparation to accommodate the use or preparation of gene therapy within a particular facility. I think, unlike some chemotherapy that may be more urgent or emergent, typically there is a little bit of a longer lead time with ordering and making available gene therapy, which would allow kind of an anticipation of creating a schedule and moving a schedule around to be able to accommodate a preparation of gene therapy. This scheduling, certainly as more products become available and as the volume of gene therapy increases over time, may become more challenging, and at that point, there is probably value in adding a separate hood or hoods for gene therapy alone.

John Petrich (01:54):

Gene therapies do not necessarily need a dedicated hood, but any hood-manipulating gene therapies require rigorous cleaning, disinfecting, and decontamination, followed by a dormant period before the next drug can be introduced into that space.

[Transcript of Video]

John Petrich (00:00):

For optimal caregiver safety, airflow with total exhaust to outside the building is an important and sometimes costly engineering control for BSL-2 handling.

Jeff Wagner (00:13):

So, gene therapies that require modifications of patients’ own cells, for example chimeric antigen receptor T-cell therapies or CAR T therapies, are generally not received back to the pharmacy. Typically, they will go back to the area that handles or processes cells, particularly the bone marrow transplant patients or otherwise.

In our institution, these therapies go back to our cell and gene therapy lab, which exists at most institutions that do bone marrow transplants and do have that capability. They have the ability to store the cells at the appropriate temperature, which is typically colder than most devices that are available in a pharmacy’s capabilities or freezers themselves.

And then, in terms of financial infrastructure, smaller institutions may not have the operating cash flow to purchase an expensive gene therapy, so there may be a need for a separate account or a provision of funds for a particular account to be able to order and procure gene therapy. But other than that, I do not think there is any infrastructure needs that are required for gene therapy in its current state, beyond what is typical at most institutions.

John Petrich (00:00):

Ideally, a clean room should have a dedicated negative pressure room for gene therapy, with multiple Class II B2 biosafety cabinets, and these should be separate from nongene therapy handling areas.