Handling and Exposure
Because gene therapies may utilize viral vectors, they are to be considered biohazardous materials and must be handled using proper procedures. We asked pharmacy professionals with experience in introducing gene therapy into their institutions to provide their insights into the key considerations for the safe handling of gene therapies
The experts touched on topics such as the properties of gene therapies that can inform handling practices, required personal protective equipment, the safe storage and transport of gene therapies, best practices for the preparation of gene therapies, decontamination and disposal of waste products, and how to address accidental exposure
[Transcript of Video]
John Petrich (00:00):
Looking at the adeno-associated virus (AAV) as an example, although it is often assumed that handling AAV vectors requires Biosafety Level 2 (BSL-2) containment, we have found a way for their safe handling using Biosafety Level 1 (BSL-1) containment.
As illustrated in the decision tree, gene therapies that utilize AAV vectors can be handled at BSL-1, provided that the following three conditions are satisfied. One, the transgene does not express an oncogenic protein or toxin. Two, it is generated without using an adenovirus or any helper virus. And three, it is not propagated using human cells.
Looking at adenoviral, lentiviral, retroviral, and herpes simplex viral vectors, the overriding principle for these viral vectors would be that they are categorized as hazardous and that they should be handled using BSL-2 containment. Each one of these vectors can be assessed individually and categorized according to whether it is integrating, replicating, oncogenic, toxic, or able to induce mutagenesis.
[Transcript of Video]
John Petrich (00:00):
The biological properties of the transgene, such as viability, toxicity, and oncogenicity, will determine the handling precautions. For a majority of the time, BSL-2 handling will be the most appropriate, as you can see in our decision tree.
[Transcript of Video]
John Petrich (00:00):
It is recommended that personal protective equipment (PPE), at a minimum, matches the US Pharmacopeia’s (USP) Chapter 797 and 800 requirements. Standard operating procedures at the institution should address the appropriate PPE to be worn when handling gene therapy during receipt, storage, transport, administration, disposal, and spills. Staff should wear a respirator if the agent is Risk Group 3 or as required by the specific institution or agent.
Theresa Mays (00:34):
I believe the appropriate PPE for handling gene therapy agents most definitely includes gloves, two pairs of gloves. In addition, people should use an impervious gown when preparing, and we should follow safe practices for gowning. And what this means is you put on your first pair of gloves. Then you put on your gown, making sure that the cuffs of the gown cover the ends of your first pair of gloves. Then you would put on your second pair of gloves, ensuring that the ends of the gloves actually cover the cuffs.
In addition, if you have the potential to have something aerosolized or splashes, you may want to consider a face shield versus just wearing a mask and eye protection. And some of the additional PPE that may be required will depend on the biosafety level of the agents that you are working with. And so, this is part of your evaluation, as you go forward to use these agents — to determine what PPE is appropriate for each and every agent your staff will be handling.
I also think it is very important that everyone who utilizes PPE knows the correct way to dispose of it because these agents are considered biohazardous versus hazardous and therefore have different waste disposal streams that need to be utilized.
[Transcript of Video]
John Petrich (00:00):
Hazardous gene therapies should be stored separately, according to USP Chapter 800 requirements, and in a negative pressure environment. Nonhazardous gene therapies do not have to be stored in a negative pressure environment, but investigational nonhazardous gene therapies should be stored separately from commercial products.
Access should be limited to those trained on biosafety level handling precautions. Additional security measures should be considered, depending on the transmission risk to the community or agricultural commodities.
Use a hazard warning sign bearing the universal biohazard symbol in required colors of fluorescent orange or orange red for all gene therapy products.
Use standardized signage that would include the biosafety level, contact information for the responsible party, and the procedures for handling and entering and exiting the room. Signage must be posted on storage units and at the entrance of any room when the agent is present.
Brian Yarberry (01:07):
Currently, we store our products in a clean room that has a hazardous medication section. We label that section with a storage sign that says: “Biological product. Caution.” The refrigerator or the actual shelf is where we place the information to warn others of this product being in the area.
Additionally, when we are preparing the product, we hang a sign that goes on outside of the door of the hazardous area where we are preparing it that warns people that a biological product is in the process of being prepared.
[Transcript of Video]
John Petrich (00:00):
To my knowledge, there are no direct studies investigating the compatibility of CSTDs with gene therapies. At our institution, we use CSTDs with all hazardous drugs, unless there is a documented incompatibility.
Brian Yarberry (00:18):
Currently, there is no evidence that supports the utilization of CSTDs with gene therapy products. However, there are some institutions that are utilizing gene therapy medications with CSTDs. Reaching out to these institutions to get their experience may be helpful in making your decision on how to use CSTDs.
Jeff Wagner (00:42):
So, in our institution at Texas Children’s, we have decided not to use CSTDs for the handling of gene therapy because of lack of evidence to support their use, currently, but we are evaluating that on an ongoing basis.
[Transcript of Video]
John Petrich (00:00):
Our policy is that the compounded final product is placed in a biohazard transport, zipper-like primary bag inside the biosafety cabinet before being placed into a secondary, impervious plastic container outside the biosafety cabinet. The final product should then be transported following temperature product-specific guidelines to the administration room and labeled with a biosafety symbol.
A spill kit should be transported with the gene therapy so it is available at all times in case of accidental spillage. However, an alternative would be to have spill kits available along the transportation route.
Brian Yarberry (00:40):
When transporting gene therapy medications, make sure the product is completely labeled, it is placed inside a bag that is sealed; therefore, the product cannot be contaminated with anything in the environment. Do not place these items in a pneumatic tube. Our policy and practice are that we hand-deliver from the pharmacy to the area of administration, preferably the administering nurse, so that we have direct handoff of the medication.
Jeff Wagner (01:08):
So, gene therapy should be transported from the pharmacy to the administration site in a way that ensures the appropriate and safe handling.
Initially, there was concern among some of our staff, given the high cost of these therapies, with concerns about whether a security guard should be needed for transport, given their kind of expense or cost. But I would say, over time, staff would become very comfortable with transporting gene therapies, and in fact, even their preparation as well.
We do have a delivery log for hazardous drugs and our high-risk drugs, which includes gene therapies. And in that log, we record the name and contact information of the person that received the medication from the pharmacy staff member or pharmacy team member to ensure that there is some level of accountability in case the drug is misplaced.
And if a dose does go missing, we have a policy in place — we will not re-prepare it until that missing dose is found because of the higher risk in that scenario of administering a hazardous drug or high-risk therapy twice than not administering it at all. And that is a concern that we have within our institution to protect the patients’ safety.
[Transcript of Video]
Jeff Wagner (00:00):
So, recommendations for decontamination of nondisposable equipment following the handling of gene therapies include, primarily, the cleaning of the biological safety cabinet or the hood where the medication is prepared. We followed the recommendations from the National Institute for Occupational Safety and Health or NIOSH for appropriate hood cleaning. We also obtained guidance from the gene therapy manufacturer on the best practices for the cleaning procedure, following preparation of their particular product. We have consulted hood manufacturers to check if certain chemicals are appropriate to use on the surfaces and the stainless steel surfaces of part of the hood. Their feedback is, over time, using harsh chemicals can lead to pitting of the stainless steel surface. But this is something that we monitor closely to make sure that further hazards are not created in the cleaning process for hazardous drugs and something that is monitored closely to ensure the safety of the equipment that we use for preparation.
John Petrich (01:05):
Pre- and postpreparation decontamination and disinfection protocols should be established. The viricidal agent utilized should be appropriate for the viral vector, including the required contact inactivation time. Some viral vectors have an envelope capsid, and some have a nonenvelope capsid. Therefore, susceptibility to viricidal agents may vary. Standard operating procedures (SOPs) should include a designated wait time between product preparation. This time is usually thought to be the time it takes for aerosols and droplets to settle, which recommendations list as about an hour. I know some institutions use more of a 15- to 30-minute window wait time, as the rationale seems to favor droplets being settled by this time. And in our institution, we periodically rotate virucides to theoretically or anecdotally prevent resistance, but I am not aware of any formal evidence to support this practice.
Brian Yarberry (02:09):
You will definitely want to have a process in your policy and procedure that addresses the utilization of decontamination solutions, deactivators, and cleaners for the sterile area where you prepare your gene therapy medication. There are some products out there on the market that you have utilized for hazardous medications that can also be utilized for gene therapy medications. However, you can simply prepare a household bleach-diluted solution that is very well tolerated and cleans the area. However, bleach solutions can be very harmful to stainless steel surfaces as well as Plexiglas.
[Transcript of Video]
John Petrich (00:00):
Preparation and administration of gene therapies are disposed of to ensure containment from the environment and people. This may include disposal of materials utilized in preparing and administering the gene therapy product, including PPE, needles, and syringes. These materials should be sealed in a labeled primary biohazard container and then placed in a secondary container bearing the biohazard symbol to be incinerated by the institutional waste department.
Nondisposable items used during preparation and administration should be cleaned with suitable disinfectant. Bed linens should be treated as infectious and sealed in laundry bags as per institutional policy.
[Transcript of Video]
John Petrich (00:00):
The health system must consider the knowledge and training of the occupational health department for an appropriate response in the event of an exposure. Pharmacy and clinical staff should be adequately trained to follow emergency procedures in events of accidental spillage of gene therapy materials. All manufacturers should include package inserts with information on the likelihood of personnel exposure to hazardous gene therapy materials in events of accidental spillage.
An occupational health officer and biosafety officer should conduct risk assessments to understand potential hazards of each gene therapy being used.
This diagram shows suggested actions associated with different types of accidental exposures. And I would like to point out that, whether it is a needle stick, a splash to mucous membranes, skin exposure, or inhalation, it is important to not only obtain prompt medical attention but also report the exposure to your occupational health department and the biosafety officer.
Brian Yarberry (01:07):
Most institutions will have a hazardous drug spill kit. The hazardous drug spill kit will be able to be utilized with gene therapy medications as well. It will contain the gown, the mask, the gloves, and the goggles that are required whenever a spill occurs.
The only addition I would recommend is to have some type of deactivator around for when these products are being administered or transported. Deactivator could be anything from a diluted bleach solution to one of the available commercial products that are on the market.
Jeff Wagner (01:38):
So, our recommendations for addressing accidental exposure to gene therapies follow our common procedures, and generally, those are the same as exposure to conventional hazardous drugs. For example, if an exposure was to the eye, the eye should be flushed, and the flushing should be appropriate based on the drug’s properties as recommended.
However, it is important to note that the procedure should be consistent and continuously revisited as other gene therapies become available on the market and the particular recommendations might come into place.
[Transcript of Video]
Brian Yarberry (00:00):
Manufacturers play a huge role in this area. Manufacturers know their products the best. They are the experts. They are the ones with the most experience and have the most clinical trials behind them to document or back up the information that they provide. They usually know the sites that have good experiences with different products, so you can heavily rely on the manufacturer to help with these products that you bring in.
John Petrich (00:28):
Initially, I looked at a manufacturer for support on the background and history of the gene therapy product. I looked for information required to create thorough SOPs and to ensure safe handling as well, and I think this is perhaps the most critical component in the relationship between a manufacturer and a site pharmacy. Also, it is helpful if the manufacturer provides compatibility studies with other drugs and solutions, and also with equipment encountered in the preparation of the gene therapy itself.
Jeff Wagner (00:59):
Some say that the manufacturer’s role in providing guidance for the policies and procedures for handling gene therapies is actually not the responsibility of the manufacturers themselves. These policies and procedures should be developed by the institution. And, while maybe particular recommendations could be addressed as recommended by the manufacturer, I do not believe that it is the manufacturer’s responsibility to create those policies and procedures.
Institutions should generally have policies and procedures in place for hazardous drugs that align well with the drugs and minor changes that would be required to account for gene therapies.
It would be useful for the manufacturer to provide guidance, best practices, or checklists for institutions to refer to when creating their own policies and procedures, and manufacturers could share examples of language that other institutions used for development of those policies and procedures. But my perspective is that providing a complete and full policy and procedure may not be useful, as there is a potential that they get copied and pasted, and one of the key considerations for an individual facility is: Does their practice align to the established policies and procedures that are put into place? And if it is copied and pasted and it does not align with practice, that would be a concern that would be highlighted during an inspection by an outside accrediting body.
