WHAT IS ALREADY KNOWN ON THIS TOPIC

Gene therapy is becoming increasingly prevalent and hospital pharmacists are expected to handle both investigational and approved gene therapy medicinal products as and when required. However, there is substantial heterogeneity in both the level of experience of hospital pharmacy teams and in the availability of up-to-date, practical guidance for handling these products.

WHAT THIS STUDY ADDS

Updated guidance is provided to assist hospital pharmacy teams in developing institutional standard operating procedures for the handling of gene therapy medicinal products, in conjunction with local regulations.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

This updated guidance will enable the safe and appropriate handling of gene therapy medicinal products in a more standardised manner across Europe, for both experienced hospital pharmacy teams and those who are new to handling these therapies.

Introduction

This European Association of Hospital Pharmacists (EAHP) guidance document for the handling of gene therapy medicinal products (GTMPs) outlines practical considerations for the hospital pharmacy handling of GTMPs. The term ‘handling’ encompasses receipt and storage, dispensing and reconstitution, transportation, administration, waste disposal, spills and accidental exposure. Practical experience from a committee of experts and published evidence were used in the development of these guidelines. All committee members provided feedback on these recommendations, which were then subsequently validated and approved by external experts.

These guidelines cover both European Commission (EC)-approved GTMPs and products under investigation in clinical trials. However, it is important to note that these guidelines are of a general nature and intended as a framework to aid the development of institutional standard operating procedures (SOPs), especially when policy-making committees may have difficulty accessing credible guidance on which to base their recommendations.1 As such, national regulations and the Summary of Product Characteristics/relevant clinical trial documents should always be consulted for country- and product-specific requirements.

This document is an update on the EAHP guidance on the handling of gene medicines, published in 2007,2 and takes into account the substantial advances in GTMP technology and marketing approval being granted for a number of GTMPs in Europe.

Overview of the guidance development process

This guidance document was developed by a Special Interest Group convened by the EAHP to update the EAHP’s Guidance on the Pharmacy Handling of Gene Medicines2 and gain insight into the preparedness of hospital pharmacy departments for the delivery of in vivo GTMPs.3 The original guidance was developed by a steering committee of representatives from the EAHP in 2007, representing Austria, Czechia, Finland, Germany, The Netherlands, Spain, Sweden and the UK.2 The Special Interest Group for this update comprised a committee of representatives from the EAHP, representing Belgium, Denmark, France, Italy, Portugal, Spain, Sweden, and the UK. All members of the Special Interest Group were recognised as experts in gene medicine pharmacy.

Areas for update were identified by a literature review of existing guidance and through the expert opinions of the Special Interest Group members. A series of draft documents were produced, with each incorporating comments and input from the members of the Special Interest Group. An initial kick-off meeting was held after development of the outline to discuss updates and additional content.

The Appraisal of Guidelines for Research (AGREE) II document was followed while preparing these guidelines.4 AGREE II consists of two global rating items and 23 further items within six domains (scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence), which allow the quality of a guidance document to be assessed.4

Aims, scope and target of the guidance

This guidance document aims to provide practical recommendations for the handling of GTMPs in Europe, throughout the entire workflow of receiving a shipped product from the manufacturer, through to medicine reconstitution, transportation, administration to the patient, advising patients/caregivers, waste disposal and procedures for accidental spills or exposures. However, we reiterate that this guidance should always be considered in the context of local procedures and regulations. Accordingly, the scope of this document is limited to the operational aspects of the contained use and handling of GTMPs in hospital pharmacies and does not consider clinical decisions surrounding the prescribing of GTMPs, governance requirements or the deliberate release of GTMPs.

Definitions of key terms used throughout this guidance have been provided in online supplemental appendix 1, and a list of EC-approved GTMPs (as of January 2024) is provided in online supplemental appendix 2.

According to the European Medicines Agency (EMA), a GTMP must fulfil two conditions: (1) the product must be a biological medicinal product and contain recombinant nucleic acid(s); and (2) the recombinant nucleic acid(s) should be directly involved in the mechanism of action, and hence therapeutic action, of the product.5 In these guidelines, the term ‘GTMP’ is used in keeping with the EMA classification. GTMPs are a subset of advanced therapy medicinal products (ATMPs), which also include somatic cell therapy medicinal products and tissue engineered products.5

This document provides guidance on the handling of in vivo GTMPs, wherein the genetic material is introduced (eg, by injection or inhalation) directly into the body within a vector (viral or non-viral) or via physical delivery of naked DNA, to be taken up by individual cells.6 7 At the time of writing, all EC-approved in vivo GTMPs were delivered via viral vectors (online supplemental appendix 2) and by injection. The handling of ex vivo GTMPs, wherein a GTMP is administered to a sample of the patient’s cells that has been removed from the body before being incubated, and the modified cells returned to the patient, is beyond the scope of this document. However, for interest, we have included approved ex vivo GTMPs in online supplemental appendix 2. We refer the interested reader to the UK’s Specialist Pharmacy Service guidelines for handling of ex vivo GTMPs (adapting as required to comply with local regulations).6

These guidelines relate to the handling of EC-approved GTMPs and products under investigation in clinical trials. At the time of writing, all EC-approved GTMPs except for Casgevy were required to be handled in accordance with biosafety level 1 or 2 procedures due to their status as genetically modified organisms (GMOs) (online supplemental appendix 2; please refer to local regulations for country-specific definitions of GMOs). According to the World Health Organization, organisms in risk group 1 (and requiring containment under biosafety level 1) pose ‘no or low individual and community risk’ and are unlikely to cause human or animal disease, while risk group 2 (biosafety level 2) organisms pose ‘moderate individual risk, low community risk’ and can cause human or animal disease, but are unlikely to be a serious hazard.8 Non-GMO GTMPs such as Casgevy may also require biosafety precautions due to their gene-editing capabilities. Nebulised (inhaled) gene therapy poses additional safe handling considerations compared with injected gene therapy due to the increased risk of aerosol formation; in this case, guidance should be sought from the manufacturer. The EMA Summary of Product Characteristics (SmPC) or clinical trial documents for individual products should always be consulted for product-specific guidance, regardless of the mode of administration. In addition, local classifications, regulations, legislation, and biosafety requirements should always be consulted and adhered to when handling GTMPs. These may vary between jurisdictions. We recommend individuals familiarise themselves with their local regulations. This guidance is intended to be used as a framework for developing local policies, including how to respond to accidents, spills and accidental exposure.

This guidance document is relevant for any person handling a GTMP, although this will most often be a hospital pharmacist or pharmacy technician. Other healthcare professionals, such as physicians, theatre and ward nursing staff, biosafety/infection control officers, occupational health representatives, and cleaning and waste disposal staff may also consult this guidance, as is relevant to their role. General information for each step of handling a GTMP is presented in a series of figures and tables, with additional considerations and information provided in the text. As mentioned above, local legislation and regulations must always be followed and these will always take priority over this guidance.

Need for updated guidance on the handling of GTMPs

The previous EAHP guidance on the hospital pharmacy handling of gene medicines was published in 2007.2 At that time, a number of GTMPs were under investigation but none had been granted marketing approval for routine clinical use, with alipogene tiparvovec receiving the first approval in 2012.9 Now, in 2024, a number of GTMPs have been approved for use in Europe,9 and additional novel GTMPs are expected to be granted marketing approval in Europe in the future.

As a result, the use of GTMPs in routine clinical practice, outside of clinical trials, is becoming more commonplace. Hospital pharmacists and other skilled personnel will be required to reconstitute and administer these agents. However, there is evidence to suggest that hospitals and healthcare professionals may not be adequately prepared to implement GTMPs.10 A recent survey by the Special Interest Group identified a wide range of experience across centres in Europe, with some centres having relatively extensive experience while other centres reported having very little experience.3

Considering this lack of experience, many institutions are expected to need to procure additional equipment and/or develop new facilities, such as ultra-low temperature freezers and biosafety devices, to provide infrastructure for the safe handling of GTMPs.1 Different set-ups can be implemented depending on an individual institution’s requirements and in accordance with local regulations. For example, in Denmark, an approach using a mobile, contained-use isolator was developed, allowing GTMPs to be reconstituted at the administration site by hospital pharmacists and in cooperation with the surgical or clinical team.11 However, it is important to note that while this approach presents an additional safety measure and aligns with local regulations, it is not equivalent to the safety standard ensured by preparation in a grade A environment within an appropriately graded aseptic preparation suite. The French Society of Oncological Pharmacy guidelines highlight the possibility of using a hybrid isolator, which has features that can be adjusted to the level of containment required (such as a removable glove panel).12 In all cases, local regulations should be followed. For example, in the UK, if an isolator is not placed in an appropriate GMP (Good Manufacturing Practices)-compliant background environment then it is simply an enhancement of the clinical area and administration must occur immediately post-preparation.

A number of resources providing guidance on the use of GTMPs in healthcare in the UK have been produced, including the Advanced Therapy Treatment Centres (ATCC) website,13 the GTMP Governance and Preparation Requirements published by the Specialist Pharmacy Service,6 eLearning programmes14 and the Scientific Advisory Committee on Genetic Modification (SACGM) Compendium of Guidance.15–17 However, the degree of national-level guidance on the use of GTMPs in Europe varies between countries.

As such, there is a need for practical guidance to help hospital pharmacies create safe and effective workflows, and to support a degree of standardisation of procedures across Europe. Handling GTMPs may be perceived as novel and challenging, but many of the procedures will be familiar to healthcare professionals, often reflecting those already applied when handling hazardous drugs, such as cytotoxic agents. Appropriate training should help personnel feel more at ease with handling GTMPs.

Review of existing guidance

The Specialist Pharmacy Service of the UK’s National Health Service (NHS) has produced specific guidelines for the handling of GTMPs, which were last updated in February 2024.6 This includes practical guidance across the entire handling procedure, as well as consideration of the facilities and personnel required for pharmacies to safely handle GTMPs.6 Guidance on differential handling of in vivo and ex vivo products is also included.6 Handling of in vivo versus ex vivo GTMPs is beyond the scope of this document as the processes are similar (although handling ex vivo GTMPs may require some additional training, particularly in aseptic technique, given that pharmacists are not routinely trained in the handling of cells and tissues, as well as specific facilities/equipment); we refer the interested reader to the above-mentioned guidelines.6 As mentioned in the previous section, several additional UK-specific resources are also available.13–17 Furthermore, other national guidelines exist, such as the French HCB Handbook for the Contained Use of GMOs.18 This handbook contains sections specific to the administration of GMOs for therapeutic purposes, as well as guidelines on the handling of GMO waste, viral vectors, and containment requirements for gene therapy.18

Experts from the USA and Australia have also produced opinion and review articles providing guidance on the handling of GTMPs in a hospital pharmacy setting.1 19–24 Common recommendations across documents include limiting access to GTMPs to trained personnel, using appropriate biosafety containment equipment and personal protective equipment (PPE), using appropriate containers for transportation, developing institutional procedures and policies, and ensuring appropriate decontamination and waste management.19–24 Additional recommendations include adding GTMPs to the institutional hazardous drugs list, following contact precautions with patient material post-administration, instating a clinical biosafety committee, caregiver training, providing appropriate personnel training/education and storage of the GTMPs in a dedicated area.20–25

In general, available guidelines and recommendations agree that GTMPs should only be handled by trained personnel in a manner appropriate for the biosafety level of the agent, following established procedures.6 19–22

General operating procedures for handling GTMPs in the hospital pharmacy

For ease of use, we have compiled suggested operating procedures into tables and charts. These tables and figures should be viewed only as a framework of guidelines to aid in the development of institutional SOPs. Thorough risk assessment should be conducted before the use of any new GTMP. The development of institutional SOPs should also consider local regulations, policies, and procedures – for example, in Denmark, each facility must go through a formal application process before using any GTMP, to ensure safety for personnel, patients and the environment. However, it has been noted that, as of 2022, few national and/or industry-wide guidelines relating to GTMPs had been developed because of the novelty of these therapies.1 All the information required for each step is included in the appropriate chart or table (or their accompanying footnotes). Additional considerations are highlighted in the text.

Handling of GTMPs and patient specimens

General requirements for the handling of GTMPs and associated patient specimens are outlined in table 1. Specific requirements may vary between countries, and as such adhering to local regulations should always be prioritised. The GTMP’s Summary of Product Characteristics or clinical trial documentation should also always be consulted.

Table 1

General guidance regarding the handling of GTMPs and patient specimens

A thorough risk assessment should always be performed for any new GTMP being introduced into a facility, preferably by a dedicated genetic modification safety committee, even if this is not required by national regulations.6 19 Any risk assessment should consider risks to human health and the environment (including the risk group of the viral vector, replication competency, and the risk group of the transgene, including oncogenicity and genome integration ability).6 21 Additional considerations may include the ability to form toxins, cause allergic reactions, produce biologically active substances and antibiotic resistance. Recommendations regarding the risk assessment of virus-derived vectors used in gene therapy have been previously published.26

Appropriate protective clothing should always be worn whenever a GTMP is handled; however, the quality of the protective clothing may differ depending on the activity. For example, receipt of the GTMP on delivery and reconstitution of the GTMP are associated with differing exposure risks, and as such, will require different levels of protective clothing. For biosafety class 1 GTMPs, universal precautions should be used unless a higher level of risk has been determined following a risk assessment; for biosafety class 2 GTMPs, protective clothing should always be worn. The quality and type of protective clothing should be appropriate for the grade of the working area and process being performed. During reconstitution of a GTMP, protective clothing must be worn in such a way as to protect the GTMP from microbial contamination, as well as protecting the person. For further details, see online supplemental appendix 3.

We recommend that dispensing and reconstitution of GTMPs be performed in a clean air device (either a (minimum) class 2, type B biological safety cabinet or a pharmaceutical grade isolator (compliant with European standard EN12469:2000)) that removes air to the outside. Recirculation of air may be acceptable when handling some GTMPs, provided that recirculation has been deemed sufficient during a risk assessment. A mobile or disposable isolator unit may be an alternative to simplify logistics or clean-up, particularly if local regulations only allow GTMP reconstitution in specific areas or if regulations discourage transportation of the reconstituted GTMP. In addition, if only small numbers of patients are being treated, utilising a mobile unit may be preferred over building a dedicated clean room.11 Alternatively, a hybrid isolator may be used, which is a unidirectional flow isolator allowing modifications to be made to the isolator depending on the level of containment required.12

Precautions for the decontamination of needles and sharps, as well as work surfaces, should be in place before the decision to initiate treatment with a GTMP is made.

Contact procedures with the patient following administration will be dependent on the biosafety level of the GTMP; for example, specimens from a patient treated with a biosafety level 1 agent often do not need to be biohazard labelled (subject to local regulations). However, patient laundry should be decontaminated/cleaned according to the procedures for blood- or body fluid-soiled laundry, unless evidence-based regulatory guidance indicates that the patient is unlikely to be shedding viral vectors and this procedure is not necessary. Viral vector shedding in stools may occur for some GTMPs, but there are no overarching recommendations regarding necessary precautions for patients eliminating stools and urine. The SmPCs or clinical trial documentation and local regulations should be considered for each individual GTMP. In particular, it should be noted that exposure to a viral vector shed by someone administered a GTMP could result in close contacts acquiring immunity against that vector, potentially resulting in siblings or other family members with the same genetic condition becoming ineligible for treatment with the same GTMP.23 Patients administered a GTMP may return home shortly after treatment, so hospital pharmacists should ensure that the risks associated with viral shedding, and their management, are considered and discussed with the patient (and their carer(s)), as necessary.

Samples from patients who have received a GTMP should be handled in a similar manner as samples from patients with infectious diseases. Handling processes should be agreed on following consultation with a multidisciplinary team and/or biosafety committee. Patient specimens should always be transported and stored in a double-enclosed, labelled, leak-proof container. Waste disposal should ensure decontamination of any remaining GTMP, by autoclaving, heat inactivation or incineration.

A spill kit should always be readily available whenever transporting, storing, reconstituting, dispensing, administering or disposing of a GTMP or patient specimens.

We strongly recommend that institutional policies and SOPs be put in place for handling GTMPs, and that all GTMPs be added to the hazardous drugs list, if applicable, to ensure adequate protection of personnel.22 These policies and SOPs should be commensurate with the risks identified during any risk assessment.

All parties involved in the handling of GTMPs must clearly understand their roles and responsibilities along the process. A suggested working model is provided in online supplemental appendix 4; this uses the RASCI (responsible, accountable, support, consulted, informed) model.27 Each institution will need to follow local regulations. Every individual involved in the process of handling a GTMP within an institution is ultimately accountable to that institution’s management team. We recommend forming a biosafety committee comprising at least a hospital pharmacist, physician, nurse, biosafety or environmental safety officer, occupational health officer, waste services personnel and laboratory scientist with relevant experience working with GTMPs. The advice of an independent biosafety committee may also be sought.

Responsibility for all aspects of GTMP handling that occur in a hospital pharmacy ultimately lies with the hospital pharmacy’s chief pharmacist, but may be delegated to other members of the hospital pharmacy team, as appropriate (online supplemental appendix 4). The broader hospital pharmacy team may also support the chief pharmacist with GTMP handling, as required. The treating physician and nursing staff should usually be informed when a GTMP is received from the manufacturer.

When the decision to initiate treatment is made, the treating physician is responsible for ensuring that the required conditions for handling and administering GTMPs are established. Treatment must not begin until all necessary processes are in place. Consultation and collaboration between the treating physician, chief pharmacist, hospital pharmacy staff, nursing staff, biosafety/infection control officer, occupational health and waste disposal services are required to establish the local workflow in advance of treatment.

The chief pharmacist or delegated responsible pharmacist, treating physician and biosafety/infection control officer should conduct a detailed assessment of the training needs of the staff and the ability of the facility to handle GTMPs. Correct use of the equipment, safe handling of GTMPs and adherence to local requirements and regulations should be included as part of mandatory training modules for personnel who handle GTMPs to generate confidence in handling GTMPs. The chief pharmacist is responsible for all hospital pharmacy-related procedures, including ensuring that appropriate equipment is available and that hospital pharmacy staff are appropriately trained for their roles. The chief pharmacist may delegate responsibility to one of their team of pharmacists. The treating physician is responsible for all clinic-related procedures, including ensuring that the required facilities are available and medical/surgical personnel are appropriately trained. The biosafety/infection control officer is responsible for all other areas of assessment.

Receipt and storage of GTMPs

Recommended procedures for the receipt and storage of GTMPs are outlined in figure 1. These procedures should be considered in the context of local procedures and regulations, which will always take priority. As such, all charts in this document should be viewed as a framework for the development of local SOPs, which may be edited as required to comply with local regulations.

Figure 1

Storage of GTMPs. aWhen GTMPs are delivered, the secondary packaging is guaranteed as not contaminated. bIf vial is damaged, the primary packaging should be decontaminated. cLocation of storage must ensure that no unauthorised person can gain access and there is no undue risk of exposure of hospital staff to the product. A biosafety label should be included on the door of the storage room and the storage unit. This chart is intended as a framework to aid the development of institutional standard operating procedures and should be amended as required to comply with local regulations. GTMP, gene therapy medicinal product.

Couriers must be licensed and use approved procedures and methods for transporting GTMPs. Given that GTMPs are both extremely costly and temperature-sensitive, cold chain transportation with temperature logging is required. If any temperature excursions occur during transport, the GTMP should be stored safely in temporary quarantine and the supplier contacted to determine the next steps.

The secondary packaging for GTMPs is guaranteed as being uncontaminated; however, PPE appropriate to the biosafety level of the GTMP should always be worn when unpacking the GTMP on delivery in case it has been damaged during transit. If the vial has been damaged, it should be disposed of immediately in line with defined waste management procedures, in accordance with local procedures.

Storage temperature requirements will vary between GTMPs; consult the SmPC or clinical trial documentation for the storage temperature required for each GTMP. Some GTMPs may require storage in liquid nitrogen.

GTMPs should be stored in separate fridges/freezers where possible, and labelled appropriately with a biohazard label, if required by local regulations. If it is not possible to use a dedicated fridge/freezer for GTMPs in isolation, a separate shelf within a fridge or freezer may be sufficient, but this depends on local regulations. Some countries in Europe require GTMPs to be stored separately. Furthermore, individual GTMPs should be stored in isolation from each other, for example, by using clearly labelled, separate shelves within a storage facility for each GTMP.

Freezers should be temperature-monitored with an alarm set to trigger if the temperature rises above a threshold. Care should be taken to limit the duration of freezer door opening when accessing GTMPs to prevent warming of the contents of the freezer. Once thawed, GTMPs should generally not be refrozen; see the SmPC or clinical trial documents for storage requirements for thawed vials.

Institutions should prepare for instances of storage equipment dysfunction. For example, an alternate freezer for storing GTMPs could be identified for use in the event of a freezer failure.17 A responsible person should be assigned and notified in the event of a freezer failure and a preformulated plan for moving GTMPs to alternate storage facilities actioned.

Similarly, procedures for validation of storage facilities should be put in place because these facilities may be used infrequently. A negative pressure room may be required for storage; consult local regulations. If storage within the hospital pharmacy is not possible due to a lack of appropriate storage facilities, an outside location may be used if local regulations allow. This location should be known to other staff members such as the physician(s) and nurse(s). The alternative location should only be accessible by authorised personnel and should not carry a risk of undue exposure to a GTMP for people or the environment.

Access to GTMPs should be restricted to authorised personnel who have been trained in their handling.

Cost may also be a significant barrier to storage that should be considered when establishing facilities for the handling and storage of GTMPs. Here, a mobile isolator unit may be a more cost-effective option when establishing procedures for GTMP handling, but this should not come at the cost of quality or safety.

Reconstitution and dispensing of GTMPs

GTMPs should be reconstituted using aseptic technique. The procedure for aseptic reconstitution and dispensing of GTMPs is outlined in figure 2. As the vast majority of GTMPs will need to be administered rapidly following reconstitution, the procedure for reconstitution and dispensing should be intertwined into one clear process when developing local SOPs. Appropriate PPE should always be worn when reconstituting and dispensing GTMPs.

Figure 2

Aseptic reconstitution and dispensing of GTMPs. aMinimum class 2, type B, with background grading per local guidance/regulations. bThe running of the safety device should be according to local procedures for aseptic reconstitution. cDecontaminant with proven viricidal activity, for example, an oxidising agent such as 1000 ppm chlorine, 1–2% Virkon or 6% hydrogen peroxide. The chosen decontaminant should be validated for each individual GTMP using data provided by the supplier/manufacturer, as detailed in the SmPC or clinical trial documents. dThe delivery device should be suitably decontaminated after use. eAny spills should be decontaminated according to figure 6. This figure is intended as a framework to aid the development of institutional standard operating procedures and should be amended as required to comply with local regulations. GTMP, gene therapy medicinal product; PPE, personal protective equipment; ppm, parts per million.

Figure 6

Decontamination of GTMP spills. aDecontaminant with proven viricidal activity, for example, an oxidising agent such as 1000 ppm chlorine, 1–2% Virkon or 6% hydrogen peroxide. The chosen decontaminant should be validated for each individual GTMP using data provided by the supplier/manufacturer, as detailed in the SmPC or clinical trial documents. bContact time is dependent on the disinfectant used. Exceeding the contact time will not improve decontamination but may damage surfaces. cUsing other disinfectants or alcohol to wash the area rather than water will likely cause frothing or smearing, which may be difficult to remove. This chart is intended as a framework to aid the development of institutional standard operating procedures and should be amended as required to comply with local regulations. GTMP, gene therapy medicinal product; PPE, personal protective equipment; ppm, parts per million.

All GTMP prescriptions should be checked according to usual hospital pharmacy procedures. Any queries should be directed to the treating physician. If necessary, theatre or ward nurses may also be consulted. Assuming that all procedures for the handling of GTMPs have been implemented, the biosafety/infection control officer, hospital hygiene services and occupational health should not need to be informed of every instance when a GTMP prescription is issued. It should only be necessary to notify appropriate personnel when a GTMP is issued within an institution for the first time. Local regulations should be consulted for country-specific requirements.

SOPs for the entire reconstitution and dispensing process should be developed, including for the transfer process between aseptic and non-sterile facilities/devices (including between institutions on occasion), reconstitution, consumables required, waste disposal, form of the final packaging, labelling of the transportation container, stability of the GTMP and spill procedures.6

Where possible, in order to uphold optimal safety standards, the GTMP should be reconstituted within the hospital pharmacy to reduce the risks of contamination and medication errors.6 However, this may not be possible in some countries due to legal requirements, for example, Denmark. In these cases, local regulations must always be followed. In the case of Denmark, a solution has been identified whereby GTMPs are reconstituted in a mobile, contained-use isolator at the administration site, which enables aseptic preparation of the GTMP, prompt administration, and close cooperation between hospital pharmacy and clinical personnel.11 However, in other countries (such as France), GTMPs must be reconstituted within the hospital pharmacy, in alignment with regulatory requirements. As such, it is essential to check and adhere to national requirements when developing institutional SOPs.

Similar guidance applies to reconstituting agents in the clinical area. While this may be allowed in some countries for class 1 or class 2 agents within a closed system transfer device, other countries may forbid it. Some hospitals may have dedicated clean rooms or aseptic facilities for the reconstitution of GTMPs.

At the time of writing, all GTMPs approved by the EC could be handled under biosafety level 1 or 2 conditions (see online supplemental appendix 2 for a list of EC-approved GTMPs). If an agent with a higher biosafety level is to be handled, for example, as part of a clinical trial, a thorough biosafety risk assessment should be performed to determine appropriate handling procedures. An overview of considerations for the biosafety risk assessment of genetically modified organisms has been previously published and may be a useful resource.28

A clean air device that complies with EN12469:2000, such as a (minimum) class 2, type B biological safety cabinet or a pharmaceutical-grade isolator, should always be used for the reconstitution of GTMPs to protect both the handler and the product. The safety device should have an exhaust to the external environment and not recirculate air into the room. Negative pressure may be required, depending on the risk level of the agent. As always, consult local regulations for specific requirements and conduct a thorough risk assessment. Generally, biosafety class 2 GTMPs and above should be reconstituted in a negative pressure clean air device.6

A biohazard sign should be posted on the outside of the door to the reconstitution room whenever a biosafety level 2 GTMP is being handled. Consult local requirements as to whether a biohazard sign is required for biosafety level 1 agents.

Steps to prevent cross-contamination should be taken, including disinfection of the device before and after use, disinfection of all equipment entering the device, and leaving the device running for its validated clean-up period (generally, 15 min to 8 hours) following reconstitution, to allow for the elimination of aerosols.1 21 29 30 Other drugs, doses and supplies should also be cleared from the hood to reduce the risk of cross-contamination.1 21 30 Decontamination of the device must occur after this time window, immediately before the device is shut down.

If possible, we recommend that a dedicated biosafety device be used for the reconstitution of GTMPs. However, if this is not possible, a common device may be used provided that strict decontamination methods before and after each use are adhered to, if this is allowed by local regulations.19 It is recommended that replication-competent GTMP vectors are reconstituted in a separate device because of the higher risk of cross-contamination.19

Before beginning to reconstitute a GTMP, always ensure that sufficient consumables (needles, labels, plasticware, etc) are available and ensure that the GTMP has not passed its expiry date. Consult the SmPC or clinical trial documents for information regarding the shelf life of the reconstituted product; some agents have a very short shelf life at room temperature, so reconstitution may need to be performed quickly and in coordination with the administration schedule.

Appropriate viricidal agents should be readily available in the event of a spill, and for decontamination of the clean air device before and after use. These may include 1000 parts per million chlorine/10% bleach, 1–2% Virkon or 6% hydrogen peroxide. Always ensure that the contact time for the decontamination agent is adhered to. Different viral vectors may have different susceptibilities to decontamination agents; if in doubt, consult the manufacturer of the GTMP for appropriate decontamination practices. However, note that some decontaminants can damage stainless steel surfaces on clean air devices; this should be monitored.

We recommend that a log book be kept for each clean air device that is used to reconstitute GTMPs, to inform other members of staff when the device was last used and to confirm that decontamination has been performed. Accountability or exposure logs may also be prudent, particularly for institutions that are new to handling GTMPs. Health surveillance requirements should be checked according to local regulations. An exposure log, if used, should be held centrally (eg, the occupational health department) and retained for an appropriate timeframe, according to local regulations. Some individuals may be at higher risk of exposure, such as pregnant or immunocompromised staff, or staff with persistent infections (such as herpes simplex) that may be related to the vector used to generate the GTMP. These individuals should be provided with sufficient information to self-assess the risk of handling the GTMP, as well as the opportunity to speak with an occupational health professional. However, local regulations should also be consulted, as some countries may prohibit these individuals from handling GTMPs.

Transportation of GTMPs

The use of the term transportation in this guidance refers to transport within the hospital or on a public road using hospital transportation. In both cases, the same recommendations apply, as described below (using a double-enclosed container, appropriate temperature control, availability of a spill kit and using a delivery log). As for all steps along the handling pathway, a risk analysis should always be conducted to ensure safe transportation of GTMPs within the hospital system. Courier transport (eg, from the supplier to the hospital/reconstitution site) is addressed in ‘Receipt and storage of GTMPs’. Some countries may not allow transportation of the reconstituted GTMP around the hospital; in this case, a mobile isolator unit may be used to aseptically reconstitute the GTMP at the site of administration.

Once reconstituted, the GTMP should be transported in a double-enclosed system, in a biohazard-labelled, leak-proof container (figure 3).

Consult the SmPC or clinical trial documents for temperature requirements after reconstitution and select an appropriate container for transport.

A spill kit should be on hand at every GTMP handling step, including transportation. Ideally, a spill kit should be carried with the GTMP, but an alternative would be to place spill kits along the delivery route. This may depend on local regulations and practicality.

Preferably, the reconstituted GTMP will be brought directly to the administration site and administered immediately, rather than being stored at the administration site.

We suggest having a delivery log as a record that each drug has been delivered, and handover should occur directly to the staff member responsible for administering the agent.

Administering GTMPs

Administration of the GTMP is usually the responsibility of the treating physician, with support from nursing staff, but appropriately trained nurses may also be able to administer GTMPs, in accordance with local regulations (online supplemental appendix 4).

Coordination between clinical and hospital pharmacy staff is essential to ensure that the GTMP is reconstituted and then administered in a timely manner. Ideally, the dose should be administered immediately rather than being stored at a second location.1

Appropriate PPE should be worn when administering the GTMP, dependent on local regulations, product-specific requirements and institutional risk assessment. Before beginning the administration procedures, ensure that the spill kit, waste disposal containers and appropriate dressings are available. Place a biohazard sign on the door if required by the biosafety class of the agent and local regulations.

A disposable mat should be placed under the body area of the patient, where the GTMP is to be administered. Standard precautions, aseptic technique and product-specific instructions should be adhered to. After administration, cover the site with a dressing and apply pressure to stop bleeding, as required. Dispose of all waste in accordance with local procedures.

It is possible viral shedding may occur from the patient following administration.17 Consult the SmPC or clinical trial documents for individual GTMPs to determine whether this is likely to occur. If viable viruses (ie, replication competent viruses) are likely to be shed, appropriate steps should be taken to protect people and the environment. This could include keeping the patient in isolation until shedding ceases. In addition, patients and caregivers should be advised on how to protect themselves, others, and the environment on returning home. As with every GTMP handling step, local regulations and procedures should be consulted.

Broad guidance for the administration procedure is outlined in figure 4; this can be used by clinical staff to help develop SOPs for the administration of GTMPs.

Figure 4

Guidance for clinical staff to develop standard operating procedures for administering GTMPs. This figure is intended as a framework to aid the development of institutional standard operating procedures and should be amended as required to comply with local regulations. GTMP, gene therapy medicinal product; PPE, personal protective equipment;.SmPC, Summary of Product Characteristics.

GTMP waste disposal

Disposal and cleaning of waste products should occur as soon as possible using the procedures outlined in figure 5 and in accordance with local waste management procedures.

Figure 5

GTMP waste disposal. aDecontaminant with proven viricidal activity, for example, an oxidising agent such as 1000 ppm chlorine, 1–2% Virkon or 6% hydrogen peroxide. The chosen decontaminant should be validated for each individual GTMP using data provided by the supplier/manufacturer, as detailed in the SmPC or clinical trial documents. bInactivation should be conducted according to local regulations. This figure is intended as a framework to aid the development of institutional standard operating procedures and should be amended as required to comply with local regulations. GTMP, gene therapy medicinal product; PPE, personal protective equipment; ppm, parts per million.