Pan UK Pharmacy Working
Group for ATMPs
Gene Therapy Medicinal
Products
Governance and Preparation
Requirements

Version 3
February 2024

www.sps.nhs.uk

1

Contents
Reference
1.0
Figure 1
Part 1
2.0
2.1
2.1.1
Figure 2
2.2
2.2.1
2.2.2
3.0
Table 1
3.1
3.2
3.3
3.4
4.0
4.1
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
4.1.6
4.1.7
4.2
Part 2
5.0
5.1
5.2
6.0
Figure 3
6.1
Figure 4
6.2
Figure 5
6.3
6.3.1
6.3.2
6.3.3
6.3.4
6.3.4.1
Table 26.3.4.2
6.3.5

www.sps.nhs.uk

Title
Executive Summary
Organisational Governance Requirements for initiating a GTMP
Governance
What is a Gene Therapy Medicinal Product?

Genetically Modified (GMO) GTMPs“In vivo” (Non-Cellular) vs “Ex vivo” (Cellular) GMO GTMP
In Vivo vs Ex Vivo GTMP

Non-GMO GTMP
mRNA Immunotherapies

Gene Editing Technology
What legislation governs gene therapy?
GTMP legislation and guidance documentation
Classification and Containment Levels for GTMP
Biosafety levels
Deliberate Release
Non-GMO GTMP
What Governance is required?
Genetic Modification Safety Committee (GMSC)
GMSC Membership
Establishing a GMSC
GMSC Terms of Reference
GMSC responsibilities
GMSC Risk assessments
General information
Notifications
Considerations for non-GMO GTMP GovernanceOperational
Receipt and storage
In vivo (non-cellular) GTMP
Ex vivo (cellular) GTMP
Gene Therapy Medicinal Product Preparation
Technical Feasibility Process
Preparation and handling of in vivo (non-cellular) GTMPGMO GTMP Preparation Location – Non CellularPreparation and handling of ex vivo (cellular) GMO GTMPGMO GTMP Preparation Location – CellularPreparation of GTMPs within aseptic facilities
Operator protection
Preparation process
Isolator/Biological Cleaning Considerations
Waste management
GMO GTMP waste management

GTMP waste containment
non-GMO GTMP
Transport

Page
4
4
5
5
5
6
6
7
7
7
7
8
8
9
9
10
10
10
11
12
12
12
13
13
14
15
16
16
16
16
17
17
19
19
20
20
21
21
21
22
22
22
23
24
24

2

6.4
6.4.1
6.4.1.1
7.0
8.0
Appendix 1
Appendix 2
Appendix 3
Appendix 4

Preparation of GTMP medicines within a clinical setting
Spillage
Decontamination of Spillage
Glossary
References
Regulations
Example of a GMSC Risk Assessment
GMSC Terms of Reference
Disposal of Waste

25
25
26
27
29
30
31
40
44

Foreword
The PAN UK Pharmacy Working Group for Advanced Therapy Medicinal Products aims tofacilitate the implementation of ATMPs into practice. Gene Therapy Medicinal Products(GTMPs) are a sub-category of ATMPs which are showing great promise to the benefit ofpatients. As such, access to GTMPs, whether in Clinical Trials, being used as unlicensed
medicines or in routine implementation of medicines holding marketing authorisations, isincreasing throughout the UK. A subgroup of the Pharmacy Working Group has produced thefollowing guidance in response to increased numbers of enquiries from organisations naïve to
Gene Therapy Medicinal Products wishing to understand governance and preparation
requirements for these innovative medicines.

Subgroup MembershipAnne Black
Lynn Morrison
Nicola StonerWith thanks to Samantha Carmichael, Beatriz Duran, Nia Evans and Sarah Tehan for supportand reviews.

Comments and enquires to Anne.Black7@nhs.net

www.sps.nhs.uk

3

1.0

Executive Summary

As GTMPs are ATMPs it is important that organisations that wish to introduce a gene therapy
medicinal product for use either in a trial, as an unlicensed medicine or as a licensed medicine
have a defined organisational governance process in place. This is recommended in Advice
for Chief Pharmacists on Advanced Therapy Medicinal Products (February 2017)[6]This document has been produced to facilitate the introduction of GTMPs into healthcareorganisations. It outlines the governance requirements and operational requirements for
GTMPs and provides useful guidance for sites wishing to undertake clinical trials involving
GTMP investigational medicinal products, and for sites wishing to implement the use of GTMP
holding marketing authorisations.
The following process flow chart outlines the governance requirements which should be inplace and require Pharmacy input when an organisation wishes to use a GTMP.

Figure 1: Organisational Governance Requirements for initiating a GTMP

www.sps.nhs.uk

4

Part 1 Governance
2.0

What is a Gene Therapy Medicinal Product?

Gene therapy medicinal products (GTMPs) are advanced therapy medicinal products(ATMPs)[1].
GTMPs are defined as a biological medicinal product which has the following characteristics:
It contains an active substance which contains or consists of a recombinant nucleic acid usedin or administered to human beings with a view to regulating, repairing, replacing, adding, ordeleting a genetic sequence; anda) Its therapeutic, prophylactic, or diagnostic effect relates directly to the recombinantnucleic acid sequence it contains, or to the product of genetic expression of thissequence.
A vaccine against infectious diseases is not to be treated as a gene therapy medicinal product.
Most GTMPs are classified as a genetically modified organism (GMO) and are therefore
subject to Contained use or Deliberate Release Regulations (see Section 3). However, there
are some GTMPs which are not classed as GMO including mRNA immunotherapies e.g. usedin cancer and a gene edited GTMP e.g. CRISPR technology. (See section 2.2.1)
This document covers both GMO and non-GMO GTMPs and aims to provide governance andoperational guidance for all GTMP scenarios.
Currently, most GTMPs are used in clinical trials[2] although there are GTMPs with marketing
authorisations (e.g. CAR-T therapy and adeno-associated viral vectors containing genes) andhorizon scanning would predict that this trend is increasing.
On occasion a GTMP may be given as an unlicensed medicine (i.e. an import or amanufactured special). Organisations should ensure that any use of unlicensed GTMPs
complies with their local unlicensed medicine policies.
2.1 Genetically Modified (GMO) GTMPs
Genetically Modified Organism (GMO) GTMP modes of action are well documented[3]. They
are designed to introduce genetic material into cells to compensate for abnormal genes or to
make a beneficial protein which then multiplies and exerts a positive effect. Another mode ofaction is in place where a mutated gene causes a necessary protein to be faulty or missing,the GTMP may be able to introduce a normal copy of the gene to restore the function of theprotein.
The manufacture of GMO GTMPs is complex as a carrier called a viral vector is required todeliver the gene to the cell. Certain viruses are often used as vectors because they can deliver
the new gene by infecting the cell. The viruses are genetically modified to ensure that they
can't cause disease when used in people. Retroviruses integrate their genetic material(including the new gene) into a chromosome in the human cell, whereas adenoviruses
introduce their DNA into the nucleus of the cell, but the DNA is not integrated into achromosome.

www.sps.nhs.uk

5

2.1.1 “In vivo” (Non-Cellular) vs “Ex vivo” (Cellular) GMO GTMPA GMO GTMP is classified as ‘in vivo’ where the GTMP consists of injection of the viral vector
directly into a specific tissue in the body where it is then taken up by individual cells, or where
the GTMP is administered intravenously (IV). An example of ‘in vivo’ GTMP is Onasemnogene
Abeparvovec.
Alternatively, a donation of cells can used as the starting material for an ex-vivo gene therapy.
In this case a viral vector is used to introduce the gene to the starting material cells in thepharmaceutical manufacturing unit. The engineered cell is then incubated and expands toform the medicinal product. The genetically modified cells, now classed as a medicine, arethen returned to the patient. Where the cells are harvested from the patient, this is called an
autologous ‘ex vivo’ GTMP e.g. CAR-T cell therapy, Yescarta®, Kymriah®, Tecartus®.
Allogeneic (starting material from a donor) ex vivo gene therapies are currently in clinical trials.

Figure 2: In Vivo vs Ex Vivo GTMP[4]www.sps.nhs.uk

6

2.2 non-GMO GTMP
Some innovative therapies are classed GTMPs but not as GMOs. For example, mRNA
immunotherapies and gene edited medicines are considered as GTMPs.

2.2.1 mRNA Immunotherapies
There are many clinical trials using mRNA technology to treat cancers – so-called “cancer
vaccine” trials. As vaccines against infectious diseases are excluded from the legal / regulatory
definition of a gene therapy the term “cancer vaccine” is frequently used incorrectly. mRNA
products to treat cancer are immunotherapies, but they are not vaccines because they are notsubstances to prophylactically treat an infectious disease (definition of a vaccine).
Additionally, in order for an mRNA immunotherapy to be classed as a GTMP, it must be abiological medicine. Hence if the mRNA is chemically synthesised – it is not a GTMP.
So, where mRNA is purely made from chemical synthesis then it is a chemical (and a molecule
made in this way could not be classified as a gene therapy medicinal product). However if
mRNA is made involving chemical synthesis from a DNA-template (called in vitrotranscription), where the DNA template is a linearised plasmid produced in E.Coli. then it isconsidered to be a biological, and therefore provided the product fulfils the rest of the definitionof a gene therapy, and the mRNA would be considered a gene therapy medicinal product.

2.2.2 Gene Editing Technology
Another type of GTMP which is not classed as GMO is gene (or genome) edited GTMP. In
these products the DNA is altered during the manufacturing process as the DNA is cut at a
specific spot. Manufacturers then remove, add, or replace the DNA where it was cut.
A genome editing tool called CRISPR, has revolutionised this process.

3.0

What Legislation Governs Gene Therapy?

The following legislation should be consulted. Investigational Medicinal Product (IMP) GTMPs
are regulated by the MHRA and HSE/DEFRA. Licensed GTMPs are governed by the
medicine’s regulators only. Unlicensed medicines require HSE/DEFRA considerations, but
their quality and clinical assessment is governed by local Unlicensed Medicines Policies.

www.sps.nhs.uk

7

Human Medicines Regulations 2012 SI: 2012 - No. 1916
Regulation (EC) NO 1394/2007 On Advanced Therapy Medicinal Products (“TheATMP Regulation”)
Health and Safety Executive (HSE) Genetically Modified Organisms (ContainedUse) Regulations 2014 (see Appendix 1)
Medicines for Human Use (Clinical Trials) 2004 SI: 2004- No.1031 as amended
Clinical trials - Regulation EU No 536/2014
The Genetically Modified Organisms (Deliberate Release) (Amendment)(England) Regulations 2022
Table 1 GTMP legislation and guidance documentation
The use of gene therapy containing GMO in nearly all clinical use falls under the Contained
Use Regulations. (See 3.1 and 3.2). The first time that an organisation undertakes activity withany class of GMO they must notify the HSE and have an entry of the premises made in the
public register. After the first notification, further notification is required for activity which isclass 2 and above only. There are fees associated with these notifications. (See 5.7)
Deliberate release of GMO is rarely applied in a clinical setting (see 3.3).

3.1 Classification and Containment Levels for GTMP
Containment Level assessment is the legal responsibility for the Trust/Site
If the GTMP has been genetically modified, the Genetically Modified Organisms (ContainedUse) Regulations 2014 will usually apply (see 3.3 for deliberate release). There are fourclasses of activities according to the regulations[5]. The classification is based on the level ofrisk to humans and the environment and will vary if the GMO is replication competent and if it
is shedding (i.e. appears in the patients’ excretions after administration).
Class 1 – activity of no or negligible risk for which containment level 1 is appropriate to protect
human health and the environment.
Class 2 – activity of low risk for which containment level 2 is appropriate to protect humanhealth and the environment.
Class 3 – activity of moderate risk for which containment level 3 is appropriate to protect
human health and the environment.
Class 4 – activity of high risk for which containment level 4 is appropriate to protect humanhealth and the environment.

www.sps.nhs.uk

8

The classification of the activity involving the genetically modified organism (GMO) isdetermined by the containment and control measures identified as necessary via the risk
assessment. Containment measures are detailed in Schedule 8 of the Genetically Modified
Organisms (Contained Use) Regulations 2014 available at:
http://www.hse.gov.uk/pubns/priced/l29.pdf
In reality, most activities involving GTMP that are currently in clinical trials and in development
for clinical use will be class 1 or 2.
For example: Containment level 1 is suitable for class 1 activities involving GTMPs such as
replication incompetent adeno-associated viruses. Containment level 2 is required for class 2
activities for example the use of some conditionally replicating virus vectors. However, theclassification for each individual activity must be determined by the risk assessment processthat identifies necessary control measures from Schedule 8 as detailed above Control
measures identified from the highest containment level determine the class of the activity. For
further details on risk assessment of GMOs see the HSE Compendium of guidance Part 2
http://www.hse.gov.uk/biosafety/GMO/acgm/acgmcomp/part2.pdf

3.2 Biosafety levels
Biosafety levels are defined as a set of biocontainment precautions used to contain andidentify the protective measures needed to protect staff, patients, and the environment forbiological products. GTMPs are classified by HSE class as detailed in 3.1, but there are someoccasions when GTMPs are classified by biosafety levels e.g. when the GTMP does notcontain a GMO and /or where the GTMP is manufactured outside of the UK. Other biologicalproducts, including somatic cell therapy, may also have a biosafety level, but as they are not a
GTMP, they do not fall under this guidance or the HSE legislation e.g. cytotoxic T
lymphocytes.

3.3 Deliberate Release
Where a GMO GTMP is assessed by the local GMSC and the conclusion is that the GMO
cannot be contained, every effort should be made to ensure that all containment options havebeen exhausted (PPE, pharmacy preparation, waste management etc). It is envisaged that
preparation and administration locations should not be insurmountable barriers; even in cases
where home preparation is required, and open systems are in use – there will usually be a way
to mitigate and contain the risk.
If the Healthcare Organisation is unable to do so, however, then they may wish to proceed withthe complex process of obtaining Deliberate Release approval.
In the first instance – the Healthcare Organisation will need to liaise with DEFRA via gmregulation@defra.gov.uk.
It is also important to note that when progressing down the deliberate release approval route,in principle it is a requirement to list the sites of administration publicly – where this will breachpatient confidentiality sites are advised to liaise with DEFRA to understand the potential for an
exception being made for patient addresses. All clinical sites would need to be listed.

www.sps.nhs.uk

9

3.4 non-GMO GTMP (e.g. mRNA and gene edited technologies) do not require consideration
under either the contained use or deliberate release regulations, since they do not containa GMO.

4.0

What Governance Is Required?

The Pan UK Pharmacy Working Group for ATMPs recommends that for introduction of
any GTMP, organisational governance is required and that a clear process should be
documented in a local ATMP Policy.
The mandatory requirements for assessment by a GMSC, in practice, apply only to clinical
trials and unlicensed medicines. These are laid out in Genetically Modified Organisms(Contained Use) Regulations 2014 Schedule 8. Full GMO Risk assessment is only mandated
for any GTMP that is also a GMO, and who can perform the risk assessment differs dependingon the classification of the GMO. For class 1 activities, the regulations allow risk assessment
evaluation from a competent individual e.g. a Biological Safety Officer, or by a GMSC. For
class 2 activities, a GMSC is required. The Pan UK Pharmacy Working Group for ATMPs
recommends, however, that any clinical trial or unlicensed GMO GTMP is assessed by a
GMSC and that organisations consider the use of their GMSC for the introduction of marketed
GMO GTMP in the absence of any other suitable local governance committee.
For non-GMO GTMP a suitable organisational governance process is required. The use of the
GMSC is not mandated but the Pan UK Pharmacy Working Group for ATMPs recommend thatits use is considered as part of a robust local governance strategy unless another distinct
organisational committee exists for this purpose (e.g. dedicated ATMP committee).
The expertise of the GMSC may be beneficial for licensed medicines and non-GMO
investigational GTMPs, as traditional access to new drugs systems (e.g. medicinesmanagement committees) and Research and Development committees may not include
specific GTMP handling expertise and therefore will benefit from having input from the GMSC
when applying organisational medicines governance. Many organisations choose to combine
their GMSC with their ATMP committee to optimise robust governance arrangements.

4.1

Genetic Modification Safety Committee (GMSC)

Requirements and Recommendations for GMSC involvement with Clinical Trial
Investigational GMO GTMPFor GMO GTMPs there is a requirement to obtain independent competent advice on therisk assessment for GMOs. For class 1 activities competent advice can be gained froma person e.g. BSO or from the local GMSC. Class 2 activities involving GMOs require
the competent advice to be gained from the local GMSC.

www.sps.nhs.uk

10

Where a clinical trial involves an investigational GTMP the Pan UK Pharmacy Working
Group for ATMPs recommends that an organisation sets up a GMSC regardless of theclass. This recommendation is in line with HSE Genetically Modified Organisms(Contained Use) Regulations 2014 and will ensure that the organisational governanceinfrastructure is in place for all GTMPs which may require future assessment.

In order to provide the competent advice required, it is recommended that the GMSC
undertake the following:o To carry out assessment of risks to human health and the environment – theproduct, the patient and the waste pathways must be risk assessed.
o To formulate local policy in consideration of working with GTMPs, including
dealing with accidents, spillages and other incidents.
o To obtain advice on the risk assessment prior to contained use commencing fromthe organisation’s biological safety officer (if one is appointed), or designated‘competent persons’. Some organisations may delegate BSO duties to thecommittee as a whole via the representation of staff appointedto the GMSC.
o To notify HSE before starting a contained use with GMOs, as appropriate.
o To ensure adherence to safety principles and application of appropriate
containment and control measures.
o To ensure HSE are notified when accidents/incidents occur.



If the product is a licenced medicinal product within the EU, then the product is exempt
from the majority of Genetically Modified Organisms (Contained Use) Regulations 2014,
other than Schedule 18 (principles of occupational and environmental safety).

4.1.1 GMSC Membership
The suggested GMSC membership includes the following groups:

Representatives of various technical disciplines and professions, representing
management and employees, and health and safety. Individual representatives cancover multiple membership roles.
Suggested membership roles:
o Trust biological safety officer/Adviser (if appointed)
o Local biological safety officers (if appointed)
o Health and Safety
o Governanceo Staff representatives (can be local biological safety officers)o Consultant Microbiologist/ Virologist/Infectious diseases (suggested Chair)o Occupational Healtho Senior Pharmacist (e.g. ATMP, Aseptic, clinical trial)o Senior Nurseo Infection Control representative (can be covered by Consultant Microbiologist/
Virologist/Infectious diseases)o Management representativeo Technical expert
o Estates representative (waste)www.sps.nhs.uk

11

4.1.2 Establishing a GMSC
Organisations should set up a GMSC in line with the HSE GMO guidance to fulfil theHSE[7] and pharmacy governance requirements[6] to advise the medicine management andtherapeutics committees on the implementation of GTMPs.
The following needs to be considered when setting up a GMSC:










Membership
Chair
Deputy Chair
Terms of Reference
Statutory notification of premises to HSE first use of premises for genetic
modification activities
Subsequent notification of projects to HSE as appropriate (class 2 or above)
Risk assessment documentation
Regular meetings, agendas, minutes
Organisational structure and governance e.g. subcommittee of clinical governance orhealth and safety committees.

4.1.3 GMSC Terms of Reference
The GMSC needs to have Terms of Reference (ToR). An example can be found in Appendix
3. The ToR must state the institutions that the GMSC advises. There can be a writtenagreement in place to confirm that arrangements are in place for one organisation to advise
another organisation using a shared committee.

4.1.4 GMSC Responsibilities
The GMSC has the following roles and responsibilities. These need to be documented in thelocal Terms of Reference:









Coordinate communication with HSE for GMO activities
Risk assessment review for gene therapy studies:o Assess risk to human health and safety to environmento Containment and control measureso Classification of organism
o Ensure written SOPs in place
Approval of premises as being suitable for the proposed activities
Review of facilities for preparation, handling, and administration
Approval of SOPs and training
Approval of projects e.g. clinical trials or studies with appropriate controls in place
Advise Medicine Management Committee on licensed GTMPs

www.sps.nhs.uk

12

4.1.5 GMSC Risk Assessments
The documentation of the risk assessment should be co-ordinated by the local clinical trial
principal investigator prior to presentation for review by the GMSC. Information to support therisk assessment will involve other healthcare professionals depending on the nature of the
GTMP.
If as recommended by the Pan UK Pharmacy Working Group for ATMPs, the organisation
decides to use the GMSC as part of their licensed medicine governance process (see Section4.0) the risk assessment should be co-ordinated by the treating consultant clinician.
An example of a risk assessment template can be found in Appendix 2.
4.1.5.1 The Pan UK Pharmacy Working Group is developing a collaborative process tofacilitate consistent pharmacy information in GMSC risk assessments. A link will be added tothis document when it is available.

4.1.6 General Information
Schedule 5 of the Genetically Modified Organisms (Contained Use) Regulations 2014 `requires that suitable and sufficient assessment of the risks to human health and theenvironment be carried out prior to any activity involving genetic modification of microorganisms taking place. A full risk assessment may have been carried out for thedevelopment and production of the material by the manufacturer. This will be an importantsource of information and should be used as a basis for the risk assessment required for the
local activities. It will still be important, however, to generate a suitable and sufficient local
risk assessment. Those members of staff completing risk assessments should have theappropriate knowledge of processes involved to be able to correctly classify the activity. The
aim of a risk assessment is thus to identify the hazards, to estimate the severity andlikelihood that the hazards will lead to actual harm, identify control measures required andhow they should be implemented to mitigate any hazards and assign an activity
classification. Through the risk assessment, the risks to human health and theenvironment from an occupational and environmental safety perspective can beestablished.
The risk assessment should be divided into the three separate, but overlapping,pathways[8]:The product pathway:o the properties of the GTMPo receipt and storage of the GTMPo preparation of the GTMP for administrationo transport and containment of the GTMP
o criteria for patient discharge post-trial
o GTMP tracking system – from receipt through to destructionwww.sps.nhs.uk

13The patient pathway:o administering the GTMPo patient handling and emergency procedureso sampling and monitoring of shedding (if required)o interactions with other patients and staff, visitors and familyThe waste pathway (see also 8.3.4)
o stages at which contaminated waste is generatedo transport and containment of wasteo inactivation and disposal

In completing the risk assessment, it is recommended that the following areas are considered,and it may be useful to refer to Schedule 8 of the Genetically Modified Organisms (ContainedUse) Regulations 2014:


Spillage
Staff training and competence

A person responsible for contained use should retain the risk assessment for at least 10 years
from the date the contained use stops. There should be review of the risk assessment after
implementation and in the event of significant change to any of the processes covered.
Therefore, the assessment should be considered as a living document which requires to be
kept up-to-date and contains sufficient information for people involved in the activity regarding
risks and controlled measures required.
There is no statutory format for the risk assessment as each occasion may requiremodification
to ensure all relevant data is gathered. However, the guidance provides an example of atemplate that is suitable to guide the applicants and wider team through the thought process
required to complete the form (see Appendix 2).
As the HSE do not review individual product risk assessments, granting authorisation falls tothe local GMSC. In completion of the risk assessment, the applicant should avoid one word
answers e.g. “yes” or “no”, lack of justification, explanation or detail. Failure to adequately
assess the impact on staff or the environment is a common issue that will result in a delay ingranting authorisation by the local GMSC to handle GTMPs.

4.1.7 Notifications
It is recommended that the Chair of the GMSC prepares the notification to the HSE for any
applicable unlicensed or investigational GTMP.
On the first occasion that any organisation uses a GTMP that is a GMO, the HSE premises
notification form - notification of intention to use premises for contained use activities, must becompleted.
The GMSC Chair must receive an acknowledgement of receipt of the notification from the HSE
prior to any GTMP work commencing in the organisation. This is usually available within 10
days of receipt of the notification.

www.sps.nhs.uk

14

If the GMSC has deemed that the contained use does not require HSE notification via thepremises notification form (this could be because it is non-notifiable[7] due to the activity
having class 1 status only), then a summary of the risk assessment should be submitted
along with information on waste management and details of any expert advicereceived.
Subsequent notifications:Class 1 activities – do not require notification.
Class 2 activities – Schedule 10 requires that all class 2 contained uses are notified to the
HSE prior to commencement of the activity. The information requested in Schedule 6 should
be provided. Where notification of the premises has not been carried out previously, the user
can undertake class 2 contained use if 45 days have elapsed since acknowledgement ofreceipt of the notification. If the premises have been previously notified or if granted forclass 3/4 contained use, then the user may undertake class 2 contained work upon notificationof receipt.
Class 3 activities - Schedule 11 states that a user cannot undertake Class 3 activities unlesswritten consent has been granted by the competent authority. The information requested in
Schedule 6 should be provided. The competent authority must provide its decision to grant orrefuse consent within 90 days of the submission, if there has been no previous notification of
the premises. Where previous notification has been granted the HSE must review and reply
within 45 days prior to commencement of any subsequentwork activities.
Class 4 activities – as Class 3. The HSE must receive notification of an intention to handle
class 4 GMMs 90 days before work is due to begin and at least 45 days prior tocommencement of any subsequent work activities.
On occasion if patients take the GMO home, their addresses may also be required to be
notified to the HSE – the organisation/sponsor must have discussions with the HSE to ensure
patient confidentiality and that these details do not appear on the public register.
https://www.hse.gov.uk/biosafety/gmo/notifications/what.htm

4.2

Considerations for non-GMO GTMP Governance

Where an organisation prefers not to convene a GMSC for non-GMO GTMPs, an alternative
local governance process is required to ensure that all aspects of medicines management(clinical, operational and financial) governance are knowledgeably considered.
In practice, the regulatory knowledge in this area is evolving and often the classification of nonGMO GTMPs may not be clear in clinical trial protocols and investigator brochures.
Pharmacists must find out from the Sponsor whether the medicine is considered to be abiological and therefore classed as a gene therapy medicinal product. If it is, then thisguidance applies.

www.sps.nhs.uk

15

Part 2 Operational
The following guidance should be applied once governance approval has been granted for the
implementation of a GTMP within the organisation.

5.0

Receipt and storage

5.1 In vivo (non-cellular) GTMP
Operators must always wear appropriate personal protective clothing when removing the
GTMP from the container in which it is delivered. In case of damage to the product integrity
action to be taken must be defined locally for each product in line with the appropriate waste
management risk assessment.
The Pan UK pharmacy working group for ATMPs recommends that GTMPs should be storedcorrectly and securely at an appropriate temperature. This temperature should be monitoredwith calibrated equipment continuously with suitable arrangements in place for dealing withexcursions at all times.
Where cold storage at -80 degrees centigrade is required, it is recommended that the in vivo
GTMP should be stored within a freezer in the pharmacy department. A dedicated locked
freezer is the preferred arrangement however a separate shelf within a designated freezer may
be acceptable. Appropriate temperature monitoring systems with audible and visual alarms toalert staff of out-of-specification situations and accompanying monitoring procedures should be
implemented.
If it is necessary to store the product outside of pharmacy, it is recommended that a risk
assessment is carried out to ensure that the same standard of storage and temperaturemonitoring is carried out as for storage within the pharmacy department. Storage locations
must be inaccessible to unauthorised personnel and must not pose a risk of undue exposure orenvironmental hazard.
5.2 Ex vivo (cellular) GTMP
Where cellular GTMPs are provided ready to administer or simply requiring a thaw and aredelivered in a shipper that is validated for storing at the correct temperature for the timerequired prior to administration, then pharmacies may be the most appropriate location toreceive, thaw and issue where stability allows, or to receive and issue prior to thaw in theclinical area.
Where any complex preparation/assembly or manipulation steps are required, then a decision
re’ the most appropriate local aseptic facilities, which may be found in a local or third party
stem cell laboratory, is required (See Figure 8).

www.sps.nhs.uk

16

If it is necessary to store the product outside of pharmacy (e.g. vapour phase nitrogen storage
tanks), it is recommended that a risk assessment is carried out to ensure that the same
standard of storage and temperature monitoring is carried out as there would be within apharmacy department. Storage locations must be inaccessible to unauthorised personnel andmust not pose a risk of undue exposure or environmental hazard. A technical agreement
should be considered and the principals for consideration are detailed in this document which
is limited to licensed ATMPs, however, the principals can be applied to unlicensed andinvestigational products: TA-for-Outsourced-Storage-for-Marketed-ATMPs-v2.pdf (sps.nhs.uk)
6.0 Gene Therapy Medicinal Product Preparation
The Advice for Chief Pharmacists on Advanced Therapy Medicinal Products (February 2017)
stated that the decision tree below should be used to establish location for ATMP preparation.

Figure 3 Technical Feasibility Process[6]www.sps.nhs.uk

17

When specifically considering GTMPs it is important to supplement the general principles
above with further detail, including an understanding of the definition of “preparation”.
•••

Preparation is the process of making the product ready-to-administer.
Often referred to as reconstitution activity.
Reconstitution can occur either in a clinical area or in aseptic facilities.

Further specific advice is found below in relation to GTMP.
In VIVO – non cellular preparation GTMPs can be reconstituted within pharmacy. Facility
requirements are described in Section 6.1
Ex VIVO – i.e. cellular GTMPs require preparation by operators skilled in handling cellular
products. The existing pharmacy aseptic workforce will not be able to handle these products.
Facility requirements are described in Section 6.2.
It is recommended that, where possible, a dedicated cleanroom within an aseptic unit or aseparate modular unit is used for the manipulation of ex vivo GTMP.
However, in the absence of such a facility, the flow charts below provide pragmatic guidanceon an acceptable approach to the suitability of available locations. It should be noted howeverthat the flow charts below should only be applied in the absence of any specific preparation
location instruction in either the SmPC, clinical trial protocol, clinical trial pharmacy manual,
stem cell lab manual or commissioning guidance.

www.sps.nhs.uk

18

6.1 Preparation and handling of in vivo (non-cellular) GMO GTMPs

Figure 4 GMO GTMP Preparation Location – non-cellular

It is recommended that where possible an in vivo GTMPs (both GMO and non-GMO) is
handled and prepared in pharmacy departments to minimise the risk of environmental
contamination, product microbial contamination and medication errors.

www.sps.nhs.uk

19

6.2 Preparation and handling of ex vivo (cellular) GMO GTMPs

Figure 5 GMO GTMP Preparation Location – Cellular
The manipulation of cellular/tissue-based medicines requires skilled operators who are trained
and understand the risks associated with handling a living product. It is therefore likely that themost appropriate operators will not be pharmacy aseptics operators. As advised in the Advice
for Chief Pharmacists on Advanced Therapy Medicinal Products (February 2017)[6],
organisations should optimise the location preparation and this will be likely to involve theworkforce from a stem cell laboratory or from specialist blood and transfusion services. Where
the optimal location falls out-with Pharmacy, Pharmacist oversight of the preparation activity isrequired to ensure that all processing and handling is in line with SmPC or protocol
requirements.
Where nurses are preparing cellular medicines, organisations should ensure that they arecompetent to do so. Training in cellular handling will be required.

www.sps.nhs.uk

20

6.3 Preparation of GTMPs within aseptic facilities
Where Pharmacy aseptic units are employed to prepare GTMPs or where non-Pharmacy
aseptic units e.g. Stem Cell Labs, have been identified as the optimal location for preparation(with Pharmacy oversight) the following good practice should be applied.
Where preparation occurs within a Pharmacy aseptic unit, the Accountable Pharmacist should
assess the risks to their unit via a change control informed by the GMSC risk assessment.
The following best practice guidance should be considered.

6.3.1 Operator ProtectionPersonal protective clothing selected must be appropriate to the environmental grade of
the room used to prepare the product. Garments should be sterile and disposable.

In the event of accidental exposure, consult the relevant Summary of ProductCharacteristics or clinical trial protocol. If recommended, medical attention should besought. Document the incident on the local clinical/health and safety incident reporting
system and inform the Principal Investigator if the GTMP is an investigational medicinal
product.

6.3.2 Preparation Process
It is recommended that process maps be used as a tool to develop the aseptic preparation
process. A risk assessment should be prepared which covers:











Transfer process in and out of the cleanroom and isolator
Reconstitution process and proceduresConsumables required
Removal & disposal of components used in the preparation/ reconstitution of thegenetherapy medicine
Form of final packaging
Transport Container Labelling – biohazard sign for class 2
Stability, shelf life and storage requirements
Development of worksheets
Development of standard operating procedures
Action to be taken in event of a spillage

This dedicated risk assessment will be used to inform the wider risk assessment used by theappropriate local governance committee.

www.sps.nhs.uk

21

6.3.3 Isolator/Biological Cleaning Considerations
Antiviral cleaning agents should be used prior to preparation, in between patients and at theend of the session. Validation of surface sanitisation techniques should be carried out.

6.3.4 Waste Management

6.3.4.1 GMO GTMP waste management
The management of GTMP waste within a hospital requires multi-departmental working.
With GTMP waste, like any waste, there is a statutory duty of care which applies to everyonein the waste management chain (9). It requires all involved in producing or managing waste(i.e. every single person in the hospital) to take all reasonable measures to ensure that thewaste is dealt with appropriately from the point of production to the point of final disposal (9).
This is important for safety of staff and patients but also for environmental and sustainability
reasons.
As the GTMP has been genetically modified, the Genetically Modified Organisms (containeduse) Regulations 2014 (7) will apply and there is further information and best practiceguidance in the SACGM compendium of guidance (Part 6 is dedicated to the use of GMOs in aclinical setting) (8). However, it must be remembered that hospitals are experienced inpreventing the transmission of infections and disposal of hazardous waste and we areencouraged to be pragmatic in their approach (8).
Waste handling is dependent on class of GTMP.
Part of the GTMP risk assessment will detail the waste pathway and considers all GMMcontaminated waste, including:• stages at which contaminated waste is generated;• transport and containment of waste;• inactivation and disposal (8).
Depending on local facilities and type/volume of GMO waste generated, there are several
acceptable methods of GMO waste management, but each must be subject to local approvalby the local Genetic Modification Safety Committee (with input from the Biological Safety
Officer) and the local Trust waste management team/ waste management outsourced contract.
All GTMPs in clinical trials must be risk assessed by a GMSC. This is also recommended forlicenced GTMP (8), as waste management needs to comply with GMO regulations.

www.sps.nhs.uk

22

The HSE regulations document (7) and the SACGM compendium part 3 (8) recommend thefollowing for waste disposal:
Containment Level
Containment Measure

1

2

Inactivation of GMMs
in contaminatedmaterial and waste (7)required by validated
means where and to extent
the risk (7)required by validated
means (7)

Autoclave (8)Required on site (8)Required in building (8)Inactivation of GMMs
in contaminatedmaterial and waste (8)Required by validated
means (8)Required by validated
means (8)Table 2: GTMP waste containment (7, 8):

As detailed in the above table class 2 waste must be inactivated by a validated means
however inactivation of class 1 waste is not required if all of the following criteria are met (7):a) do not have the potential to cause harm to human health or the environment;b) must be biologically contained (e.g. possess multiple disabling mutations or restrictive
nutrient requirements that cannot be met outside the laboratory);c) do not have the capacity to establish and multiply in the environment; andd) do not have capacity to transfer genetic material to other micro-organisms (e.g. nonmobilisable plasmid) [B].
The risk assessment should conclude whether inactivation of waste at class 1 is required andthe methods for achieving this. For the purposes of the Regulations, any of the following
methods, i.e. disinfection, off-site treatment (e.g. rotaclave, incinerator), or on-site autoclave
may be considered to be validated means and comply with the Regulations. This is provided
appropriate steps are taken to confirm the efficacy of the method, the appropriate control
measures are put in place for the safe transport and storage of the waste material and theprocess is completed in a safe manner (7).
Recommended best practice for Class 2 waste is to be autoclaved in the building prior to
offsite treatment/disposal (9).
The usual waste management system should be used where appropriate for class 1 GTMPs.
Sharps and other contaminated disposable equipment must be placed in appropriate
containers (sharps bins) or yellow bags (swabs etc) for disposal. If class 2 GTMPs areautoclaved or chemically inactivated prior to disposal, it is not considered necessary in suchcircumstances for the incinerator or waste contractor to be registered under the Contained Use
Regulations.

www.sps.nhs.uk

23

Autoclaves are generally available in the microbiology department, however, if there is not one
on site, alternative means of waste inactivation should be used, for example, the use of
appropriate disinfection procedures (8). If no autoclave is available derogation may be soughtfrom the HSE as long as a validated means of inactivation is in place (8).
Alternative methods, including waste removal by waste management contractors, may also be
acceptable provided that the contractor has a license to dispose of GMO waste and a contract
with the Trust to dispose of GMO waste. The waste will have to be stored and transported in a
way that does not increase risk and aligns with HSE guidance. It is advised to discuss this with
the Trust waste manager to ensure the appropriate contracts and licenses are in place.
See Appendix 4 for an example of a waste disposal SOP for class 1 and class 2.

CAR-T cells are autologous T-cells which have been genetically modified, there are several
products licenced and NICE approved. The SmPCs for current licensed products must be
followed with local guidelines on handling class GTMP biological waste.
CAR-T cells are class 1 GMO and autoclaving of waste is not required. Class 1 GTMP waste
disposal can therefore be followed.

6.3.4.2 non-GMO GTMP
Non-GMO GTMP waste should be dealt with in line with local organisation medicines waste
policy, clinical trial protocols and the manufacturer’s guidelines.

6.3.5 Transport
GTMPs should be transported from the aseptic unit to wards and departments in closed,labelled, leak-proof containers sealed in a plastic bag or secondary leak proof container. A spill
kit to be available at all times.
Transport of GTMPs should be carried out directly to point of administration where possible.
The outer container must be labelled as “biohazard”.
Where preparation is undertaken on a different site to administration, this must be consideredin the risk assessment. An appropriate good distribution practice compliant arrangement
should be in place with assurance of chain of custody e.g. pharmaceutical courier.

www.sps.nhs.uk

24

6.4 Preparation of GTMPs within a clinical setting
If pharmacy or non-pharmacy aseptic facilities are not available to handle GTMPs, or the shelflife prevents aseptic unit handling, consideration can be given in the risk assessment tohandling them in the clinical setting. Appropriate SOPs and worksheets should be in place andapproved by appropriate pharmacy staff in line with Figures 4 and 5. It should be noted
however that Figures 4 and 5 should only be applied in the absence of any specific preparation
location instruction in either the SmPC, clinical trial protocol, clinical trial pharmacy manual,
stem cell lab manual or commissioning guidance. The organisational governance has to haveapproved non pharmacy handling in the clinical setting.
GTMPs should be issued immediately prior to preparation/administration to avoid prolonged
storage in the clinical area.
The product and label must be
preparation/administration procedures.

checkedaspernormalnursing

medicine

Protective clothing must be used as appropriate for the GTMP being handled.
Staff with appropriate training and competency levels should be assigned to the handling andpreparation of GTMP. All staff handling GTMPs should have documented evidence ofcompetency.
Roles and responsibilities assigned across multi-disciplines should be clearly documented.

6.4.1 Spillage
A spill is a potentially serious incident, even if there is no obvious accidental exposure.
Examples may include: breakage of a sample container and/ or spillage of whole vials.
Where the risk assessment has recommended that a spillage kit is required during
manipulation, transportation and administration, a spillage kit must be made available.
Suggested spillage kit contents are listed below:
1. 2x plastic aprons
2. 2x disposable gowns
3. 2 pairs of disposable gloves
4. 2x masks
5. 1x safety goggles
6. Absorbent wipes (e.g. paper towels)
7. Yellow clinical waste bag
8. Disinfectant (e.g. Virkon and water container to make 2% virkon solution, 1,000 ppm
chlorine, or 6% hydrogen peroxide).

www.sps.nhs.uk

25

6.4.1.1 Decontamination of Spillage
1. All non-essential personnel will leave the contaminated area.
2. Collect the spillage kit.
3. Staff attending the incident will wear personal protective clothing appropriate to theclass of spilled agent (disposable gown, apron, gloves - available in the spillage kit) andgoggles for eye protection.
4. Pour sufficient disinfectant onto the spill.
5. Leave for 5 minutes. Longer exposure does not increase hygiene whilst risking
damaging surfaces.
6. Use absorbent cloth/pad to absorb all the liquid.
7. Thoroughly wash the area using water. Do not use other disinfectants or alcohol, as it
is likely to cause frothing or smearing which may be difficult to remove.
8. Dry area using absorbent cloth, e.g. paper towels.
9. All waste from the spillage must be treated as appropriate for that Class in line with thewaste disposal procedure.
10. Treat affected clothes, uniform or bed linen as for infectious linen.

www.sps.nhs.uk

26

7.0

Glossary

Contained Use

The term “contained use” covers any activity involving GMOs
in which measures are taken to limit contact between them andpeople and the environment thus providing a high level ofsafety. It relates to the process of genetic modification and also
to the use, storage, transport anddestruction of GMOs.

DEFRA

Department for Environment, Food and Rural Affairs.

Genetic Modification(GM)

Genetic modification (GM) occurs when the genetic material ofan organism (either DNA or RNA) is altered by use of a methodthat does not occur in nature and achieved by one of thetechniques set out in Part 1 of Schedule 2 of the Genetically
Modified Organisms (Contained Use) Regulations 2014. The
requirements of the regulations e.g. risk assessment andapplication of control measures apply to the activity in which
GMOs are created, used or disposed of rather than thetechniques themselves.

Genetically Modified
Organism (GMO)

The organism that has been altered is referred to as a
Genetically Modified Organism (GMO)

GMSC

Genetic Modification Safety Committee

Gene Therapy

Treatment of certain disease states by the deliberate
introduction of genetic material into the cells of patients or the
deliberate introduction of nucleic acids into human somatic cells
for therapeutic, prophylactic or diagnostic purposes.

Gene Therapy
Medicinal Product(GTMP)

Any therapeutic agent which meets the WHO or HSE definitionsof gene therapy / GMO as described above. GTMPs can beclassified as GMO and non-GMO GTMPs as detailed in section
2.0.
The full regulatory definition of a gene therapy medicinal
product (HMR 2012 Regulation 2A) is:
A gene therapy medicinal product means a biological medicinal
product which has the following characteristics:(a) it contains an active substance which contains or consists of arecombinant nucleic acid used in or administered to humanbeings with a view to regulating, repairing, replacing, adding ordeleting a genetic sequence.

www.sps.nhs.uk

27

(b) its therapeutic, prophylactic or diagnostic effect relates directly
to the recombinant nucleic acid sequence it contains, or to the
product of genetic expression of this sequence.
Gene therapy medicinal products shall not include vaccines
against infectious diseases.
Genome editing
technology

See description provided in 2.2.2.

HSE

Health and Safety ExecutivemRNA

Messenger ribonucleic acid. See description provided in 2.2.1.

www.sps.nhs.uk

28

8.0

References1.

European Union (2001) Directive 2001/83/EC of the European Parliament and of the Council on
the Community Code relating to Medicinal Products for Human Use
Available at : EUR-Lex - 32001L0083 - EN - EUR-Lex (europa.eu)

2.

Catapult Cell and Gene Therapy (2022) Clinical Trials database
Available at : https://ct.catapult.org.uk/resources/cell-and-gene-therapy-catapult-ukclinical-trials-database (accessed 05 January 2024)3.

National Library of Medicine (2023) Genetics
Available at : https://ghr.nlm.nih.gov/primer/therapy/procedures (accessed 05 January
2024)

4.

Nicola Stoner “Personal Training Materials 2017”5.

Health and Safety Executive (2023) The approved list of biological agents
Available at : http://www.hse.gov.uk/pubns/misc208.pdf (accessed 05 January 2024)

6.

Specialist Pharmacy Service (2017) The Role of Pharmacy in the Successful Delivery of
Advanced Therapy MedicinalProducts Information for Chief Pharmacists
Availableat:https://www.sps.nhs.uk/articles/atmps-the-role-of-pharmacy-in-thesuccessful-delivery-of-advanced-therapy-medicinal-products-atmps-information-forchief-pharmacists (accessed 05 January 2024)

7.

Health and Safety Executive (2014) The Genetically Modified Organisms (containeduse) Regulations
Available at : http://www.hse.gov.uk/pubns/books/l29.htm (accessed 05 January 2024)

8.

Health and Safety Executive. The SACGM Compendium of Guidance
Available at : https://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp (accessed 05
January 2024)

9.

NHS England (2022) Health Technical Memorandum 07-01: Safe and sustainable
management of healthcare waste
Available at : https://www.england.nhs.uk/publication/management-and-disposal-ofhealthcare-waste-htm-07-01 (accessed 05 January 2024)

10.

Immunisation against infectious diseases “the Green Book” Chapter 14a
Available at :https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/948757/Greenbook_chapter_14a_v4.pdf (accessed 05 January 2024)

www.sps.nhs.uk

29

Appendix 1
Regulations
Genetically Modified Organisms (Contained Use) Regulations 2014
The regulations are made under the powers of the Health and Safety at Work Act 1974 andEuropean Communities Act 1972 and are concerned with the harm to human health or theenvironment that arises from contained use involving genetically modified organisms (GMOs).
The regulations state that contact with GMOs must be limited through the use of biological,
chemical and physical barriers and the risk to human health and the environment must be
considered through a risk assessment process.
Most contained use activities involve organisms which do not cause disease and are very
unlikely to survive in the environment outside the contained facility.
However, it is important to assess the risks of all activities relevant to the preparation andhandling of gene therapy medicines to ensure that all necessary controls are in place toprotect patients, staff and the environment.
Main duties under the Regulations are to:









Carry out an assessment of the risks to human health and the environment of every
contained use activity before carried out. The assessment should be reviewed andrevised as necessary and approved prior to commencing contained use.
Establish a genetic modification safety committee to advise on risk assessments.
Classify all activities according to the Regulations.
Make a notification to the competent authority before starting a contained use of with
GMOs, in respect of first use of a premises as well as ongoing.
Notify the HSE and other relevant authorities of the intention to use premises forcontained use activities and to prepare gene therapy products on an ongoingbasis.
Adhere to the safety principles and apply the necessary containment risk control
measures as defined in classification level to protect human health and theenvironment.
Design any necessary contingency plans in event of containment failure.
Notify the competent authority of any accidents.

EAHP guidance on handling of gene medicines provides specific requirements for each step inthe process from storage, dispensing and administration to the disposal of materials involved
in handling such therapeutic agents.
Clinical trials - Regulation EU No 536/2014
Medicines for Human Use (Clinical Trials) legislation 2004 as amended.
Similar arrangements regarding trial set up, management and data evaluation can be applied
to gene therapy and local processes and SOPs should be used.

www.sps.nhs.uk

30

Appendix 2
Example of a GMSC Risk Assessment
RISK ASSESSMENT FOR HANDLING OF GENETICALLY MODIFIEDMICRO-ORGANISMS FOR GENETIC MODIFICATION SAFETY COMMITTEE (GMSC)SECTION 1
Basic Information
Project Title
Trial Organisers/Sponsor
Principle Investigator (PI)PI Address
PI Telephone
PI e-mail
Date submitted to Trust
GMSC

Does the project have
GTAC approval?
State any provisional
containment level that has
been assigned for the GM
product/activities.
(see SACGM for guidance)www.sps.nhs.uk

31

SECTION 2
Information on the proposed Investigation/trial and GMTP productThis information should be available in the risk assessment from the trial sponsor or GMTP
manufacturer.
Overview of the proposed
investigation/trial.
Full description of thevector. Include
information on the extent
to which it isattenuated/disabled.
Full description of theinsert including function.
How will the product beadministered?
Where will the product beadministered?
SECTION 3
Assessment of risk to humans
This information should be available in the risk assessment from the trial sponsor or GMTP
manufacturer.
Vector: Factors to consider include whether the recipient microorganism is listed in ACDP hazard
groups 2, 3 or 4. Other relevant factors may be the micro-organism’s mode of transmission,disease symptoms, host range, and tissue tropism as well as an indication as to whether
vaccines or chemotherapeutic agents are available.
Information should also be provided on any disabling mutations and whether there is any
possibility of any disabling mutations being complemented or reverting.
Insert: Consideration should be given to whether the inserted DNA encodes a toxin, an
oncogenic protein, an allergen, a modulator of growth or differentiation (hormone or cytokine) or
any other protein, which may result in potentially harmful biological activity. Please note that evena normal human gene may be harmful if over expressed, especially if the over expression is intissues that do not normally express the protein.

www.sps.nhs.uk

32

Risks associatedwith the vector

Risks associatedwith the insert

Is there thepotential for
genetic material to
be transferred to a
related microorganism?
(e.g. gene transfer/
recombination)www.sps.nhs.uk

33

SECTION 4
Assessment of risk to the environment
This information should be available in the risk assessment from the trial sponsor or GMTP
manufacturer.
Vector: Factors to consider include whether the recipient microorganism is capable of infecting
any plants, animals or insects in the environment and whether there is any possibility of any
disabling mutations being complemented or reverting. In particular it should be ascertained
whether the recipient micro-organism is a pathogen that is controlled by DEFRA.
Insert: Factors to consider include whether the sequence encodes an insect or animal toxin or a
product which can cause silencing of a gene encoding a crucial metabolic enzyme in susceptible
hosts.

Environmental
risks associatedwith the vector

Environmental
risks associatedwith the insert

www.sps.nhs.uk

34

SECTION 5
Nature of the work and control measures
This information should be contained in information/SOPs/risk assessment provided by thetrial sponsor or lead investigator for multicentre studies. HOWEVER, it is important to take into
account and detail local arrangements.
a) Handling of the GMTP product prior to administration.
It is strongly recommended that the Trust pharmacy is consulted when completing thissection.
Specifyarrangements forsafe receipt of the
GMTP
Specifyarrangements forsafe storage of the
GMTP
Specifyarrangements forthe safe preparationof the GMTP
Specifyarrangements for thesafe transport of the
GMTP to the site ofadministration.

www.sps.nhs.uk

35b) Administration of the GMTP.
Investigators may wish to discuss this section with the GMSC chair and/or Infection Control
and/or /Pharmacy
Identify any procedures which will
involve sharps, and specify
arrangements for their safe use
Identify any work procedures likely togenerate aerosols, and the control
measures to be applied.
Specify the protective clothing andany other personal protective
equipment to be used at each stage.
Specify the disinfectants to be used ateach stage.
Specify specific actions in the event ofan accidental spill.
Does the nature of this work preclude
it being undertaken by any workers
who have a serious skin condition(e.g. eczema) or other healthproblems that might make them more
susceptible to infection?
Specify any health surveillance
requirements for staff involved in thework.
Will potentially contaminated clinicalsamples (e.g. fluids, tissues) becollected from the patient for routine
analysis by hospital laboratories?
Specify arrangements for their safe
handling.
Is there potential for shedding of the
GMTP after administration?
If yes answer the following questions:
Will the patient be isolated following
the procedure?

www.sps.nhs.uk

36

Provide details.
Specify precautions for HCWs incontact with the patient or patient’s
body fluids.
Identify any specific precautions or
restrictions required for visitors to thepatient.
Other than standard arrangements, are
any additional safety measures orprocedures required forcleaning the patient’s bed linen orlaundry?

Other than standard hospital cleaning
procedures, specify any additionalarrangements required when cleaning
the patient’s room during and at theend of the treatment period.

Will the patient need to be transported
within the hospital following
administration of the GM product?
Identify any specific safety procedures
required for such transportation of thepatient.

www.sps.nhs.uk

37c) Management of Waste.
It is strongly recommended that the Trust Waste Officer is consulted when completing thissection.
Detail how residual/unused
GMTP will be safely disposedof.
Detail what contaminatedwaste is expected duringadministration and how thiswill be safely disposed of.
Is there potential for sheddingof the GMTP afteradministration? If so, how willsubsequent contaminatedwaste be disposed of.

d) Identify any stages of the work or manipulations of the GMTP not already covered,
which may pose increased risk, and the measures which will be applied to control thoserisks.

www.sps.nhs.uk

38

SECTION 6
Final assignment of containment measures and risk class

The following aspects of this project are assigned to class 1.

The following aspects of this project are assigned to class 2.

Each Trust will have capability approved by HSE. Where the classification is out with theapproval the HSE must be notified.

www.sps.nhs.uk

39

Appendix 3
Genetic Modification [GM] Safety Committee Terms of Reference

Title

Genetic Modification Safety Committee: Terms of Reference

History

Terms of Reference were developed in xxx for the Genetic Modification
Safety Committee
Revised version approved by Trust Management Executive Meeting: xxxx

Hospital Board
ApprovalDate

1.

Authority
1.1 The Genetic Modification [GM] Safety Committee is constituted as a sub-group of the
Hospital Infection Prevention and Control Committee (HIPCC), a sub- committee of theClinical Governance Committee, which is in turn accountable to the Trust Management
Executive. The constitution and terms of reference of the GM Safety Committee shall be
as follows, subject to amendment at future meetings of the HIPCC.
1.2 The Committee is authorised by the HIPCC to undertake duties and investigate any
activity within its terms of reference. It is authorised to seek any information from any
member of staff and all members of staff are directed to co-operate with any request
made by the Committee.
1.3 The Committee has no executive powers other than those specified in its Terms ofReference.

www.sps.nhs.uk

40

2. Purpose
2.1 The purpose of the Committee is to provide advice to the Trust on the contained use of
Genetically Modified Organisms [GMOs] within the clinical and research facilities
provided under the auspices of the Trust.
2.2 Although not a statutory requirement, the GMSC may also be convened to provide
advice regarding the implementation of gene therapy medicinal products holding
marketing authorisations, or which do not contain a GMO.

3. Membership
3.1 The Chair of the Committee has the overall responsibility for the performance of theCommittee and also has the final decision on actions required in order to comply with
the Terms of Reference.

4. Attendance and Quorum
4.1 The quorum for any meeting of the Committee shall be attendance by the Chair orVice-Chair (or a nominated deputy) and a minimum of two other people, subject to the
Chair or Vice-Chair (or nominated deputy) determining that those attending canprovide sufficient expertise, relevant to the issues which are due to be considered, forthe meeting to proceed.
4.2 All members of the Committee are expected to attend at least half of all meetings. An
annual register of attendance of members will be maintained by the Committee.
4.3 If a member is unable to attend, a nominated deputy may attend with the agreement of
the Chair. Deputies will be counted for the purpose of the quorum.
4.4 The Chair may request attendance by relevant staff at any meeting.

5. Frequency of meetings
5.1 Meetings of the GM Safety Committee shall be held at least annually. Other meetings
may be held at the discretion of the Chair.

6. Specific Duties
6.1 To consider risk assessments for new activities for the contained use of GMOs on
Trust premises and/or involving Trust employees, ensuring full compliance with therequirements of the Genetically Modified Organisms (contained use) Regulations 2014,
Requirements include that:www.sps.nhs.uk

41






6.2

Proper and valid assessments have been made of the risks to human healthand an Occupational Health Risk Assessment has been carried out.
Proper and valid assessments have been made for safety of theenvironment.
The criteria for classification of GMOs have been properly applied.
The premises where the activity is to be carried out have been notified to theHSE.

To consider the feasibility of conducting the activity in the premises, ensuring that: The GMOs can be stored and transported safely and appropriately.
 Appropriate measures are in place to deal with accidental spillage, waste
disposal and that accident /incident reporting and review procedures are inplace.
 Standard Operating Procedures and local rules are in place.
 Staff training needs for those involved in using GMOs have been adequately
considered.

6.3

To check that the premises have access to expertise e.g. from a local Biological
Safety Officer.

6.4

To check that other approvals have been sought and received as appropriate:





6.5

Gene Therapy Advisory Committee (GTAC)
NHS ethics committee
University or other GMSCs if appropriate
Medicines Regulator

To liaise as appropriate with the Trust’s Health and Safety Committee, and theJoint
Research and Development Committee.

7. Sub-committees
7.1

The GM Safety Committee has no established sub-committees.

8. Administrative Support
8.1

Describe administration arrangements.

9. Accountability and Reporting arrangements
9.1

Describe reporting arrangements.

9.2

Describe escalation arrangements.

www.sps.nhs.uk

42

10. Monitoring Effectiveness and Compliance with Terms of Reference
10.1 The Committee will carry out an annual review of its effectiveness and provide anannual report to the relevant local governance group detailing work in discharging its
responsibilities, delivering its objectives, and complying with its terms of reference,
specifically commenting on relevant aspects of the Board Assurance Framework andrelevant regulatory frameworks.

11. Review
11.1 The Terms of Reference of the Committee shall be reviewed at least annually by theCommittee and approved by the HIPCC.

www.sps.nhs.uk

43

Appendix 4
Example of waste disposal section of SOP
Disposal of Waste
1. Class 1 GMO waste
1.1. Class 1 waste only requires single packaging and can be collected with the usual clinicalwaste collections.
1.2. Seal all soft waste (e.g. personal protective clothing) in an United Nations (UN) approved

yellow bag OR place all waste in a yellow sealed rigid container for hard or more complex
waste. Use department traceability zip tie to identify the origin of the waste on the yellow
bag or yellow sealed rigid container. Dispose of waste immediately after use. Yellow
sealed rigid containers to be used are limb bins.
1.3. Place all sharps and used containers (e.g. empty IV fluid bags and administration sets) ina yellow lidded sharps bin.
1.4. Seal the limb bin (solid rigid container) or yellow bag and the sharps bin as soon as theprocedure is complete.
1.5. Use the Trust traceability ties for the yellow bags, sharps bin, and limb bins, and take it to

the designated waste collection point without delay.
2. Class 2 GMO waste
2.1. Inactivation via validated means via autoclave within the building. If the autoclave is on

the same site but in a different building, then a risk assessment is required to move theproduct between buildings on the same site for autoclaving.
2.1.1. See separate autoclave SOP for local area to ensure waste will be appropriately
autoclaved.
2.1.2. Place all sharps and used containers (e.g. empty IV fluid bags and administrationsets) in a yellow lidded sharps bin and seal as soon as the procedure is complete.
2.1.3. Seal all personal protective clothing, equipment and materials and in a yellow bag(a tied single yellow HTI sack) immediately after use.
2.1.4. Autoclave waste in sharps and yellow bag within the building.
2.1.5. Place autoclaved yellow bag and sharps bin in a yellow limb bin.
2.1.6. Tag the limb bin with a yellow HTI tag to identify the origin of the waste with thedepartment zip tie.
2.1.7. Take waste to waste collection point.

www.sps.nhs.uk

44

2.1.8. The limb bin will be taken directly to the main waste compound and placed it inside
a separate 770I, UN approved, all yellow wheeled bin for collection by waste
contractor.
2.2. Chemical inactivation is permitted as a validated means in non-clinical areas, e.g.
pharmacy. Chemical deactivation can be undertaken with 2% Virkon, 1,000 ppm chlorine,
or 6% hydrogen peroxide.
2.2.1. Place all chemically deactivated sharps and used containers (e.g. empty IV fluidbags and administration sets) in a yellow lidded sharps bin and seal as soon as thechemical deactivation procedure is complete.
2.2.2. Tag the sharps bin with a yellow HTI tag to identify the origin of the waste withthe department zip tie.
2.2.3.

Take waste to waste collection point.

3. GMO waste will be collected from the designated waste collection point by the Trust waste
contractor in line with Trust waste policy.
4. Clean all non-disposable items used when handling a gene therapy medicine with a viricidal
agent as detailed in product specific risk assessment or with e.g. 2% Virkon, 1,000 ppm
chlorine, or 6% hydrogen peroxide.
5. Non disposable bedlinen/patient gown should be laundered following Trust Infectious Waste
procedures.
6. All other waste will be disposed of securely as per Trust waste policy.
7. Procedure for autoclaving








Microbiology departments may require advance notice of generation of GMO waste forautoclaving. Trust documentation to accompany the waste must be completed as
appropriate.
Place sharps into a small sharps bin, closing the bin slightly to prevent spillage, but notlocking or taping.
Place the sharps bin in the yellow clinical waste bag along with all PPE and consumables/
infusion bag/ vial/ infusion lines.
Seal the yellow clinical waste bag and place into a large sharps bin, ensuring the lid is notlocked.
Wipe the outside of the sharps bin with disinfectant as specified in the agent specific SOP.
Place the sharps bin in a yellow bag and tag/label as ‘GMO infectious waste’.
The waste must be transported by suitably trained staff to Microbiology where theautoclave is situated, following a route with minimal footfall.

www.sps.nhs.uk

45