Pharmacy Institutional
Readiness for Exagamglogene
autotemcel (Casgevy®):
Checklists for Pharmacy
Services
Guidance for Chief Pharmacists

Pan UK Pharmacy Working
Group for ATMPs
Written by:
Bahareh Amirloo
Lead ATMP Pharmacist, Manchester
University NHS Foundation Trust
Raakhee ShahLead Pharmacist for Haematology, HSCT
& ATMP, University College London
Hospitals NHS Foundation Trust
Edited by:Anne BlackRQA Specialist Pharmacist
SPS
August 2024
Version 1

The first stop
for professional
medicines advice
1Pharmacy Institutional Readiness for exagamglogene autotemcel(Casgevy®) – an ex-vivo non-GMO Gene Therapy Medicinal Product
Guidance for Chief Pharmacists
1.

BackgroundCasgevy® is classed as an Advanced Therapy Medicinal Product (ATMP). It is subclassified as a nongenetically modified organism (non-GMO) Gene Therapy medicinal product. Therefore, Chief
Pharmacists are required to ensure that governance arrangements in line with the safe and secure
handling of medicines are in place to manage this medication within their organisations, as
recommended by the SPS document titled “The Role of Pharmacy in the Successful Delivery of
Advanced Therapy Medicinal Products Information for Chief Pharmacists”. Similar to any otherautologous product (i.e. medicine which is manufactured using patient’s own cells), it is paramount thatchain of custody is maintained to ensure that the correct patient receives the intended product.
Casgevy® is the world’s first CRISPR–Cas9 gene editing therapy, which aims to cure sickle cell disease
and transfusion-dependent β-thalassemia. This cellular therapy consists of autologous CD34+ humanhaematopoietic stem and progenitor cells edited by CRISPR/Cas9-technology. The guide RNA enables
CRISPR/Cas9 to make a precise DNA double-strand break at the critical transcription factor binding site
(GATA1) in the erythroid specific enhancer region of the BCL11A gene. As a result of the editing, GATA1
binding is irreversibly disrupted and BCL11A expression reduced (see Figure 1). Reduced BCL11A
expression results in an increase in γ-globin expression and foetal haemoglobin protein production inerythroid cells, addressing the absent globin in transfusion-dependent β-thalassemia and the aberrant
globin in sickle cell disease, which are the underlying causes of disease.

Figure 1. (A). Hematopoietic stem and progenitor cells (HSPCs) taken from the patient are modified exvivo. Subsequently the modified cellular product is infused back to the patient after conditioning regimen.
(B) and (C) CRISPR/Cas 9 precisely targets the erythroid-specific enhancer region of the BCL11A gene
resulting in reduce expression of BCL11A in erythroid lineage cells. Reduced BCL11A expression leadso an increase in HbF levels in erythroid cells in vivo, thus restoring functional tetrameric haemoglobin
complexes with α-globin in individuals with SCD. Figure taken from (Rao et al., 2024).

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2. Purpose
The purpose of this document is to outline the key areas where chief pharmacists should focus
pharmaceutical expertise prior to and during the onboarding of Casgevy®.
This document presents a flow diagram outlining a stepwise approach to implementing Casgevy®. It isfollowed by sample checklists which relate to the various steps presented in the diagram. These arepresented as appendices.
It is recognised that Pharmacy Services do not currently have the expertise to handle cellular products
and that, routinely, Pharmacy Services may not come directly into contact with the product. However, it
is important that where Pharmacy Services are not directly performing some of the outlined steps thatthe roles and responsibilities of those undertaking these steps are clearly documented in an overarching
technical agreement1 with reference made to organisational pharmacy approved SOPs. The checklists
may be used as appendices to local procedures as a way of documenting key steps or as an aid against
which to check that local procedures are comprehensive.

1 The template for a technical agreement for marketed CAR-T will be a useful guide but will require tailoring

for non GMO GTMP Casgevy® Outsourcing the Receipt, Storage, Preparation and Onward Supply of Marketed
Cryopreserved ATMPs – A Template Technical Agreement – SPS - Specialist Pharmacy Service – The first stop for
professional medicines advice3Process Flow Encompassing Points for Consideration by Chief
Pharmacists
Governance

Chief pharmacists should ensure that governance for GTMPs is documented as follows:
1. Centres will need to be able to meet the commissioning requirements set out by NHSE/SMC in order
to become a commissioned provider.
2. National clinical approval re patient selection:• An approved centre will need to understand the national processes for patient selection if
applicable.
3. Local Governance:
•

•
•
•
•

As referenced in Requirements for Governance and Preparation of Gene Therapy: Pan UK
Pharmacy Working Group for ATMPs document organisational governance prior to providing any
ATMP is advised. This may involve an ATMP Committee and/or Medicines Management
Committee. Even though there is no statutory requirement for a GTMP holding a marketing
authorisation to be approved by a Genetic Modification Safety Committee (GMSC), the Pan UK
Pharmacy Working Group recommends the use of a risk assessment process as part of a licensed
medicine governance process. Local requirements for non-GMO GTMP should be defined prior to
implementation of the product in an organisational policy.
Implementation sites will be asked to complete Commercial Agreements which can include supply
and technical quality agreements with the relevant pharmaceutical company. These will require
review by Pharmacy. The commercial agreement will often be signed by the chief pharmacist.
Due to the cost of the GTMP, local financial governance requirements may need to be documented
in an SOP as there may be a variation to routine standard financial instructions. Financial approval
processes should be defined as part of organisational governance.
A centre wishing to provide Casgevy® will define additional local governance requirements e.g.
for private patients.
Pharmacy specific process documents outlining the process for ordering, receipt and productcancellation should be drafted.

An example of a Pharmacy Governance Checklist and Clinical Pharmacist Checklist
and has been provided in Appendix 1 and 2.

Risk Assessment

A risk assessment is recommended for all GTMPs regardless of GMO or license status. Therefore, a risk
assessment should be completed for this non-GMO GTMP by the requesting clinician in collaboration with other
healthcare professionals involved in the handling and management of the product.
GMSC approval of the risk assessment is mandated for GMO IMP and ULM. Where organisations choose
not to use their GMSC for marketed and non-GMO GTMP, the risk assessment should be considered as partof the governance process to establish optimal operational implementation of the non-GMO GTMP as per Gene
Therapy and Preparation which involves assessment of the product, the patient and the waste.

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Approval of the Order• The commercial operating systems (e.g. Vertex Connects Portal) requires a pharmacist’s approval and/or
the provision of a pharmacy purchase order. Access to the portal needs to be arranged for trained pharmacy
staff to review the order and enter a PO on the portal. This will require an SOP to be defined, recognisingthat time pressures will exist, the pharmacy SOP should ensure that the process covers all governanceaspects detailed above, and any appropriate clinical verification.
• Pharmacy procurement setup should be completed for this product.
• Provisions for prescribing of the drug should be in place (i.e. design of prescription form, build on electronicprescribing system).
• Additionally, links with pharmacy purchasing systems, and prescribing systems will require definition andmay form part of this SOP or be documented separately.

An example Clinical Pharmacist Checklist covering product ordering is available inAppendix 2

Mobilisation, Apheresis and Manufacture

•
•
•
•

•
•
•

Check for relevant medication restrictions (medicines that must be omitted for a defined time period) whenplanning the apheresis schedule.
Stem cell mobilisation with G-CSF + Plerixafor (for Thalassaemia patients) or Plerixafor only (for Sickle Cellpatients) will be required prior to apheresis.
Off-label use of plerixafor should be according to the Trust unlicensed medicine policy.
Criteria for commissioning of plerixafor is covered by a separate NHS England policy.
The Apheresis centre will procure the starting material for the autologous GTMP manufacture under their local
Human Tissue Authority licence (human application).
Manufacture of Casgevy® occurs in the UK, therefore an HTA export Licence is not required.
Local site documentation should be clear that during manufacture, GMP compliance is required and that the
Qualified Person employed by the manufacturer has overall responsibility for certification of the product.

Product Receipt•

Pharmacy is responsible for overseeing and approving all procedures relating to the handling and storage of
GTMPs. Ex-vivo (cell based) GTMPs are not routinely handled in pharmacy (usually in stem cell laboratories)
but receipt, storage, preparation, and issue are pharmacy responsibilities and should be co-ordinated underpharmacy oversight.

•

An SOP for receipt of the licensed GTMP is required to include integrity of the product, labelling andtemperature compliance during transit. QP certificates/release documents detailing the dose in the vials
should be reviewed by an appropriately trained clinical pharmacist as part of product release process.

An example product receipt checklist is available in Appendix 3

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Storage•

Casgevy® must be stored in the vapour phase of liquid nitrogen at ≤ -135 °C and must remain frozen until
the patient is ready for thaw and administration.
Vials must be kept in original cartons for storage to maintain Chain of Identity until the vials are prepared
for infusion.
Continuous temperature monitoring and alarms are required. Actions in the event of an alarm should bespecified.
Deviation processes should be clarified e.g. if short period temperature out-of-specification occurs, the
SOP should state actions to be taken. Pharmacy should be made aware of any on-site storage deviations.
Details of the receipt, storage and handing must be covered in the local product specific SOP.

•
•
•
•

Conditioning Chemotherapy

•
•
•

•
•
•
•
•

Only when the GTMP has been received onsite can myeloablative conditioning start.
Check for relevant medication restrictions prior to starting myeloablative conditioning and Casgevy®
infusion.
Single agent Busulfan is used for myeloablative conditioning. The dosing regime varies and is patient
specific based on pharmacokinetics (PK) ranging from once-a-day administration to every 6 hours for four
consecutive days with dose adjusted based on PK. The dose is calculated based on body weight recorded
3-7 days before first day of busulfan administration. Please refer to the national haemoglobinopathy guidefor further information on busulfan dosing, PK monitoring and target AUC.
PK sampling times will depend on the test method and should be confirmed by the laboratory undertaking
the testing.
Myeloablative conditioning will be prepared in the aseptic unit.
Clinical pharmacist should check myeloablative conditioning regimen and confirm completion ofchemotherapy prior to GTMP administration.
Supportive care should be prescribed with myeloablative conditioning e.g., anti-seizure agents, VOD
prophylaxis, anti-emetics.
The cells are infused at least 48 hours after completion of busulfan and no more than 7 days after completionof myeloablative conditioning.

Issue & Transportation to clinical area
The SmPC mandates that preparation occurs in the clinical area. Chief Pharmacists should ensure that the
medicine is handled by trained staff. Where this is delegated e.g. to the stem cell laboratory, the Chief
Pharmacist should ensure that the following are included in the approved SOP:
• Confirmation that myeloablative conditioning is completed• Release of cell by pharmacy or with pharmacy oversight according to local governance agreements• Procedure for retrieval from liquid nitrogen tank/freezer required or reference to SOP if no different toroutine.
• Transportation on dry ice/vapour phase dewar to clinical area to ensure that vials remain at ≤-135°C.
• The product is transported by stem cell lab staff (i.e. trained staff).
• Communication with pharmacy for booking out, and billing purposes, if required.
Pharmacy checks will be documented as part of the clinical pharmacist checklist (see Appendix 2 for an
example checklist)

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Clinical Area Preparation

•
•
•
•
•
•
•

Information regarding the transfer of product to the ward and administration should be captured on the risk
assessment. A clinical area preparation checklist has been included in Appendix 4.
Handling and administration should be undertaken by trained and competent staff according to localorganisational policy.
A national preparation worksheet has been designed, outlining the step-by-step preparation instructions
for Casgevy® which may be helpful to incorporate into local systems.
Casgevy® is thawed and administered at bedside.
A dose of Casgevy® may be contained in one or more cryopreserved patient specific vial(s). When thedose consists of multiple vials, thaw and administer one vial at a time.
Each vial should be infused within 20 minutes of thaw.
Details regarding withdrawal of Casgevy® from the vial have been outlined in the SmPC.

Administration & Monitoring• The pharmacist with clinical responsibility for the patient needs to be an expert on any required premedication, concomitant medication, and post GTMP administration medication. They also need to be awareof toxicity management and contra-indicated medicines.

• Resources available include SmPC and company literature.
• The clinical subgroup of the Pan UK Pharmacy Working Group for ATMPs will endeavour to produce specificclinical guidelines where risk assessment deems it appropriate.

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Appendix 1

NEW LICENSED/UNLICENSED ATMP PRODUCTPHARMACY GOVERNANCE CHECKLISTGeneric:
Product Name
Brand Name:
Supplier
Manufacturer(If different to above)
Regulatory status

Type of ATMP
(Tick as many as apply)

Checking step
NHSE commissioned
treatment site status (licensed
only)
JACIE accreditations(For admin of immune effector cells,
allo and auto transplantation,
apheresis, cell processing)☐ Licensed☐ Unlicensed☐ Gene Therapy Medicinal Products (GTMP)- Specify the type:☐ In vivo☐ Ex vivo
Containment level (if applicable): ______☐ Tissue Engineered Products (TEP)☐ Somatic Cell Therapy Medicinal Products (sCTMP)☐ Combined ATMPs
Governance Arrangements
StatusChecker initial
Date☐ Site Selected as a site
☐ Site Not Selected as a site
☐ Not Applicable☐ Accredited☐ Not Accredited

HTA licensing status☐ Covered under current HTA
licence☐ New licence requiredlicensed issued☐ New licence requiredapplication in progressTechnical Agreement☐ Established☐ Not Established

Site qualification status by
manufacturer

Local Governance approvals(medicine management/ATMP
committee)

Trust funding process☐ Qualified (audit andinspection conducted)☐ Not Accredited☐ Approval issued☐Approval in progress☐ Application not submitted☐ Approval by othercommittees
Specify:☐ Approved☐ Not Approved8Supply agreement☐ Signed☐ In progress
Pharmacy arrangements

Checking stepNPSA ATMP risk assessment

ATMP preparation

Prescription build status on theelectronic system

Product added to Pharmacy
Ordering system
ATMP added to formulary
Pharmacy specific documents(Covering ATMP ordering, receipt,
storage, clinical check etc.)

Blueteq required*
Arrangements in place to track
the product and seek
reimbursement by medicine
finance teamPharmacist final check sign off:
Pharmacist nameand signature:

StatusChecker initial

Date☐ Completed and submitted tothe committee☐ Not Completed☐ Not applicable☐ No preparation required☐ Preparation by SCL/nursesworksheet designed:
☐ Yes
☐ No
☐ Product built☐ Request form completed
and submitted by the leadclinical pharmacist, awaiting
build☐ Request form not completed
☐ Yes
☐ No
☐ Yes
☐ No
☐ SOP covering pharmacy
process finalised☐SOP covering pharmacy
process drafted
Financial arrangements☐ Yes- Blueteq available☐ Yes- Blueteq not available
☐ No
☐ Yes
☐ No

Date:

*Blueteq will only be enabled once regional contracts have been signed off between regional commissioner andcommissioned provider.

9Appendix 2

CASGEVY CLINICAL PHARMACIST CHECKLISTPart 1: Approval/Ordering
Product Name
Supplier
Patient name
Patient Date of Birth (dd/mm/yyyy)
Patient Hospital Number
Patient NHS Number
COI ID
Checking step

Confirm/Enter details(✓)

National patient selection approval
confirmation (Patient MDT ID code)☐

BlueTeq Form A (Apheresis) completed☐

ID number:

Checker
Initials

Date

To be
Checked/completed by*PHCT------------

Patient consent documented☐

CT

Purchase order raised☐PT

PO number:-----------PH

Pharmacist check on manufacturer’s
ordering portal completed
Pharmacist final check all details
complete (Print name, sign, date)☐
Print Name

Signature and DatePH

Comments(NOTE: Record patient weight)* Pharmacist (PH), Procurement Team (PT), Clinical Team (CT)10

Appendix 2 (cont.)

CASGEVY CLINICAL PHARMACIST CHECKLISTPart 2: Mobilisation(To be completed with each mobilisation attempt)
Product Name
Supplier
Patient name
Patient Date of Birth (dd/mm/yyyy)
Patient Hospital Number
Patient NHS Number
COI ID
Checking step
Mobilisation attempt number:

Confirm/Enter details(✓)
1st / 2nd / 3rd☐

BlueTeq Form A (Apheresis) completed
ID number:

Checker
Initials☐CT
CT

CT and PH
CT

Patient weight (kg)
Blood tests checked (e.g. renal
function)☐

Mobilisation prescription prescribed☐

G-CSF counselling (if selfadministering) inc. dose & timing☐

CT and PH
CT
PH

PH

Mobilisation prescription clinicallyverified☐

Plerixafor doses ordered☐

Pharmacist final check all details
complete (Print name, sign, date)

To be
Checked/completed by*------------

Medication restrictions checked

Total number of plerixafor doses used

Date-----------Print Name

Signature and Date

PH
PH
PH

Comments* Pharmacist (PH), Clinical Team (CT)11

Appendix 2 (cont.)

CASGEVY CLINICAL PHARMACIST CHECKLISTPart 3: Myeloablative chemotherapy
Product Name
Supplier
Patient name
Patient Date of Birth (dd/mm/yyyy)
Patient Hospital Number
Patient NHS Number
COI ID
Checking step

Confirm/Enterdetails(✓)

Receive Casgevy® on pharmacy
dispensing system when receipt
confirmed by stem cell lab☐

Medication restrictions checked☐

Checker
Initials

Date

SCL, PH and PT

CT and PH
CT

Patient weight (kg)CT and PH

Blood tests checked (e.g. full bloodcount, renal & liver function, virology)☐

Myeloablative conditioning prescribed &clinically verified☐

Supportive medicines prescribed☐

Pharmacist final check all details
complete (Print name, sign, date)Teams involved*

CT and PH

Print Name

CT and PH
Signature and DatePH

Comments* Pharmacist (PH), Procurement Team (PT), Clinical Team (CT), Stem Cell Lab (SCL)

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Appendix 2 (cont.)

CASGEVY CLINICAL PHARMACIST CHECKLISTPart 4: Receipt/Release/Issue
Product Name
Supplier
Patient name
Patient Date of Birth (dd/mm/yyyy)
Patient Hospital Number
Patient NHS Number
COI ID
Checking step
Receive Casgevy® on pharmacy
dispensing system when receipt
confirmed by stem cell lab (if not alreadydone)

Confirm/Enterdetails(✓)

Checker
Initials

Date

Teams involved*☐

SCL, PH and PT

Myeloablative chemotherapy completed☐

PH to check

Patient is fit to receive Casgevy®
infusion☐

CT to confirm
PH to check confirmation

Clinically check Casgevy® prescription☐

PH to check(By checking certification of analysis,
checking the dose and matching patient
identification)☐

PH and SCL

Issue Casgevy® on Pharmacy
Dispensing system☐

PH and PT

BlueTeq Form B (productadministration) completed☐

Cells authorised by pharmacy and cellrelease communicated to the SCL

ID number:Pharmacist final check all details
complete (Print name, sign, date)CT-----------Print Name

Signature and Date

Once cells are administered to patient, file the following in the product specific folder which is kept in Pharmacy:•
Copy of certificate of analysis (if available)•
Copy of the completed cell receipt checklist (provided by SCL)•
Copy of the completed preparation and administration worksheet•
Completed copy of this checklist

Comments(NOTE: Record patient weight)* Pharmacist (PH), Procurement Team (PT), Clinical Team (CT), Stem Cell Lab (SCL)

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Appendix 3

Ex-vivo GTMP Receipt Checklist
Product Name
Patient Name
Patient Date of Birth (dd/mm/yyyy)
COI Number
Donor Identification Number
Relevant patient virology details
Supplier
Manufacturer (if different to above)
Courier Job Number (& other ref no)
Date & time received
Received by
Checking step\dataTamper-evident ties intact?
Outer
Inner

Yes / No / NA
Data

Checker
Initials

Date & time

Yes / NoYes / No

Transit data logger temperaturechecked on receipt as per
requirement

Yes / No

Data logger within specification(no alarms)

Yes / NoAll required documentation received:
Shipping log
Returns documents
Certificate of Analysis / QP release

Yes / No / NA
Yes / No / NA
Yes / No / NA

COI ID number matches

Yes / No

Patient name matches

Yes / No

Patient date of birth matches

Yes / No

Donor Identification Number
matchesYes / No

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Appendix 3 (cont.)
Checking step\dataChecker
Initials

Date &
time

Print Name

Signature

Date

Print Name

Signature

Date

Yes / No / NA
Data

Overwrap
Dose as prescribed and within range

Yes / No

Quantity received – no of vials / bags
Product integrity visual check

Pass / Fail

Products labelled correctly

Pass / Fail

Lot/batch number
Within Expiration Date

Yes / No

Storage requirements
Time and Date product placed intostorage
Storage location
Receipt documented

Yes / No

1st Check (Print name, sign, date)

2nd Check (Print name, sign, date)Completed receipt checklist sent toPharmacy

Comments

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Appendix 4

Ex-vivo Clinical Area Preparation Checklist
Process Set Up/GovernanceYes / No

Roles and responsibilities documented

Yes / NoIs the medicine a Class I Gene Therapy
or non-GMO GTMP*

Yes / NoIs the shelf life <4hrs post
thaw/reconstitution*

Yes / No

Does the SmPC or Pharmacy Manual
allow preparation in a clinical area

Yes / NoIs a Pharmacy approved Worksheet and
SOP available

Yes / NoHas the governance process approved
clinical area preparation

Yes / NoIs the clinical area appropriate forpreparation e.g., enough space for
equipment and staff members

Yes / NoAre operators trained and competentYes / NoIs a process in place for communicating
patient readiness to Pharmacy/SCL (toavoid prolonged GTMP storage in theclinical area)

Yes / No

Required PPE is available

Yes / No

Required waste container(s) available

Yes / No

Checker
Initials

Date & time

Approval
Print Name

Signature

Date*If the answer is no to either of these questions, then check that clinical area preparation is optimal.

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The Pan UK Pharmacy Working Group for ATMPs would like to thank the following people for theircontribution towards this document:
Elizabeth Davies- Consultant Pharmacist Adult Haematology, Manchester University NHS Foundation
Trust
Rabia Gowa- Pharmacy Lead - Innovative Treatments, National Specialised Commissioning
Directorate, NHS England
For further information or comments contact Anne.Black7@nhs.net.

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