Preparation risk assessment tools for cell and tissue-based Advanced Therapy Medicinal Products (ATMPs) and in-vivo Gene Therapies.

Risks with injectable medicines

The National Patient Safety Agency introduced a methodology to determine the risks associated with preparation of injectable medicines based on a number of risk factors. NPSA Patient Safety Alert 20 was published in 2007 in response to the limited capacity for preparation of injectable medicines in Pharmacy Aseptic Units.

Many of these risk factors apply to ATMPs, however due to the nature of cell and gene therapies there are additional risks to be considered when introducing preparation of cell/tissue and gene therapy medicinal products.

Assessing risks for ATMPs

Two risk assessment templates have been developed.

Proforma 1 for Cell and Tissue-based ATMPs

Proforma 1 for preparation of Cell and Tissue-based ATMPs (including ex-vivo gene therapies e.g. CAR-T cells).

Proforma 2 for Gene Therapies

Proforma 2 for preparation of Gene Therapies, including adeno-associated virus products (such as Onasemnogene) and non-GMO GTMPs (such as mRNA).

Both templates may be utilised for marketed ATMPs, advanced therapy investigational medicinal products (ATIMPs) or unlicensed ATMPs.

ATMP governance

Organisations should have an ATMP policy.  This should include governance arrangements required to introduce a new ATMP, which for GMO Gene Therapies must include a GMSC risk assessment. The GMSC risk assessment is wider in scope than just preparation, and would be supported by the output of the specialist preparation-focussed risk assessments described in this resource.

For further details consult national guidance on Gene Therapy Governance and Preparation.

Mandatory preparation aspects

The following guidelines must be followed when considering the location for preparation.

Clinical trials

Where a Clinical Trial Protocol mandates a particular preparation method or process, this must be adhered to. Where the treatment site considers this to be bad practice (such as if the output of these risk assessments indicates high risk), they should discuss this with the Clinical Trial Sponsor. Where agreement cannot be reached, the Pan-UK Pharmacy Working Group for ATMPs may be contacted for guidance.

Marketed products

Where the SmPC for a Marketed product requires a particular preparation method or process, this should be adhered to. Where sites consider this to be bad practice discussion with the Pan-UK Pharmacy Working Group for ATMPs is encouraged to ensure a national consensus is reached.

Aseptic preparation

Where an ATMP prepared for administration has sufficient shelf life to permit preparation in suitable aseptic facilities, it should be prepared in facilities under the remit of Assurance of Aseptic Preparation of Medicines inspections by Regional Quality Assurance Specialists.

Undertaking a risk assessment for preparation of ATMPs

Risk assessments should be conducted when new ATMPs are introduced, or when there are changes to the handling, storage, or preparation requirements for established ATMPs.

When considering the introduction of a new ATMP:

  • risk assess individual ATMP preparation requirements to aid in determining the most appropriate preparation location (proforma 1)
  • a pharmacist and a senior clinical practitioner or specialist in ATMPs should carry out the risk assessment

Before undertaking the risk assessment, refer to national guidelines on institutional readiness for implementation of the relevant type of ATMP, Summary of Product Characteristics, Product Handling Manual or Pharmacy Manual as appropriate.

Using the relevant template:

  • determine the risks associated with each Risk Factor
  • tick all factors that apply
  • add all risk scores together
  • calculate an overall risk rating using the limits stated

Multi-component ATMPs

For multi-component ATMPs, assess each component separately and add all scores together.

In this scenario, do not double-count individual risks, for example:

  1. complete the whole risk assessment for component 1
  2. only complete additional risks for component 2 (likely to be sections 3, 5, 8 and 9 from the cell and tissue-based risk assessment)
  3. repeat this for all components and add all scores together to determine the overall risk score (existing limits apply)

Evaluating risk

Where the calculated risk rating is medium or high on completion of initial risk assessment, identify risk reduction strategies and record the new scores assuming successful introduction of these strategies. Note that it may not always be possible to reduce the score. Where the risk mitigation actions have been identified in the course of the risk assessment, these must be implemented before receiving the ATMP.

Where the mitigated risk score remains high, and cannot be reduced further, residual risks must be accepted by the organisation and recorded in the organisation’s risk register.

Example of risk reduction strategies

Risk reduction strategies have been suggested to minimise risks with ATMPs.


Provide essential general training on ATMPs and for individual ATMPs including:

  • the management of spills
  • waste pathway
  • technical information
  • written procedures including guidance on how to prescribe, prepare and administer

Ensure that cellular products are only administered by appropriately trained or accredited staff.

Standardise practice

Ensure Standard Operating Procedures (SOPs) for administration are in accordance with SmPC or IMP manual. Manufacturers or sponsors may have specific requirements.

Ensure national Pharmacy Institutional Readiness Checklists for ATMPs are incorporated into local guidance and SOPs.

Use ready-to-administer products

Provide ready to administer products where possible. If it is not possible to provide a ready-to-use product to the clinical area, consider the following:

  • use closed systems for preparation
  • provide worksheets for preparation in clinical area (discuss with manufacturer/trial sponsor)

Note that some products are not suitable for preparation in clinical area due to class and containment requirements (this will be identified in the GMSC risk assessment).

Rationalise products

If possible, simplify and rationalise the range of ATMPs available so that staff become familiar with processes.

Ensure stock management

Products must be labelled appropriately to ensure product and expiry check can be performed and patient chain of identity is maintained. Chain of custody must be documented; this is especially important for autologous ATMPs.

Arrange administration time

For ATMPs that have stipulated infusion times and rates ensure that the SmPC/IMP manual is followed. Ensure the patient is ready and cannulated prior to preparing the product. For some products, the use of an infusion pump or syringe driver may be inappropriate

Unlicensed medicines policy

For unlicensed ATMPs follow trust procedures for unlicensed medicines to ensure scrutiny and governance. Provide locally approved protocols that clarify approved unlicensed and ‘off-label’ use

Ensure accurate dose calculation

Provide dose calculating tools, for example, dosage charts for a range of body weights that eliminate the need for dose calculations. Utilise dose worksheets and guidance provided by sponsor that minimise the necessity for calculations. Ensure any transcription of pre-determined or pre-calculated doses from sponsors are double checked.

Use digital systems

Consider the provision of electronic prescriptions, stickers and worksheets. This will help ensure that information on the prescription about preparation and administration of high-risk products is clearer

Independent second check

Use double-checking system, an independent second check from another practitioner and/or the use of dose-checking software in ‘Smart’ infusion pumps and syringe drivers where appropriate.

Document process

Use an infusion monitoring form or checklist. This will help to ensure that infusions are monitored throughout administration. Ensure the form captures all relevant information, such as thaw start and finish times, bedside credential checks, water bath temperature at thaw, infusion start and finish time, etc.

Ultra-low temperature requirements

If product is transported on dry ice or in dry nitrogen shipper, ensure staff are trained in the use of ultra-low temperature shipments and local policies allow receipt in the area.


Where services are outsourced ensure technical agreements are in place which cover the proposed activity.

Non-ATMP injectables

For non-ATMP injectables, consider risk reduction methods outlined by NPSA Appendix 1 Injectable Medicines Risk Assessment Tool.

Risk assessment templates

Proforma 1: Preparation risk assessment tool for cell and tissue-based ATMPs

Risk assessment template for cell and tissue-based ATMPs. This tool can be used for marketed, clinical trial (IMP) or unlicenced ATMPs.

Proforma 2: Preparation risk assessment tool for in-vivo gene therapy ATMPs

Risk assessment template for in-vivo gene therapy ATMPs. This tool can be used for marketed, clinical trial (IMP) or unlicenced ATMPs.


This risk assessment tool may evolve over time and your feedback is welcome.

Contact us with suggestions.

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