8.1 Aims and introduction - Evaluation of novel blood components, production processes and blood packs – generic protocols

This chapter aims to describe how a proposed novel blood component, production process or blood pack is to be evaluated to:

Gain sufficient data to validate the component and production method.
Gain sufficient data to support the clinical use of the component.
Allow the Standing Advisory Committee on Blood Components (SACBC) to recommend to JPAC that the component should be included in the Red Book, either within chapter 7 as a blood component specification or within annex 3 as a provisional component specification.
Provide sufficient information to prevent all Blood Establishments (other than those performing a full evaluation) from having to complete a full validation of the novel component before it enters routine production. They will only need to undertake installation and process validation.

The steps that a group of investigators will need to undertake to submit a novel blood component for inclusion in the Red Book, thereby allowing it to be produced on a routine basis throughout the UK, are detailed below (see 8.1.1 below).

Guidance on assessing the degree of novelty of components, to be carried out prior to embarking on the process, is also given below (see 8.1.2 below).

It is recognised that some novel components may be developed by a group of investigators in conjunction with a commercial company undertaking speculative research. As a result, the group of investigators may wish to enter the process at Step 8. In this case, SACBC will expect any requirements for data collection in the preceding steps to be complied with when the protocols and reports are submitted to SACBC for consideration. If sufficient data are not included then a request for extra data will be made (Step 9).

It is also recognised that there may be a need for Blood Establishments to produce blood components for clinical use on a temporary basis. This may be to undertake a clinical study or operational assessment of a new component in order to inform the decision as to whether there is a need to manufacture the component on an ongoing basis. In such circumstances, the most appropriate course of action is to seek approval for a provisional component specification (see 8.1.3 below).

Guidance on how specific novel components should be tested is included in the following chapters:

For red cell components, see chapter 8.2
For platelet components, see chapter 8.3
For plasma components, see chapter 8.4
For plasma for fractionation for immunoglobulin manufacture, see chapter 8.5

This guidance is followed by information on generic protocols for the evaluation of apheresis equipment (see chapter 8.6) and blood packs (see chapter 8.7).

For guidance on phases of validation and sample size, please see 8.1.4 below.

8.1.1: Steps for evaluation of novel components

Step 1 - Investigators identify requirement for a novel blood component

Information

The new component may be derived from a commercially available product. In this case, data to support the submission may be derived from the manufacturer.

Investigators must critically appraise data already available.

All data must be maintained on file. Data will be used to demonstrate validation has been completed in support of Blood Establishment licensing activities. Data required may include clinical outcome.

Details

The requirement must be derived from research and development (R&D) work or as the result of clinical discussions.

The blood component needs:

To fulfil an unmet clinical need.
OR
Provide production benefit and have a Blood Service proposer.

Investigators will need preliminary data to support their application.

Step 2 - Investigators consider whether the component should be treated as novel

Investigators may obtain initial advice from SACBC. Likely degrees of novelty and clinical use of components are described in 8.1.2 below.

Information

The proposed new component may require evaluation, even if it complies with existing Red Book guidelines, if:

A new production technique is involved (e.g. leucocyte-depleted red cells produced by apheresis).
There are different steps in the production process (e.g. white-cell filtration immediately following collection).
Definitive advice about the need for full-scale evaluation will be provided from SACBC following a written submission.

Details

If yes, the component is novel: go to Step 3.

If no, the component is not novel: undertake local validation and produce the component locally under the general principles of good manufacturing practice and the Red Book (see 8.1.4 below).

Steps 3 to 7 relate to characterisation of the blood component

Step 3 - Investigators define the intended specification for the blood component

Information

Specify all key points which will allow subsequent production of the component to be well controlled.

Details

Written specification to include:

Expected characteristics (e.g. leucocyte count).
Testing characteristics (blood grouping, microbiology etc).
Sampling time, sampling method and sample handling conditions to confirm that the component meets specification.

Reference should also be made to the research papers from which the specification is derived.

Step 4 - Investigators write the protocol for component evaluation (Phase 0)

Information

Principles of good clinical and good manufacturing practice should apply. Comply with generic protocols (see 8.1.4 below and chapters 8.2 to 8.4). Laboratory studies should comply with local standards.

Must include in the procedure the sampling regimes, data analysis and expected ranges, which will be used to confirm that production of the component is under control.

Must include detail of the data analysis methods.

Details

Investigators' group writes procedures for:

component production
monitoring of performance
clinical use
outcome measurement
adverse incidents in production/use of the blood component

or uses manufacturer's documentation to produce 'in-house' protocols.

Step 5 - Investigators should ensure their protocol complies with guidance in this chapter

Investigators may seek advice from SACBC.

Step 6 - Investigators obtain ethics committee approval, if required

Must comply with local consenting and ethics policies for the use of donated material.

Step 7 - Investigators apply protocol

Information

Audit may be carried out on behalf of collaborating manufacturers even though this may be confidential regarding the data collected.

A summary outlining non-compliances against good clinical and manufacturing practice must be made available to the Blood Transfusion Service involved, for submission as part of the supporting documentation to SACBC.

Details

Document evidence of protocol being implemented.

Investigation should be subject to independent quality audit.

Steps 8 and 9 relate to obtaining SACBC listing of the component

Step 8 - Investigators submit draft component specification to SACBC for consideration

This should include validation report and supporting data.

Information

Investigators who have been conducting speculative research with a manufacturer may enter the process at this point.

This may also include data supplied by manufacturers, other Blood Services, and published studies.

Investigators should submit a draft specification for the component.

Details

Investigators review outcomes and produce a report, which summarises findings and supports the case for a new blood component to be listed.

SACBC decides if:

The blood component is novel.
The data support the ability to produce the blood component on a regular basis.
The blood component is efficacious and safe.

Step 9 - SACBC decides whether the component may be recommended for inclusion in the Red Book

Approved component specifications are published in chapter 7.

Information

SACBC may request further data in support of the submission prior to listing the blood component.

Details

If SACBC decides that the blood component will be listed, it submits this recommendation to the JPAC Board, providing copies of the data and report used to accept the new blood component.

If SACBC decides that the blood component will not be listed, it informs the submitting group and provides an explanation.

Step 10 is the responsibility of the JPAC Board

Step 10 - JPAC Board considers the recommendation to list the new component specification

Details

Notify SACBC of the decision. If not accepted, provide SACBC with detailed reasons for the decision. If accepted, notify Medical Directors and Quality Managers of the UK Blood and Tissue Services.

Include the component specification in chapter 7.

Step 11 is the responsibility of SACBC

Step 11 - SACBC communicate the JPAC Board's decision to appropriate parties

Information

Component Code Request form is available on the Blood component codes page (which also includes guidance on requesting codes for non-novel components).

Details

If accepted, inform investigators who must complete a Component Code Request form and submit to Chair of SACBC. The form is assessed by SACBC and, if approved, this request is passed to the Standing Advisory Committee on Information Technology (SACIT) to proceed with the provision of appropriate labels.

If not accepted, inform investigators with supporting reasons.

Steps 12 and 13 require input from SACIT

Step 12 - SACIT provides codes for the new blood component

Details

Code will be unique. ISBT 128/ABC Codabar will be supported.

Step 13 - SACIT provides a component label and updates the UKBTS Component Portfolio

Information

Label text will describe the key attributes of the component.

Details

Label will be unique.

Completed Component Code Request form returned to SACBC and requestor.

Steps 14 and 15 are actions for Blood Establishments

Step 14 - Blood Establishments proceed to phase 1 and 2 studies

Information

Demonstrates, without redoing the above validation, that the blood component produced is equivalent to that defined in the UK guidelines.

Details

Base procedures on those used during validation studies. Complete installation and process validation (Phase 1, see 8.1.4 below).

Step 15 - Blood Establishments produce the blood component routinely

Information

Continue to monitor production to the Red Book specification (Phase 2, see 8.1.4 below or routine quality monitoring).

Details

Confirm procedures.

8.1.2: Degrees of novelty of blood components

Guidance on assessing the degree of novelty of components prior to embarking on the process of evaluation is provided below. Degrees of novelty include:

Very high
High
Medium
Low
Standard component (therefore not a provisional specification)

8.1.2.1: Very high degree of novelty

Regulatory

Produced using medical device/process that is not CE/UKCA/UKNI marked, or covered by manufacturer's IFU.

A notice of no objection from the MHRA would be required for any trial.

Clinical data/experience

No clinical use in humans.

Extent of laboratory validation required

Extensive laboratory validation and data in relevant animal models. Likely to have to define all key critical variables that determine product quality.

Clinical use

First-in-human/phase I studies. MHRA approval required and not to be used outside of approved study.

8.1.2.2: High degree of novelty

Regulatory

Produced using medical device that is not CE/UKCA/UKNI marked, or covered by manufacturer's instructions for use (IFU).

A notice of no objection from the MHRA would be required for any trial.

Clinical data/experience

Clinical data likely to be limited to small scale studies as part of R&D, or historical use or use outside of Europe.

Extent of laboratory validation required

Extensive laboratory validation. Likely to have to further define some critical variables in product quality.

Clinical use

Likely to be a phase II/III research study. MHRA approval required and not to be used outside of approved study.

8.1.2.3: Medium degree of novelty

Regulatory

Produced using medical device that is CE/UKCA/UKNI marked, but outside of its intended use or manufacturer's IFU.

A notice of no objection from the MHRA would be required for any trial.

Clinical data/experience

Clinical data likely to be limited to small scale studies as part of R&D.

Historical/small scale clinical use or use.

Extent of laboratory validation required

Laboratory validation required guided by data to date and intended use. Likely to have to validate changes to key variables such as temperature or duration of storage.

Clinical use

Likely to be a phase II/III research study. MHRA approval required and not to be used outside of approved study.

8.1.2.4: Low degree of novelty

Regulatory

Produced using medical device that is CE/UKCA/UKNI marked within its intended use & manufacturer's IFU.

Currently no specification in Red Book or not for the usage proposed.

Likely to be a specification for product elsewhere (e.g. Council of Europe or AABB guidelines).

Use would not be precluded by content of BSQR or relevant EU directives.

Use would require local validation and approval by SACBC/JPAC.

Clinical data/experience

Not used recently in UK, or change in clinical use of an existing component.

Might be in routine use elsewhere internationally but not the UK.

Extent of laboratory validation required

Extent of laboratory work guided by nature of change to be made and any uncertainties in published data (e.g. shelf-life).

Clinical use

Use might either be considered a change in clinical practice or as part of an approved research study, to be determined based on clinical usage/data to date.

Use might be restricted in first instance to pilot sites.

Safety might be monitored through haemovigilance which might be enhanced above standard based on risk.

8.1.2.5: Standard component

Regulatory

Produced using medical device that is CE/UKCA/UKNI marked within its intended use & manufacturer's IFU.

Has approved specification in Red Book.

In routine use in the UK and manufactured to approved specification in Red Book.

Clinical data/experience

Widespread clinical experience from routine use in the UK and elsewhere.

Extent of laboratory validation required

Introduction would require local validation.

Clinical use

As per clinical guidelines.

8.1.3: Steps for evaluation of provisional components

This process should be used where it is uncertain whether there will be a requirement to produce the novel component on an ongoing basis, yet there is a need for clinical use of the component. Once approved, provisional component specifications will be posted in annex 3 of the Red Book.

The purpose of approval of a provisional component specification is to:

Ensure that there is sufficient data to support progression from phase 0 to phase 1 and 2 studies and the clinical use of the component.
Document a draft specification for the component including suitable quality monitoring parameters and testing regime for phase 1 and 2 studies.

Investigators undertake steps 1 to 7 in 8.1.1 above

Information

Seek advice from SACBC in advance with respect to validation requirements if needed.

Details

Gather Phase 0 and other data necessary to proceed to step 8.

Steps 8 and 9 relate to obtaining SACBC listing of the component

Step 8 - Investigators submit draft provisional component specification to SACBC for consideration

This should include validation report and supporting data.

Information

Investigators who have been conducting speculative research with a manufacturer may enter the process at this point.

This may also include data supplied by manufacturers, other Blood Services and published studies.

Investigators should submit a draft specification for the component.

Details

Investigators review outcomes and produce a report, which summarises findings and supports the case for a provisional component to be listed.

SACBC decides if:

The blood component is novel.
The data support the ability to produce the blood component for its intended use.
The blood component is efficacious and safe.
The specification and associated quality monitoring for subsequent phases of study are adequate.
Data support progression to phase 1 and 2 studies and clinical issue of the component.

Step 9 - SACBC decides whether provisional component may be recommended for inclusion in the Red Book

Provisional component specifications are published in annex 3.

Information

SACBC may request further data in support of the submission prior to listing the blood component.

Details

If SACBC decides that the blood component will be listed, it submits this recommendation to the JPAC Board, providing copies of the data and report used to accept the new blood component.

If SACBC decides that the blood component will not be listed, it informs the submitting group and provides an explanation.

Step 10 is the responsibility of the JPAC Board

Step 10 - JPAC Board considers the recommendation to list the new component specification

Provisional component specifications are published in annex 3.

Details

Notify SACBC of the decision. If not accepted, provide the SACBC with detailed reasons for the decision. If accepted, notify Medical Directors and Quality Managers of the UK Blood and Tissue Services.

Include the component specification in annex 3.

Step 11 is the responsibility of SACBC

Step 11 - SACBC communicate the JPAC Board's decision to appropriate parties

Information

Component Code Request form is available on the Blood component codes page (which also includes guidance on requesting codes for non-novel components).

Details

If accepted, inform investigators who must complete a Component Code Request form and submit to Chair of SACBC. The form is assessed by SACBC and, if approved, this request is passed to SACIT to proceed with the provision of appropriate labels and component code.

If not accepted inform investigators, with supporting reasons.

Steps 12 and 13 require input from SACIT

Step 12 - SACIT provides codes for the new blood component

Details

Code will be unique. ISBT 128/ABC Codabar will be supported.

Step 13 - SACIT provides a component label and updates the UKBTS Component Portfolio

Information

Label text will describe the key attributes of the component.

Details

Label will be unique.

Completed Component Code Request form returned to SACBC and requestor.

Steps 14 and 15 are actions for Blood Establishments

Step 14 - Blood Establishments proceed to phase 1 and 2 studies

Information

Monitor component against trial specification.

Details

Base procedures on those used during validation studies. Complete installation and process validation.

Step 15 - Blood Establishments produce the blood component routinely

Information

Submit report on phase 1 and 2 studies and clinical data, if relevant, to SACBC and the final specification for the component to be included in the Red Book.

8.1.4: Validation and sample size

8.1.4.1: Whole blood collection processes

For whole blood collection processes, the following testing numbers are required.

For component evaluation

Phase 0: 10 to 16 (see tables in 8.2, 8.3, 8.4 and 8.5)
Phase 1: None
Phase 2: None (see 8.7)
Local process validation: None

For quality monitoring

Phase 0: 10 to 16 (100% tested)
Phase 1: 125 (100% tested)
Phase 2: 2000 from each of two batches (minimum 1% tested or as determined by statistical process control) (see 8.7)
Local process validation: 125 (100% tested)

8.1.4.2: Apheresis collection processes

For apheresis collection processes, the following testing numbers are required.

For component evaluation

Phase 0: 10 to 16 (see tables in 8.2, 8.3, 8.4 and 8.5)
Phase 1: None
Phase 2: None (see 8.7)
Local process validation: None

For quality monitoring

Phase 0: 10 to 16 (100% tested)
Phase 1: 125 (100% tested)
Phase 2: 300 (100% tested) (see 8.7)
Local process validation: 10 for each machine (100% tested)

Last updated on 22 June 2022