hta draft guidance on coding and import draft... · 2017-02-28 · hta draft guidance version 1...

HTA draft guidance on Coding and Import

For tissues and cells in the human application sector

HTA DRAFT Guidance Version 1 published February 2017

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About this document This guidance is intended to support establishments in the Human Application sector in preparing for the EU-wide implementation of Commission Directive (EU) 2015/565 and Commission Directive (EU) 2015/566. This guidance is in draft format, pending transposition of these Directives into UK law. If you have any feedback on its contents, you can submit this to us by email, marking the subject heading ‘HTA draft guidance on coding and import’. The first part of the document is general guidance. This is applicable to all establishments in the Human Application sector. For some subjects, specific guidance has been provided for the following subsector groups of establishments:

private tissue banks/establishments that store tissues and cells for potential future use;

commercial importers and distributors;

haematopoietic stem cell (HSC) registries and transplant centres;

tissue banks; and

establishments that procure starting material for the manufacture of Advanced Therapy (Investigational) Medicinal Products (AT(I)MPs).

This subsector-specific information is supplementary and should be read alongside the general guidance where indicated.

http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2015.093.01.0043.01.ENG

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1428582345653&uri=OJ:JOL_2015_093_R_0007

mailto:[email protected]?subject=HTA%20draft%20guidance%20on%20coding%20and%20import


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General guidance for all establishments

Two new European Directives have been put into place for the coding and import of cells for human application. These are being transposed into UK law via The Human Tissue (Quality and Safety for Human Application) (Amendment) Regulations 2017. The coding Directive will affect all HTA establishments licensed for human application through the implementation of the Single European Code (SEC). The import Directive will affect any establishment that currently is, or will in the future be, importing tissues and cells for human application.


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Introduction to the Single European Code

Commission Directive (EU) 2015/565 sets out the technical requirements for the coding of human tissues and cells through the implementation of a Single European Code (SEC). The SEC is a standardised coding system for facilitating the traceability of tissues and cells used for human application. After [the date that the UK Regulations come into force] all establishments licensed for HA will need to be aware of and use the SEC. The SEC needs to be applied to all tissues and cells before they are distributed for human application. The following guidance explains:

the different parts of the SEC;

when each should be allocated and applied; and

any exemptions which may mean you do not have to allocate or apply the SEC.

Structure of the Single European Code The SEC is made up of two sections:

1. the Donation Identification Sequence (DIS); and 2. the Product Identification Sequence.

Donation Identification Sequence The ISO country code for the England, Northern Ireland, Scotland and Wales is ‘GB’. Your tissue establishment number is a 0, followed by your 5 digit licence number. For example, if your licence number is 99999, then your tissue establishment number will be 099999. The Unique Donation Number is a unique number linked to a particular donation event.

http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2015.093.01.0043.01.ENG


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If your organisation works with more than one tissue type under a single HTA licence, you will need to ensure the donation number is unique across all tissue types that you work with. If this is not possible, please contact the HTA for further advice.

Product Identification Sequence The Product Coding System Identifier shows the coding system you have used. These are:

‘E’ for the EUTC system;

‘A’ for the ISBT128 system; and

‘B’ for the Eurocode system.

The product number is the tissue or cell product number as specified by the coding system in use. If this is the EUTC, then this will be listed in the EU Tissue and Cell Product Compendium. The split number distinguishes between tissues and cells which have the same unique donation number, product code and tissue establishment code. This should be used where one donor has donated more than one unit of tissues or cells at the same tissue establishment at one time. Finally, the expiry date is the final date when the tissues and cells can be applied in the format YYYYMMDD.

What do the terms ‘allocating’ and ‘applying’ mean? Allocation is when the DIS or SEC is formally assigned to a unit of tissues or cells using your internal traceability system. Application is when the DIS or SEC is physically recorded in accompanying documentation and/or on the tissue or cells label. The SEC needs to be applied in a format that is eye-readable although it may be used alongside other labelling and traceability systems.

https://webgate.ec.europa.eu/eucoding/



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When do the DIS and SEC need to be allocated and applied? The DIS must be allocated after procurement or after tissues and cells are imported from a third country supplier (3CS). A full SEC must be applied to all tissues and cells released for human application. There may be other situations where tissues and cells are released for circulation, for example, where tissues and cells are transferred to another establishment for further processing. In these cases, the tissues and cells must, as a minimum, have the DIS applied in accompanying documentation. In certain cases exemptions may apply. Further information for private tissue banks/establishments that store tissues and cells for potential future use Further information for registries and transplant centres working with haematopoietic stem cells Further information for establishments that procure starting material for the manufacture of AT(I)MPs

Who is responsible for applying the SEC? Although the Directive requires that the SEC be applied at the latest before distribution for human application, it may be applied earlier. Establishments may also delegate application of the SEC to a third party as long as this provision is stipulated in a written agreement. Further information for commercial importers and distributors

Can the SEC be amended once it has been applied? The DIS should not be altered once it is allocated to tissues and cells released for circulation. The only exception to this is when it is necessary to correct an encoding error. Such alterations require proper documentation. Other amendments to the SEC may be made in accordance with a documented change control procedure that ensures that only the final version of the SEC is visible on the product label at the point of release. Any changes must be properly documented, and included in all primary packaging and accompanying documentation. Changes to the primary packaging can be achieved through relabelling of the container, with the previous version of the SEC being clearly invalidated on the packaging. The new SEC must not be attached over the invalidated version of the SEC. Further information for commercial importers and distributors Further information for tissue banks


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Which coding system can I use to maintain traceability? You can use the EUTC, ISBT128 or Eurocode system to allocate and apply the SEC when required. In the event that a product code is not available in the system you normally use, you can use an appropriate code from an alternative coding system. If a product code that matches your product is not available, please use the EUTC category ‘other’ and specify the product type in the free text. The EU Coding Platform is available here: https://webgate.ec.europa.eu/eucoding/, where you can find further information on the EU Tissue Establishment Compendium and the EU Tissue and Cell Product Compendium.

Exemptions relating to the SEC

1) Same centre Article 10(3) of Directive 2015/565 outlines that the DIS/SEC do not need to be applied to tissues and cells that remain within the same centre from import/procurement to application, provided that the centre comprises a tissue establishment authorised, designated, accredited or licensed to carry out these activities. Within the same centre means that all steps from procurement/import to human application are carried out under the same responsible person, quality management system and traceability system, within a healthcare centre comprising at least an accredited, designated, authorised, or licensed tissue establishment and an organisation responsible for human application at the same location. The HTA proposes that this could include where the licensed tissue establishment and the organisation responsible for human application are part of the same Trust, but on different hospital sites, providing there is suitable DI oversight and a single quality management system and traceability system are in place. Further information for registries and transplant centres working with haematopoietic stem cells Further information for tissue banks

2) Small labels Where the size of a label is too small for the SEC to be applied in full, it may be applied in the accompanying documentation providing that it is unambiguously linked to the tissues or cells.

What arrangements are in place for tissues and cells already in storage at the point that the UK Regulations come into force? Article 10d of Directive sets out transitional period arrangements for tissues and cells that were in storage before 29 October 2016. In the UK, these provisions will account for tissues and cells placed in storage before the date that the UK Regulations come into force.



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For any tissues and cells placed into storage before [date that the UK regulations come into force]:

products that are released for circulation before the 29 October 2021 will be exempt from the obligations relating to the SEC provided that full traceability is ensured by alternative means; or

for products that are released for circulation after 29 October 2021 and for which the application of the SEC is not possible, in particular because the tissues and cells are stored under deep-freeze conditions, the small labels exemption (as outlined in article 10b 1(f)) may be used.


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Introduction to the Import Directive Importing tissue establishments are responsible for ensuring the quality and safety of imported tissues and cells. Tissues and cells must meet standards equivalent to the ones laid down in Directive 2004/23/EC. Equivalent standards means the tissues and cells are of the same safety and quality as tissues and cells procured within the EU. For example, they have been subject to the same mandatory serology testing, donor selection process and processing conditions. Commission Directive (EU) 2015/566 applies to the import of human tissues and cells, from third countries, into the EU. It applies to:

human tissues and cells intended for human application; and

manufactured products derived from human tissues and cells intended for human applications, where not covered by other Union legislation.

Tissues and cells cannot be imported into the UK, other than by a licensed importing tissue establishment. This Directive will affect all establishments licensed for human application, whose licensable activities currently include import, or who are looking to carrying out this activity in the future.

Will I need an import licence to bring to the UK material that has been procured within the EU? Outside the EU? An import licence is not required for material brought into the UK from a licensed TE in another EU country. Material should only be brought in from organisations in the EU that are licensed or accredited under the EUTCD, as implemented by the country of origin. If implementation of the EUTCD in the country of origin does not include licensing of procurement organisations, please contact the HTA for further advice. Third countries are those outside of the EU. An import licence is required to bring material into the UK from outside the EU. Further information for commercial importers and distributors Further information for registries and transplant centres working with haematopoietic stem cells Further information for establishments that procure starting material for the manufacture of AT(I)MPs

Can I import material under a third party agreement with an establishment licensed for import? No. All imports of tissues and cells from third countries must be undertaken by importing tissue establishments licensed by the HTA for the purposes of these activities. It is not possible to import material under a third party agreement with an establishment licensed for import.

http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1428582345653&uri=OJ:JOL_2015_093_R_0007


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What do the changes to the import licensing framework mean? After [the day the UK Regulations come into force] establishments will only be licensed to carry out the import of cells from outside of the EU under the terms specified in an Importing Tissue Establishment Licence certificate. This certificate will be issued by the HTA as part of an import licence. In order to be licensed for import and to hold this certificate, establishments will need to submit information to the HTA for assessment. This will include the information set out in Annex I of the Directive as well as copies of written agreements with 3CS. Written agreements must contain the information set out in Annex IV of the Directive. Establishments will need to contact the HTA for approval and may be required to submit new information prior to undertaking any substantial change in their import activities. Establishments that are licensed to perform one-off imports are exempted from certain documentary requirements. Establishments intending to undertake one-off imports should read the applicable guidance here. Establishments will also need to hold the information set out in Annex III and provide this when requested. This may be as part of a site visit inspection, or at any other time as deemed necessary by the HTA. Establishments will need to perform a self-assessment against the requirements of Annex III when applying for an import licence.

My establishment is already licensed for import. Do I need to submit a licence application under the new import Directive? The draft Regulations allow for existing import licences to transition to the new licensing framework on [the day after the UK regulation come into force] providing that the HTA has assessed the requirements of Directive 2015/566 as being met and has issued the establishment with an Importing Tissue Establishment Licence certificate as detailed in Annex II. In order to facilitate a timely transition, we anticipate asking all establishments licensed for import to submit information for assessment in advance of the new Regulations coming into force. Establishments will have to provide the HTA with the information set out in Annex I of the Directive and with copies of written agreements with third country suppliers; written agreements must contain the information set out in Annex IV of the Directive. Establishments will also need to carry out a self-assessment against the requirements of Annex III and to submit a copy of this self-assessment to the HTA. The HTA will need to have assessed this information as being suitable in order for an establishment to continue to be able to carry out import activities after [date the UK Regulations come it force]. All importing establishments, that have provided the HTA with sufficient evidence of compliance with Directive 2015/566, will be issued with an Importing Tissue Establishment Licence certificate that is effective from [the day that the UK Regulations come into force].


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The HTA will provide further guidance on the submission process and timeframes for the import transition following the consultation.

Who is my third country supplier? The term ‘third country supplier’ (3CS) refers to a person in a third country who has an agreement with an importing licence holder for exporting tissues or cells intended for import into the United Kingdom for human application. Further information for private tissue banks/establishments that store tissues and cells for potential future use Further information for registries and transplant centres working with haematopoietic stem cells

Exemptions

What is the one-off import exemption? A one-off import is the import of any specific type of tissue or cell for an intended recipient(s), known to the importing tissue establishment and the third country supplier before importation. These types of imports will be exempt from the requirements of documentation and written agreements set out in Annex I, Part F. They should, however, only be carried out by licensed importing tissue establishments that have been issued with an Importing Tissue Establishment Licence certificate that includes one-off imports within its scope of activities. Establishments looking to apply the one-off import exemption should contact the HTA for further advice.

https://www.hta.gov.uk/make_an_enquiry


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Guidance for private tissue banks or establishments that store tissues

and cells for potential future use

Single European Code

Will I need to apply the SEC to tissues and cells procured, processed and stored in the UK? Tissues and cells banked for potential release for human application [under the Quality & Safety Regulations] without further manipulation – cord blood units Private tissue banks will need to apply the full SEC to products prior to distribution for end use for human application. This is most likely to apply to cord blood units.

For products that are going to be stored frozen, establishments may wish to consider applying the SEC prior to storage.

Where this is not the case, the HTA expects establishments to have a documented and validated process in place to ensure that the SEC will be applied in full on the label of the product concerned in an indelible and permanent manner, at the latest before its distribution for human application. Certain tissues and cell types that are banked privately will only ever be released as a starting material for the purposes of AT(I)MP manufacture – for example cord tissue, dental pulp and adipose derived cells Establishments do not need to apply the full SEC to tissues and cells that are procured as a starting material for AT(I)MP manufacture. Instead, a DIS has to be allocated after procurement and applied in the accompanying documentation prior to release. Establishments that procure starting material for the manufacture of AT(I)MPs will have ‘other’ listed as a tissue category on the TE Compendium, with clarification of the tissue type and the statement that it is procured as a starting material for the manufacture of an AT(I)MP. Return to general guidance

Importing tissues and cells

Who is my third country supplier? For the purposes of private tissue banking, a partner organisation that is responsible for client management, providing information and seeking consent, or supplying procurement kits to clients may be considered a 3CS. This is the HTA’s preferred model. Where the UK establishment has a direct relationship with the client in a non-EU country then the client may be considered to be the 3CS for the purposes of the import Directive. If this applies to your establishment please contact the HTA for further advice. Return to general guidance


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Guidance for commercial importers and distributors


Who is responsible for applying the SEC? For material imported from outside the EU, importing tissue establishments should ensure that the SEC is applied to imported tissues and cells. This can be done by applying the SEC themselves. Alternatively, it can be delegated to a 3CS as part of the terms of their written agreements. Further information for importers that act as brokers Return to general guidance

Will I need to apply the SEC to frozen products? Importing tissue establishments (ITE) may routinely receive frozen products into their establishments from a 3CS. Where this is the case, ITE should have a process in place to ensure that it is able to apply the SEC to these products.

One way in which this could be achieved is by the 3CS applying the SEC on behalf of the ITE, prior to the product being frozen. Such arrangements should be included in any contractual arrangements with the 3CS. Return to general guidance

Importing and Brokers

Will I need an import licence if I act as a broker? An Importing Tissue Establishment (ITE) is an organisation based in the UK which holds an HTA licence for import. The ITE will be party to a contractual agreement with a third country supplier for the import of tissues and cells. The ITE will also be responsible for ensuring the quality and safety of tissues and cells are equivalent to those procured within the EU. An organisation offering brokerage services will normally be considered to be an importing tissue establishment if:

it is party to a contract with a 3CS; and

it has responsibility for verifying the quality and safety of the tissues and cells.

If another organisation is responsible for ensuring the quality and safety of the imported tissues and cells, it will need to hold an import licence. Return to general guidance


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Who will be responsible for applying the SEC if I act as a broker, and the material is imported directly from the third country supplier to the end user? An organisation offering brokerage services is usually considered an ITE if it is party to a contract with a third country supplier and has responsibility for verifying the quality and safety of the tissues and cells. For material imported from outside the EU, the ITE is responsible for ensuring that the SEC is applied to imported tissues and cells. The ITE will normally be the first tissue establishment within the EU to receive the tissues or cells. If this is the case, the ITE will be responsible for allocating the Donation Identification Sequence (DIS), including the ITE’s TE code. The SEC can be applied by the ITE. Alternatively, it can be delegated to 3CS as part of the terms of their written agreements. If carried out by the 3CS, they will still need to use the ITE’s TE code.

Return to general guidance


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Guidance for haematopoietic stem cells – registries and transplant

centres


Haematopoietic stem cells procured in the UK

Will I need to apply the SEC to haematopoietic stem cells procured and distributed for end use within the UK?

where haematopoietic stem cells are procured and sent straight to the end user for immediate use without any storage, then we anticipate that these can be specified by the HTA under Article 6(5) of Directive 2004/23/EC. This means that there is no requirement to apply the SEC. However, the receiving TE should ensure that appropriate traceability of these tissues and cells is guaranteed throughout the entire chain from donation and procurement to human application;

where cord blood is sent from a cord blood bank to an organisation responsible for human application(ORHA) or end user, this should have the SEC applied. However, the SEC does not need to be applied for directed donations, which are collected and distributed directly to the ORHA, as these would be analogous to immediate transplantation;

where haematopoietic stem cells remain within the same centre, there is no requirement for the SEC to be applied; and

where hematopoietic stem cells are procured within the UK and the intention is that they will not be used for immediate transplantation, the SEC will need to be applied at the latest prior to distribution unless the cells remain within the same centre.

Haematopoietic stem cells procured outside the UK

Will I need to apply the SEC to imported haematopoietic stem cells procured within the EU?

where haematopoietic stem cells are procured within the EU and sent straight to the end user for immediate use, then the HTA anticipates that these can be specified under Article 6(5) of Directive 2004/23/EC. There is no requirement to apply the SEC;

where cord blood is sent from a cord blood bank to an organisation responsible for human application (ORHA) or end user, this should have the SEC applied. However, the SEC does not need to be applied for directed donations, which are collected and distributed directly to the ORHA, as these would be analogous to immediate transplantation; and

haematopoietic stem cells received from within the EU via a UK registry that are not intended for immediate transplantation but for future treatment will need to have the DIS allocated and applied to the accompanying documentation. If the receiving establishment distributes the cells to another establishment, the full SEC will need to be applied.


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Will I need to apply the SEC to imported haematopoietic stem cells procured outside the EU?

where peripheral blood stem cells (PBSC) or bone marrow are procured and sent straight to the end user for immediate use, then these can be specified under Article 6(5) of Directive 2004/23/EC. There is no requirement to apply the SEC;

where cord blood is sent from a cord blood bank to an organisation responsible for human application(ORHA) or end user, this should have the SEC applied. However, the SEC does not need to be applied for directed donations, which are collected and distributed directly to the ORHA, as these would be analogous to immediate transplantation; and

haematopoietic stem cells imported from a third country via a registry that are not intended for immediate transplantation but for future treatment will need to have the DIS allocated by the registry and applied to the accompanying documentation. If the receiving establishment distributes the cells to another establishment, the full SEC will need to be applied using the DIS allocated by the registry.


Exemptions

Can I use the immediate transplantation exemption? Tissue and cells which are distributed directly for immediate transplantation in the recipient may not need to have the SEC applied. The tissues and cells which may be exempt are referred to in Article 6(5) of Directive 2004/23/EC.

My establishment does not routinely apply the SEC as it operates within the same centre exemption. How do I apply the SEC for a one-off transfer of cells where the product is already frozen and the patient moves to a different facility?

In some establishments, it may not be usual practice to apply a SEC, where all activities from procurement through to human application are occurring within the same centre. Occasionally a patient within one of these centres moves to a different hospital, necessitating the transfer of tissues or cells to another licensed establishment. Where this occurs, the establishment would need to apply the SEC. This may not always be possible, for example where the product has been stored under deep-freeze conditions. As a one-off transfer is an exceptional circumstance (as opposed to a routine process), establishments may use the small-label exemption, meaning that the SEC could be applied in the accompanying documentation (rather than on the product label).

A process for how to apply the SEC should be included in any documented procedures that describe one-off transfers. Return to general guidance


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Who is responsible for allocating and applying the DIS and when? The DIS must be allocated either: after procurement; or, after import from a third country supplier by the tissue establishment responsible for the procurement or import of material, which in most cases would be the registries.

Who will be responsible for the application of the SEC if I import haematopoietic stem cells via a registry? In this instance, the registry would be considered as the importing tissue establishment and would be responsible for application of the SEC. In some cases, exemptions will apply. Return to general guidance

Import licences

Will I need an import licence if I import haematopoietic stem cells via a registry from outside the EU? If material is brought in from outside of the EU and the import of the material is controlled by a licensed registry, the facility into which the cells are being brought does not require an import licence. This is currently the case for most haematopoietic stem cell products. UK registries should contact the HTA for further advice. Return to general guidance

Who is my third country supplier? The term ‘third country supplier’ (3CS) refers to a person in a third country who has an agreement with an importing licence holder for exporting tissues or cells intended for import into the United Kingdom for human application. For example, an organisation that procures hematopoietic stem cells in a third country, and subsequently exports the cells to the UK via a registry, or otherwise, would be considered as a 3CS. Return to general guidance

https://www.hta.gov.uk/make_an_enquiry


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Guidance for tissue banks


Will the same centre exemption apply if a tissue bank has a licence at the same site as the end user? Tissue banks will not be able to apply the same centre exemption if they distribute tissue to end users outside of their traceability and governance system/establishment, even if tissues and cells are to be used at the same hospital as the premises of the tissue bank. Return to general guidance

What expiry date do I use within the SEC if the expiry date of a product changes, depending on the storage conditions? The full SEC includes an expiry date, which is defined as ‘the date by which the tissues and cells can be applied’ in the format YYYYMMDD.

For certain products, the final expiry date may be dependent on storage conditions by the end user, or may be amended if the product has been returned and then re-released. This would mainly apply to products maintained in frozen storage.

The HTA proposes that for frozen products, where it is not possible to define a single fixed expiry date due to it being dependent on storage conditions by the end users, the expiry date within the SEC may be given as 00000000.

Any details of expiry date that are dependent on storage by the end user, or release conditions, may then be recorded, and/or amended separately, according to the establishment’s usual processes.

Alternatively, if an establishment anticipates that it may need to amend the SEC on certain products once applied, it should have a documented and validated process in place to do so.



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Guidance for establishments that procure starting material for the

manufacture of AT(I)MPs


Will I need to allocate and apply the DIS to material used as starting material for an AT(I)MP? If tissues and cells are procured as starting material for the manufacture of an AT(I)MP, a DIS has to be allocated after procurement and applied to the accompanying documentation prior to release to the manufacturing site. Establishments that procure starting material for the manufacture of AT(I)MPs will have ‘other’ listed as a tissue category on the TE Compendium, with clarification of the tissue type and the statement that it is procured as a starting material for the manufacture of an AT(I)MP.

Will I need to apply the full SEC to a product classified as an AT(I)MP? No, the full SEC should only be applied to tissues and cells products released for human application under the Quality & Safety Regulations. Return to general guidance

Import licences

Will I need an import licence to bring to the UK starting material for an AT(I)MP from inside the EU? Outside the EU? The EUTCD and Directive 2015/566 cover the donation, procurement, testing and import of human tissues and cells, that are to be used as starting material for AT(I)MP manufacture. An HTA licence for import will be required if tissues and cells are imported into the UK from a third country as starting material. An import licence is not required for starting material brought to the UK from inside the EU, as long as material is brought in from organisations in the EU that are licensed or accredited under the EUTCD, as implemented by the country of origin. If implementation of the EUTCD in the country of origin does not include licensing of procurement organisations, please contact the HTA for further advice.

Will I need an import licence to bring to the UK an AT(I)MP from inside the EU? Outside the EU? If tissues/cells have been manufactured into an AT(I)MP in a third country and no further manufacturing steps take place before clinical use apart from reconstitution, then import will


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be regulated by the Medicines and Healthcare products Regulatory Agency (MHRA), subject to the authorisation referred to in Article 13(1) Directive 2001/20/EC, cf. Article 9(1) Directive 2005/28/EC. Similarly, if partial manufacture of the AT(I)MP has already taken place in a third party country before import of the intermediate product, this will also be covered by the same legislation and its import will be regulated by the MHRA.


hta draft guidance on coding and import draft... · 2017-02-28 · hta draft guidance version 1...

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