Stem Cell Prepa­ra­tions

A license pursuant to Section 21a of the German Medicines Act (AMG) is required for the marketing of tissue preparations

• that are not manufactured industrially,
• whose manufacturing processes are well known in the EU,
• the effects and side effects of which are shown in scientific information material.

These include hematopoietic reconstitution stem cells derived from bone marrow, peripheral blood or umbilical cord blood intended for autologous or targeted use for a particular individual.

Ap­pli­ca­tion for Au­tho­ri­sa­tion

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Change No­ti­fi­ca­tion

Pursuant to the Geman Medicines Act (Arzneimittelgesetz, AMG), applicants and license holders are obliged to notify the Paul-Ehrlich-Institut of changes in the approval documents.

Pursuant to Section 21a ( )7 AMG, applicants and license holders are obliged to notify the PEI without delay if any changes have occurred in the information and the documents pursuant to Sectioin 21a (2) and (3) and to attach the appropriate documents. Besides, the license holder is obliged to inform the competent senior federal authority on any new or changed risks or any changes in the risk/benefit risk of the tissue preparation. Section 29 (1a, 1d, and 2) shall be applied mutatis mutandis.

"The following changes may only be performed if the competent senior federal authority has given its consent:

1. any changes in the information as to the type and duration of the use or the indications,
2. a reduction in the risks,
3. any changes in the excipients as to type or amount,
4. any changes in the pharmaceutical form,
5. any changes in the information on the collection of the tissue and the laboratory tests required for the collection,
6. any changes in the treatment or processing procedures or the testing procedures,
7. a change in the method or assuring the shelf-life or an extension of the shelf life,
8. any changes in the type of keeping or storage, and
9. for haematopoetic stem cell preparations, any change in the information on the dosage or the quantity of active ingredient."

A prerequisite is that the competent land autority (authority of the appropriate federal state) has already granted all the approvals required, when the PEI is notified of the changes. If the PEI is notified of a change which relates to a change in the manufacturing license document, a copy of the appropriate document must be submitted together with the notification of change, or submitted at a later date as soon as possible.

Change in the test for donor examination

A change in the test for donor examination for infection markers (screening and confirmation test) must be reported online by the appropriate entry in the “donor testing” database.

• In the event of a change in a test which has not already been entered in the “donor testing” database, the entry for the test must be newly created in the database indicating the manufacturer, the complete description of the test, the article or order number, and the equipment platform. Additional documents must be submitted for screening tests for HIV, HBV, and HCV, providing proof that the criteria of Guideline 98/79/EG on in vitro diagnostic devices, concretised by the required minimum standards for screening tests for donor examinations, have been fulfilled. (cf. Requirements ordererd as per 7 January 2013).
• Additional information must be given for NAT tests, if required, as described in the "Requirements for the validation and/or the routine practice of nucleic acid amplification techniques (NATs) for the detection of virus nucleic acids in donor blood".
• If a notification is made for new tests, i.e. tests not yet entered in the “donor testing” database (including a change in the version or the article number), package leaflets must be submitted for the testing of new/changed entries in the database, preferably in electronic form.

Donor Test­ing

In Vitro Diagnostic Medical Devices (IVD)

Tests for infection markers used for donor testing in the production of cellular blood components, single therapeutic plasmas and stem cell preparations for hematopoietic reconstitution must be reported for the corresponding authorisations; as well any change in these tests.

To simplify the procedure, the database “donor testing” has been established in order to be able to report these tests or changes in these tests.

All tests that fulfill the requirements of the Paul Ehrlich Institute (PEI) for donor testing will be stored in the donor testing database after appropriate testing.

Basic Requirements for IVD for Donor Screening

Test systems for the detection of infections with HIV, HBV and HCV (screening tests) must have a high sensitivity in accordance with the current state of science and technology. In addition, consistent quality must be ensured for each IVD batch. For each screening test, therefore, certain criteria must be assigned, which are recorded in a central reference documentation. This reference documentation is used by the PEI to assess the safety of blood components and haematopoietic stem cell preparations.

After the entry into force of the "Introduction of Minimum Standards for Blood Screening Tests", only those HIV, HBV and HCV screening tests may be used that meet the requirements described in the edition.

If the use of screening tests is provided for further clarification in the confirmatory test (Vote 42, Appendix B2: clarification of anti-HBc specificity with two further screening tests after a 2:1 decision, clarification HBsAg using a second HBsAg test system), tests must meet the basic requirements for IVD for donor screening.

Subsequent changes to test systems stored in the donor testing database must be reported to the PEI accompanied by appropriate documentation:

• Any changes that affect the identification of the tests (e.g., test name, catalogue number, manufacturer).

• Any changes that may affect the test performance (especially sensitivity and specificity), such as

  • Modification of the main components (antibodies, antigens, conjugates, primers, probes, reverse transcriptase / polymerase) of a test,
  • Changes in the test procedure with regard to the sample and reagent volumes, incubation conditions and washing procedures,
  • Adaptation of the tests to new device systems,
  • Changes in the limit value (cut-off),
  • Modification of the test procedure, such as altered extraction conditions of nucleic acids or altered temperature profiles,
  • NAT test execution with a larger than the validated pool size.
• Changes in the sample material (e.g., new anti-coagulants) or evaluation (e.g., introduction of a quantitative evaluation).

The documentation should contain a brief description of the changes. For changes that may affect the test performance, additional data must be submitted, which provide evidence for conformity to the requirements of the above arrangement in the graduated plan of 7 January 2013.

Requirements for NAT Tests

In-House Method

• Self-developed NAT tests,
• Modified CE-marked NAT tests that changed critical parameters (such as the extraction method).
• Donor screening with these tests is possible in both single and pool testing.

CE-Marked NAT Tests in Off-Label Use

• CE-marked NAT tests where the purpose has been changed, but which have been used conforming to the manufacturer's specifications and are not intended for donor screening by the test manufacturer (use other than specified).

  Donor screening with these tests is possible in both single and pool testing.

CE-Marked NAT Tests for Donor Screening:

• Donor screening with these tests is possible in both single and pool testing.

Database Donor Testing

by means of the donor testing database, the pharmaceutical entrepreneur must display all IVDs with which blood and stem cell donors are screened for infection markers.

Contact

Access data for the communication between the applicant and the PEI per

Email: transfusionsmedizin@pei.de

NAT Test­ing for CMV and Par­vovirus B19

Testing for Stem Cell Preparations from Umbilical Cord Blood (UCB)

The "Requirements for the validation or the routine operation of NAT for the detection of viral nucleic acids in donated blood" form the basis for the validation of the CMV-NAT (human cytomegalovirus nucleic acid amplification techniques) and the parvovirus B19-NAT.

CMV Testing

Testing Material

Wholeblood (UCB)

Since CMV can be cell-bound, plasma or serum is not optimally suited for CMV-NAT testing. UCB cells (enriched according to Ficoll gradient) would be useful as test material, but cannot be implemented due to the high sample requirements in UCB. For this reason, the test material is UCB whole blood.

Sensitivity

The NAT detection limit for CMV DNA of 500 IU / ml whole blood (UCB), relative to the individual donation, is considered acceptable according to the guideline for the production and application of hematopoietic stem cell preparations (version of the German Medical Association of 17 January 2014).

This limit can be reached with commercial, CE-marked tests as well as with the so-called in-house methods. For the validation of the analytical sensitivity of CMV-NAT, a WHO standard preparation is available: Human Cytomegalovirus (HCMV) for Nucleic Acid Amplification Techniques (1st International Standard). This standard (code number 09/162) can be ordered from the National Institute for Biological Standards and Control (NIBSC).

Diagnostic Specificity

The number of negative samples to be tested (CMV DNA negative, confirmed by another NAT method) laid down in the recommendations for the validation of the NAT for blood donation is also accepted for comparable test material due to the limited availability of UCB whole blood, e.g. whole blood or cell material from blood donors.

Parvovirus B19 testing

Testing Material

UCB Plasma

Sensitivity

The NAT detection limit for parvovirus B19 DNA of 500 IU / ml UCB plasma, relative to the individual donation, is considered adequate in accordance with the guideline for the production and application of haematopoietic stem cell preparations (version of the German Medical Association dated January 17, 2014). This limit can be reached with commercial, CE-marked tests as well as with the so-called in-house methods. A WHO standard has been available since November 2000 for the validation of the analytical sensitivity of parvovirus B19-NAT. Due to the world-wide demand for this standard, the third WHO standard has already been established (3rd WHO International Standard for Parvovirus B19 DNA for Nucleic Acid Amplification (NAT) Assay). This standard (code number 12/208) is available from the National Institute for Biological Standards and Control (NIBSC). In addition, a Parvovirus B19 genotype panel is available for NAT testing, which can also be ordered via the NIBSC (1st WHO International Reference Panel for Parvovirus B19 Genotypes for NAT based assays, NIBSC code: 09/110). This reference panel is suitable for reviewing the NAT method for the efficient detection of genotypes 1, 2, and 3a.

Diagnostic Specificity

The number of negative samples to be tested (B19 DNA negative, confirmed by another NAT method) laid down in the recommendations for the validation of the NAT for blood donation is also accepted for comparable test material due to the limited availability of NSB whole blood, e.g. whole blood or cell material from blood donors.

Mi­cro­bi­o­log­i­cal Con­trol of Hematopoi­et­ic Stem Cell Prepa­ra­tions

In extensive experimental studies, the Paul-Ehrlich-Institut (PEI) has determined the basic conditions that are suitable for a meaningful microbiological control of haematopoietic stem cells.

For this purpose, the conventional manual methods are applicable only to a very limitedextent, because, on the one hand, after addition of cells turbidity of the microbiological culture media occurs naturally, but on the other hand, turbidity is used as a parameter for bacterial growth. This problem can be addressed by the use of culture machines, because here, the production of carbon dioxide is used as a parameter for bacterial growth. The conditions for a meaningful microbiological control of haematopoietic stem cells by means of culture machines are shown in the "Statement of the PEI on the the Microbiological Control of Haematopoietic Stem Cell Preparations".