Au­tho­ri­sa­tion of Blood Com­po­nents for Trans­fu­sion

Explanations, Forms and Templates for Applications

The application format complies with the Common Technical Documents under consideration of German pharmaceutical legislation. The documentation has to be put together in five modules.

Module 1: Drug Detection

• Table of contents,
• application form with enclosures,
• wording for the leaflet and technical information and for the container labeling,
• information on the experts,
• details for the bibliographic submission

Module 2: Summaries (Expert Report, § 24 AMG)

• Quality-related Global Summary,
• Preclinical Overview,
• Clinical Overview,
• Preclinical Summary,
• Clinical Summary

Module 3: Chemical, Pharmaceutical and Biological Information on Medicinal Products Containing Chemical and / or Biological Agents

• Data on development,
• manufacturing process,
• quality control,
• shelf life,
• composition,
• dosage form

Module 4: Preclinical Reports

• Investigation reports on pharmacology,
• pharmacokinetics, toxicology,
• local tolerance on the basis of animal experiments

Module 5: Clinical Trial Reports

• Results of biopharmaceutical studies,
• pharmacokinetic and pharmacodynamic investigation reports,
• post-marketing experience.

Special Considerations for the Approval of Pathogen-Inactivated Blood Components - Possibility of Reference to Preclinical and Clinical Data

Pathogen inactivation procedures are typically developed by medical device manufacturers rather than individual blood establishments. This also applies to the preclinical and clinical studies required for the approval as well as their summary presentation.

If several blood banks intend to use the same procedure for pathogen inactivation and to apply for the corresponding authorizations, it is sufficient to submit the preclinical and clinical documents provided by the medical device manufacturer (referred to here as the "central documentation for reference") with the first applicant's dossier to submit to the PEI.

Findings on preclinical and clinical data obtained after approval must be provided to the Paul-Ehrlich-Institut (PEI) by the marketing authorization holder. In addition, this information may be made available to the PEI by the medical device manufacturer or the author of the "central documentation for reference" as an update.

Attention: In applications, which are made after the announcement of these new findings, these current data must be included and evaluated.

Independent of the preclinical and clinical documentation described above, the technical documentation for the respective pathogen inactivation procedures ("central technical medical device deposit") can still be submitted centrally by the medical device manufacturers to the PEI. This means that the information required for the approval can be limited to the device name and number or the article name and number.

Changes are communicated to the PEI directly by the medical device manufacturer. Depending on the relevance for the production, the blood donation facility must be notified to the PEI as a change, accompanied by appropriate information.

General Information about the Application

All pages of the application should be provided with a header containing the name of the medicine and a consecutive page numbering.

Each of the modules must be preceded by a table of contents.

The container labeling, the user and specialist information and the expert reports must also be submitted electronically in accordance with AMG-EV. It also recommends the additional electronic filing of the flowchart, final product specification, list of equipment, collection sets, primary containers, list of infection marker tests and quality and durability data. The inclusion of work instructions (SOPs) should be avoided as any change would require a change display.
According to the publication of May 16, 2003, published in Federal Gazette No. 104 of 6 June 2003, p. 12 408, applications for authorizations of blood components for transfusion are no longer dependent on the blood group.
Further information in particular on modules 2, 4 and 5 can be found in the Notice to Applicants (Volume II B) on the websites of the Directorate-General for Enterprise and Industry of the European Commission ("EudraLex"). Specific explanations on modules 1 and 3 as well as application form (module 1.2) and sample systems are available.

Please activate the word break character in the menu bar of Word in order to be able to read any hidden text with explanatory notes in the files offered there.

Submission of Documents

The submission of documents is usually done electronically.

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Stem Cell Prepa­ra­tions (Spe­cif­ic Re­quire­ments)

In addition to the explanations "Specific requirements for an application for the authorisation of blood components for transfusion", these additional explanations are issued for an application for authorization of stem cell preparations from umbilical cord blood in order to meet the specific technical characteristics of these medicinal products.

These explanations are based on European licensing regulations. The template with the name of the medicinal product requested and the signature of the applicant should be placed before the registration documentation. Applicant is the pharmaceutical operator under whose name the medicinal product is placed on the market. The registration documents are to be structured according to the breakdowns. All pages of the application should be accompanied by a header containing the name of the medicine and a consecutive page numbering.

Please note that we assume the authorization of the cryopreserved finished medicinal product. Please provide all details of the application for the cryopreserved product.

Alternatively, thawed medicines would be authorized if you market exclusively thawed / washed preparations intended for transfusion.

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Fol­low-Up Pro­ce­dures

Authorisation Extension

Pharmaceutical companies placing these medicinal products on the market are requested to submit the following documents with the application for renewal. The documents must be submitted in duplicate in folders stapled.

1. Application form
2. A list of all changes related to the quality, efficacy and safety of the medicinal product.
3. Report according to § 31 Abs.2 AMG, which contains information on whether and to what extent the evaluation features of the drug have changed within the last 5 years. If necessary, the corresponding expert reports have to be completed.
   

For the presentation of the current pharmaceutical quality are listed:

a) drug detection

• Composition (active and active ingredients, remaining cells with indication of the reference)
• packaging size (s)
• Shelf life and storage conditions
• Containers including sets for whole blood collection and / or apheresis, apheresis device (devices, collection sets, primary containers)

b) final product specification

c) Flow chart of the preparation

d) Donor selection criteria (including donor questionnaire)

e) donor testing (List of Infection Marker Tests) and other tests to characterize the donor's blood, indicating the method

f) look back process

g) Container labeling according to § 10 AMG (also electronic)

h) Package leaflet and technical information according to §§ 11 and 11a AMG (also electronic).

If there is a donation master file, it can be referenced for the documents to d) to f).

Because blood components eliminate the ability to assess drug quality based on batch releases, the results of measuring appropriate quality parameters on samples are used to assess the consistent quality of the drug. This information should be provided in the form of a list (excel charts for platelet concentrates, red blood cell concentrates, frozen fresh plasmas, other medicinal products) of the quality control data for the previous 12 months by volume, broken down by month (including electronic).

Changes are not subject to the application for renewal. If the need arises for changes from the process, these are awarded separately.

Notification of a Variation

This refers to documents to be submitted with variation notifications subject to approval in accordance with Section 29 (2a) No. 3a and No. 4 AMG (German Medicines Act) in the event of a change in the manufacturing or testing procedure for blood components.

Changes in the information and documents in accordance with Sections 22 to 24a AMG must be reported by the pharmaceutical company without delay pursuant to Section 29 (1) AMG, stating the name of the medicinal product and the marketing authorisation number and accompanied by the appropriate documentation (exceptions are notifications of change pursuant to Section 29 (2b) AMG).. A list of documents must be provided showing the changes in a comparative table.

Changes pursuant to Section 29 para. 2a may only be implemented if the Paul-Ehrlich-Institut (PEI) has approved the change.

Notifications of variations can also be submitted electronically by e-mail to [email protected] or, if requested, via the database "donor testing". It is assumed that the respective competent Land authority has already granted all necessary permits if changes are reported to the Paul-Ehrlich- Institut.

Examples of Documents to be Submitted

• In the event of a change in the other components, documents relating to quality and shelf-life must be submitted and evaluated after production and after the end of the shelf life.
• In the event of a change in the manufacturing process (modification or introduction of a manufacturing step such as filtration, apheresis, centrifugation and separation, new blood bag systems), documentation on the changed production process and data on quality and shelf life must be submitted and evaluated, taking into account the storage and transport conditions. The assessment should include a risk assessment that also provides information on the safety and efficacy of the drug after the change.
• When using new equipment for drug manufacturing, data on the validation for the equipment should be provided and evaluated (e.g., collection efficiency, freezing kinetics, dosimetry). The assessment should include a risk assessment that also provides information on the safety and efficacy of the drug after the change. Data on the quality and shelf-life must be provided, if it cannot be demonstrated that the conditions of production remain unaltered, guaranteeing that the quality of the medicinal product remains unchanged after the change in equipment,. The same applies to the use of new / modified disposable materials.

• Changes in donor screening tests for infection markers (screening and confirmatory tests) must be reported online by en entry into the database "donor testing".

  • When changing to a test not already stored in the "donor testing" database, the test must be entered again as a new item indicatiang details of the manufacturer, the complete test name, the article number or order number and the device platform. Additionally, for screening tests for HIV, HBV, HCV, documentation must be submitted demonstrating compliance with the criteria of Directive 98/79 / EC on in vitro diagnostic medical devices, substantiated by the minimum standards required for donor screening tests (see also Order of conditions of 7 January 2013).
  • Additional information may be required for NAT testing, as described in the "Requirements for the Validation or Routine Operation of Nucleic Acid Amplification Techniques (NATs) for the Detection of Viral Nucleic Acids in Donor Blood".
  • When notifications of new tests, i.e. tests not yet stored in the database "donor testing"(including a change in version or change the article number), the appropriate package leaflets must be submitted for the purpose of checking the new / changed entries in the database preferably in electronic form.
• In the event of a change in other testing methods (such as modification or introduction of new quality control methods), documentation shall be submitted for the validation and implementation of the method.
• To extend the shelf life, quality and durability documents should be submitted, to demonstrate validity past the end of the newly requested shelf life.
• If there is a change in the pack size, documentation must be provided to demonstrate compliance with the new pack size, with the drug specification remaining otherwise unchanged.
• In the event of changes to the package leaflet and the summary of product characteristics, as well as in the container labels, the new version of the wording must always be submitted in an editable file (.doc or .docx). The changes must be clearly marked (e.g., track changes mode).
• If a change is reported to the Paul-Ehrlich-Institut, which is in connection with a change in the manufacturing license, a copy of the amended certificate must be submitted with the variation notification or submitted as soon as possible after such a submission.

Data on quality and shelf-life (see module 3 Application for approval marketing authorisation) must be prepared in the form of the sample tables. In principle, the same requirements apply to the documents to be attached as apply to an application for a marketing authorisation.
Deviations from the mentioned method are allowed in the following cases.

Frozen Fresh Plasma (GFP)
The change notification must at least provide data after production and after one month of frozen storage. The data applicable after the end of the shelf life can be submitted later. The prerequisite is that the shelf-life data for the approved model are available for the entire storage period. For the determinations relating to clotting physiologiy determinations after production, a sample can be frozen and retested within a short period of time.

Red blood cell concentrates (RBC)
With the change notification for RBC, at least data must be submitted after production and after the end of the shelf life.

If a drug is to be manufactured at additional manufacturing facilities, this should be reported. The uniformity of production at additional production sites has to be demonstrated only once as an example for another production site (results from the quality control of the first 6 months).

Contact

Email: transfusionsmedizin@pei.de

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Donor Screen­ing

Database Blood Donor Deferral

The database provided by the Paul Ehrlich Institute for blood donation facilities provides information on the exclusion of blood donations from travelers returning from endemic areas. For each country, the worldwide endemic occurrence of infections caused by certain pathogens in a total of 284 countries and 50 states of the USA is shown.

To the Database

Donor Testing Database

In vitro diagnostic medical devices (IVD)

In vitro diagnostic medical devices (IVDs), i.e. for infection markers used for donor testing in the production of cellular blood components, single therapeutic plasmas and stem cell preparations for haematopoietic reconstitution, must be reported for the respective authorisations or permits (as applicable); the sample applies to any change of these tests. The donor testing database for these notifications has been established to simplify the procedure.

All tests that fulfill the requirements of the Paul-Ehrlich-Institut (PEI) for donor testing are stored in the donor testing database after testing.

To the Donor testing Database (German only)

Fundamental Requirements for IVDs for Donor Screening

Test systems for the detection of infections with HIV, HBV and HCV (screening tests) must have a high sensitivity in keeping with the current state of science and technology. In addition, consistent quality must be ensured for each IVD batch. For each screening test , certain criteria must therefore 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.

Following the requirement "Introduction of minimum standards for blood screening tests", only those HIV, HBV and HCV screening tests must be used which meet the requirements described in the appropriate edition.

If the use of screening tests is intended for further clarification in the confirmatory test (Opinion 42, Appendix B2: Clarification of anti-HBc specificity with two further screening test after 2: 1 decision, clarification HBsAg with second HBsAg test system) the tests used for this purpose must also 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 Paul-Ehrlich-Institut (PEI) accompanied by the 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:

  • a 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,
  • execution of NAT tests with a pool size larger than the validated size.
• changes in the sample material (e.g., new anti-coagulants) or in the 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 that conforms to the requirements of the above. Order of a graduated plan of 7 January 2013 occupy.

Requirements for NAT Tests

In-house NAT tests

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

CE-marked NAT tests in off-label use

• CE-marked NAT tests used with a change in the purpose, but in conformity with the manufacturer's specificationsthat are not intended for donor screening by the test manufacturer (use not in keeping with the intended purpose).
• Donor screening with these tests is possible in both single and pool testing.

CE-marked NAT tests for donor screening

• Donor screening with CE-marked NAT tests is possible in both single and pool testing.

Contact

The person authorised to communicate between the applicant or the license holder and the PEI receives the access data by
Email: transfusionsmedizin@pei.de

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Uni­form Blood and Plas­ma Donor Ques­tion­naire

The Paul-Ehrlich-Institut (PEI) provides a uniform blood and plasma donor questionnaire. This questionnaire takes into account socio-scientific findings of the questionnaire design and the specific needs of blood donors as well as those of the donation institutions. The use of this sample questionnaire is recommended in the amended haemotherapy guideline.

Update 2018

Due to new requirements laid down in the overall amendment of the guideline for the collection of blood and blood components and the application of blood products (haemotherapy guideline) from 2017, the uniform blood donor questionnaire introduced since 2015 has been revised.

The update

• considers the modified donor selection criteria of the amended haemotherapy guideline,
• lays down deadlines that take into account current knowledge on the retention time of drugs toxic to human reproduction in donor plasma,
• is better understood thanks to linguistic and formal changes and
• ensures that the questionnaire can be used without restriction by institutions that only produce plasma for fractionation.
  

Introduction of the short version of 2019

At the request of many donor centres, the working party “Uniform questionnaire for donating blood and plasma” has prepared a short version of the questionnaire, in addition to the standard version, which can be used for persons donating blood frequently. The idea behind this is to increase the acceptance of the questionnaire, and thus the preparedness to donate blood, by markedly reducing the number of questions.
The short version of the uniform questionnaire may be used instead of the standard version only in the following cases:

1. The person willing to donate blood has already provided 2 donations within 2 years with the standard version of the uniform questionnaire being used,
2. the last donation was provided not more than 200 days ago, and
3. the standard version was used again, once each time if the last use of the questionnaire was more than 2 years ago. After that, the short version of the uniform questionnaire can be used again for a follow-up period of 2 years, if the intervals between the donations do not exceed a period of 200 days.

Option of an additional question concerning WNV – supplement WNV

In 2019, multiple cases of a WNV infection acquired within Germany emerged. Presumably, the virus will be endemic all over Germany within the next years. Therefore, from 1st of June 2020 onwards, the PEI will issue an obligation to test certain blood, plasma and stem cell donations for West Nile Virus. Alternatively, individuals who spent at least 2 consecutive days in a region within Germany affected by WNV can be temporarily excluded from donating.

Blood establishments, which want to take advantage of this option, are obliged to use the supplement WNV, which contains the additional question about stays and a German map, which highlights affected regions ("Landkreise" and "kreisfreie Städte"). This map is available in pdf format.

Do the registration documents have to be adapted when using the questionnaire?

The blood and plasma donor questionnaire is part of the marketing authorisation documents. Blood donation institutions that have already indicated the use of the current standard blood and plasma donor questionnaire can use the updated 2018 version without a new notification of variation. Blood donation institutions that use the single blood and plasma donor questionnaire for the first time will indicate this in relation to their medicines or the donation master file with a declaration that they will track any future changes and implement them within a reasonable time.

Development of the questionnaire

The development of the questionnaire began in 2004. Until its completion, it was up to each blood donation facility to translate the donor selection criteria from the haemotherapy guideline into appropriate questions to be included in the donor questionnaire. The correct implementation was checked for the marketing authorisations of each individual institution.

The effectiveness of a questionnaire for the detection of unsuited donors can only be checked under conditions in the day-to-day practice. For this purpose, a new uniform questionnaire was developed in a subgroup of the AK Blut (Working Party ‘Blood’) (version 1), which takes into account findings gained in the field of sociology for the questionnaire design as well as the specific needs of the donor situation and the situation in the donation institutions. In a multicenter study (2006-2007), this questionnaire was successfully tested on several thousand new donors. As a result, donor acceptance and suitability for the daily practice were very high. In addition, acute illnesses and risk donors were detected significantly better than with the usual questionnaires.

In its Opinion No. 41 on 07 June 2010 The Arbeitskreis Blut (Working Party ‘Blood’ recommended that a nationwide donor questionnaire be introduced.

However, experts expressed their fear that the directly addressing sexual risk behavior as newly introduced in the version of the multicenter study could lead to unacceptably high donor losses.

For this reason, in a follow-up field study (2011-2012), data on donor provisions were collected as part of the routine blood bank operation to assess the suitability of the questionnaire regarding its effects on the blood supply prior to mandatory use. The result of this follow-up field study was a questionnaire (Version 2) revised in some points compared to the version of the Multicenter study, which was developed by the Working Party Blood with representatives of the German Society for Transfusion Medicine and Immune Hematology and the Association of German Transfusion Medicine.

This resulted in the updated Single Blood and Plasma Donor Questionnaire, which takes into account the amended requirements of the amended haemotherapy guideline for donor selection, new findings on the half-life and thus deferral periods for medicinal products. This questionnaire can also be used without restriction for the exclusive extraction of plasma for fractionation.

This update has been developed by a working group of representatives of blood and plasma donation agencies and the Robert Koch Institute under the auspices of the PEI.

The questions of the unified blood and plasma donor questionnaire cover the donor selection criteria set out in the haemotherapy guideline. They are grouped by topic. Donors will be able to derive information on why these questions are asked, simply by reading the headings.

Questionnaire and Haemotherapy Guideline

According to the haemotherapy guidelne, the health status and relevant pre-existing conditions of the donor must be determined before each donation by means of a questionnaire and a personal survey. This may contribute to the identification and permanent exclusion or temporary deferral of persons whose donation may pose a health risk to themselves or a risk of disease transmission to others.

The use of a standard sample questionnaire provided by the Paul-Ehrlich-Institut is recommended in the amended Haemotherapyguideline.

Deferral periods changed

after the use of reproduction toxic medicines 3 years instead of permanent exclusion from the donation (Question 26)

According to the BfarM (Bundesinstitut für Arzneimittel und Medizinprodukte, Federal Institute for Drugs and Medical Devices), the retinoids Isotretinoin and Alitretinoin (e.g. Akennormin, Toctino) for the treatment of serious forms of acne and hand eczema have half-lives which would permit a blood donation already one month after the administration of the product has been discontinued. Solely for products with the active ingredient Acitretin, the use of which includes the treatment of serious disorders of keratinisation or psoriasis (e.g. Neotigason®), and which, due to their potential formation of etretinate can have a relatively long half-life of 120 days, a deferral from a donation of 3 years is considered as required. The marketing authorisation for Tigason (etretinate) expired more than 20 years ago.

As we can never assume that all donors can remember exactly which product they took, and when they took it, the question above refers to the treatment, and, to ensure the safety of the blood donations, the longest deferral period of 3 years was chosen.

after the use of growth hormones before 1996 instead of before 1986 (Question 29)

In the mid-1980s there was some evidence of possible prion-mediated diseases after the use of human Somatotropin. According to the BfArM as the competent regulatory authority, however, there is no official information when this product was last used in Germany or in other countries. In 1985, manufacturers of the human products had to include a warning into the package leaflet. In the same year, they discontinued the sale of this product entirely and renounced the marketing authorisation in 1989. In spite of this, the product was still marketable from the pharmaceutical law point of view until 1992. In the mid-1980s there was some evidence of possible prion-mediated diseases after the use of human Somatotropin. According to the BfArM as the competent regulatory authority, however, there is no official information when this product was last used in Germany or in other countries. In 1985, manufacturers of the human products had to include a warning into the package leaflet. In the same year, they discontinued the sale of this product entirely and renounced the marketing authorisation in 1989. In spite of this, the product was still marketable from the pharmaceutical law point of view until 1992.

Although, two products manufactured by genetic engineering have been available since 1986, there is no official information on which countries have already access to these products, either.

The new wording of the questionnaire both takes into account the unclear data situation in Germany and includes persons willing to donate blood who, during the period in question, possibly received treatment with grow factors of human origin.

This information was previously not available to this extent so that the changed deferral periods regarding treatment with growth factors could only now be in included into the new version of the questionnaire.

Contact

Donor questionnaire
Email: pharmakovigilanz2@pei.de

Registration procedures
Email: transfusionsmedizin@pei.de

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Sam­ple Texts and Tem­plates

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