The Generative Brain

CHMP reflection paper on Creutzfeldt-Jakob disease and plasma-derived and urine-derived medicinal products, revision 3 (EMA, 2024)

This is the European Medicines Agency text that sets the EU scientific position on prion risk for medicines made from human plasma (such as immunoglobulins, albumin and clotting factors) and from human urine (such as some fertility hormones and urokinase). Revision 3, reference EMA/CHMP/BWP/303353/2010 Rev 3, was adopted by the CHMP on 30 May 2024 and published on 31 May 2024, replacing the 2011 position statement. Its main change is that the long standing advice to exclude donors who spent a cumulative year or more in the UK between 1980 and 1996 from giving blood or plasma for fractionation is no longer maintained, and country-based exclusions are no longer recommended at all. It keeps precautionary recall of batches when a plasma donor later develops variant CJD, adds guidance for cases where variant and other CJD cannot be told apart, keeps no recall for sporadic, genetic or iatrogenic CJD but now ties that to the manufacturer having shown prion reduction steps, and keeps the duty to estimate the prion reduction capacity of each manufacturing process. It is a reflection paper, and no date of coming into effect is stated. Information only, not medical, legal or regulatory advice.

Key facts

  • Revision 3 was drafted by the Biologics Working Party (draft agreed 12 September 2018), released for consultation by the CHMP on 18 October 2018 with comments due by 31 October 2019, agreed by the working party on 17 April 2024 and adopted by the CHMP on 30 May 2024; the draft was still titled a position statement, the final a reflection paper.
  • The text traces back to the CPMP position statement on new variant CJD and plasma-derived medicinal products of February 1998 (CPMP/201/98), replaced in February 2003 by EMEA/CPMP/BWP/2879/02, revised in June 2004 and June 2011; only the 1998, 2003 and 2004 versions carry a legal effective date on the EMA page.
  • Removed: the 2011 recommendation that donors with a cumulative 1 year or more in the UK between the beginning of 1980 and the end of 1996 be excluded from donating blood or plasma for fractionation, which in 2011 also let countries set a stricter national limit such as 6 months. Revision 3 says the exclusion is no longer requested and that country-based exclusions, including for time in France or other countries, are no longer recommended.
  • The stated reasons for dropping the UK-stay exclusion are no transfusion-transmitted vCJD in the UK since 1999, prion removal steps in modern manufacturing, the faster than predicted fall in UK vCJD cases (last UK case reported in 2016), and France having fractionated its own plasma for 20 years without vCJD transmission.
  • Donor deferral that remains in force comes from Commission Directive 2004/33/EC, which the paper cites as permanent deferral of people with a family history placing them at risk of a TSE, people who received a corneal or dura mater graft, and people treated in the past with medicines made from human pituitary glands; the paper makes no change to donor selection and recommends no donor testing, since no screening test exists.
  • Recall when a donor to a plasma pool later develops variant CJD: recall of batches and intermediates is still recommended, including medicines that contain plasma-derived products as excipients, with competent authorities weighing the impact on essential products that have no alternative; look-back and notification of regulators, Official Medicines Control Laboratories, surveillance centres and the supply chain apply in confirmed or suspected variant CJD.
  • New in revision 3: where post-mortem differentiation between variant and other CJD is not possible or not yet available, not recalling can be justified after a risk assessment of epidemiology, the donor's clinical data and the process prion reduction capacity; if epidemiological indications, clinical tests or signs typical of the variant form exist, precautionary recall is recommended. This was added after a PPTA comment that some countries quarantine products until post-mortem results exclude variant CJD.
  • Sporadic, genetic and iatrogenic CJD: recall is still judged not justified when a donor is later confirmed with these forms or with risk factors, but revision 3 adds the condition that the manufacturer has shown with appropriate methodology that the process includes steps minimising prion contamination; in 2011 the no-recall position had no such condition.
  • Credit for prion reduction steps is qualitative: manufacturers must estimate their process reduction capacity in five steps (comparison with published data, product-specific biochemical studies where needed, infectivity assays only for a critical step lacking a biochemical correlation, an overall estimate, and considering added steps if capacity is limited), consult competent authorities at each milestone and include the estimate in every new marketing authorisation application. The paper sets no numerical log reduction threshold.
  • Leucoreduction of plasma for fractionation is still not recommended, and prion affinity filters are judged unproven; in its response to comments EMA noted that much of the prion load in blood sits in cell-free plasma, so the emphasis should be on downstream reduction steps.
  • Revision 3 dropped two 2011 items: the suggestion of permanently excluding UK transfusion recipients as a possible further criterion, and the advice that companies choose plasma source countries to limit recall risk for albumin excipients. Albumin used as an excipient now gets a case-by-case recall analysis.
  • Urine-derived products are unchanged: urine should come from countries with human and animal TSE surveillance, the same CJD and variant CJD donor exclusions apply, excluding donors with kidney inflammation is encouraged, and the same stepwise process review is required; the paper cites abnormal PrP detected in 40 percent of sporadic CJD and 93 percent of variant CJD urine samples.
  • On tests, the paper says blood PMCA studies found variant CJD in all 14 or 18 clinical cases tested but have not been fully validated against the EU common technical specification, and a steel bead capture immunoassay detected 15 of 21 variant CJD patients; no blood screening test is recommended.
  • The paper notes newer data that raise a concern about sporadic CJD: plasma from two of four sporadic CJD patients transmitted disease to transgenic mice, and two UK plasma product recipients were later diagnosed with sporadic CJD, with no causal link established and chance not excluded.
  • Seven parties commented on the 2018 draft: the European Haemophilia Consortium, PPTA, IPFA, the UK health departments, the UK blood services' joint advisory committee, UK Plasma Action and the UK Primary Immunodeficiency Network; several asked for the UK-stay exclusion to be reviewed after Ireland ended its UK-residence deferral in 2019.
  • Context cited in the paper: the UK allowed UK plasma for immunoglobulins in 2021 and for albumin in August 2023, the US FDA and Australian TGA lifted UK-stay restrictions in 2022, and ECDC issued risk assessments in 2021 and 2023. The UK albumin decision of 15 August 2023 came from the Commission on Human Medicines and the MHRA.

Timeline

  1. 1998CPMP position statement on new variant CJD and plasma-derived medicinal products (CPMP/201/98) takes effect.
  2. 2003First CPMP position statement on CJD and plasma-derived and urine-derived products (EMEA/CPMP/BWP/2879/02) takes effect.
  3. 2004Revision 1 takes effect.
  4. 2004EMA guideline on investigating manufacturing processes for plasma-derived products with regard to vCJD risk (EMEA/CPMP/BWP/5136/03).
  5. 2009Concept paper on the need to update the position statement published.
  6. 2010Draft revision 2 released for consultation, open until 30 September 2010.
  7. 2011Revision 2 adopted by the CHMP, with the UK 1980 to 1996 stay exclusion for plasma for fractionation; published 28 June 2011.
  8. 2018Draft revision 3 adopted for consultation; published 16 November 2018.
  9. 2019Consultation on draft revision 3 closes.
  10. 2023ECDC guidance on donors who stayed in or visited the UK.
  11. 2023UK regulators allow UK plasma for albumin manufacture.
  12. 2024Biologics Working Party agrees revision 3.
  13. 2024CHMP adopts revision 3, dropping the UK-stay exclusion.
  14. 2024Revision 3 and the overview of comments published.
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