The Generative Brain

Cai K et al. Prion removal capacity of plasma protein manufacturing processes: a data collection from PPTA member companies (Transfusion 2013)

This is an industry paper in which member companies of the Plasma Protein Therapeutics Association (PPTA), the trade body of plasma fractionators, pooled more than 200 of their own laboratory studies on how well the steps used to make plasma medicines (such as immunoglobulins, albumin and clotting factors) remove prions. It was published online on 17 December 2012 and in print in Transfusion in September 2013 (volume 53, issue 9, pages 1894 to 1905). The 14 authors came from Baxter BioScience, Biotest, CSL Behring, Grifols, Kedrion and PPTA itself. The authors report that results from independent groups agreed well, that biochemical tests for abnormal prion protein tracked animal infectivity tests, and that each step gave similar reductions whatever spike was used, except highly purified prion protein in some cases. The European Medicines Agency cites it in revision 3 of its CJD and plasma reflection paper (May 2024) as one of two references for the statement that spiking studies established which manufacturing steps reduce prions. The full text is behind a paywall and was not read, so the step-by-step numbers are not recorded here. Information only, not medical, legal or regulatory advice.

Key facts

  • Bibliographic record: Transfusion 2013;53(9):1894-1905, doi 10.1111/trf.12050, PMID 23252676; online ahead of print on 17 December 2012, print issue September 2013. Europe PMC lists no PMC copy and marks it not open access.
  • The 14 authors are Cai K, Gröner A, Dichtelmüller HO, Fabbrizzi F, Flechsig E, Gajardo R, von Hoegen I, Jorquera JI, Kempf C, Kreil TR, Lee DC, Moscardini M, Pölsler G and Roth NJ. The combined affiliation line names Baxter BioScience (Vienna), Biotest AG (Dreieich), CSL Behring (Marburg and Berne), Grifols (Research Triangle Park, North Carolina, and Parets del Vallès), Kedrion (Castelvecchio Pascoli) and PPTA (Brussels). No grants are listed.
  • Background given by the authors: variant CJD incidence peaked about a decade before and has fallen, and epidemiology suggests the agent has not been a real contamination threat to large-scale plasma fractionation, but manufacturers still studied prion removal by their process steps; pooling the results was meant to test reproducibility and find trends and mechanisms.
  • Method: more than 200 prion removal studies on precipitation, adsorption, chromatography and filtration steps, and on combined steps, using a range of model spiking agents and laboratory-scale copies of production steps; results were grouped by key manufacturing variables and the log reduction values of each group compared.
  • Results reported in the abstract: overall removal capacities from independent groups were in good agreement; removal measured by biochemical assays matched infectivity removal in animal bioassays; for a given step, reductions were similar across spiking agents, the exception being highly purified prion protein in some circumstances; single-step and combined-step studies pointed to complementary or overlapping removal mechanisms; the steps with the highest removal were those where prions and the therapeutic protein differ most in physical and chemical behaviour.
  • Conclusion of the authors: certain plasma manufacturing steps have an inherent ability to remove prions, which they describe as a safeguard in the unlikely event of contamination. The paper was written by the industry whose products it assesses.
  • The same journal issue carried an editorial by Peter R. Foster, formerly of the Scottish National Blood Transfusion Service, titled "Plasma products and prion removal: Is you is or is you ain't ...?" (Transfusion 2013;53(9):1873-1875); its content was not read.
  • EMA's CHMP reflection paper revision 3 (30 May 2024) lists the paper as reference 110. In section 7 it is cited with Foster 2004 for the statement that a significant number of spiking studies have investigated partition and removal of abnormal prion protein or infectivity during fractionation; the paper adds that most such studies used hamster 263K brain homogenate or microsomal fractions, relied on Western blot or conformation-dependent immunoassay confirmed by bioassay, and established the contribution of precipitation followed by centrifugation or depth filtration, specific chromatography steps and nanofiltration.
  • The same EMA section adds a caveat relevant to reading the paper: since 2004, studies have shown that prion removal can vary with the spike preparation (its dispersion and the prion strain), especially for steps that work by retention, and that endogenous infectivity in rodent blood may persist through fractionation more than brain-derived spikes predict.
  • Revision 3 relies on manufacturing removal: it lists modern prion removal steps among the reasons for dropping the UK-stay donor exclusion, and makes no recall for sporadic, genetic or iatrogenic CJD donors conditional on the manufacturer showing such steps; manufacturers must estimate capacity stepwise, starting by comparing their process with published data.
  • The 2004 EMA method guideline that governs such studies asks for the most challenging spike for each step and warns that a prion clearance figure deserves less confidence than one for a model virus; the paper's finding that purified prion protein can behave differently bears on that spike choice.
  • Europe PMC counts 20 citing records. They include a 2014 review of pathogen removal for clotting factor concentrates written with CSL Behring authors and funded by CSL Behring, which cites the paper for prion reduction by precipitation, chromatography and filtration without giving numbers; LFB's 2017 IQYMUNE safety paper; a 2023 Vox Sanguinis paper arguing UK plasma is safe for fractionation; a 2024 LFB and INRAE paper on microsomal prion spikes for nanofiltration studies; and the German Arbeitskreis Blut statement S 27 on vCJD donor exclusion, adopted 6 December 2024 and published May 2025.
  • PPTA lists the paper among its pathogen safety publications next to two earlier PPTA data collections on virus removal (cold ethanol fractionation, 2011, and solvent/detergent treatment, 2009); the page gives no prion reduction figures.

Timeline

  1. 2004EMA guideline on investigating plasma manufacturing processes for vCJD risk sets the method for prion clearance studies.
  2. 2012Paper published online ahead of print in Transfusion.
  3. 2013Print publication in Transfusion 53(9):1894-1905, with an editorial by P. R. Foster in the same issue.
  4. 2013Klamroth, Gröner and Simon review on clotting factor pathogen safety, citing the paper, published online.
  5. 2017LFB IQYMUNE biological safety paper cites the data collection.
  6. 2024CHMP reflection paper revision 3 adopted, citing the paper as reference 110.
  7. 2024German Arbeitskreis Blut adopts statement S 27 on vCJD donor exclusion, which cites the paper (published May 2025).
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