{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:11:38Z","timestamp":1747185098971,"version":"3.40.5"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,9,27]],"date-time":"2023-09-27T00:00:00Z","timestamp":1695772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Haemophilia"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Hereditary factor X deficiency is a rare bleeding disorder, with limited treatment options. This paper describes the approach to pre\u2010clinical development and characterization of a high\u2010purity plasma\u2010derived factor X concentrate, to achieve orphan drug marketing authorization for the treatment of hereditary factor X deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A chromatographic process was developed, to purify factor X from human plasma for fractionation. The product was characterized using in vitro, in vivo and ex vivo tests for potency, purity, thrombogenicity, immunogenicity, toxicity and stability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The production process complied with good pharmaceutical manufacturing practice. It achieved 6000\u2010fold purification and 100\u2010fold concentration of the factor X protein compared to human plasma. The factor X protein was 94%\u201396% pure. Other residual plasma proteins were well below levels in plasma, minimizing potential interference in hemostasis after therapeutic administration. Effective virus\u2010reduction during manufacture, and the absence of thrombogenicity, toxicity and immunogenic potential were confirmed, addressing the main safety concerns historically associated with plasma\u2010derived therapeutics. The freeze\u2010dried product remained stable between +2\u00b0C and +30\u00b0C for at least three years. After reconstitution with water for injections, the factor X activity was maintained for at least 48\u00a0h at +18\u00b0C to +22\u00b0C.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Targeted pre\u2010clinical development of the first highly\u2010purified concentrate to treat hereditary factor X deficiency is described. Following international guidelines for nonclinical safety testing, particular strategies were adopted for unmodified products derived from human blood plasma. This approach may also be relevant to the development of other ultra\u2010orphan medicinal products.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hae.14875","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T06:13:17Z","timestamp":1695881597000},"page":"1394-1409","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical development and characterization of a human plasma\u2010derived high\u2010purity factor X concentrate for therapeutic use"],"prefix":"10.1111","volume":"29","author":[{"given":"Joanne","family":"Lloyd","sequence":"first","affiliation":[{"name":"Research &amp; Development Department Bio Products Laboratory, Dagger Lane  Elstree UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2439-6113","authenticated-orcid":false,"given":"Peter","family":"Feldman","sequence":"additional","affiliation":[{"name":"Research &amp; Development Department Bio Products Laboratory, Dagger Lane  Elstree UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,9,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102516.1997.00106.x"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102516.2002.00633.x"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365\u20102516.2001.00100.x"},{"volume-title":"Factor X P Behring product monograph 110073 E 0706\/PC","year":"2007","author":"CSL Behring","key":"e_1_2_10_5_1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2009.03473.2.x"},{"volume-title":"Excellence NIfC. 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