Guide for the Assessment of Clotting Factor Concentrates

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treatment, and therefore samples should be drawn and analyzed to assess patient viral status andmeasure inhibitor levels. The documents from the EMEA may provide guidance on this and individualauthorities may tailor these guidelines to suit their particular circumstances. The relevant laboratorytests are similar to those used to assess the quality of the plasma for viral status and factor levels. Itmay be possible to enter into contractual agreements with the relevant manufacturers to performthese analyses as part of any supply arrangement.7. People receiving factor IX for the treatment of hemophilia B should be given concentrates specificallyenriched in this factor and purified to remove other coagulation factors. Highly purified concentratesof factor VIII and factor IX are preferable, when possible, as long as the manufacturing processesare secure in relation to known viral agents and do not cause products to form inhibitors, and aslong as purchase of such concentrates does not result in restriction of treatment due to excess cost.Example scenariosTo illustrate the application of these principles, examples of the types of choices facing authorities areprovided.Example 1As a result of a tendering process, the following factor VIII products have been offered:Product A: A concentrate made from plasma about which the manufacturer has little knowledgeexcept the country of origin. The manufacturer claims to test for the serological markers of the transfusiontransmitted agents HIV, HCV, and HBV on the plasma pools after plasma has been thawed for manufacture.The manufacturer also performs NAT testing for HCV on these pools, and the final product is viralinactivated with solvent-detergent and dry-heat treatments. Limited viral inactivation studies havebeen generated by the manufacturer for the conditions and plasma source specific to the product. Theproduct is the cheapest of those offered.Product B: A concentrate made from plasma which is characterized by a fully documented quality systemincorporating the tenets of the European plasma master file concept. The product is subjected to solventdetergenttreatment. The manufacturer has validated this process for inactivation of viruses in accordancewith the requirements of the EMEA’s Committee for Human Medicinal Products (CHMP).Product C: A concentrate made from plasma which is characterized by a fully documented quality systemincorporating the tenets of the European plasma master file concept. The product is highly purified onmonoclonal antibody affinity columns and solvent-detergent treated. The product is stabilized withalbumin; the cost of the product is double that of the next most expensive product.Product D: A concentrate made from plasma collected by centres under contract to the manufacturer. A fullquality system is not evident but the manufacturer has data on donor viral epidemiology and selectionprotocols to exclude high-risk groups. The product is manufactured using two ion-exchange purificationsteps which have been demonstrated in literature studies to eliminate significant levels of infectiousmaterial including vCJD-like agents. The product undergoes two viral inactivation steps: solvent-detergentand pasteurization. The manufacturer has limited clinical studies and has offered literature-based evidencefor efficacy.Product E: A concentrate made from plasma which is characterized by a fully documented quality systemincorporating the tenets of the European plasma master file concept. The product is an intermediate-purityconcentrate incorporating terminal dry heat at 80 o C for 72 hours in its manufacture. The plasma pool is24 Guide for the Assessment of Clotting Factor Concentrates
tested for HCV and HIV using NAT. The product as manufactured by the company has a long history ofsafety with appropriately designed clinical studies.EvaluationSome of the considerations when evaluating the products in this scenario should include:1) There is a total lack of knowledge about the plasma quality of Product A. The manufacturer’s use ofpool testing is not an acceptable substitute for a fully documented quality system. Despite the use ofwell-accredited viral inactivation steps, the manufacturer’s limited ability to validate these is a deficiency.This product, despite its favourable price, should not be considered further.2) Product B is singly inactivated using solvent-detergent treatment, the best method for eliminatingthe most highly infectious viruses. However, the lack of any other viral inactivation step is a disadvantage,and regulatory authorities should further consider other products.3) Product C is very highly purified and is solvent-detergent treated, two attractive features. However,its cost-effectiveness against the other products is probably low. Other products should be considered.4) Product D has attractive features but the manufacturer should perform its own validation studies onthe elimination of the infectious agents from which it claims product safety. The company’s contractfor plasma supply should be rigorously assessed for its adherence to the crucial features of the plasmamaster file requirement. Although a full clinical trial may not be required, some evidence of normalpharmacokinetics and efficacy would be desirable.5) Product E is satisfactory in all features except in the lack of a second viral inactivation step. This doesnot reflect best practice, but the product’s good clinical safety record makes it worthy of consideration.Some evidence exists that dry heating may decrease the risk of transmission of non-envelopedviruses. The manufacturer should be asked for details of its validation process for the inactivationof viruses other than HCV, HIV, and HBV. It should also be asked to comment on the capacity ofthe manufacturing process to eliminate vCJD-like agents, and for details regarding its plans tomove to a double viral-inactivated product.Example 2As a result of a tendering process, the following factor IX products are offered:Product X: A prothrombin complex concentrate manufactured from plasma which is characterized by afully documented quality system incorporating the tenets of the European plasma master file concept.The product is subjected to dry-heat treatment at 80 o C for 72 hours as the sole viral inactivation step.Product Y: An intermediate-purity concentrate specifically enriched in factor IX by affinity chromatography.It is viral inactivated by solvent-detergent treatment and nanofiltration. The plasma source is satisfactorilycharacterized and the plasma pool is NAT tested for HCV and HIV.Product Z: A concentrate made from a satisfactorily characterized plasma source containing factor IXpurified to biochemical homogeneity (100% purity) by monoclonal antibody chromatography andtreated with solvent detergent as the sole viral inactivation step.Guide for the Assessment of Clotting Factor Concentrates 25
Page 1: GUIDE FOR THE ASSESSMENTOF CLOTTING
Page 5 and 6: INTRODUCTIONSelecting therapeutic p
Page 7 and 8: SECTION 1FACTORS AFFECTING THE QUAL
Page 9 and 10: and authorities need to assess each
Page 11 and 12: There are a number of different vir
Page 13 and 14: Treatment Advantages Points to cons
Page 15: measures may have only limited bene
Page 18 and 19: • FDA draft guidelines• FDA ins
Page 20 and 21: Common strengths of U.S. & EU regul
Page 22 and 23: • Audit potential suppliers who m
Page 24 and 25: on HCV reactivity in product sample
Page 26 and 27: Basic requirementsThere are a numbe
Page 30 and 31: EvaluationSome of the consideration
Page 32 and 33: Figure 2: Production of cryoprecipi
Page 34 and 35: Some measures which should be inclu
Page 37 and 38: APPENDIX 1REGISTRY OF CLOTTING FACT
Page 39 and 40: TABLE 1A: SEROLOGIC TESTS ON INDIVI
Page 41 and 42: TABLE 2. FACTOR VIII CONCENTRATES M
Page 43 and 44: BRAND COMPANY SITE OF MANU-FACTUREP
Page 45 and 46: TABLE 7: OTHER CLOTTING FACTOR CONC
Page 47 and 48: APPENDIX 2MODEL PRODUCT ASSESSMENT
Page 49: (D) STABILITY AND SHELF LIFEInclude
Page 52 and 53: Nucleic acid testing (NAT): Testing
Page 56: World Federation of Hemophilia1425

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