Plasma fractionation 2011 and beyond

Transcription

1 The not-for-profit fractionators view Jan Over Plasma Products division PPB11, Cyprus, May 9-12,

2 Outline The plasma fractionation field at present Aims of the not-for-profit and for-profit sectors Competitiveness Market opportunities and R&D Differences between the sectors? The future PPB11, Cyprus, May 9-12,

3 The plasma fractionation field (1) As of 2007: 20 not-for-profit fractionators (21 plants): - total capacity 8.9 million liters - total throughput 6.0 million liters 28 commercial fractionators (38 plants): - total capacity 27.7 million liters - total throughput 19.9 million liters - the 10 largest plants representing 90% of the throughput Source: Marketing Research Bureau, 2008 PPB11, Cyprus, May 9-12,

4 The plasma fractionation field (2) Concurrent plasma Source plasma Total Source: Marketing Research Bureau, 2011 PPB11, Cyprus, May 9-12,

5 The top 10 plasma products Manufacturers Total Not for profit Commercial Products (48) (20) (28) - albumin i.v. immunoglobulin i.m. / s.c. immunoglobulin factor VIII (+ / - vwf) (single) factor IX prothrombin complex antithrombin fibrin sealant fibrinogen alpha-1 antitrypsin Sources: Manufacturers websites; Marketing Research Bureau, 2008 PPB11, Cyprus, May 9-12,

6 Hyperimmune immunoglobulins Manufacturers Total Not for profit Commercial Specificity (48) (20) (28) - rhesus (D) hepatitis B tetanus rabies Varicella CMV Vaccinia Staphylococcus Sources: Manufacturers websites; Marketing Research Bureau, 2008 PPB11, Cyprus, May 9-12,

7 Aims of both sectors Not for profit: 1) serve patients needs 2) achieve and maintain a secure (national/regional) product supply: self-sufficiency / self-reliance 3) primarily expansion within the region 4) community driven 5) generate financial surplus to assure continuity - [no private shareholders] Commercial: 1) serve patients needs 1) maximize profit for the benefit of shareholders 3) grow by expansion of world-wide markets 4) generate financial surplus to assure continuity PPB11, Cyprus, May 9-12,

8 Goals of the not-for-profit sector (1) Achieve self-sufficiency / self-reliance: plasma procurement from non-remunerated donors and from not-forprofit partners collect source plasma to add to the recovered plasma supply to meet the local/regional demand for the plasma driver maintain continuity of supply irrespective of events on global markets PPB11, Cyprus, May 9-12,

9 Goals of the not-for-profit sector (2) Assist other bodies: Developing countries: - assistance in increasing collection and quality of plasma from non-remunerated donors - provision of technology, toll manufacture, training,. - assistance in development of regulatory / quality systems Regulatory bodies: - providing scientific advice PPB11, Cyprus, May 9-12,

10 Goals of the not-for-profit sector (3) Stay competitive: invest in high-quality products of reasonable price continuation and strengthening R&D maintain good customer service PPB11, Cyprus, May 9-12,

11 Sound economics are key optimize product yields develop and maintain a balanced product portfolio produce at sufficiently large scale maximize use of available plasma (export channels for surplus products) establish strategic alliances (also for R&D) and harmonize product portfolios seek toll fractionation for third parties seek niche indications and markets / orphan drug designations PPB11, Cyprus, May 9-12,

12 High-quality plasma products (1) Safety: are there any issues left? - (known) viral risks are under control; caveat: emerging pathogens - no significant impact of source material from remunerated vs. non-remunerated donors (in closely regulated environments) on finished products - prions: still on the watch - adverse events still occur: immunogenicity (factor VIII), thrombo-embolic complications (ivig and scig),. - insufficient supply is a safety issue - pharmacovigilance: new regulations upcoming - risk analyses / risk management (incl. appropriate application of precautionary principles) PPB11, Cyprus, May 9-12,

13 High-quality plasma products (2) Efficacy: are there more effective or less effective products? - multimeric composition of vwf in concentrates - factor VIII content of vwf concentrates - composition of prothrombin complex concentrate - antibody profile of source material for ivig - 10% versus 5% ivig - appropriate product dosing should be advised Clinical tolerability: are there more or less tolerable products? - i.v. immunoglobulin - factor VIII immunogenicity (presence of vwf) - effect of excipients PPB11, Cyprus, May 9-12,

14 High-quality plasma products (3) Purity: high purity is a good objective, but not always ideal: - stabilisation by a carrier protein may be needed (albumin) - presence of vwf in factor VIII products may be an advantage - (in principle) high purity leads to lower process yields but. would a new crude product (like PCC) nowadays be easily accepted by the authorities? PPB11, Cyprus, May 9-12,

15 High-quality plasma products (4) Quality comes first: - 35 nm filtration does not make much sense for viral safety (Sanquin) - double (instead of single) virus filtration (Sanquin) - F IXa-free factor IX product at the expense of yield (Sanquin) - 15 nm filtration of factor VIII (LFB) - 35 nm filtration of vwf (LFB) - purity of factor X and haptoglobin (BPL) PPB11, Cyprus, May 9-12,

16 Achieving cost-effective processes Keep direct production cost low: process yield is of primary importance (plasma being the major cost factor) which technology to use for capturing and purification? Either cheap or high-yielding, preferably both.. And highly selective, and directly applicable to plasma, and stable, and.. increase process scale increase scale of operation (plasma throughput) Dilemma: How to increase scale of operation when the available plasma volume is bound to a maximum? PPB11, Cyprus, May 9-12,

17 Process scale Is big always better? Yes, it usually is: - investments are more cost-effective - more efficient use of production space - less mechanical losses - less QC costs - viral/prion safety risk is lower (or not influenced) But: some limitations may be set by the technology: processing times, temperature control, chromatographic columns,. Caveat: rejection/recall in case of look-back issues (e.g. a donor develops vcjd) PPB11, Cyprus, May 9-12,

18 Technologies The fractionation industry is very conservative, because of regulatory hurdles for technical innovation (e.g. clinical trials, virus safety issues), cost of changes, timescales,. But what if a plant is designed from scratch? Will it adopt the so-called cascade system of protein isolation? The future: chromatography, chromatography, chromatography, chromatography,.? ( classical, multimodal, affinity chromatography) - focus on selectivity, binding capacities, flow properties, cleanability,. - disposable use? PPB11, Cyprus, May 9-12,

19 Market opportunities and R&D New products, New indications, New blockbusters, where are they? PPB11, Cyprus, May 9-12,

20 Blockbusters of the past., and present? 1980s: fibronectin 1980s-2000s: modified hemoglobin 1990s: mannan-binding lectin antithrombin alpha-1 antitrypsin? PPB11, Cyprus, May 9-12,

21 Niche / orphan products Has the not-for-profit sector always been leading the way, then and now? And how about the future? PPB11, Cyprus, May 9-12,

22 Existing niche products (+ ceased ones) Manufacturers Total Not for profit Commercial Products (48) (20) (28) - thrombin 3 (?) 1 (+1) 2 - von Willebrand factor C1-esterase inhibitor (+1) - protein C activated protein C factor XI factor XIII 1 0 (+1) 1 - activated prothrombin complex (+1) -IgM haptoglobin factor VII 1 0 (+1) 1 - factor VIIa 0 0 (+1) 0 Sources: Manufacturers websites; Marketing Research Bureau, 2008 PPB11, Cyprus, May 9-12,

23 Existing niche products: new ones Manufacturers Total Not for profit Commercial Products (48) (20) (28) - thrombin 3 (?) von Willebrand factor C1-esterase inhibitor protein C activated protein C factor XI factor XIII activated prothrombin complex IgM haptoglobin factor VII Sources: Manufacturers websites; Marketing Research Bureau, 2008 PPB11, Cyprus, May 9-12,

24 Niche products Examples: C1-inhibitor: developed by CLB/Sanquin in the 1970s, to serve about 20 patients in NL (and a few abroad) Now Cinryze in USA and Cetor/Cinryze in EU, serving hundreds of patients Factor XI: process still being improved by LFB; orphan drug designation in USA Transferrin: developed by Finnish Red Cross BTS in 1990s, to serve patients with (temporary) free iron overload. Now produced by Sanquin for cancer drug targeting (in trial), and to serve transferrin-deficient patients (compassionate use) PPB11, Cyprus, May 9-12,

25 New plasma products in development, the not-for-profit sector Protein Indication(s) Developer new hyperimmunes chikungunya LFB complement factor H hemolytic uremic syndrome LFB (apo)transferrin atransferrinemia Sanquin apotransferrin + donor organ preservation Louvain Univ. / C1-inhibitor Sanquin inter-alpha inhibitor protein sepsis ProThera Biol. / Sanquin factor X surgery in factor X deficiency BPL haptoglobin haemolysis (sickle cell anemia) BPL Gc globulin liver intoxication, trauma, sepsis SSI Sources: Manufacturers websites, press releases, PPB meetings PPB11, Cyprus, May 9-12,

26 New plasma products in development, the commercial sector Protein Indication(s) Developer new hyperimmunes anthrax, botulism, ricin Cangene hepatitis C Kedrion / Biotest apolipoprotein A-1, hypercholesterolemia, CSL Behring reconstituted HDL acute coronary syndrome plasmin peripheral arterial occlusion, Talecris acute ischemic stroke factor V factor V deficiency Kedrion plasminogen ligneous conjunctivitis Kedrion in plasminogen deficiency (apo)transferrin coadjuvant in antibiotic therapy Kedrion; Kamada butyrylcholinesterase nerve gas poisoning Baxter fibronectin wound healing Benesis alpha-2-macroglobulin? Shanghai RAAS Sources: Manufacturers websites, press releases, PPB meetings PPB11, Cyprus, May 9-12,

27 Not for profit vs. commercial, a comparison Difference in: Not for profit Commercial Donors non-remunerated remunerated Aims self-reliance product follows price Average process scale smaller larger Scale of operation relatively small, large, regional global R&D limited budgets recombinants, long-acting factors But no(t much) difference in product quality, technologies, product portfolio, niche/orphan product development PPB11, Cyprus, May 9-12,

28 The future (1) The plasma fractionation field in 10 years time: Will the product range be the same? Getting smaller? Will there be more niche products? What will be the main plasma industry driver in 2020? Survival/growth of the industry is critically dependent on sustained growth in clinical demand for IVIG is this a safe assumption for planning? What will be the likely impact of treatment for common diseases (e.g. Alzheimer s) using plasma products? PPB11, Cyprus, May 9-12,

29 The future (2) The plasma fractionation field in 10 years time: Can we be sure that the plasma fractionation industry will continue to grow? Will the industry continue to be dominated by needs of rich developed countries? Is there a prospect of technological developments to meet the needs of developing countries? How many fractionators will still be active? Does the number of fractionators need to increase to meet global demand and increase security of supply? Will there be more fractionators starting in developing countries? Producing cheaper products? PPB11, Cyprus, May 9-12,

30 Some risks. Too few manufacturers (supply may fall short in case of disasters) Closing down of more not-for-profit fractionators will disturb the existing balance Concentration of plasma collection is a risk in case of emerging bloodtransmittable pathogens: spreading of collection over the world is better. Is this another task for the not-for-profit sector? PPB11, Cyprus, May 9-12,

31 Conclusions The not-for-profit and commercial sector have different goals Both sectors have about the same solutions for staying in business The not-for-profit sector has been innovative in the past and needs to stay so (In a free market and without protection by the government) increasing the scale of operations is an important way to ensure continuity for a not-for-profit plasma product manufacturer Partnering is another option PPB11, Cyprus, May 9-12,

32 Thanks to: Robert Perry, Theo Evers Françoise Rossi, Marc Grosdemouge, Monique Ollivier John More, Tara Dolan Ruth Laub Leni von Bonsdorff, Paul Strengers, Ruud Zoethout, Robert Tiebout, Marcel Jansen PPB11, Cyprus, May 9-12,