生物分离工程双语版8

1、I IntroductionvBioseparation and Downstream processing cost:v(1) 50% (drug, protein, biological product)v(2) 80% (recombinant protein)vRatio of recovery to fermentation costv(1) 2.0 (enzyme)v(2) 1.0 penicillinv(3) 0.16 (ethanol) Downstream processing equipmentv1 20% of equipments grow per year(1.0 b

2、illion $ v (1991) to 5.2 billion $ (2000)v2 Key to cutting production cost:v(1) Improvement in bioseparation equipmentsv(2) Upstream processv A minor changes in upstream significantlyv impact economic or otherwisev B purification process must consider upstream Bring a drug to market v1 Cost : $ 100

3、million to $ 300 million (1985- v 1992) , 350 $ to 400 million (1995) v2 Time : 7 to 10 years v3 Research-focused companies combined with v drug development, manufacturing and marketing v resources v(1) 1 to 3 fully integrated biopharmaceutical companies, v(2) 10-15 platform companiesv(3) 50-100 suc

4、cessful boutiques(小商店，小公司）v4 Allergan ($ 1 billion in annual sales) combining Ligand (13 v million in annual research revenues）.Development time of biopharmaceuticals from FDAv1 Development time of drugsv (1) 4-10 years (7 years) , large part of drugsv (2) 7-23 years (12 years), small part of drugsv

5、2 Risks and financial supportv (1) Few biotechnology companies were profitable in v 1993v (2) Considerable effort on developing credibility, and v appealing to investors to attract capital.v3 Very little effort on consumer needs and marketsBiotechnological product ready for marketv1 conform to FDA s

6、tandardv2 safe, potent and purev3 stable in injectable formv4 minimize the number of steps while v maintaining high yields and product purity, v quality and activityv A reduce the opportunity of product loss v B minimize product contamination.Process development consideratonv1 purpose v2 goalsv3 sta

7、ndardsv4 propertiesv5 native environmentv6 sourcev7 Prevent unnecessary and unexpected v loss of activity Downstream processing costs play a major rolev1 many academic and laboratory efforts are v focused on the isolation of a particular productv2 scant attention is paid to the economics of v proces

8、sv3 operational data from laboratory and pilot plant v are rarely reported Difficulties1 Not all the variables are completely known as the process is scaled-up.2 There should be enough flexibility in the process to take care of the unexpected needs. Centrifugation1 In biotechnology, centrifugation i

9、s effectively used to separate products that exhibit very small differences in specific gravity. 2 Compactly designed centrifuges have efficient economies of scale.3 Costs Economic considerations are a key factor in utilizing centrifuges .They can be broken down into 4 categories:1.Capital costs The

10、 capital costs of centrifuges runs from $50,000 to $500,000 depending on the size and configuration selected. Often the cost is strongly dependent on the specification required of the centrifuges.2.Operating costs Include utility, chemical and labor requirements. Product recovery specification signi

11、ficantly influence the operating costs.4.Nontangible（不确定性的） costs Often neglected when purchasing a centrifuge pact centrifuge may save or make available floor space on the shop floormicrobial cells have a disposal cost associated with them, the drier the cake is, the less is the disposal cost 3.Mai

12、ntenance It runs from 5 to 10% of the total labor costsThe improvements in the processI.Switching（转换） host cells from E. coli. to Chinese hamster cells.II.Changing the roller process to suspension-culture process.The costs per gram fell by about 100-fold.Example 8.2 The dosage for tPA increased by t

13、wo orders of magnitude to 100 mg which was expected to be 1 mg.In designing a process, the objectives should be clearly statedMany of the process variables change from the laboratory scale to the pilot plant scale.The time of transferring the purification process from the laboratory scale to the pil

14、ot plant scale is important. Emphasized 1 only chromatography offers the high resolution required to obtain a very pure product.2 Initial volume reduction steps may require clarification.3 The chromatography steps may be required.4 The sequence of purification steps is largely dependent on the produ

15、ct to be purified.Scale-up should be attempted only when:a) a suitable processing strategy in accord with the product to be purified has been developed b) The process has been optimized on the laboratory scaleThe parameters that are perhaps easily controlled at the laboratory scale may be different

16、and unpredictable at the pilot plant scale. Adjustments are often required.The modifications:Process optimization needs to be carries out continuously to improve the economics of the modified process.Example 8.3At the larger scale there was compression of particles in the column that decreased flow

17、rate and caused significant back pressure.Silica was suitable.Three ways to change a chromatographic column Maintaining a constant column area extremely long columns Increase column diameter while holding the bed height constant:Perfusion chromatographyv110 times faster than conventional liquid chro

18、matographyCost function vThe cost of the activated column per unit volume labor maintenance utilities depreciation（折旧）This is a profit function, not include investment cost, (i.e. research).Development of nondeformable gel materials Cost in running separationsvCost structureOperating cost (solvent c

19、ost )Column packing costCapital costs (columns, pumps, etc)Conclusionsv1 Data are scarcely availablev2 Economics determine bioseparation processv3 Meet the market demands and the government v standards Bring a drug to market v1 Cost : $ 100 million to $ 300 million (1985- v 1992) , 350 $ to 400 mill

20、ion (1995) v2 Time : 7 to 10 years v3 Research-focused companies combined with v drug development, manufacturing and marketing v resources v(1) 1 to 3 fully integrated biopharmaceutical companies, v(2) 10-15 platform companiesv(3) 50-100 successful boutiques(小商店，小公司）v4 Allergan ($ 1 billion in annua

21、l sales) combining Ligand (13 v million in annual research revenues）.1.Capital costs The capital costs of centrifuges runs from $50,000 to $500,000 depending on the size and configuration selected. Often the cost is strongly dependent on the specification required of the centrifuges.2.Operating costs Include utility, chemical and labor requirements. Product recovery specification significantly influence the operating costs.The modifications