The Impact of Disposables on Project Economics ina New Antibody Plant: A Case Study José M. Pais-Chantrau, Katia Zorrilla, Emeste Chico ABSTRACT This paper compares two project alternatives for he construction f a new 100.9 Toman fityinagne ispasable technology has ined importance in tec ent years. One of its significant sxivantages is that it reduces ‘the initial capital busden and spresds ‘out capital costs more evenly over the life of 4 manufacturing project A fully disposable plant is siill a technologi- cal dream, however. That concept has some potential applications in small- seal production, ar in pilot plants for process development, but seems less likely to have a significant impact on the current paradigm for large-scale biotech plants that have fermentation ‘capacity greater than 10Q000 L2 “There is less doubt nowadays, how. ever, that a combination of disposable and reusable equipment is beneficisl for process econamics in both new andi existing mami facturing plants. Such ‘hybrid models ean be applied with dif- ferent degrees of disposable integra- ‘ion, and (hat degree generally depends mainly on process scale and the Bio tech manufacturers’ experience with disposable technology. Mid-size plants ‘will probably benefit the most from tie asf tthe pit delynengree, ions chemtalengh aed Ee hn stencil dea, ne Tedmialreion et ont thereto Molen munch Hr, Cob, #87 ME deat, ‘antibody plant, based on o real case. The chosen hybrid approach which integrates disposable and stainless steel lechnolagias, is compared with on equivalent stoiness - steel model, in terms of capital investment, operating eosts, and nat present value, we of this hybrid model, but data from seal cate studies afe not yet available to validate this hypothesis. The Center of Molecular Immunology (CIM), in Havans, Cubs, hhas built a strong pipeline of newanti- bodies and cancer vaccines. Some of these products are in early research, and others afe in clinical develop- ment or commercial distribution. Several years ago, to meet this growing demand to produce therapeutic grade antibodies, CIM began the design and construction af a new plant with ae annual eapecity of 100 ky. CIM has integrated disposable tech- nologies into its biopharmaceutical processes for more than. 10 years, and the use of disposable technology has been a ley element in CIM's approsch to proces: innovation, cost contrat, and regulatory robustness. Current apple cations include plastic culture ware and d le systems for formulation operations and medium handling up to 2,500 L. Based on this practies! experi ence, a new antibody active pharma- ceutical ingredient (API) production 62 Blofharm Intemational www.biophamintemationsleim Oecenber2009SLE estes Figure 2. Pisnt youl of ie lacy whee service and liquidhanding sree have been, we Je euene serine in bags. wo Coa W Secren Coke ford tenage mai In re costars plant was designed to integrate dispasable technology to the extent that it has been ‘validated in our processes. Thi approach was chosen to maximize our antibody produc tion capscity in a context of limited cxpital availability. In contrast to most large facility invest- ment projects carried out By biotech camp.e ‘nies, CIM's manufacturing project is based ‘on continuous perfusion culture rather than the more widespread febhstch fermentation. Because af the higher productivity of pet. sion, production levels similar to those af the fecebatch mode can be achieved with smaller fermentation volumes. Hawever, the high medium tumover required for the continu is Opeiation of perfusion requires the we ‘of several medium and harvest storage vessels for each production fermenter. A large-scale perfusion operation also invalves almost daily purification runs (usually hundreds of Jots pet year) With intensive buffer preparse tion and storage operations. In our ease, all ‘this led to a smaller, but more sophisticated, manufact ufing facility compared to 3 ty picsl biotech plant. This paper discusses the economic com- parison of two project alternatives far the ‘construction of a new 100 kg antibady plant, based on 4 real case. The antibody plant, ‘with its significant integration of disposable technology, will be referred! to asthe “hybrid project” (HYE) and will be compared with an ‘Squivalent stainlesssteal (85) project based Gn reusable equipment, The two project alternatives will be compared in terms of capital inwestmant, operat ing costs, and net present value, THE NEW ANTIBODY PLANT ‘The basic production pro- cess used! in the new plant is very similar to standand feporied antibody produce tion schemes, Cell culture and fermentation are cafe fied out in a continuous erfusion mode that lasts jor several months, with harvests being collected at regular intervals. The puti- ication scheme starts with 8 capture step based on Protein A chroma- tography, followed by several chramatng- saphy steps for contaminant removal snd product polishing. Adequate viral reduction is achieved by viral (nang) filtration as well 5 by viral inactivation steps along with the chromatographic operations, ‘The plant was designed with two segre- gated production trains, which esch have 2,000 L of fermentation capacity. This setup allows two products to be manufactured simultaneously. The layout was organized to facilitate guid handling in bags at large sealk, based on experience with our current plocess Cell culture medium anf buffers ate stored in a central service carridor, from Wiieie all the process rooms are fed throixgh 8 closed liquid distribution system (Figure 1). ‘This open space alkws for flexible allocation of movable pallet tanks with bag containers up to 2,500 T. Larger bags are not available, however, 0 fixed stainless-steel tanks are used for volumes of 3,000 L and greater. A significant reduction of highly controlled cleanroom space was achieved with this approach Ligh storage in bags sccounts for the most extended use of disposable elements in the hybrid facility. Table 1 deseribes the level of subst ution of stainless steel tanks by dispos= ble containers in the warious slaps of the man wiscturing process in this model. Disposable bags rephead 73% of the total Lquid storage capacity of the plant, estimated st 117 mt ant 66 Blofharm International wwwblopharmintemationsl com December2009pets CETTE distributed over more than & hundred process vessels. Other disposable elements were also intreduced, such 35 chiomatogeaphic ment- branes and disposstie viral fillsation, but those had & limited effect an equipment cost savings. BSTIMATE OF CAPITAL INVESTMENT Figute 2 shows the total capital costs for econstruct- ing 2 100 kg antibody plant under each proj- et alternative, This cal- culation started with a detailed estimate of equip- ment purchase costs (PC) based on recent price quotes. Prices were cor fected for volume and currency depreciation where needed. To avoid Significant distortions of the results because af land prices and construction costs in Cuba, the total capital casts were calew lasted using Lang coat ficients, a5 updated by Petrides for the biotech sectors4 This method makes it possible to cal- culate the warious items of the eapital cost based on the equipment purchase cost using several muilti- pliers for coefficients). The use of thete coefficients for disposable and stain- lessesieel technology has heen discussed in the past bby various authors.'4 After making the calcu lations for our ease study using the combination of the selected Lang coef ficients, we found that direct fixed capital was seven times greater than the equipment purchase cost for the stainless steel ans steed (SS)andhybid (HYB) models. a) ae] Tes mee | naw | a] MB] ons |g deme | i) 2} ar | ig winsecs | i] op] ome | tk aa eee pap oe macnn | 2 | am| me | in a veveteeee | 1] ten] ae | ag alttaiites [| HB] | Taeymatin | tepapatrems |r] am] ee] en ee co eae | aa] ee} 8 wat. |e] Bl a | a secre; |e] am} ar | pemgen | ft] ae] oat | og ss Tesvauovea |} ap} ae] au wmewe || ae] fe | as Soames | 7] uel oa | a foreereet |i [ ma] or | Teaamane Tranvee [2] am) aa) ee 2 wince | a] i] BE ~ anmerew |G] Bl as | a +] w]e — 3] Bl & | B ?] SB] & | 8 ee en ] a] a | og i ihaieae Tasgeent [op i] ae [ee Fur 2 ea ote wl a courbes Patri Peet tnd alpen? aeetenete snipe att ath hase coat (se) ore 5 ae Met ca oa La se ween tant toma? te pico tied qemtiad Dscenterz009 wawlophammirternstionsleom BioPharm Intemational 6?