Genetic Engineering & Biotechnology News

DEC 2018

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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Page 18 of 57 | Genetic Engineering & Biotechnology News | DECEMBER 2018 | 17 dollars," said Cintavey. Elaborating on these statements he con- tinues, "we have developed a single-use con- tainer composed of a PTFE composite that can be used to store drug substances at low (–86°C) temperatures while remaining flex- ible and not becoming brittle." PTFE's use in the STA-PURE™ flexible freeze container makes sense because one of PTFE's most interesting qualities is its durabil- ity when frozen. PTFE is also well known for its high purity, inertness, and biocompatibility. "Because of the molecular stability of fluoropolymers, like PTFE, used in the con- struction of these containers, contamination of the product due to leachables and extract- ables is not a concern as is the case with tra- ditional polymer-based container materials," added Cintavey. Although Gore's PTFE material is en- dowed with a number of positives as a con- struction material for low temperature storage containers, it cannot be gamma sterilized, the method of choice in pharmaceutical process- ing. "We have found that irradiation is not an option, as it causes unacceptable degradation to the molecular structure of the material," he stated. Instead, the bags are sterilized with ethylene oxide, an approach commonly used in implantable medical devices. Ramping Up Single-Use Manufacturing for Commercial Production The decision to pursue single-use technol- ogies in biologics manufacturing as opposed to multiple use is by its nature complex, but even more so in large pharmas with foot- prints that cover the planet, as exemplified by Bristol-Myers Squibb (BMS). With op- erations in many countries, its bioprocess- ing protocols are under constant updating and revision, as companies scramble to keep ahead of one another. "As we move our molecules into clinical production, we are converting previous hybrid operations to entirely single use," said Lance Marquardt, associate director for upstream processing at the BMS Hopewell, NJ, facility. The biologics under scrutiny at the vari- ous plants are mAbs, manufactured on a small scale with single-use consumables. These products are noteworthy as they allow decreased turn around time and do not re- quire validation. However, "we had to triple our warehouse storage space," Marquardt stated, "as moving to full single-use process- ing required a one month's supply of single- use consumables." With a large number of different mol- ecules, the Hopewell site is geared to handle 10 different projects with up to 4 underway at any one time. There are two separate suites, and the upstream and downstream facilities may simultaneously process differ- ent molecules. These turn around activities can be completed in as little as one day in the upstream phase. The Hopewell facility and the com- pany's clinical manufacturing facilities in Devens, MA, are now 100% single use with the exception of the downstream pu- rification columns. Another site, in Cruiser- ath, Ireland, has integrated single use for production up to the 2000-L scale in the seed train and up to 1000-L for media and buffer preparations, with about 30% of all operations done in single-use or disposable systems. The company's large-scale plants in Devens, MA, and Syracuse, NY, utilize mainly stainless steel, but employ single use and disposables throughout the cell expan- sion phase to the 25-L scale and up to 200 L for media and buffer preparation. Less than 20% of all operations at these plants are single use. Facilities typically have their own site-lev- el management structure. There is a supply planning group that coordinates overall com- mercial and clinical supplies with internal and external manufacturing capabilities and determines which plant site will be asked to manufacture which product and how much to be produced in a given campaign. Looking to the future, Marquardt as- serted, "We are looking at expanding the implementation of single-use equipment within the BMS manufacturing network; while there are many challenges, we do not see any that are insurmountable as we move forward." Lean Principles Applied to Single Use MilliporeSigma is currently carrying out a major program for improving site design, ac- cording to William Faria, head of operations, and Sara Bell, senior marketing manager, both of whom work out of the company's Danvers, MA, facility. The aim is to advance efficiency and speed the delivery of product. "We use the 'lean principles' approach, a new program for improving the process flow, that uses cultural modification and incorporation of ideas from our teams to make the operations more cost-effective and productive," said Faria. "We improved our production floor configuration, modeling the space by using cardboard cutouts laid out on the floor, to yield a full-scale picture of traffic flow. Then, with input from our staff operators, we were able to greatly improve the efficiency of the process. The redesign of the workspace resulted in a lead time that was cut in half, and there was a dramatic de- crease in customer complaints." In addition, the team introduced other updates and modifications, such as "English As a Second Language" instruction. "Since communication and workforce input are a major part of our program, given our inter- national team, we felt a responsibility to op- timize the process," said Bell. "But the main focus of the program is to build a culture of continuous improvement, by encouraging the staff to aim constantly toward improv- ing product quality, producing more, and working more efficiently." As a company with an international presence, MilliporeSigma operates facilities all over the world. But while water, utilities, construction costs, and salaries may vary widely, these are not the deciding factors in plant location and design. Strategic fit, customer reach, and availability of talent are the most important part of this deci- sion. But the primary need "is the overall footprint and how it fits into our long-range strategic plan," states Faria. Can SUBs and SUMs Be Best Friends with QC Micro and EHS? "Single-use technology can reduce new manufacturing facility startup timelines since clean-in-place and sterilize-in-place (CIP-SIP) cycles do not have to be developed and be- come certified," stated Katherine Leitch, di- rector of technical services at Alexion; she discussed microbiology quality control (QC Micro) guidelines and environmental, health, and safety (EHS) guidelines and their impact on the adoption of single-use bioreactors (SUBs) and single-use mixers (SUMs). In a wide-ranging discussion, she elabo- rates on how the properties and constraints of single-use technologies affect planning deci- sions for ongoing capital project at Alexion's Athlone, Ireland manufacturing facility. "The implementation of safety aspects that are im- portant to consider with single-use technol- ogy are minimizing ergonomic and potential for falls from heights," she explained. The current Alexion Athlone manufacturing facil- ity capital project utilizing single-use technol- ogy has incorporated worker safety consider- ations early in the project during the user re- quirement specification (URS) development and subsequent design reviews. The potential employee safety risks are lower with single- use technology since by design there is less interaction with hazardous energy." The safety advantages of single-use tech- nology include the reduction of high hazard safety risks to operators. When using single- use technology there is less potential expo- sure of operators to hazardous energy since there are no CIP cycles, no SIP cycles, and no high processing pressures. Leitch asserts that an important advan- tage of SUBs is that any sterile boundary in- tegrity issues are highly visible so there aren't unknown concerns, as is the case with stain- less-steel systems which may be endowed PendoTECH 5 Station TFF Screening System 6WDWLRQVRID7DQJHQWLDO)ORZ)LOWUDWLRQ&URVVÀRZ)LOWUDWLRQ3URFHVVZLWK FRPSOHWHO\LQGHSHQGHQWVWDWLRQFRQWURO,WSURYLGHVWKHDELOLW\WRFRQGXFW SDUDOOHOH[SHULPHQWVLQDFRPSDFWIRRWSULQW &RPSOHWHEDWFKFRQWUROZLWKEXLOWLQ SURJUDPPDEOHUHFLSHV 6\VWHPLQWHUDFWLRQYLDD3&EDVHG *UDSKLFDO8VHU,QWHUIDFH 5HDOWLPHWUHQGLQJDQGDOOGDWDLVZULWWHQ WRD¿OHIRUWKHSHUPDQHQWUHFRUG )HDWXUHVXVHRI3HQGR7(&+3UHVVXUH Sensors TM DYDLODEOHLQDUDQJHRIVL]HV %XLOWLQ3URSULHWDU\3HQGR7(&+7KURWWOH 9DOYHWRFRQWUROEDFNSUHVVXUH +LJKSUHVVXUHSXPSLQJZLWKGLDSKUDJP SXPSWKDWFDQSURYLGHXSWRSVLEDU RISUHVVXUH &RPSDFWORDGFHOOVXVHGIRU¿OWUDWH YROXPHPHDVXUHPHQWDQGWRHVWLPDWH ¿OWUDWHÀRZDQGÀX[ 'HOWD3FRQWURORSWLRQWKDWIDFLOLWDWHV SURFHVVLQJWRKLJKYLVFRXVFRQFHQWUDWLRQV RSWLRQDOLQSXWVSHUVWDWLRQIRU FROOHFWLRQRIDGGLWLRQDOSURFHVVGDWD NEW! Princeton, NJ USA • • ISO 9001:2015 Certified Bioprocessing See Single-Use Systems on page 18

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