	GlaxoSmithKline (GSK)’s R&D Biopharmaceutical Pilot Plant in Upper Merion, PA is a R&D clinical trial material (CTM) manufacturing facility with an aggressive processing schedule that requires minimal shut-down interruptions. Utility reliability is paramount to achieve production demands and regulatory quality requirements. To meet the utility demands for increased CTM output, a capital investment project was required to replace the existing, obsolete high purity water (HPW) generation system and water-for-injection (WFI) generation system with new, reliable technology.

		Existing generation systems (HPW and WFI) had insufficient capacity for current operations and were unable to meet the demands of the growing pipeline.

		Spare parts for the existing systems were either not available or becoming more difficult to source.

		Existing systems were costly to maintain, not energy efficient, not reliable, and had insufficient redundancy, increasing the potential for unscheduled production downtime.

	The primary objective for the project was to provide water system(s) generation reliability with the following additional requirements:

		Deliver more environmental sustainable systems (i.e., lower water and energy usage)

		Have no impact on ongoing GMP operations.

	GSK engaged Hargrove Life Sciences to complete the design for this project. The conceptual design phase included evaluation of new equipment technologies, a sustainability evaluation including energy and operating cost comparisons, and visiting other recently installed GSK water systems at other locations. Also, because the pilot plant was landlocked, with no available space inside the facility for new equipment, investigation and analysis of where to install the new water systems was required.

	Selecting the equipment and technology for the HPW and WFI systems was based on evaluations that took into consideration sustainability goals including reduction of energy, water, and carbon footprint. It was also determined that the best way to achieve system generation reliability was to have complete redundancy for all mechanical equipment (i.e., essentially two of everything).

	Redesigning the high-purity water system

	The existing HPW distribution system provided a continuous flow of 30 gallons per minute (gpm) of purified water at 25 °C. Purified water was constantly circulated to the utility systems in the basement mechanical room and also to the three GMP operating floors using dual, sanitary variable-frequency drive (VFD) pumps rated at 150 gpm. The basement utilities supplied with HPW feedwater included a WFI still and two clean-steam generators.
	
	This existing system produced water with a resistivity greater than 10 Mohm and total organic carbon (TOC) with less than 5 ppb, and GSK wanted to maintain this high quality for the new system while also incorporating a sustainable design.
	Criteria for the new HPW system included the following:
	 

		Redundant mechanical equipment (i.e., two of everything). Reliability would be achieved through redundancy, with dual multimedia filters, softeners, carbon filters, reverse osmosis (RO)/continuous deionization (CDI) skids, distribution pumps, and vent filters.

		The existing 34 gpm generation system did not always adequately maintain building operating demands. The new system(s) would require larger capacity (40 gpm) for existing building operating demands, increased WFI generation, and future building expansion or increase in users/processes.

		Start/stop technology was a requirement to reduce electrical energy and water consumption rates.

		The generation system must be designed for hot water sanitization at 80 °C (65 °C minimum).

		A mixed-bed polisher would be required on the new system design to meet resistivity quality requirements.

		A new stainless-steel, HPW storage tank must be provided that would include increased storage capacity to meet larger instantaneous demands of water from expected increases in production. The new tank would also retain a nitrogen blanket that was installed on the existing storage tank, which had proven to be successful in helping to maintain a low bioburden in the system.

	Based on these criteria, it was decided that the RO system only needed to be single-pass technology to meet HPW quality requirements. The project team also decided to implement carbon filtration instead of bisulfite injection or ultraviolet light technology as the primary method to remove residual chlorine/chloramines. Although carbon filtration represents the most expensive initial cost, it is the most effective method of removing residual chlorine/chloramines. The downside of using carbon filtration is the carbon filters are an ideal breeding ground for bacteria. However, because the carbon filters would be hot water sanitizable, the concern of bacteria growth was reduced. Other design considerations included:

		Installing a new bulk brine storage system to eliminate the need for manual material handling of the salt required for softener regeneration

		Installing a RO reject water recovery system used for makeup water to the building’s cooling tower

		Supplying HPW to an adjacent biopharm process development facility, thus enabling the decommissioning of a second water purification system serving this adjacent building, which further reduced site operating expense

		Installing a new online microbial detection system.

	The online microbial detection technology was released for commercial use in pharmaceutical clean utility systems just prior to the design phase of this project. After various on-site pilot testing scenarios, it was concluded that this online microbial detection technology would be installed on the HPW distribution system, greatly reducing the system’s water sampling and analysis work load. The project purchased and installed one of the first commercially available units in the United States. This online microbial detection system complements the online TOC and conductivity systems, which are typical to GSK water system designs.
	 

	The existing WFI generation system was a 25-year-old multi-effect (ME) still. The unit produced a maximum of 470 gph of WFI at 82 °C. As the facility’s GMP processing manufacturing capacity increased, the WFI generation system had inadequate generation capacity, which resulted in rigid planning for various manufacturing users so that the WFI storage tank would not be completely drained during use. WFI manufacturing capacity studies indicated that the maximum WFI usage in the facility could approach 1325 gallons in a two-hour period. With the existing WFI still make-up rate, the WFI storage tank volume would fall dramatically and cause the WFI distribution system to shut down. It was determined that the existing WFI storage tank would not be replaced because of limited head room and access space into the basement utility area.

	With maximum site plant steam pressure limited to 90 psig, replacing the existing still with another ME still would require an oversized (de-rated) system, as these are designed to normally operate with plant steam at 115 psig. In addition, the ME still would require an external cooling exchanger to remove excess heat, which would have an impact on the building’s process glycol system.
	
	With reduced plant steam pressure and the desire to minimize process glycol loads, the engineering team determined that the replacement WFI stills would be vapor compression (VC) type stills. VC stills are designed to operate with 50 psig plant steam in lieu of 115 psig required for ME stills, which yields energy savings from reduced steam usage. Also, the cooling load could be virtually eliminated, which would reduce approximately 25 tons of process glycol that was required for the ME still. Although VC stills are more expensive from a capital installation cost perspective, they are more economical to operate from a utility demand.
	The existing WFI distribution system consisted of three independent supply loops with a dedicated pump for each GMP operating floor of the facility. The new pumping distribution system design consisted of two new VFD-controlled redundant pumps each capable of serving all three floors simultaneously. If one pump were to fail, the remaining pump was designed with sufficient capacity to maintain WFI distribution for the entire facility.
	 

	At the completion of engineering design, the project team determined that the two new water systems must be delivered using a phased construction and validation approach to minimize shutdown interruptions to the manufacturing areas.
	
	Phase 1 included the construction, installation, and validation of a new HPW generation, storage, and distribution system in a location that would not impact the facility’s planned GMP manufacturing schedule. Phase 1A included replacement of the WFI distribution pumps and the main WFI control panel including validation testing. Phase 2 involved the demolition of the existing HPW generation and storage equipment in the building basement to establish the location for the installation of two new VC WFI stills. Phase 2 could only be completed after Phase 1 HPW generation and distribution systems were released for GMP use.
	
	


	Phase 1 would entail the construction of a strategically placed new mechanical room in an unused courtyard that was isolated between existing facilities, as shown in 

. The new mechanical room in the chosen location was required to be two stories, providing a location to install, commission, and validate the new HPW system prior to connecting to the operating pilot plant and decommissioning the existing HPW system.

Figure 1. Courtyard between two buildings that was chosen as the site of the new, two-story mechanical room. All figures are courtesy of the authors.
	The redundancy requirement proved to be a challenge because two HPW generation trains would need to reside in the proposed two-story mechanical room, which was constrained in a space that was only 14 ft. wide and 110 ft. long. A thorough and iterative study was done to confirm the equipment could be installed and be serviceable, which included the development of a three-dimensional design model (see 

). Once the proposed space design was proved out, the detailed design of the water system and proposed addition began. The GSK/Hargrove team worked closely together to design every aspect of the project to ensure minimal impact to the existing adjacent operating facilities.

Figure 2. Three-dimensional design model of two-story mechanical room.

	Phase 1 construction of the HPW mechanical room in the unused courtyard required the removal of a portion of Building 38’s exterior glass façade, potentially exposing the pilot plant to the elements of nature (e.g., weather, insects). Therefore, prior to removing any portions of the building’s existing façade, temporary weather-proof interior walls were constructed. As the façade was then being removed, the daily limit of removal was controlled to an area that could be sealed back up in the same day with a temporary facade.
	
	

Installation of equipment into the new HPW mechanical room


	
	With the new mechanical room completely surrounded on all sides by existing buildings with no access for bringing in large pieces of equipment, it was necessary to install all the major pieces of equipment using a hydraulic crane. The challenge with doing this is that the room construction took place prior to equipment delivery. Therefore, the project team staged the construction of the new room to essentially have a section of the mezzanine floor and roof to be constructed after equipment installation. Once the missing building sections were constructed, equipment could then be shifted to its final location, as shown in 

Figure 3. Installation of equipment into the high-purity water mechanical room.
	
	


	Phase 1A included the installation of two new WFI distribution pumps and the new WFI control system. The existing WFI distribution system consisted of three independent loops for each GMP operating floor of the building, each with its own pump. The new distribution system consists of two new VFD-controlled redundant pumps each capable of serving all three floors. This phase was the most critical to ongoing operations because there was no backup plan (i.e., everything had to go right the first time to bring the WFI system back on-line in the shortest possible time frame). Therefore, extensive planning was required including: the development of process operational descriptions for the new control system, which included 86 instruments and 106 input/output points and the development of the WFI system hydraulics using Fathom Modeling for the entire building’s distribution system, which turned out to be extremely valuable for vetting the design. The plan to control the distribution system was to use flow control on the return from each parallel floor loop to maintain minimum velocities. Also, the third-floor return pressure, which was the most remote location in the system, would be used to adjust the speed of the pumps to maintain minimum loop pressures.
	
	Once Phase 1 and Phase 1A were completed, the pilot plant would be supplied with high purity water from the new HPW generation system and supplied with WFI using the existing ME still, new redundant WFI distribution pumps, and new WFI control panel. Phase 2 could then commence, which included the demolition of the existing HPW system in the basement mechanical room and the installation of two new WFI VC Stills.
	
	


	Phase 2 construction activities were conducted similarly to Phase 1 given that the new WFI stills would be installed, commissioned, and validated while the Pilot Plant was fully operational. Due to the challenge with bringing the new equipment into the basement mechanical room through a constrained access door, the new stills were designed to be disassembled and shipped in multiple components that would then be reassembled onsite.

Utility tie-ins for the different project phases


	
	All supporting utility system tie-ins (e.g., nitrogen, air, clean steam) and the connecting of generation systems to the building’s existing distribution systems were completed during preplanned windows when the pilot plant was not operating and had no water demand.
	
	


	
	The project team decided early to use a leveraged factory acceptance test (FAT) qualification approach to reduce the overall project validation schedule. All GSK equipment FATs are executed and documented in a manner that may allow GSK to “leverage” the FAT execution documentation (FAT turnover package) during future commissioning and validation on-site at their facility by referring back to FAT-executed approved testing and results. The FAT is a GMP activity approved by all stakeholders including the equipment vendor, GSK Engineering and Validation group, Quality Assurance group, and Facilities Operations group to eliminate the need for redundant testing once the system has arrived on site.
	Testing that has been successfully completed at the FAT and poses a low risk of being impacted by transport of the system from the factory to the site in a manner that would change the results of the testing will not be repeated. This testing is detailed and leveraged under a later lifecycle qualification document. Testing that has not been successfully completed within the FAT or that poses a higher risk of impact during transport is either repeated or conducted for the first time at the site under a later lifecycle qualification document. This approach reduced the qualification schedule by three weeks.

	The total duration of construction was approximately 60 weeks. The majority of this time (44 weeks) was spent on Phase 1, which was the construction of the new HPW mechanical room and installation and validation of the HPW system. Phase 2, which was the removal of the existing HPW equipment in the building’s basement and the installation and qualification of the new WFI generation systems, took another 16 weeks to construct and validate.

	The main challenges included the small area to construct the new HPW mechanical rooms and the limited utility shutdown opportunities available to tie-in two new water systems. Another major concern was installing the new WFI distribution pumps with a new WFI control panel because there was no turning back when the old pumps and control panel were removed. The WFI concern was reduced after full programmable-logic-controller simulations were completed along with hydraulic modeling of the WFI distribution system. In fact, the installation and validation of the WFI pumps and controls went exactly as simulated.

	The phased approach for construction, validation, and testing provided for the installation of state-of-the-art water generation systems with minimal plant operation downtime and no impact to ongoing production. Since the release of the project for GMP use, benefits were realized quickly by the business, such as ample supply of water, reliable supply of water, lower energy usage, and lower overall operating costs. The GSK Engineering design team worked with selected equipment vendors to minimize water and electrical usage wherever possible, which has resulted in significant environmental sustainability benefits and operational cost savings. Annual operational expenses were reduced by approximately $170k per year, and annual carbon emissions were reduced by 348 tonnes CO2.

	The two new redundant HPW generation systems (see 

) represent the latest technology for energy and water efficiency in the production of USP grade water. They are designed using commercially available technology that enables one of the systems to automatically be brought off-line to be sanitized and put back on-line when required. This control technology also consumes significantly less water and energy and produces significantly less waste-water compared to conventional systems. This system translates into operating savings, with more environmentally responsible, energy-efficient, purified water generation processes. In addition, customized software programming requirements were implemented to reduce potable water usage during the softener regeneration cycles, and the RO membrane cleaning is now determined on normalized differential pressure software monitoring in lieu of a traditional totalized flow rate approach.

	Major benefits included in the implementation of the new HPW generation systems included the following.

		Water make-up and sewer savings were approximately 11,000 gallons per day (or 4M gallons per year).

		Electrical costs were reduced by 88% because the HPW generation system shuts down if there is not a demand for HPW storage tank make-up.

		The on-line microbial detection system has reduced manual quality grab samples by 20%.

		The bulk brine tank system reduced site labor costs because the manual salt replenishment process has been eliminated.

		Additional operational savings were realized by having the new HPW system supply the biopharmaceutical development pilot plant, thus eliminating a costly vendor service ion-exchange contract.

	The two, new, redundant VC stills provide additional capacity and ensure reliability. The VC stills were also designed and validated to operate using variable compressor speeds to reduce electric demands when providing WFI to the storage and distribution system. For example, if the required WFI fill rate is minimized, the still compressor can operate on a slower speed to lower electrical operating costs.

	Major benefits included in the implementation of the new WFI generation systems include:

		Electrical costs reduced by 66% (VC does not have a feed water pump)

		Chilled water consumption reduced by 97% (not required by VC for cooling)

		Blow down of high purity water to drain reduced by 91% (VC does not blow down in standby mode).

	The water systems were installed with minimal planned downtime, and the two water-generation systems were constructed and validated in approximately one year. All project objectives were exceeded.

Figure 4. First floor of the new water treatment room with the new high-purity water generation system (reverse osmosis and continuous deionizer skids).

Figure 5. Second floor of the new water treatment room showing the top of the high purity water storage tank with multimedia, softeners, and carbon filters in the background.

:
	When referring to this article, please cite it as B. Lipko, S. Walter, and B. Termine, " Case Study: Retrofitting Two New High Purity Water Systems," 


	Brian Lipko, PE is leader of Projects and Steve Walter,CPIP is Process Technology leader, both with Hargrove Life Sciences, www.hargrove-epc.com, Tel. 1.215.789.9662; Brian Termine, PE is Maintenance Engineering manager at GSK. 

Articles

Features

a capital investment project was required to replace the existing, obsolete high purity water (HPW) generation system and water-for-injection (WFI) generation system with new, reliable technology.

Case Study: Retrofitting Two New High Purity Water Systems

Sean J. Morrison, the author of an editorial that analyzes scientific reproducibility, wrote, “Studies with revolutionary ideas commonly lead to many follow-on studies that build on the original message without ever rigorously testing the central ideas” (1). In addition to being a senior editor at the open-source journal 

and an expert in stem cell biology, Morrison is the director of the Children’s Medical Center Research Institute at UT Southwestern, the Mary McDermott Cook Chair in Pediatric Genetics, and an investigator at the Howard Hughes Medical Institute.

	If Morrison’s statement is true, the value of follow-on studies may be exponentially diminished, leading to an eventual erosion of scientific understanding over time. Revisiting and testing the protocols that were employed during groundbreaking studies, then, is a crucial element of damage control in the life-science industry. This idea is equally true for studies on bioprocessing techniques, especially as biologic drugs become more complex and new technology to manufacture them emerges.

	The inability to reproduce results from a successful bioprocessing run is not only frustrating for manufacturers, but can also increase the costs of drug development and contribute to overall inefficiencies. In 2015, Leonard Freedman-who is the president at The Global Biological Standards Institute (GBSI) and has done work on reproducibility and cell lines-and coauthors estimated that the annual economic cost of irreproducible research in the life sciences is approximately $28 billion (2). For each run that does not produce the anticipated result, several thousands of dollars are likely lost to reagent and reference material costs, says Freedman. While study design, laboratory protocols, data analysis, and reporting can also contribute to irreproducibility (2), researchers lose precious time when reagents don’t perform as expected-and this is one of the variables of irreproducibility that is likely easiest to control.

	Although reproducibility exercises can be expensive, refraining from critically evaluating previous research and conclusions from past experiments may be costlier in the long term than investing in reproducibility studies. If a reagent’s purity and homogeneity is not scrutinized early on, it is possible that studies testing its uniformity will have to be conducted at a later date anyway, contributing to the overall cost of manufacturing operations. Thus, improving the validation and characterization of biologic materials reduces operating costs.

	In 2011, researchers from Bayer found they could only validate approximately 25% of the studies on therapeutic drug targets from published data (3).

	In 2012, researchers from Amgen were only able to validate 11% (6 of 53) of “landmark” papers that were used to justify the launch of various drug-discovery programs (4). And a 2016 survey published in 

revealed that 70% of researchers have tried to replicate another author’s research findings, but nearly half of these researchers were unable to verify original conclusions (5).

	In the literature: Run reproducibility in biomanufacturing

	Efforts to monitor reagent origin and purity have not been the focus of widespread evaluation in academic papers on bioprocessing. The specific topic of reproducibility in bioprocessing has not been examined in much depth, either, although biomanufacturers do try to understand why high or low yields occur, says Veronique Chotteau of the KTH Royal Institute of Technology, given that yield has such a high impact on the economics of a process and on drug safety. Historically, Chotteau says that variation between runs in the same facility can be up to 50%.

	Although process development and characterization improve reproducibility, biomanufacturers still regularly encounter differences between runs, notes Chotteau, who adds that cell growth is rarely exactly the same from batch to batch. Efforts to maintain reproducibility have prompted the biopharmaceutical industry to opt for serum-free media for the manufacture of cellular therapies (6); other studies stress that batch-to-batch reproducibility of glycosylation is essential to get a consistent end product (7).

	Measurement of critical quality attributes (CQAs) for each run provides the most important information on run reproducibility, says Richard D. Braatz, the Edwin R. Gilliland professor of chemical engineering at Massachusetts Institute of Technology, who works on the mathematical modeling of bioprocessing plants. “In addition to direct measurement of CQAs for each run, reproducibility from run to run can be improved by operating a plant-wide mathematical model in parallel with manufacturing. Feeding process inputs from the real manufacturing process into the mathematical model would allow the model to make predictions that can be compared with the measurements.” Braatz adds, “Differences between the model predictions and measurements can be used to track changes in operations from run to run, and used to test hypotheses on potential causes,” a technique which he says has been applied in the oil refining, chemicals, and petrochemicals industry for decades, but has so far had limited applications to biologic pharmaceutical manufacturing.

	Although some advances in design for manufacturing principles (8)-which factor cost of large-scale manufacture into design plans-have helped the industry plan for gaps in manufacturing reproducibility, and quality-by-design efforts have helped engineers gain better control over resulting outputs, there is little available literature testing the assertions of biomanufacturing models of best practice.

	In addition, while there are many experiments in academic literature that use scale-down models to inform large-scale manufacturing, there are few examples of outside labs or researchers testing the so-called “optimal” set-ups touted by the original researchers in the academic papers. Nor are there studies that test what are thought to be the “optimal reference materials” for bioprocessing runs. Industry stakeholders say that a product is defined by a process, but who tests a process once it has been defined?

	When a platform process does not deliver acceptable results, says Bruce Hamilton, head of characterization at antibody and life-sciences tool provider Abcam, suppliers refer to literature reports to examine relevant parameters of a product in development. Hamilton adds that process engineers “might also run a small-scale trial scouting lots of parameters [of the monoclonal atibody (mAb)] as a first test, but this is not primarily guided by the literature.”

	The most efficient processes are those that can predictably be reproduced run after run. Given the concern circulating the industry about reproducibility in drug development experiments and clinical trials, there should also be industry concern that pivotal bioprocessing experiments cannot be replicated, both in scale-down models and at the commercial level. Production runs sometimes are not similar to one another after a process has been optimized for large-scale operation, or after a process has been transferred to a contract manufacturing organization. Are these run differences a result of subtle changes in protocol and methodology, or are materials the main culprit? When does the ability to reproduce a run correlate with good process understanding-and when is a good run simply a fluke?

	“Reproducing a run does not mean a process is understood, only that the conditions perceived to be necessary could be performed again to obtain a similar result,” notes Tim Errington, who is metascience manager at the Center for Open Science and co-leader of the Reproducibility Project: Cancer Biology, a project which is attempting to replicate results from pivotal studies in cancer drug development (9). “Both runs could be the result of some unknown variable not thought to be a necessary part of the process-some aspect of the starting materials or a specific step.” Adds Errington, “The reverse is also the case, that an inability to obtain the same result does not correlate with poor process understanding. It could be an undocumented mistake confounding the result. But, importantly, as a result is replicated, it increases the reliability of the process and as more variables not thought to impact the result are varied (different lots/sources of reagents, different personnel, different manufacturing location, etc.) and the same result is achieved, it further increases the reliability and utility of the process.”

	In the five initial studies that are part of the Reproducibility Project: Cancer Biology, Errington and his colleagues were only able to validate the findings in two of the studies (10). The cancer project is similar to the Reproducibility Project, which was conducted to test the reproducibility of key psychology experiments (11).

	Errington and colleagues concluded that while errors can be caused by the improper execution of an experimental technique, they can also be caused by problems with samples and materials. The researchers “undertook authentication of key biological materials (such as [short tandem repeat] STR profiling of cell lines)” to prevent the likelihood that a validation failure was due to error. To improve the probability of replication, the authors of the original studies were asked to “share any original reagents, protocols, and data in order to maximize the quality and fidelity of the replication designs.”

paper that validation of reagents is a key factor influencing whether a study’s findings can be replicated-and he found that many investigators relied on findings from earlier papers for information on reference material validation, even though many of those preliminary papers did not include specific validation data either (12). Begley added, “There are also examples of investigators using an antibody even when the manufacturer declares it unfit for that particular purpose.” Antibody supplier Cell Signaling Technology (CST) shares that even a validated reagent, if used incorrectly, “can induce changes in the specificity and sensitivity of an antibody.”

	Anita Bandrowski, founder and CEO at SciCrunch, the company that runs the Antibody Registry, tells this publication that a reagent from a reputable company should include information about the protocols in which the reagents will likely work best. And, as CST notes, an antibody should be validated using the application in which it actually will be used in practice. The company says that validating with a Western blot, for example, is of little value to inform a researcher about an antibody’s ability to work by immunofluorescence or immunohistochemistry. Even if the correct validation method is chosen, Karin Lachmi, PhD, co-founder, chief scientific officer, and president of Bioz, a public website that chronicles reagent mentions in methodology sections of scientific studies, notes that achieving the exact binding or enzyme level in an assay is still difficult: “The cause of this inconsistency can be attributed to quality variability in antibody/enzyme batches, different target systems, and different techniques” used in labs.

	Exact reagents are sometimes difficult to pin down because an original researcher has left an institution, taking his or her knowledge with him or her. A 2013 paper that reviewed several hundred journal articles found that 54% of resources were not uniquely identifiable in publications (13).

	When reagents are not validated, researchers may draw conclusions from their experiments that are simply inaccurate. They run the risk of using an antibody that recognizes the wrong protein, or may base conclusions on a cell line that is not of interest to researchers. To make the situation even more problematic, sometimes antibodies cross-react and recognize the wrong targets (14), which is why some researchers use Western blots that rely on the recognition of at least two different epitopes. Gathering appropriate reagents, doing controls, and optimizing conditions is a major time sink, asserts Bandrowski, who is an expert on citing biological reagents. “If the original protocol is not adequately described, including a poor text description of the reagents, this part of the experiment can take weeks or months instead of days to weeks,” she says.

	Although suppliers should make their best attempt to alert purchasers when changes in reagents occur, this can be challenging, says Bandrowski. “In academic labs there is a purchasing department and [supplier] companies often can’t track down who is actually making the purchase and using the product, so they are stuck with adding this information to their website and hoping that their customers come back before publishing.” Lachmi argues that revenue generation is a supplier’s top goal, and that currently, “changes that occur to reagents are insufficiently characterized and documented.” Because vendors have no incentive to alert customers about reagent changes, she reasons, a “vendor-neutral” clearing house such as Bioz is necessary to guide buying decisions.


	Freedman says that to overcome the problem of reagent identification, standards and verification strategies for reagents must be developed for all reference materials (15). National Institutes of Health’s (NIH’s) Rigor and Transparency Guidelines, which went into effect in 2016, required that any researchers wishing to receive a grant for their research must incorporate a validation/authentication plan for every study (16). According to a section of the guidelines called “Authentication of Key Biological Resources in Grant Applications”, antibodies should be “validated by Western blot, ELISA, immunoprecipitation, immunofluorescence, or flow cytometry using knockdown cells and positive and negative controls, depending on the assay proposed” (17).

	A big part of the scientific rigor that NIH supports-through the thorough description of methodology and experimental design-relies on the ability of outside scientists to replicate the study’s findings in some incarnation. Whether it is statistical similarity, or similar effect size, some of the parameters must be met. As the American Statistical Association suggests, “Reproducibility shouldn’t be thought of as a binary state-either reproducible or not reproducible-but as a continuum from hard-to-reproduce to easy-to-reproduce” (18). 

	In 2014, the NIH developed a Data Discovery Index where researchers could analyze raw data from experiments, and a 

 in which researchers could contribute their concerns about research protocols and methodologies (19, 20). NIH’s Resource Identification Initiative (

) was launched to help study authors authenticate (as well as properly cite) organisms and cell lines (21). Errington argues that if all data and methodology items in a paper were automated and shared, this would further drive the discoverability and reuse of information. He says the burden to communicate research findings should not solely be on the researcher, but should be built into the “research ecosystem.”

	Characterizing antibody/reagent performance

	Because there are so many ways to get to a final product, and the types of products that are now in development are becoming increasingly complex (e.g., incorporating fusion proteins and bispecific antibodies with multiple active domains), researchers need to be as specific as possible when it comes to describing the starting raw materials used in studies and the characterization methods that were used to validate starting reagents. According to Freedman, there are some standards developed for antibody validation and cell-line authentication, but there is currently no standard for reporting serum characteristics (15).

	Proper citation of an antibody is necessary for study reproduction, insists Tove Alm of the School of Biotechnology in the KTH Royal Institute of Technology. She says The Antibody Registry (

) assigns stable, unique identifiers (called Research Resource Identifiers, or RRIDs) to antibodies, which protects their identification should the companies that provide antibodies undergo mergers, acquisitions, or brand-name changes. Even antibodies under development (i.e., non-commercial antibodies) are assigned RRIDs in the Antibody Registry, says Alm. Assigning an RRID assures a product is “machine readable,” says Errington, which is important to track a product’s use and utility in an experiment. According to those who run the portal Antibody Registry, in 2017, more than 1% of papers (approximately 1700 papers) in biomedicine publish RRIDs for reagents-which is an increase from 2014, in which approximately less than 0.02% of papers included this information (22).

 that antibodies included in experiments be identified by genus and species and that trial sponsors list the citation, catalog number, and clone number for antibodies used in investigation (23). It also suggests adding information about the validation of an antibody, which is information that can be obtained through portals such as Antibodypedia, 1DegreeBio, and Biocompare. Other sites, such as Addgene Vector Database, allow users to search for expression vectors in published studies. Cell Press implemented STAR Methods in 2016, which are guidelines for reporting. 

’s requirements, as well as the National Centre for the Replacement, Refinement, and Reduction of Animals in Research’s ARRIVE guidelines, which were 

 (24). Another reproducibility initiative is the 

Center for Open Science’s Transparency and Openness Promotion (TOP) guidelines

, which seeks to encourage “shared standards for open practices across journals” (25).

	Antibodypedia is a database that allows antibody manufacturers to submit validation data on antibodies, inviting them to divulge information on antibody performance in different applications using “pillars” of antibody validation-first described by Uhlen 

.-to help researchers and editors determine if an antibody is properly validated and appropriate for a specific experiment. The thought is that through use of at least one of these parameters measuring antibody specificity, researchers can more accurately predict antibody performance and reproducibility of antibody function (26). One of the pillars described by Uhlen 

. is the use of an orthogonal strategy where an antibody-based strategy is compared with an antibody-independent method; to verify antibody specificity, the level of detected expression of the antibody’s target protein using a specific application (e.g., Western blot) is compared with the level of the target protein that is identified using mass spectrometry.

	Antibody supplier CST says it defines the models to be used to validate an antibody in tandem with the selection of new targets for antibody development. This information includes definition of the most critical applications for which the antibody should be used, which cell lines and tissues express high or low levels of the protein in question, the feasibility and availability of knockdown or knockout reagents, and what orthogonal methods would help validate a new antibody. CST adds that if an appropriate validation system is not known when an antibody is under development, when a method becomes available, the company retroactively validates the product. CST says besides being one of the few companies that validates its products, it is also one of the only companies that prefers to sell reagents by dilution instead of concentration, because “changes in assay performance are often specific to a single assay instead of antibody performance overall.”

	CST admits that as its portfolio of polyclonal antibodies has grown, so has the burden to generate consistent product lot to lot-a main factor that drove the company’s decision to move toward rabbit mAbs, which they say are less variable. However, the company says it still sells polyclonal antibodies because they are inexpensive, easier to generate, and are still preferred by many scientists. The company says this preference is likely due to the fact that polyclonal products are “highly cited in the literature” already. Lachmi concurs that researchers rely on literature sources (typically through PubMed, she says) for reagent identification and selection. “Market studies have demonstrated that product use in journal publications is the number one attribute that drives the purchase of life-science reagents by researchers,” she remarks.

	Some of the latest techniques to validate antibodies include using mass spectrometry, peptide arrays, and knockout cell lines, says Hamilton. By using knockout cell lines-which were produced using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and Horizon Discovery’s library of haploid human cell lines-Abcam was able to validate more than 1000 antibodies. Abcam’s push to authenticate antibodies, dubbed the Knockout Validation Initiative, began at the end of 2015 and is still an ongoing project.

	The resale of antibodies has become a particular concern as of late, especially when a researcher encounters an antibody that does not work as intended, or if he or she is looking for two antibodies binding to different parts of a target, notes Alm. It would be most helpful if antibody producers shared target sequences or provided details about epitope mapping studies, says Alm, but she says this information is typically not provided. She says using the compare function in Antibodypedia can usually help researchers tease out when an antibody is the same as one they have already tried, but is just being resold by another company. She adds that when identical images are presented for antibodies with different names in the portal, it is likely a case of antibody reselling at play. CST comments that product clones are sometimes obvious because of the inclusion of a company’s clone name or identifier, but that some suppliers intentionally leave information about clonality obscure.

	According to Bandrowski, antibody reselling is a dangerous game, primarily because problems with an original product being resold may not be detected if there is no clear chain of provenance from which the reagent came. “Think of it as the discovery of E. Coli on a batch of lettuce from a farm-that lettuce may have entered many products and a recall needs to be complete otherwise people will get sick,” she says. “In the scientific literature, there is no mechanism to create a recall and this cripples all efforts to improve reproducibility in science.”

	Even with a properly referenced RRID, supplier changes still confound the source of some products, says Bandrowski, mostly because people hold onto their products in deep freezers. She recalls an instance with a Chemicon product that was listed with its RRID in a paper, but was cited in different ways by other researchers referencing the paper. “By this time, Chemicon had been part of Millipore for over eight years and Millipore was transitioning between EMD and Sigma. Another author using the same product cited the company name as Chemicon/Millipore and a third [cited it as] EMD Millipore. She adds, “This is actually one of the easiest cases to deal with because even though we had some confusion about which product came from which company, the smaller companies were bought in whole and their catalog numbers did not change.”

	The misidentification of cell lines has likely affected the conclusions of hundreds of thousands of papers, according to researchers (27). An 

found that during a five-month period in 2013, only 19% of papers performed cell-line verification studies (28). And, according to numerous studies, approximately one-third of cell lines contain a mixture of species types, are contaminated, or are misidentified (29, 30). Another paper found that only 43% of cell lines were identifiable (13). As Bandrowski points out, some argue that product codes (outside of an RRID) should be generated for the use of the same cell line by two or more companies, “because the quality control steps in various companies can vary drastically-or at least the products at the end of the process are different.”

	Agencies such as NIH are asking that cell lines be authenticated by chromosomal analysis or STR profiling prior to the agency making any decisions on fund allocation for grants. Many journals are now asking that submissions identify the cell lines used in experiments. 

 guidelines require researchers to clarify if their cell line is among those that have been commonly misidentified according to the International Cell Line Authentication Committee (ICLAC) database, and provide justification for using the cell line they have selected. Of the ICLAC database’s 488 listed cell lines, 451 are misidentified and have no known authentic origin (26, 31).

	Surprisingly, some stakeholders from the pharmaceutical industry think that regulatory agencies should focus more on the quality of a finished drug product than on the cell lines used to produce biologics. In a piece that appeared in the journal 

 in 2016, representatives from Eli Lilly, Amgen, Biogen, Genentech, Janssen, Bristol-Myers Squibb, and Pfizer wrote that regulatory agencies should not focus on the “clonality assurance” of cell lines as heavily. They wrote the “genomic plasticity” of immortalized cell lines precludes “absolute genetic homogeneity,” so cell lines should not be referred to as clones; rather, cell lines are a population of cells that are “clonally derived” (32).

	The representatives from pharma explained that when cells are grown in culture, genetic and phenotypic changes occur as a result of drift, regardless of where the precursor cells came from. The drift can occur even in the absence of any contamination. The ability of these cells to undergo genetic change is what allows them to accept transgenes via genetic engineering and adapt to changing process conditions, the authors argued. They noted that cell lines cannot be adequately controlled, and say that genetic heterogeneity in cell lines has not been measured by most cell-line vendors. Furthermore, they pointed out that many vaccines originate from non-clonal cell lines-and despite this fact, vaccines have a good track record of safe and effective use. While the authors acknowledged that a clonally-derived cell line can reduce the resulting heterogeneity of a cell population, they emphasized that health authorities should put more of a focus on the purity and stability of the final proteins produced from the cell lines, rather than on the cell lines themselves.

	However, because genetic changes to cell lines can occur simply as a result of being cultured repeatedly (15), Freedman counters that periodic cell-line authentication studies should occur numerous times during the course of an experiment. Errington notes that it is also valuable to measure the flexibility of raw materials, or their ability to undergo small changes while supporting the same experimental outcome.

	Further efforts to standardize biological resources

	GBSI’s Freedman, an outspoken advocate of reagent validation, is currently working with stakeholders (including members of the industry, academic leaders, funders, and journal editors) to develop antibody validation guidelines. He says, “The producers engaged with our initiative are committed to assuring that quality antibodies are made available and developing new standards for quality assurance/quality control [QA/QC],” and shares that some biopharma players have already developed in-house QA/QC systems for the selection of cell lines.

	The National Institute of Standards and Technology (NIST) launched a project in February 2017 to try to characterize the mouse cell lines that are using in the biomanufacturing of recombinant proteins (33). The number of short tandem repeat (STR) markers present in an assay is specific to an individual mouse cell line within a species, which NIST is able to measure with its new invention. NIST was granted a patent for this assay, which it says is the first of its kind for mouse cell lines (34).

	The Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom is taking validation for stem cells into its own hands, announcing in February 2017 the launch of “regulator ready” stem cells for use in clinical development. The cell lines, released by the not-for-profit UK Stem Cell Bank (UKSCB) at the National Institute for Biological Standards and Control, will come with a certificate of analysis. UKSCB is also working on including a “starting materials dossier” for each of its cell lines to further inform researchers (35).

	It’s clear that standardization, coupled with the public funding for the research of manufacturing best practices (such as the initiatives launched by NIST), can help shed light on the performance of a process by unearthing details about starting materials. Reputable suppliers should also support this approach, says CST: “Validating and optimizing a reagent prior to use should be a requirement for academic training, publication, and funding.”

	Although there are ongoing efforts to provide open access to certain experimental data published in scientific journals (The Gates Foundation; The Wellcome Trust; and various preprint servers, such as the 

, etc.), there are also companies that are beginning to emerge that seek to bolster protocol transparency. Ultimately, access to protocols in high-profile journals may help drive reagent selection and/or purchasing decisions by researchers in the industry-but because of paywalls, much of this information remains under lock and key. As Alm tells this publication, the success of an antibody in particular is dependent on its application and the context where the antibody will be used.

	To search for how reagents are used in a specific context-for a precise biomedical application--academics can use online tools such as Bioz. Lachmi argues that researcher authentication of every reagent is impractical, and instead, researchers need “structured scientific article data to bring to the surface unbiased reagent and assay ratings.” A sample search of antibody vendors in Bioz, for example, yields 37 suppliers, although two of the oft-mentioned suppliers located in the United States--Sigma-Aldrich and EMD Millipore-have since merged and are now one company (MilliporeSigma), but sell under two brands. The suppliers are organized by category and assigned an aggregated rating ranging from 1 (concern) to 5 (very good). The rating is calculated by way of an algorithm. The algorithm is governed by nine parameters, which include the consideration of how recent a paper is, its protocol relevance, and the impact factor of the journal in which the reagent was mentioned.

	Invitrogen, Abcam, Santa Cruz Biotechnologies, Jackson Immunoresearch Laboratories, CST, Covance, Life Technologies, Aves Labs, and GeneTex are among the 10 most highly rated companies within the antibody space, according to a Bioz search. Although some smaller antibody vendors appear in the list (albeit with mostly lower aggregated ratings), the largest vendors appear to dominate-a fact which is not surprising when one considers that most of the largest vendors actually buy antibodies from smaller vendors and relabel them to beef up their overall antibody portfolio offerings (36).

	Lachmi states that the platform pulls information from 26 million life-science articles across 5000 academic journals, and the website already has 250,000 users from 191 countries. Plus, estimates Lachmi, “The number of Bioz users is growing rapidly, at a rate of 10% per week.”

	Rather than risk sourcing antibodies from a vendor with which a researcher has no experience, a better option may be for the industry to shift paradigms and use standardized antibodies made in recombinant cells, proposed Andrew Bradbury and Andreas Plückthun in a 2015 

 article (37). Recombinant antibodies are thought to have greater authentication potential, and this shift in practice could save researchers the costs of having to test expression levels and perform binding assays of purchased reagents. Says Abcam’s Hamilton, “Unlike polyclonal or hybridoma-based methods, recombinant antibodies are defined by a DNA and protein sequence, which means they have excellent batch-to-batch consistency and provide specific and reproducible results.”

	But the plan to switch all antibodies to recombinant versions for better antibody quality control, while well-intentioned, would be difficult to enforce and would probably negatively affect smaller reagent biorepositories. In addition, the suggestion that all antibodies currently made with hybridoma technologies be switched to recombinant cell technologies could be dangerous from a patent protection perspective; there are patents, such as the Genentech-owned Cabily patents, that protect specific antibodies, methods of antibody manufacture, and the techniques that are necessary to isolate and purify antibodies. Changing the way antibodies are made to better serve potential clients could also make an antibody supplier vulnerable to patent infringement claims (38). Regardless of clonality or the antibody production method chosen (i.e., recombinant vs. hybridoma), CST says a bulk of the company’s activities would still be ensuring that each new lot performs identically to the previous lot.

	Instead of changing the composition of all of the reagents currently in commerce, GBSI supports a simpler approach-encouraging reagent vendors to refrain from selling any products that aren’t validated. This change of paradigm, however, must be supported by all industry stakeholders to be truly effective, insists Freedman.

	Reproducibility is crucial to the advancement of the field of bioprocessing, especially when it comes to testing new methods or technologies that could inform more cost-effective manufacturing techniques. “What I find most amazing in all of this is that biopharma loses millions of dollars in dead-end R&D and has not, thus far, stepped up to the plate to help NIH and journals improve reproducibility in science,” comments Bandrowski. While unknowns about reagent origin and composition can dramatically skew reproducibility attempts, Freedman reiterates that flaws in study design, laboratory protocols, and data analysis/reporting can also render an experiment irreproducible.

	In a “publish-or-perish” world, there is not as much pressure (or incentive) to reproduce previous experiments. The focus of many new studies is to explore a brand new concept, and there is also little interest in funding replication studies. Verification studies, however, could test processes that are considered “the gold standard” in the bioprocessing industry and could uncover significant economic inefficiencies. The ability to replicate may be especially important for the optimization of end-to-end continuous processing for biologics, as much of the new published material on continuous processing for biologics focuses on finding the technologies, the sequence of processing steps, and the combination of reagents that will result in the highest yield and purity possible. Errington says he thinks an initiative for informing bioprocessing techniques, one similar to the Reproducibility Project: Cancer Biology, would be “extremely beneficial,” adding, “I’d be happy to have discussions with others to organize a similar project.” Errington says that another useful idea would be to “conduct a many-lab study to test the reliability of specific bioprocessing techniques” and to measure how certain techniques vary across facilities.

	It is also possible, of course, that replication studies could be the source of new ideas, concludes Bandrowski. “The results that are not robust to replication may not be incorrect, but highly dependent on something that is not being directly controlled-some of the attempts to reproduce a study, when published, can lead to important discoveries.” She quips, “With a good, well-controlled experiment, if we still don’t get the same answer as another lab, perhaps there is another force at play-and that is where the biology gets interesting.”

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Cover Story

Can bioprocessing runs be consistently replicated in an inherently variable production environment?

Enhancing Bioprocessing Efficiencies through Run Reproducibility

	The population of robots working on parenteral fill/finish lines is increasing rapidly. The expansion mirrors growth in biotech products, particularly self-injected therapies, which require autoinjectors that can deliver a safe, effective, and consistent experience. Robotic systems excel at maintaining aseptic conditions and protecting operators from toxic substances. In fact, Comecer Group has offered robot-equipped systems to handle radiopharmaceuticals for more than a decade.

	Robots not only provide precise, consistent handling, but also offer a high level of flexibility so systems can accommodate a wider range of containers and components with minimal or no change parts. “Flexibility is crucial for high-value, relatively low-volume products,” says Eric Petz, senior marketing manager at Vanrx Pharmasystems. “Batches are smaller, so you can’t have long changeover and startup times,” he explains.

	Robots also can reduce or eliminate glass-to-glass and glass-to-metal contact, which are major causes of container failure. But the most important benefit that robots provide is improved quality due to minimization or elimination of human intervention, the biggest source of product contamination. To prevent contamination, regulatory agencies worldwide are looking for less human intervention, and original equipment manufacturers (OEMs) are working on ways to remove operators from the process. “It’s all about risk mitigation,” says Simon Cote, principal engineer, Technical Customer Support at West Pharmaceutical Services. In fact, “I would be highly surprised if the industry doesn’t incorporate more robots,” he says.

	West Pharmaceutical Services is adding a robotic system to its equipment lineup with the purchase of a dual-robot KCP 5060 system from Bausch + Stroebel Machine Co. The model, which was shown at INTERPHEX 2017, features cleanroom-compatible robots that reach upward to perform their tasks. Mounting the robots below the containers maintains laminar air flow. Capable of handling vials, cartridges, or syringes in pairs or nests, the system can be equipped with up to four processing stations. Hydrogen peroxide decontamination cleans the work area including the robots. The compact machine, which occupies less than 14 feet of linear space, operates at speeds up to 1200 units per hour, a rate particularly well-suited for self-therapy products. Container size ranges include vials from 16–52 mm in diameter with heights up to 94.5 mm, syringes from 0.5–20 mL, and cartridges from 6–14 mm in diameter with heights from 40–90 mm. 

	Biotech products have been a driving force behind robot-equipped fill/finish systems. When the founders of Vanrx Pharmasystems couldn’t find a filler for small volumes with sufficient flexibility, they studied automation. Inspired by the use of robotics in the semiconductor industry, they began designing a robotic fill/finish system from the ground up. The resulting machine needs no glove ports, relies on ready-to-use containers and closures, and eliminates aluminum crimp caps, a common source of particulate contamination. “There’s no intervention the robots can’t perform,” explains Petz. “All sources of jams have been eliminated,” he adds.

	Because containers never leave the nest, there’s no potentially damaging container-to-container contact. Press-fit closures, also supplied in nests, streamline the capping and lyophilization process. In addition, Petz says, “Conventional [parenteral] filling lines are generally custom-designed. This one is standard and scalable.” Designed to be deployed worldwide, the standardized system simplifies validation and standard operating procedures. Scalability shortens time to market and maximizes the patent protection period for brand owners.  

	The Vanrx system performs filling and closing with nested groups of containers and closures. An operator loads nests into the carousel and closes the door. At the conclusion of a vapor hydrogen peroxide sterilization treatment, the chamber is aerated, and Tyvek lidstock is removed from the nests. Containers are filled and closed and shuttled back to the carousel.

	Vanrx has installed systems at two contract manufacturing organizations, Singota Solutions and AB BioTechnologies. “Two more systems will be installed in the United States this year,” reports Petz. He predicts, “It’s a technology that is going to be widely adopted. We’re seeing a wide uptake.”

	Lines from Luciano Packaging Technologies also demonstrate the advantages robots can bring to fill/finish operations. In one example, robots transfer product and load preformed pouches. “The ability to manipulate and transfer uniquely and/or irregularly shaped syringe products … significantly decreases the complexity of the mechanism required for manipulations like inverting, placing, and spacing … while maintaining a high degree of orientation and control,” says Larry Luciano, president of Luciano Packaging. “The robots also provide the ability to re-direct product into alternate paths.”  

	Other OEMs, including M&O Perry Industries, ESS Technologies, Marchesini Group, and MG America, offer robotic fill/finish systems. The NSF nested syringe filler from M&O Perry Industries features a Yamaha robot. Capable of filling powders, liquids, or powders and liquids, the system also can handle vials. The robot controls powder filling and achieves speeds up to 40 units per minute. Higher speeds are possible by adding fill needles.

	The Model SF20 TaskMate robotic aseptic syringe filling and capping system from ESS Technologies integrates a FANUC robotic cell with an OEM-supplied restricted access barrier system. A FANUC LR200iD clean class robot receives syringes from a flexible feeder and uses vision and a mechanical gripper to pick the syringe and place it on the filling station. The second FANUC LR Mate 200iD robot picks a cap from the tray and places it into the torque station. A servo-driven pick-and-place unit transfers the syringe from the fill station to the torque station. Capped syringes descend a divided chute to a discharge/reject bin. Fills range from 50 µL–60 mL at speeds up to 15 syringes per minute. The machine also can handle vials and various cap styles. Changeover generally can be accomplished in less than 15 minutes.

Marchesini’s Extrafill syringe filling and stoppering machine features a robotic de-lidding station, monobloc design, and two tub opening and syringe filling/stoppering stations. Up to three more stoppering stations can be added to boost output to 12,000 syringes per hour. Dosing range is 0.1–50 mL.  

	The Steriline RVFCM50 filling and capping machine, supplied in the US by MG America, handles vial sizes from 2 mL–100 mL without changing format parts. Rated at up to 3000 vials per hour, the system can be integrated with an RA-V4 rotary vial washer, ST2 CCS depyrogenation tunnel, and EDM-C external decontaminating machine.  

	Robotic inspection and packaging systems

	Beyond the fill/finish operation, robotics play a role in inspection and secondary packaging of parenteral products. Robotic inspection systems can overcome problems with limited floor space. “A typical, commercially available manual inspection line for two operators that includes automatic de-nesting and re-nesting is a linear line using three machines for the primary operations and is in the order of 40 feet long,” explains Luciano. “The LPT robot cell [HPI-30M nested syringe inspection machine] is only 10 feet long because the robot is able to perform multiple operations-de-nesting, syringe presentation for flange inspection/rejection, and labeling path transfer or re-nesting. In this case, the robot is picking five syringes from the Hypak that supports a matrix of 10 staggered rows of 10 syringes per row. And since there is extra spacing between each tub, there are four different pick positions and 12 different re-nesting positions, so you can see how the programmable flexibility of the robot (in combination with a servo-indexing Hypak conveyor) is helpful in reducing mechanical complexity.” If higher speeds are needed, manual inspection can be replaced by automated vision systems, and a second robot can be added for discharging.

	An example of a robot-equipped line for secondary packaging functions was shown by Marchesini Group at CIPM Qingdao (April 19–21, 2017, Qingdao, China). The customizable line integrates a deep-draw FBZ 320 thermoformer with a continuous-motion BA 400 Argento cartoner (see Figure 1). Operating at up to 240 cartons per minute, the system thermoforms trays, loads syringes and vials, and cartons filled trays. A centerpiece of the thermoformer is a four-axis Robomaster system. Positioned between the forming and sealing stations, it picks syringes or vials and places them into trays. Infeed options include plug-in belts and vibrating tables.

	Many robot providers offer cleanroom models compatible with hydrogen peroxide sterilization for parenteral fill/finish applications. When designing robotic equipment, the first consideration is whether a robot is the best option. “You don’t want to use robots where simple mechanics could accomplish the task,” says Massimiliano Cesarini, global sales manager, Isolation Technology Division at Comecer.

	A primary consideration when specifying a robotic fill/finish system is speed. “Robot lines are typically slower,” says Gregor Deutschle, business development manager at Schott North America. Batch size is another consideration. Shorter runs mean more frequent changeover. “Robots eliminate a lot of change parts and star wheels,” notes Deutschle.

	Robots also replace traditional container handling mechanisms. “Eliminating turntables and infeed belts definitely helps reduce glass-to-glass contact,” he adds. As a result, robots can provide gentler handling and may be especially well-suited for polymer containers, which scratch easily.

Robotic fill/finish systems reduce human intervention, improve flexibility, and allow more gentle handling of containers.

BioPharm International-05-01-2017

Case Study: Retrofitting Two New High Purity Water Systems

Enhancing Bioprocessing Efficiencies through Run Reproducibility

Robots Package Parenteral Products

Keeping an Eye on Quality

Combination Products Raise New Manufacturing Challenges

Fusion Proteins Pose Manufacturability Challenges

Continuous Bioseparations: Fitting the Pieces Together

Engaging with Interest Groups or Industry Associations

CMOs and CROs Have Different Trajectories

New Directions in Bioreactor Design

Japan Common Technical Document: Bracketing Strategies for the Manufacturing Process

BioPharm International, May 2017 Issue (PDF)