Pharma Manufacturing Biotech

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15VOLUME 14, ISSUE 9WWW.PHARMAMANUFACTURING.COM

BIOPHARMACEUTICALTECHNICAL RESOURCE GUIDE

Bio Pharma in 2015 Overview P.10 Continuous SHM P.14

Downstream Efficiencies P.20

Antibody Facility Design P.24

Leveraging Audits P.26

Biomagnetic Separation P.30

Single-Use Integrity P.33

Endotoxin Testing P.36

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7. GettinG to Know BiosimilarsAlthough generic style competition is unlikely, biosimilars cost-savings potential remains By steven e. Kuehn, editor-in-Chief

10. soarinG to new heiGhts: Bio Pharma 2015Bio Pharma’s ascendancy continues as the industry maturesBy steven e. Kuehn, editor-in-Chief

14. Continuous shm assures Pfizer’s automation system PerformanCeAutomation system health needs to be continuously transparent; fortunately Emerson has an app for thatBy riChard dedzins, Pfizer BioteCh,

matt James, emerson ProCess manaGement

20. new teChnoloGies for downstream effiCienCiesIndustry sees promise in continuous purificationBy eriC s. lanGer, BioPlan assoCiates inC.

23. ProCess and faCility desiGn for a monoClonal antiBody faCilitySingle-use technology delivers strategic flexibility to EMD MilliporeBy Christian Cattaruzza & seBastien riBault, milliPore sas, franCe

26. leveraGinG suPPlier audits in Pharma/ BioteCh industriesFinding ways to reduce complexities eliminates redundancies and streamlines operations while staying compliantBy daniel fishman, ComPlya ConsultinG

30. BiomaGnetiC seParation: thinKinG BiGGer, Part iContrary to popular belief, biomagnetic separation is ready for large-scale processingBy lluis m. martinez, Ph.d., Cso at sePmaG

33. sinGle-use inteGrity testinG Goes moBileManufacturers adopting point-of-use testing with flexibility and mobilityBy amBer sherriCK, asi

36. inside 2015 endotoxin testinGWhy LER is here to stay, the need to safeguard test supply, revisiting the definition of alternative assays and moving towards automationBy laKiya wimBish, lonza

41. Classifieds

Pharmaceutical Manufacturing (USPS number 023-188) is published monthly by Putman Media Inc. (also publishers of Food Processing, Chemical Processing, Control, Control Design, and Plant Services), 1501 E. Woodfield Road, Suite 400N, Schaum-burg, IL 60173 (Phone: 630-467-1300 Fax: 630-467-1179). Periodicals Postage Paid at Schaumburg, IL and additional mailing Offices. POSTMASTER: send change of address to Pharmaceutical Manufacturing, Post Office Box 3431, Northbrook, IL 60065-3431. SUBSCRIPTIONS: To receive a complimentary subscription go to www.pharmamanufacturing.com. Subscription rate for non-qualified U.S. subscribers is $68/yr. Single copy rate is $15.00. Other international is $200/yr (airmail only). Canada Post International Publications Mail Product Sales Agreement No. 40028661. Canada Mail Distributor Information: Frontier/BWI, PO Box 1051, Fort Erie, Ontario, Canada L2A 5N8.. Copyright ©2015 by Putman Media Inc. All rights reserved. The contents of this publication may not be reproduced in whole or in part without consent of the copyright owner. Reprints are available on a custom basis. For a price quotation contact [email protected]. Subscriptions/Customer Service: (888) 644-1803

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In March 2015 the U.S. FDA approved Zarxio (filgrastim-sndz), the United States’ first biosimilar product to earn the distinction. According to the FDA, Sandoz Inc.’s Zarxio is biosimilar to Amgen Inc.’s Neupogen (filgrastim), originally licensed in 1991. At the time FDA Commissioner Margaret A. Hamburg, M.D., explained “Biosimilars will provide access to important therapies for patients who need them. Patients and the health care community can be confident that biosimi-lar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.”

Zarxio’s approval, said the FDA, is based on review of evidence that included structural and functional characterization, animal study data, pharmacokinetic and pharmacodynamics data plus clinical immunogenicity data and other clinical safety and effectiveness data. Under the BPCI Act, a biological product that has been approved as an “interchangeable” may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

Rand Corp.’s study, “The Cost Savings Potential of Biosimilar Drugs in the United States,” notes “the introduction of biosimilars is expected to reduce prices, albeit to a lesser degree than small-molecule generics.” Rand’s analysts explain this perspective combines prior research and recent data to estimated U.S. market cost savings. “We predict that biosimilars will lead to a $44.2 billion reduction in direct spending on biologic drugs from 2014 to 2024, or about 4 percent of total biologic spending over the same period, with a range of $13 billion to $66 billion.” At the time of the study’s release Rand added this caveat: “Actual savings will hinge on the specifics of the final FDA regulations and on the level of competition.”

Forbes magazine contributor David Kroll succinctly reported a bit of truth last March: “… it’s fair to say that manufacturing a biologic agent that acts similarly to the original branded drug is an order of magnitude more difficult and has more places where it can go wrong.” No kidding. It takes a highly competent, experienced player to succeed, and that’s why Seeking Alpha’s analysts singled Amgen out as one biopharmaceutical company well-poised to be an early biosimilars champion.

Amgen has three Phase III candidates right now, including ABP 215, its answer to bevacizumab (Avastin), developed and currently marketed by the Genentech arm of Roche; ABP 980, Amgen’s biosimilar answer to Herceptin, another Genentech/Roche blockbuster; and ABP 501 currently under trial for moderate to severe rheumatoid arthritis, targeting the replacement of AbbVie’s Humira. Seeking Alpha says Amgen’s IPR petition against Humira patents could set a precedent for biosimilars in patent law going forward.

Seeking Alpha says when Amgen reported its second-quarter 2015 results in its earnings call, the company reiterated its focus on biosimilars. “According to a 2014 analysis, it costs Amgen somewhere in the region of $200 million to develop a biosimilar, compared to the average cost-to-market of a new pharmaceutical treatment of $2.6 billion.” The point being that companies with experience innovating and processing biologics have a real leg up when it comes to manufacturing economics, but also the ability to price competitively, and to some minds that might mean more fairly as well.

from the editor

November 2015 7

by SteveN e. kuehN, editor iN Chief

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editoriAL teAM

Steven e. Kuehn eDItOR In ChIeF

[email protected]

KatIe WeIleR managIng eDItOR

[email protected]

KaRen langhauSeR DIgItal COntent

[email protected] manageR

KeIth laRSOn v.p., COntent

[email protected]

editoriAL AdviSory boArd

ALi AfNAN, Step Change Pharma

JiM AgALLoCo, Agalloco & Associates

CArL ANderSoN, Duquesne University

JAMeS bLACkweLL, Bioprocess Technology Consultants

JohN bLANChArd, ARC Advisory Group

toM CAMbroN, P&G Pharma

JAMeS CheNey, Celgene

bikASh ChAtterJee, Pharmatech Associates

eMiL CiurCzAk, Doramaxx Consulting

robert dreAM, HDR Company

eriC LANger, BioPlan Associates

robbe C. LyoN, FDA

ivAN Lugo, INDUNIV, Puerto Rico

giriSh MALhotrA, Epcot International

ferNANdo PorteS, Stevens Institute of Technology

gAry ritChie, Consultant

deSigN & ProduCtioN teAM

Stephen C. heRneR v.p., CReatIve &

[email protected] pRODuCtIOn

DeReK ChambeRlaIn SenIOR aRt DIReCtOR

[email protected]

RIta FItzgeRalD pRODuCtIOn manageR

[email protected]

AdMiNiStrAtive teAM

JOhn m. CappellettI pReSIDent/CeO

JaCK JOneS CIRCulatIOn DIReCtOR

In Memory of Julie Cappelletti-Lange,

Vice President 1984-2012

USPS number (023-188)

Getting to Know BiosimilarsAlthough generic style competition is unlikely, biosimilars cost-savings potential remains

PM1511_07_Edit.indd 7 11/3/15 10:48 AM

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� ere are generally three approaches to investment recovery: 1. Complete in-house management using an in-house team dedicated to investment recovery;2. Outsourcing of all investment recovery services, typically arranged by the purchasing department; and3. � e use of an in-house program manager with support from outside used equipment service providers.

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For an in-house program to be successful, the pharmaceutical manufacturer must not only have appropriate storage space (that often must be compliant with Good Manufacturing Practices), personnel, handling inventory and sales management systems, and an advertising budget are required. Outsourcing shifts most of these burdens to the service provider, but someone must take responsibility for overseeing the selection of the provider and for ongoing management of the program at each of the company’s locations.

It is also crucial for the investment recovery team – whether in-house or external – to understand the level of return expected by the owner and weigh the other relevant factors important to each individual project, such as the location, project timeframe, and removal costs. If done properly, a customized plan can be developed that maximizes the firm’s goals. In addition, experienced teams will not only look for external sales opportunities, but consider internal redeployment as a mechanism for avoiding unnecessary capital expenditures elsewhere in the company.

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What’s the future of Bio Pharma? While no one’s crystal ball is clear enough to exactly predict where the industry is headed, it remains perfectly clear Bio Pharma is soaring, climbing to a new cruising altitude, flying higher than ever as it becomes the carrier of choice for the future of the pharmaceutical industry.

John J. Castellani, president and CEO of Pharmaceutical Research and Manufacturers of America (PhRMA) offered this in his letter introducing the association’s “2015 Biopharmaceutical Research Industry Profile:” Massive change continues across the United States and global health care systems driven by new health care policies, demographic shifts, changes in lifestyle, but — most of all — evolving, accelerating science.” His final remark, “evolving, accelerating science” succinctly describes the force from which Bio Pharma has and will continue to derive its lift. Research and development spending by its members, according to PhRMA, grew from $2 billion in 1980 to an estimated $51.6 billion in 2013. The percentage of sales that went to R&D in 2013 reached 23.4 percent of domestic sales.

Apparently a lot of that R&D money was spent by the Bio Pharma sector. The U.S. biopharmaceutical industry is one of the most research-intensive industries in the country, says PhRMA’s report, investing more than 13 times the amount of R&D per employee than manufacturing industries overall. According to the National Science Foundation, the U.S. biopharmaceutical sector accounts for the single largest share of all U.S. business R&D, representing about 1 in every 5 dollars spent on domestic R&D by U.S. businesses.

Of the billions of dollars spent on R&D each year by the biopharmaceutical industry, the vast majority is spent on clinical research, says PhRMA’s report, accounting for roughly 90 percent of all spending on clinical trials of medicines and devices in the United States. In 2013, PhRMA says the biopharmaceutical industry sponsored an impressive 6,199 clinical trials.

Everyone knows developing biopharmaceutical drugs is expensive. Average time to develop a new drug is more than 10 years, and the percentage of drugs entering clinical trials resulting in an approved medicine equal less than 12 percent. Current estimates peg the cost to successfully develop and bring to market a new drug at more than $2.6 billion. PhRMA notes rapid changes in molecular science have ushered in a new era of innovative biopharmaceuticals and their rise has been spectacular, especially over the last 10 years. From the first angiogenic medicine for Cancer in 2004 to oral treatments for Hepatitis, 17 new drugs for rare diseases and 7,000 medicines in development in 2014, Bio Pharma has truly ascended to a new level.

Money Well spentForbes Magazine contributor Bernard Munos notes in a recent article that 2014 was a great year for pharmaceutical innovation for both New Chemical Entities (NCEs) and New Biological Entities (NBEs): “The best, in fact, since the industry’s all-time record of 1996.” Munos says in 2014 the FDA approved a total of 44 drugs, 39 by CDER, and 5 by CBER. Explaining that the total excludes imaging agents

10 November 2015 Pharmaceuticalmanufacturing•www.Pharmamanufacturing.com

Bio Pharma’s ascendancy continues as the industry matures

soaring to new heights

Bio Pharma 2015By steven e. Kuehn, editor-in-Chief

PM1511_10_13_Overview.indd 10 11/2/15 5:03 PM

and includes only the biologicals drugs that are of rDNA origin, Munos re-ported that biologicals captured “a to-tal of 16 approvals (35 percent) — a big hike from 2013 when they garnered 22 percent. Seventeen of these drugs (39 percent) featured novel modes of action, as in 2013 (37 percent).”

Munos says that compared to innovation during the pre-2010 decade that was dominated by mediocre, overpriced drugs, “we are now seeing cure rates (hepatitis) or remission rates (cancer) that are nothing short of stunning.” Regarding biopharmaceutical innovation, Munos says the industry is “witnessing rapid progress with a range of new technologies such as CAR T-cell, gene editing, synthetic biology, biochips, bioprinting, and tissue engineering that promise to transform treatments for entire therapeutic areas — such as rare diseases — as well as produce tools that will speed drug R&D and lower its costs.”

To Come: Hyper InnovaTIonMunos notes that far from running out of innovation, “we are actually on the cusp of a hyper-innovation age that will see treatment options expand from small molecules, monoclonals and peptides to a whole range of new and more effective therapies.” But this innovation won’t be free from challenges or a fair measure of risk, and companies that will emerge as leaders will need to be more aggres-sive, less conservative and push past their comfort zones to succeed. “These innovation champions,” says Munos, “include Novartis, J&J, GlaxoSmith-Kline, as well as recent converts such as AstraZeneca that are working hard at restoring a vibrant culture of inno-vation to their R&D operations.”

In its report “Advanced Biopharmaceutical Manufacturing:

An Evolution, Underway,” Deloitte’s analysts find the past 10 years have seen a significant shift in the nature of the products being manufactured and sold by the Bio Pharma industry. “The global biopharmaceutical portfolio of today reflects increased therapeutic competition, a greater prevalence of large molecule drugs, expansion in the number of personalized or targeted products, and a rise of treatments for many orphan diseases.” These trends, says the report, have driven a rise in biopharmaceuticals with “extremely limited production runs, highly specific manufacturing requirements, and genotype-specific products.” This fundamental shift in the overall product mix, says Deloitte, and a focus on improving the efficiency and “effectiveness of production is spurring an evolution in the technologies and processes needed to support advanced biopharmaceutical manufacturing.”

According to Deloitte, innovation in manufacturing technology will drive better economics, flexibility and quality while benefiting patients

both directly and indirectly. Where will Bio Pharma’s players

be investing their capital dollar? Deloitte identifies the following as targets for improving the operational excellence of biopharmaceutical manufacturing assets:

• Continuous manufacturing to im-prove scalability and facilitate time to market, while lowering capital and operating costs and enhancing quality.

• New process analytical tools to im-prove process robustness, accelerate scale-up to commercial produc-tion and drive more efficient use of resources.

• Single-use systems to increase flex-ibility and reduce production lead times, while lowering capital invest-ment and energy requirements.

• Alternative downstream pro-cessing techniques to improve yields while lowering costs, green chemistry to reduce waste, and new vaccine and therapy produc-tion methods to increase capacity, scalability and flexibility.


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figure 1

future facilities will allow for greater productivity in a smaller footprint


Amgen’s TAkeAmgen’s vice president for Process & Product Development Jim Thomas, offered Amgen’s take on how to achieve operational excellence in the presentation “Biopharmaceutical Manufacturing Technology: Vision for the Future.” Thomas explains that only the highest quality manufactur-ing environments will answer the de-mands of a rapidly changing industry earmarked by “a more competitive business environment, a more chal-lenging reimbursement environment, and a more conservative regulatory environment.”

Thomas and his team at Amgen describe their strategy in a holistic way using the mantra “Design the molecule. Design the process. Design the Plant,” and that molecule heterogeneity can be influenced by the manufacturing process. Compared to current methodologies, there are both upstream and downstream opportunities to reduce variation and improve yields.

Trends in analytical tools, notes Thomas, will support operational excellence and quality

goals in biopharmaceutical process by measuring host cell proteins, measuring molecule fragmentation, and measuring protein microheterogeneity. Thomas and Amgen point out that the tools for analysis (a key element to their corporate manufacturing strategy) have come a long way since the ’90s and that by 2020 mass spectroscopy-based analysis will provide host protein fingertips, top-down analysis and routine analysis of CQAs to support biopharmaceutical development and manufacturing.

How will biotherapeutics be manufactured in the future, Amgen wonders? To Thomas and his colleagues the most likely scenario won’t involve transgenic animals, transgenic plants or cell-free systems, but center on cell-based systems. That makes correctly mapping the design space of critical unit operations all the more a priority and will be important for building quality into the manufacturing process. What is called for, says Thomas, is two-fold: High throughput processes and high throughput purification.

HolisTic ApproAcH To opTimizATionTo achieve higher yielding processes, greater plant flexibility, and better utilization of capital, as well as a sig-nificant reduction in operating costs, Thomas and Amgen are pursuing a holistic approach to optimization that encompasses process design, plant design and process control.

In keeping with its history of manufacturing innovation and excellence, Amgen launched its “Transforming Biotechnology Manufacturing” initiative, which the company touts as “leading the way in the development and use of manufacturing technologies that will set the standard for the future.” Amgen says future facilities will allow for greater productivity within a smaller footprint. According to Amgen’s infographic, cost and footprint make geographic expansion difficult and that its new facility concept allows for expansion “almost anywhere in the world to support local market needs.” Indeed, especially when Amgen is projecting 60-70 percent square foot reductions at 1/5 the cost of existing plant designs, which Amgen puts at more than $1 billion. (See Figure 1: Future Facilities Will Allow for Greater Productivity in a Smaller Footprint.)

Flexibility within this advanced biomanufacturing environment is another goal; Amgen says this will come from streamlining processes — moving from complex, varied processes at different stages of drug development to standardized processes across all stages of development —something many will recognize as a direct path to operational excellence and cost efficiency. (See Figure 2 —left.)

Putting its capital where its mouth is in 2013, Amgen announced plans to build a new manufacturing facility in the Tuas Biomedical Park area


BIOPHARMACEUTICALtechnical resource guide

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fIgURE 2

sTREAMLInEd PROCEssEs REsULT In InCREAsEd fELxIBILITy


of Singapore. At the time, Amgen anticipated investing approximately $200 million to build its innovative new facility, based on its professed strategy and, according to the press release, will initially focus on expanding Amgen’s manufacturing capability for monoclonal antibodies.

PAT And ConTrolDeloitte’s analysts agree with Amgen explaining that new process analytical tools can help improve process robustness, accelerate scale-up to commercial produc-tion and drive more efficient use of resources. The FDA defines process analytical technology (PAT) as “a system for designing, analyzing and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes.”

Deloitte’s analysts explain that when it comes to biopharmaceutical process monitoring, PAT equipment is helpful in understanding biological, chemical and physical attributes, as well as univariate factors. “In manufacturing with PAT,” says Deloitte, “continuous monitoring determines if the process is operating as expected and allows correction of errors at the time of their occurrence.”

This is fortunate, because most understand the overarching goal of PAT is to ensure final product quality. Process analytical technology, say Deloitte analysts, is based on the FDA’s perspective that “quality cannot be tested into products; it should be built-in or should be by design.”

Similarly, PAT is well aligned with the R&D process, says Deloitte, “as companies can begin using it in clinical manufacturing and then continue to use it during scale-up in an effort to ensure consistent quality and reduce time to market.” Deloitte’s report affirmed PAT’s role in operational efficiency and excellence in that it enables both real-time release testing and parametric batch release to further quality assurance goals.

From a cost-control perspective, Deloitte finds PAT can promote fewer recalls and less scrap inventory, more efficient equipment deployment and capacity utilization, as well as an organization’s ability to manage raw material variability, for instance, all of which can potentially reduce the overall price tag associated with manufacturing biologics of all types. “Finally,” notes Deloitte, “the advancement of continuous manufacturing is largely connected to PAT, as continuous processes by definition do not have stoppages or support traditional product quality testing, PAT addresses the need to monitor product continuously, raise any specification exceptions immediately, or adjust the process through advanced process controls based on predictive manufacturing process models.”

A ConTinuous FuTure?Some companies have developed continuous technology for certain parts of their manufacturing process, say De-loitte’s analysts, “but few, if any, have announced the use of a fully continuous bioprocessing system in commercial production.” Bayer and Genzyme, cites Deloitte, have been using continuous perfusion technology for large molecules in the initial phase of upstream processing for the past two decades and have manufactured at least 12 products via these methods.

The industry is well aware of continuous processing’s potential for the manufacture of small molecule drugs, but for large molecule drugs not so much. According to Deloitte “it can improve quality by constantly maintaining media nutrients and avoiding lags that reduce cell viability.”

The FDA, says Deloitte’s study, views continuous manufacturing as consistent with the FDA’s quality by design efforts, as it has resulted in a more modern manufacturing approach, enables quality to be directly built into process design, and has the potential to improve assurance of quality and consistency of drugs. Regardless, continuous manufacturing has its challenges and biopharmaceutical manufacturers aren’t likely to adopt the operational doctrine wholesale anytime soon. Amgen, as outlined, is committed to optimizing batch operations for its processing future and this kind of long-term investment, notes Deloitte, is just one headwind continuous process faces within the Bio Pharma segment.

Deloitte points out that for the purposes of biopharmaceutical process quality control, manufacturers are challenged, among other things, on how to define a batch in cases of product recall, for example. “As a result, continuous manufacturing requires new methods of measuring quality and gathering metrics.” Continuous manufacturing is not necessarily the most economical method for low-volume, high-value products and would not offer any production gains as opposed to the efficient, well-planned and engineered facilities Amgen and other Bio Pharma innovators are instituting to attain their own vision of biopharmaceutical manufacturing’s future.


flexibility comes from streamlining processes — moving from complex, varied processes at differ-ent stages of drug development to standardized processes across all stages of development.


Over the past 20 years, it has become an essential busi-ness requirement for process manufacturing plants to use digital automation systems to compete in a global econ-omy. During this time period, the reliability of electronic equipment has also significantly improved. As a result, management has often redirected limited plant resources to perform higher value-added continuous improvement projects, with less time being allocated to manage the auto-mation system. Today’s lean manufacturing environment provides limited technical expertise and reduced staffing levels. In turn, some plant site’s awareness and processes are not fully optimized for reacting to disruptive events or unexpected failure(s) in their automation system. Even when a plant is in full regulatory compliance, any loss in monitoring and control functionality while diagnosing a problem increases risk to the plant’s overall site health, safety, product and the environment (HSE).

To address these challenges, many plant sites are investing in an affordable system health monitoring (SHM) solution that continuously monitors the health and fitness of the automation system, detects trends and uses diagnostic best practices to proactively notify plant staff to take corrective action and avoid unexpected failure(s). As a result, scarce plant resources can be directed to work on higher priority projects without having to worry about handling an unexpected system failure.

Why is MOnitOring a Challenge?Retaining experienced automation professionals to work at plant sites is often challenging for many reasons. Con-sistently finding the appropriate level of expertise in all plant locations around the world can be equally difficult. The task of managing an automation system is often del-egated to a system administrator, who is responsible for the operation and maintenance of the system.

With continuous improvements in automation technology, it’s often technically difficult and administratively challenging for a systems administrator to keep the hardware and software revision levels up to date and within allowable budget and production schedules. Obtaining around-the-clock, continuous coverage to monitor the automation system is not only tough, it’s often cost prohibitive. Thus, with limited expertise and available time, the amount of resources available for monitoring the automation system are scarce and must be used wisely.

All automation systems offer maintenance and diagnostic displays to indicate operational status of the system and generate alarms in case of failures. However, the type of information provided by the automation system is typically after the fact, that is, after the failure event. Visibility to information leading up to the event(s) that caused the system failure is often not readily available. The response time to react to the system failure may be longer than desired since engineering staff must conduct an investigation to determine root cause and implement the necessary corrective action.

inCreasing systeM reliability, reliablyPlant staff at Pfizer’s Biopharma facility located in Sanford, North Carolina, faced a challenge of increasing automation system reliability, availability and production uptime, while reducing infrastructure support costs. To address these issues, the plant staff explored industry best practices for shifting monitoring activities from after-the-fact or reactive to implementing proactive processes that improve automation system availability and avoid unscheduled downtime. Secondly, the plant staff explored options for an affordable 24x7x365 system health moni-toring solution that would centralize the data collection while providing maximum value for the investment.


AutomAtion system heAlth needs to be continuously trAnspArent; fortunAtely emerson hAs An App for thAt

BIOPHARMACEUTICALtechnicAl resource guide

COnTInUOUs sHM AssUREs PfIzER’s AUTOMATIOn sysTEM

PERfORMAnCE

PM1511_14_18_Automation.indd 14 11/2/15 5:04 PM

DEVELOPING SHM REQUIREMENTS While there are many commercially available IT-related network health monitoring systems on the market, the SHM solution P� zer adopted was tailored to speci� cally monitor a DeltaV distributed control system infrastructure. Require-ments for the SHM solution included automatically check-ing health information of all automation system components including controllers, servers, workstations and safety controllers. Firewalls, cyber security protection devices, uninterruptible power systems and other non-automation system servers and workstations connected to the automa-tion network were also included. � e SHM solution had to provide trending and automated diagnostics to help leverage best practices and shi� maintenance practices from a reac-tive to proactive stance. P� zer expected the SHM solution to deliver a centralized, consolidated monitoring service for the entire plant. � e SHM service also needed to integrate and be complementary to existing remote monitoring services.

IMPLEMENTATION TIMEWithin a year of addressing the challenge and exploring options, the plant sta� partnered with the digital automa-tion systems supplier and its local service provider to implement the SHM solution at the site. Figure 1 reveals an architecture diagram of the SHM system. � e SHM monitoring device is coupled to the control network and to the plant-wide information network behind a corpo-

rate � rewall. An SHM monitoring device automatically checks health information of any network device con-nected to the control network.

Figure 2 illustrates the SHM monitoring device based centralized health monitoring of network devices. � e SHM health monitoring solution centralizes the data collection function by monitoring network devices or nodes including DCS controllers, application servers and workstations, safety instrumented system (SIS) controllers, switches, � rewalls, UPS’s, and non-DCS PCs, servers and workstations (e.g., data historians, batch servers, operator stations, and similar devices).

Referring to Figures 1 and 2, the SHM monitoring device is con� gured to monitor detailed parameters indicative of the health, integrity and performance of the automation system. Server health checks may include monitoring of availability status, hard disk space utilization and performance, CPU and memory usage. Network switch health monitoring may include availability status, redundant power supply status, temperature, communications status, network communication error rates, and number of packets/second sent and received (See Figure 3). Controller health checks may include monitoring of availability status, CPU usage, availability of free memory, and controller redundancy status. Additional details of the device level parameters that o� er a quick overview of the system health are shown in Figures 4 and 5.

PHARMACEUTICAL MANUFACTURING • WWW.PHARMAMANUFACTURING.COM NOVEMBER 2015 15

BY RICHARD DEDZINS, PFIZER BIOTECH, & MATT JAMES, EMERSON PROCESS MANAGEMENT

DCS network

ApplicationStation

Remote Monitoing CenterPlant LAN

SHM Monitoring Device

MailServer


Remote Monitoing Center

Switches Firewalls

Computers

Automation System Infastructure

x365

SHM SYSTEM ARCHITECTUREFIGURE 1


A PROACTIVE FUTUREParameters being monitored by SHM are typically useful in performing proactive analysis of future events. For example, repeated ping failures may indicate an insecure connection and may require re-termination of a cable to avoid a network failure. Since the SHM device is continu-ously monitoring health of the automated system on a continuous non-stop basis, it eliminates the need for site maintenance sta� to perform periodic, manual health checks via internal system diagnostic tools. Any deviation conditions are automatically detected and reported.

An increased level of system security is also a feature of Pfizer’s SHM. Continuous monitoring of control system servers, smart firewalls and smart switches supports effective cybersecurity protection measures by assuring these devices are online and operational. SHM is integrated with Emerson’s Guardian Support service to improve decision making. The support service requires up-to-date system information in order to provide the site staff with current system-specific actionable information. The SHM enables frequent and automatic collection of automation system related profile data and securely emails it to Guardian. Any changes made to the system content are automatically checked against previously published critical KBAs for potential conf licts. The integration between SHM and support service ensures the latest

safety and security updates for the automation system, and applicable operating systems are always readily available to the site staff for download.

Figure 3 illustrates a SHM solution work� ow from an initial health alert detection, to analysis and diagnosis of root cause, to resolution of the problem. � e SHM solution sends noti� cations and alerts via email to the automation system supplier’s Remote Monitoring Center (RMC) that operates continuously. � e noti� cations are automatically sent by the SHM device when any observed health parameter exceeds expected or normal operating values. � e automation supplier provides pre-de� ned templates with recommended limits rooted in best practices. � ese limits can also be con� gured as needed for site-speci� c conditions. � e SHM device sends a periodic heartbeat message to the RMC to indicate that it is operating normally. � e RMC sta� includes dedicated resources and subject matter experts that use so� ware tools to monitor and analyze real-time alerts from the plant.

Diagnostic data related to the initial alert message is analyzed by the experts at the RMC to determine the root cause(s) of the problem and identify a potential solution. A� er that, RMC sta� collaborates with local service experts and site engineering personnel to recommend an action plan and ensure any required corrective actions are taken. � us, SHM proactively noti� es plant sta� to

16 NOVEMBER 2015 PHARMACEUTICAL MANUFACTURING • WWW.PHARMAMANUFACTURING.COM

DCS network

ApplicationStation

Remote Monitoing CenterPlant LAN


MailServer


Remote Monitoing Center

Switches Firewalls

Computers

Automation System Infastructure

x365

CENTRALIZED, CONTINUOUS SYSTEM HEALTH MONITORINGFIGURE 2


make corrective changes well before the initial alert notification escalates into a system failure. The RMC staff can monitor multiple plant sites from a central location on a continuous and concurrent basis.

Figures 4 and 5 are illustrative display screens available at the monitored site for real-time monitoring of current health, integrity and performance of the automation system. SHM displays can provide information about the automation system at an overview level, an individual network device level, or at an individual parameter level within each device.

With a simple observation of the colors displayed on a screen, any authorized user can intuitively and instantly ascertain the operational status of the automation system. A green indicates normal operation, a yellow implies caution or warning, a blue indicates a communication link problem that may require reconfiguration between a sender and receiver device, and a red indicates a critical alert condition. All displays contain hyperlinks that may be used to call up other displays for further detail.

Figure 6 illustrates trend data collected on any analog variable in the system. Historical data related to performance of each network device and analog parameters within each device connected to the control network may be collected and trended without utilizing data historian tags and incurring additional data historian license fees. The site engineering staff and/or the local service provider often use the trend data to perform root cause analysis that can link an alert event with a root cause, such as a controller running on low memory.

Challenges enCountered at the sanford site during implementationSimilar to configuring an automa-tion system, a first step in configur-ing the SHM system is to identify all network devices connected to the control network. The SHM solution provides a utility to read configura-tion files of the automation system and convert them to text. The text file is then modified by the system administrator and imported into the SHM device. The SHM device can monitor any device or node on the control network that has an IP ad-dress and has a communication pro-tocol supported by the SHM device.

Initial challenges at the Sanford site included limited SHM device installation and configuration documentation, along with limited local expertise on technical issues related to the SHM solution. This partially stemmed from early Pfizer adoption of the initial SHM release. The most recent SHM release now addresses these challenges, and installation manuals and overall guidance documents have significantly streamlined the deployment process. The SHM

monitoring appliance is configured to send SMTP messages to the mail server (through the control system layer firewall) at the plant site. The plant site mail server then sends out health alerts by exception via email to the Remote Monitoring Center.

Once the initial SHM system was up and running, the next challenge was to better manage the large quantity of email alerts originally being generated. Similar to the need for better management of the operator alarming function in an automation system, a tuning effort is needed to focus on allowable tolerance levels for each SHM measurement and eliminate nuisance alarms. Today, assessing the health of the automation system is very simple — no email alerts received from SHM means there is a high degree of confidence that everything is functioning normally. This allows plant staff to focus on more value added activities that have a direct impact on the business.

shm solution delivers results The system health monitoring service adds value by continuously monitoring performance data used


Site

RemoteMonitoring

Center

Local Service ProviderCustomer

1. Health Alert Detected and Communicated

2. Alert Monitored, Analyzed, and Tracked

3. Additional Analysisand Diagnosis

4. Local Service Provider and/or Site Personnel

Resolve Condition

SyStem HealtH monitoring Service WorkfloWfigure 3


as an indicator of the health of the automation system. The SHM solu-tion includes a proactive monitor-ing service that alerts plant and local service provider staff to take corrective action that preempts the occurrence of a potential failure and avoids unexpected downtime. For example, since initial installation, the SHM monitoring device has already identified several significant conditions at Pfizer including ping failure(s) due to a loose connector, low controller memory during spe-cific production operations, network time protocol offset drifts during backup operations and an unse-cured primary switch fiber connec-tion. SHM’s proactive monitoring and alert notifications enabled site personnel to address these condi-tions before they became major issues, which resulted in optimal system availability.

The SHM service supports centralized operations as well as the affordable monitoring and managing of all automation systems at the Sanford site without a large upfront investment in capital and staff resources necessary to build and maintain a site-specific operations monitoring center. Thus, the remote monitoring center’s centralized operations increased control system availability while reducing plant staff resources for continuously monitoring the health and performance of all automation systems at the site. SHM’s early detection of events and proactive alert notifications also resulted in an overall process improvement and personnel efficiency gain at Sanford, which were two of the primary objectives for Pfizer for deploying SHM.


SyStem Overview DiSplay

netwOrk Device Detail DiSplay

trenD DiSplay

figure 4

figure 5

figure 6


For more information, call +1 212 366 4455 or visit www.thatsnice.com

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PM1511_FPA.indd 19 11/2/15 5:21 PM

The biopharmaceuTical industry has seen dramatic improvements in upstream manufacturing yields over the past 30 years[1]. However, increased efficiencies in upstream operations have contributed to downstream bottlenecks, as these filtration and purification operations have failed to keep pace with upstream developments.

Indeed, according to preliminary results from our industry study, 12th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, a majority of biotherapeutic developers continue to suffer capacity constraints as a result of downstream processing. More than seven in 10 respondents (biomanufacturers, excluding CMOs) report experiencing at least minor problems attributed to downstream processing, including more than four in 10 experiencing more serious bottlenecks today.

This is certainly not a new problem: Downstream processing has impacted capacity and overall production for upwards of six in 10 biomanufacturers and contract manufacturing organizations (CMOs) surveyed.

There’s obviously a lot to be gained from improving downstream operations. Separate results from our survey indicate that the impact of improved downstream production operations on biomanufacturing performance at respondents’ facilities over the past year has been on par with the impact of respondents’ use of disposable/single-use devices. In past years, improved downstream production operations have also been in the top half of factors creating improvements at respondents’ facilities.

how To improve DownsTream operaTionsAs part of our study, we measure the ways in which or-ganizations tackle the problems associated with down-stream processing, asking them which of 19 specific ac-tions they have implemented in the past year to improve downstream purification operations.

So far this year, the top five reported activities are:• Optimizing running conditions (62 percent)• Used ion exchange membrane technologies (45 percent)• Used membrane-based filtration technologies (44 percent)• Cycled columns more frequently (41 percent)• Developed downstream processes with fewer steps (41

percent)

These are similar to biomanufacturers’ responses last year, although results to date this year suggest that companies have been more likely to optimize running conditions.

new DownsTream Technologies in consiDeraTionAside from tracking the activities implemented by the industry to improve downstream operations, we also measure the new downstream purification (DSP) technologies that respondents are actively considering to address production issues or problems. It’s worth noting that this question only asks about active consideration, indicative of potential future adoption, and as a result


Year Serious Bottleneck Today

2015 12.5%

2014 7.7%

2013 6.8%

2012 8.5%

2011 11.8%

2010 9.0%

2009 8.1%

2008 4.6%

Fig. 1: Impact of Downstream Processing on Overall Capacity, 2008-2015 [2]

Source: “12th Annual Report and Survey of Biopharmaceutical Manufacturing,” April 2015, www.bioplanassociates.com/11th Preliminary Data


industry sees promise in continuous purification

NEw TECHNOLOgIEs fOR

DOwNsTREAM EffICIENCIEs

PM1511_20_22_Downstream.indd 20 11/2/15 5:06 PM

does not include those respondents already using these technologies or those considering them but not “actively” pursuing them as an interest.

In our results, respondents actively considering at least one of the 22 new DSP technologies we identified were led by Continuous purification systems (60 percent); Disposable UF systems (48 percent); and Single-use filters (48 percent).

This year’s preliminary list of “Most Innovative Downstream Systems” from the 12th Annual Report include: • Continuous purification systems• Disposable UF systems• Single use filters• Use of high capacity resins• Single use disposable TFF membranes• Membrane technology• In-line buffer dilution systems• Buffer dilution systems/skids• Single use-prepacked columns• Alternatives to chromatography• On-line analytical and control devices• Use of filters instead of resin chromatography• Centrifugation• Moving beds• Precipitation• 2-phase systems• Countercurrent• Development of MAb Fragments

While these top technologies in active consideration are similar to those seen in last year’s study, survey results to-date suggest a greater interest in continuous purification systems, which were actively considered

by only 30 percent of biomanufacturers last year. It’s also notable that roughly one in five biomanufacturing respondents in this year’s study said that they worked with continuous chromatography purification (e.g. simulated moving – SMB) within the prior 12 months to improve downstream purification operations, a figure which would represent a step up from 15 percent in last year’s study.

The apparent increase in active consideration of continuous purification technologies this year is interesting, as development of these technologies tends to have lagged behind advances in upstream continuous bioprocessing, with new bioprocessing methods typically pairing continuous upstream processing with conventional batch purification. The lag in adoption of continuous purification potentially relates to its more complex nature, as many more smaller aliquots requires processing. Adoption of continuous purification may also depend on newer chromatography technologies, which are yet to be ready for mass-market adoption.

We’re likely to see a focus on this area in coming years, though, as new technologies appear that allow for continuous and semi-continuous operation. The excitement generated by these technologies owes to their potential to enable a jump in the titers processed by downstream operations. Should this come to pass, we could expect to see smaller, more modular and disposable downstream facilities be constructed, ultimately leading to fully disposable facilities, which are currently constrained by the lack of downstream options. Despite their promise, though, we do not foresee continuous purification technologies reaching widespread use at commercial scale this decade.


By Eric S. LangEr, prESidEnt and managing partnEr, BiopLan aSSociatES inc.

New TechNologies for

DowNsTream efficieNcies

Survey Methodology

The 2015 Twelfth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields

a composite view and trend analysis from over 200 responsible individuals at biopharmaceutical manufacturers

and contract manufacturing organizations (CMOs) in 30 countries. The methodology also included over 150 direct

suppliers of materials, services and equipment to this industry. This year’s study covers such issues as: new product

needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends

and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and

employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic

developers and CMOs. It also evaluates trends over time, and assesses differences in the world’s major markets in

the U.S. and Europe.


AlternAtives to Protein AAn interesting trend that seems to be continuing this year relates to alternatives to Protein A: Although a significant portion of biomanufacturers are investigating alternatives to protein A, few have actively switched to alternatives. Specifi-cally, early data from our study suggests that almost one in five (17 percent) of biomanufacturers investigated Protein A alternatives during the past year, but just 7 percent switched.

Still, if those figures were to hold true, they would represent a shift from last year’s ratio: That year, 33 percent of biomanufacturers had investigated Protein A alternatives, compared to just 59 percent switching. So the percentage evaluating these new chromatography technologies appears to be on the decline.

The high mAb purification efficacy of Protein A resins is one of the attractive qualities of Protein A compared to many proposed alternatives. Protein A resins — now estimated to represent a $400 million per year market — have become increasingly robust and reliable, becoming a dominant downstream mAb purification platform technology. This success and consistent popularity causes difficulties for any improved and/or cheaper alternatives to gain market adoption, although for the time being there remain few cost-effective alternatives. Indeed, while Protein A affinity chromatography has been targeted for replacement from the start due to high acquisition costs and limited recycling, few alternative options have emerged to pose a real challenge to conventional resins.

That’s not to say that alternative approaches don’t resolve problems (e.g., the high costs, leaching and recyclability). But for them to be successful and gain more rapid adoption, it appears that Protein A resin alternatives will need to display radical rather than incremental improvements.

Putting it All togetherEarly results from our 12th annual biopharmaceutical manufacturing survey indicate that biomanufacturers are taking active steps to improve downstream operations, such as optimizing running conditions and evaluating an assortment of technologies. There remain few who have switched to alternatives to Protein A, and recent stud-ies indicate that fewer industry suppliers are working on such alternatives. In fact, the percentage of suppliers last year who indicated that they are working on chromatog-raphy alternatives to protein A (12.7 percent) was almost half the share from 2011 (23.4 percent).

Last year, technology innovators and suppliers were more likely to report new product development on continuous chromatography. This may be in response to increasing demand, as continuous purification appears to be a notable area of interest for biomanufacturers. Other new DSP technologies of interest to biomanufacturers include a range of disposable applications such as disposable UF systems and single-use filtration devices.

For now, though, technological innovations in downstream purification have yet to lead to the same productivity improvements experienced in upstream operations, as the majority of survey respondents report at least some bottlenecks at their facilities owing to downstream purification issues. It remains to be seen when downstream innovation will make up that deficit.

references[1] White Paper: Analysis of Biopharmaceutical Manufacturing: Historical and Future Trends in Titers, Yields and Efficiency in Commercial-Scale Bioprocessing, BioPlan Associates, Inc. July 2014, Rader, RA, Langer, ES[2] 11th Annual Report and Survey of Biopharmaceutical Manufac-turing Capacity and Production, April 2014, Rockville, MD www.bioplanassociates.com/11th

About the AuthorEric S. Langer is president and managing partner at BioPlan Associ-ates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufactur-ing”, and many other industry reports. [email protected] 301-921-5979. www.bioplanassociates.com.


Technological innovations in downstream purification have yet to lead to the same productivity improvements experienced in upstream operations as most respondents report at least some bottlenecks at their facilities.



The biological drug products market is expand-ing, especially in emerging economies. With the improve-ment of living standards in those countries, the number of patients accessing drug treatments is growing rapidly. In Brazil alone, an estimated 40 million people joined the middle class between 2000 and 2010. In China rapid economic growth and the emergence of a middle class with growing disposable income in the last decade have contributed to an increased demand for high-quality healthcare services. In India the number of middle-class households (earning between $4,413 and $22,065 a year) is estimated to increase more than four-fold, from $32 million in 2010 to $148 million by 2030.

Countries that are growing in size and wealth are looking to establish more domestic industries to support a growing population that can afford to buy more goods and services. In particular, government-driven incentive programs are multiplying to encourage local investments in biologics production facilities. For example, if a company in Brazil decides to build a modern manufacturing plant to produce a product for the local market, the government will buy this product from the company. Companies that do not have plants in Brazil will eventually be eliminated from the market for a particular product. In India the government has been proactive and supportive in driving the growth of the biotechnology sector by offering grants and tax incentives, and implementing investment-friendly regulations.

Since the mid-1980s, South Korea is by far the best example of government support for the biotechnology industry. One of the fastest-aging countries demographically in the Organization for Economic Co-operation and Development (OECD), South Korea needs to prepare for and deal with the rising incidence of chronic diseases such as diabetes, Alzheimer’s and Parkinson’s. The government provides various incentives

such as tax reductions or cash grants to companies targeting treatment of those specific diseases.

In other cases, governments apply a protectionism strategy favoring a model where drugs must be produced locally to be eligible for local healthcare system reimbursement or to be available for patients. In Russia, for example, local pharmaceutical companies are able to meet only a small percentage of the country’s requirements and 80 percent of drugs are imported. To change this situation, Russia is implementing extreme protectionist policies such as a law that allows discriminatory procurement practices by giving the government the right to enforce a ban on foreign goods in public procurement tenders.

At the same time, some biologics blockbuster patents going to public domain lead to development of multiple biosimilar programs, benefiting the broader population with lower treatment costs. With more than 200 biosimilar drug development programs — spanning from research to Phase III — in China, Brazil, India, Turkey and Russia alone, biosimilars are becoming a public health challenge and a large business opportunity in many countries.

This overall situation is leading to a new “for country in country” strategic trend in biopharmaceutical industry supply chains where biopharmaceutical companies are considering localizing small scale production facilities to serve specific countries or regions.

However, there is a high level of risk related to investments in emerging countries. Political instability can be of great concern in some countries, turning a winning market environment into a real no-go in a matter of months. Economical fragility and a government’s inability to fund existing incentive programs often limit attractiveness of those markets. Also, the limitation — or absence, in some cases — of healthcare systems, as well as relative complexity of drug reimbursement processes may limit populations’ access to drug treatments.

Single-uSe technology deliverS Strategic flexibility to eMd Millipore

Process and Facility design For a Monoclonal antibody Facility

bioPHarMaceUticaltechnical reSource guideBy Christian Cattaruzza & seBastien riBault, Millipore s.a.s., FranCe

PM1511_23_25_Facility.indd 23 11/2/15 5:07 PM

Companies interested in investing in biologics in emerging countries such as Brazil, Russia, India, China and in middle-eastern and Asian-Pacific countries must solve an equation which consists of investing quickly to be the first to enter, lowering the financial risks and ensuring drug products cost of goods sold (COGS)are competitive and affordable. The key to this equation is the flexible factory concept.

The flexible factory concept is a single-use facility designed with ease of use, minimized contamination risk and flexibility in mind. A wise implementation of single-use technologies allows drug manufacturers to get the best possible outcome from those technologies: easy and fast re-purposeability for a variety of processes, increased capacity with rapid changeovers between batches, minimization of SIP/CIP steps with associated time and costs savings. The ability to run some of the process steps closed and continuously also allows fewer cleanroom classifications and reduced capital expenditures while increasing facility flexibility and adaptability to meet local market demand.

Despite the introduction of single-use new technologies, the majority of biotech processes and facilities still contain a number of stainless-steel and multi-use equipment. At EMD Millipore, a subsidiary of Merck KGaA, Darmstadt, Germany, the company made the decision to move away from this traditional setup and implement full single-use processes at both the laboratory and manufacturing scale. This change from multi-use to single-use was developed in parallel with the revamping of EMD Millipore’s Biodevelopment Center in Martillac, France, as well as part of the company’s global strategic development of flexible facilities concepts.

ALL STEPS UP, AND DOWN STREAMWith the adoption of single-use equipment, all steps from upstream to downstream and fill and finish can be completed in a single-use manner. This is not only true for small and medium scale; large scale disposable systems are now available on the market and routine manufacturing can be done using disposables as well. EMD Millipore’s implementation of disposables is go-


Figure 1. The design of Flexware assemblies assures

correct installation every time.


ing from development scale to routine manufacturing at the 2,000 liter scale.

EMD Millipore has seen a number of advantages to implementing single-use equipment including reduced risk of contamination, ease of use and enhanced flexibility. The risk of contamination is reduced at all steps as the disposable systems arrive sterile with no need to clean or sanitize, and are set up for the run without opening. As an example, bioreactor bags are connected to media bags through sterile connectors so there is no open phase and the harvest is completed the same way. Welders can be used as well, depending on the scale.

Ease of use is threefold. First, operators require less training than with stainless-steel equipment (less piping, no spare parts, no cleaning or sanitization, etc.). Second, the assemblies used on the hardware part are typically preconfigured for simplified installation (connectors with “two clicks” confirm good connections, asymmetric pieces avoid bad orientation, etc., Figure 1). Finally, operations are mostly automatic and the recipes used are virtually foolproof.

In terms of enhanced flexibility, EMD Millipore has found implementing single-use equipment to yield a range of advantages. For one, bioreactors are no longer fixed; they can be moved from one room to another depending on needs. Downtime is reduced to a few hours rather than several days, as is the case with stainless steel. When running a single-use upstream suite, drug A can move from one bioreactor to three in parallel for the validation runs of drug B in less than a day. The ability to reconfigure in a day or less provides superior flexibility and allows quick changes in production plans.

Buffers are prepared in single-use mixers and then pushed into the suite for use. As nothing is fixed, there is no need for hard piping and maximum flexibility in the options. A new buffer can be brought in or taken out without impacting the suite and the rest of the process.

New generations of equipment, such as the Mobius’ FlexReady System, make it possible to have one piece of equipment for several operations. The tubing has been replaced by a new type of consumable that prevents operator errors (Figure 2). These systems enable either chromatography or TFF with a single piece of equipment. The additional cart will contain pumps for chromatography or a tank for TFF. This new concept not only reduces footprint, but also investment and operator training. Flexibility is embedded in the equipment

design. All of this equipment can be connected using sterile connectors or welders, making running a closed process now feasible.

IN THE BAGInstead of using a vial, cells can be stored in a bag at -80°C or in Nitrogen. This bag is connected by welding to the first seeding bioreactor and cells are transferred by gravity. Cells are grown to the desired concentration and transferred again by sterile connection to the next bioreactor and so on until the production unit. The next steps through clarification are similar and the resulting clarified harvest is collected into a closed bag.

Purification can also be performed in a closed and continuous manner using several columns consecutively loaded, washed, eluted, cleaned and regenerated. Virus inactivation happens in a closed bag between protein capture and a series of membrane absorbers. The process ends with virus filtration and aliquoting.

This closed process has several advantages, including reduced risk of contamination and the ability to run a multiproduct facility with ballroom suites for upstream and downstream or several products in the same area. These benefits are creating a clear global trend toward single-use equipment and f lexible facilities concepts.


The flexible factory concept is a single-use facility designed with

minimized contamination risk and flexibility in mind.


Those of us in the competitive and highly regu-lated pharmaceutical, biotechnology and medical device industries understand the need to balance operational efficiency with regulatory compliance. We must find ways to reduce complexities, eliminate redundancies and streamline operations while staying compliant with an array of regulations, guidance documents and regula-tory expectations (some explicit, others less so). Making changes to our processes requires overcoming challenges arising from these often competing interests.

When publishing guidance documents, the FDA includes language implying that industry can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. Using this language as a stick by which to measure well-intentioned process optimization proposals, this article will explore considerations for creating desired efficiencies while maintaining compliant processes.

For illustrative purposes, let’s look at a common process optimization example of streamlining a supplier audit program.

opTimizing The supplier AudiTs progrAmOnsite audits are an important and well established tool for assessing suppliers. Still, there are ways to optimize supplier audit programs.

At this point, you have already sliced and diced your list of suppliers by establishing risk-based categorizations of the types of services and/or goods they provide. While retaining other supplier oversight mechanisms, you have eliminated onsite audit requirements for suppliers with no potential impact to your products. You have also reduced onsite auditing frequencies for the suppliers with a lower potential for product impact.

Nonetheless, the list of annual required audits remains daunting. Many have dwelled for the millionth time on the

fact that they are not the only one auditing each supplier. The dozens of times each year that other entities audit a supplier can make you wonder: Is there a way to leverage those activities to reduce onsite auditing requirements?

A process optimization idea is born. Fewer onsite audits mean:• Spending less time on scheduling and audit preparation• Reduced execution and reporting activities• Decreased travel time and costs• Fewer findings to track to resolution• Simplified metrics and management reporting

purchAse An AudiT reporT?Various industry proposals for leveraging common audit reports have been circulating for years. Typically a third party audits a supplier, prepares a report and sells it to companies that want to avoid conducting their own audit.

There may be a place for common audit reports, particularly with regard to low-risk suppliers. Before taking such an approach, though, consider the following factors: • The report may not adequately address the scope

needed, but one likely won’t realize that until after it has been purchased. You alone know the importance of the services and/or goods that the supplier is providing; the auditor might not have placed sufficient emphasis on what is critical to you.

• Even if it does satisfy the scope required, the report may grow stale. The supplier may experience impactful regulatory inspections and/or changes to procedures, personnel, facilities, equipment, etc. Will a window into the past suffice?

• Perhaps a proprietary process is involved, and the third party would not have had access to audit those process-es. And if the third party did have access, it would not be prudent to share those details with other companies.


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LEvERAgIng SUPPLIER AUdITS In

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PM1511_26_29_Audits.indd 26 11/2/15 5:10 PM

Assessment: Purchasing common audit reports can fulfill some of one’s needs. Let’s call this option a “Maybe.”

Leverage QuaLity SyStem CertifiCationS?Leveraging your suppliers’ qual-ity system certifications to certain standards such as ISO 13485 (ap-plicable for medical devices) may be an option. To gain and maintain that certification, quality system experts must audit the suppliers routinely.

Whether your organization makes medical devices, pharmaceuticals or biologics, many may potentially benefit from this approach. However, be sure to consider the following questions:

• Who issued the certificate? There are vast differences in the weight that certificate-issuing organizations carry. For the harmonized European version (EN ISO 13485), the certifi-cate should be issued by a group with rigorous standards called an autho-rized notified body. Organizations with similarly rigorous qualifica-tion requirements exist to audit and issue quality system certificates to ISO 13485 for other regions, such as Canada (recognized registrars).

• Is the certificate relevant? If, in addition to medical devices, the supplier’s scope includes pharma-ceutical and/or biotechnology (and one is only interested in these two areas) and if the quality systems are independent of each other, then the medical device ISO 13485 qual-ity system certificate may not be relevant enough.If there are common quality

system elements, then the certification may provide some level of assurance that your needs are being met. The FDA combination

products regulation — 21CFR Part 4 — is intended for the development of a combination product quality system. That regulation gives a view into why a pharmaceutical or biotechnology company might find it acceptable to leverage at least part of the elements present within a medical device quality system for a supplier audit program.• Which certificate should be ac-

cepted? One complication is that a supplier can have both a notified body and a registrar, each of which issues a certificate to ISO 13485. Furthermore, the notified body and registrar can be different organi-zations. Or the supplier can have more than one notified body or registrar, each of which may issue their own certification for the scope of activities that they are covering.The question of which certificate

to accept is even harder to answer if the supplier is not manufacturing a medical device or component for you (in which case, you can at least pinpoint which organization has oversight of the type of device or component that you will be

procuring). Just picking one is not the best strategy, so it’s important to discuss this with the supplier to understand which certificate will best cover services and/or goods.• Is the certificate alone enough?

No. The quality system certificate must encompass the scope of your services and/or goods. The only way to really know if a quality system certificate is meaningful and can be leveraged is to review the underly-ing audit reports associated with the certificate.

• Which audit reports should one review? Some notified bodies or registrars may break up the areas they are evaluating into small pieces and do multiple audits each year before gaining the full picture of the quality system’s performance. In those instances, multiple reports may need to be reviewed before the scope relevant to you has been covered.

• What if the supplier won’t release their audit reports? This can hap-pen. Citing client confidentiality or proprietary technology reasons, your supplier may not be willing


By Daniel Fishman, senior Consultant, Complya Consulting

PM1511_26_29_Audits.indd 27 11/2/15 5:10 PM

to share their most recent noti� ed body or registrar reports. And they may or may not be willing to share redacted reports.

Assessment: Leveraging quality system certi� cates and associated audit reports must be a thoroughly vetted process to understand exactly what scope they cover and thus how to best use them as part of a supplier audit management process. � is may be an acceptable strategy to reduce the frequency of onsite audits. Conversely, with all of the considerations mentioned here, one may conclude it is easier and less time-consuming to perform onsite audits yourself.

Let’s call this option another “Maybe,” but note that it will require careful implementation.

LEVERAGE REGULATOR AUDITS AND INSPECTIONS?If suppliers are willing to share regulator audit/inspection reports (e.g., FDA Establishment Inspection Reports), that option might be worth exploring. Considerations with this approach include:• What is the scope of the report? Th e same concerns

apply here as with the previously discussed reports. For you to leverage it, the report must cover the scope of your services and/or goods. Each time a regulator audits or inspects a supplier, it is just a snapshot and unlikely to be inclusive of the full scope of a supplier’s activities.

• Was the audit relevant? How can you leverage a regula-tor’s report if it was focused on a di� erent government’s regulations? While eff orts have been ongoing to har-monize as many of the regulations as possible, there are still di� erences, and it will require an understanding of what you are trying to leverage. If the regulations map-ping methodology described within the aforementioned 21 CFR Part 4 is extended through a comparison of the other global regulations performed, then one can make a legitimate argument for leveraging those reports.

Assessment: � is scenario is not very di� erent from leveraging quality system certi� cates. But it is advised to restrict which regulator reports one is willing to leverage; otherwise, it may require a good deal of work unless someone is already mapping the various global regulations. � is option, then, is yet one more “Maybe.”

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REGULATOR PERCEPTIONWhat would regulators think about industry leveraging third-party audit reports? It is important to � rst put into perspective that, like anyone in this industry, regulators are under a tremendous burden to ful� ll their audit obligations within mandated timeframes. And they, too, have been evaluating options to leverage the work of third parties.

One pilot program for the regulators is already underway. � e International Medical Devices Regulators Forum (which includes, but is not limited to regulators from the United States, Canada, Brazil and Australia) is leveraging third-party audits using the Medical Device Single Audit Program (MDSAP). An extensive framework surrounding the MDSAP governs the quali� cations for authorizing a third party to perform the audits and de� nes the required audit report content (among the establishment of many other criteria).

Suppose this program reduces for regulators the number of required audits for medical devices while maintaining the integrity of the regulators’ respective missions. In that case, you can bet that pharma and biotech regulators will also want to participate in such programs. If the regulators have seen the bene� t of leveraging third-party audit reports and have begun implementing those processes, they would likely have no issues with industry taking a similar approach (as long as appropriate controls are employed in doing so).

A FINAL NOTE� e example provided in this article relates to the process optimization of a supplier audit program. How-ever, with regard to other process optimization activities that might be considered, it’s hoped that the prin-ciples discussed here could be applied

to help strike the balance of creating e� ciencies while also maintaining regulatory compliance.

ABOUT THE AUTHOR Daniel Fishman is a senior consultant at Complya Consulting. He has over 23 years

of industry experience and global regula-tory compliance/quality systems consulting that spans the broad range of the medical device, pharmaceutical and biotechnology industries. He received his BA in biochemis-try from Brandeis University. Fishman can be reached atd� [email protected].

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Separation iS a key process used in life science. Cells, proteins and genetic material of interest for medical and pharmaceutical use are rarely obtained in a purified form. The molecules that the industry usually is interest-ed in are found in a matrix that contains numerous other biological substances. Therefore, it’s critical to extract/isolate these molecules from the supernatant before work can start. Even high-value pharma processes such as pro-tein purification, the downstream process (i.e. purifica-tion) can lead to losses of 50-80 percent of the product.

When working on a small scale, using magnetic beads or particles as solid support for separation has become increasingly popular, particularly when it involves immunocapture. Coated with the right antibody, magnetic carriers can capture the molecule of interest in seconds and retain this by magnetic force while washing out the supernatant. When the magnetic field is removed, the beads can then be re-suspended in a clean buffer.

With such obvious benefits, it makes sense to use this technology on a larger scale. It is commonly believed that biomagnetic separation is not suitable for large volumes, which may explain why people are so doggedly attached to centrifugation, filtration and packaged columns — even though the methodology is slow, complex, requires extremely expensive equipment and can be a cleaning nightmare.

CLia’S SuCCeSS tranSferabLe One life science industry has already tackled these ques-tions. Efficiency, rapidity and simplicity of biomagnetic separation are among the reasons behind the success of chemiluminescent immunoassays (CLIA). The rapid growth of this market has prompted In-Vitro Diagnostics (IVD) manufacturers to scale up magnetic-bead processes to cope with demand. The lessons learned by this indus-try can be very helpful in other life science companies and cell capture or protein purification may be of benefit to processes in the IVD industry for coping with volumes up to tens of liters.

At the beginning of the current century, the IVD industry had similar challenges to those now facing other life science companies. Attempts made to scale up biomagnetic separation processes beyond a few milliliters proved unsuccessful. The paradox was that the main cause of failure lay in its success with small volumes. Easy


Contrary to popular belief, biomagnetiC separation is ready for large-sCale proCessing

BIOPHARMACEUTICALteChniCal resourCe guide

BIOMAgnETIC SEPARATIOn

THInkIng BIggER, PART I

PM1511_30_32_BioMag.indd 30 11/2/15 5:12 PM

implementation of biomagnetic separation at milliliter scale had allowed researchers to focus on selecting the right magnetic beads and how to coat them with the antibody or biomolecule. Given that almost any magnetic separator (or even a simple magnet) would capture the beads in few seconds, little emphasis is placed on the workings of the process. Descriptions of the biomagnetic separation conditions were limited to a description of the magnet and, at most, the separation time. When the volume was scaled up, the initial attempts used a “larger” magnet, usually with no more specification than the material (NdFeB magnet) or the required magnetic field on the surface. However, with this approach, the scaled-up biomagnetic separation process did not work as expected. Separation time increased exponentially, magnetic beads losses were

significant and the beads became irreversibly aggregated. The process is no longer fast, reliable or consistent technology when the working volume is increased.

Around 2000, when the SEPMAG team and I were approaching the problem, IVD manufacturers were considering several options. One was to replicate the small volume process. To increase production by a factor of 10 it was necessary to build 10 production lines. This option involved large-scale investment and proportionally increased labor costs with virtually no economy of scale. Worse still, a new problem arose: The need to guarantee batch-to-batch consistency between the different lines. As one of our customers said, “It is far simpler to validate one ten-liter batch than to guarantee that 10, one-liter batches are the same.”


Coated with the right antibody, magnetic carriers can capture the molecule of interest in seconds and retain this by magnetic force while washing out supernatants.

By LLuis M. Martinez, Ph.D., CsO at sePMaG

PM1511_30_32_BioMag.indd 31 11/2/15 5:12 PM

� e problem was so signi� cant that some IVD manufacturers considered using tangential � ltration to separate the coated beads from the incubation bu� er. � is investment may have made economic sense despite the complex process (� ow, pressure and temperature, etc., all of which need to be controlled ...) and running costs were relatively high.

Our discussions with IVD production managers focused on � nding the ideal solutions from both technical and economical standpoints. � e result of these discussions was clear. � ese operations-centered managers wanted a large-volume permanent magnet-based system with 100 percent magnetic bead recovery, a separation time of few minutes and perfect in-batch and batch-to-batch consistency. Permanent magnet-based systems would mean no maintenance and no running costs.

High recovery meant high magnetic force, even on the beads, which are farther away from the retention area and a high-enough magnetic retention force to prevent aspiration of magnetic beads when the supernatant was pumped out. In-batch consistency would mean that all the magnetic beads in the vessel would be subjected to

the same force, avoiding crushed beads and forming clumps due to high forces while other are gently attracted. Finally, batch-to-batch consistency would require a well-validated process and, if possible, a means of monitoring the process for traceability of every single batch.

This list of requirements seems to pose a big challenge, as many of them are, and at first sight, often contradictory. Then, there’s the temptation to look for trade-offs. What is the acceptable loss rate? Could the separation time be increased to one hour? Should we find more aggressive re-suspension techniques to disaggregate the clumps?

However, closer analysis of the requirements reveal that no trade-o� s were necessary. All we needed to do was the homework that was neglected when working on a small scale to understand how magnetic beads move under the in� uence of magnetic � elds. � is would enable us to correctly parameterize the biomagnetic separation process, validate the right conditions and then de� ne the characteristics of the separation systems, regardless the working volume.

Editors note: Because downstream biopharmaceutical processing e� ciency is so critical the topic merits further examination. To learn how and why biomagnetic separation is so e� ective, please look for Part II online and in print in the very near future.

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There is little debate single-use systems have found a permanent place in bioproduction facilities. Once revolu-tionary, now commonplace, the acceptance and adoption of single-use technologies continues to grow. In addition, incorporating single-use technology in processes that are further and further downstream means that single-use bags are now closer to final product delivery, something that is changing how the industry views quality testing for single-use systems.

Focus on DownsTream QualiTyIn upstream processes, most of the liquids are media or buffer solutions, which are of comparatively lower value and recoverable by sterile filtration in the event of a problem. However, for downstream process equipment, and for containers used to store product fur-ther downstream, quality concerns magnify.

Downstream protein purification (where the protein is isolated and purified) is one of the final steps in bio-pharmaceutical manufacturing. With such high value relative to the rest of the process, and no way to recover or decontaminate materials as there is upstream, sterility and leak detection of single-use bags becomes a QSM-oriented operational imperative.

Manufacturers adopting point-of-use testing with flexibility and Mobility

Figure 2: Operators initializing a validated fine leak test.

BIOPHARMACEUTICALtechnical resource guideby aMber sherrick, asi

SIngLE-USE InTEgRITy TESTIng

gOES MOBILE

PM1511_33_35_SingleUse.indd 33 11/3/15 10:52 AM

To a great extent, concerns involving bag integrity issues associated with poor manufacturing quality control are a thing of the past. Single-use technology manufacturers, including ASI, have instituted well defined and documented quality procedures that assure performance and reliability. As a result, bag quality and integrity inspection routines as well as operator handling have now become more of a focus, particularly for single-use systems used in downstream production.

Care in Handling and OtHer issuesEven when single-use bags’ integrity is verified and in perfect shape com-ing off the delivery truck, there are multiple opportunities for flaws to be introduced between the truck and in-stallation on the process floor. Flaws can be introduced by such things as improper loading of the bag into the equipment, connecting tubes and hoses, or simple inadvertent mishan-dling that goes unnoticed. Handling errors can cause microscopic tears or

worse, and the further downstream this occurs in the process the more it can impact final product quality.

get as ClOse as YOu CanMost operational staff understands the best time to test single-use bags is just prior to use, when the bags are in place and ready to use. Called point-of-use testing, the procedure is usu-ally part of a thorough QSM regime to detecting flaws that in practice can be introduced through handling errors or installation mistakes. This type of test can lower the risk of lost time, loss of product, and even improve operator safety.

Point-of-use testing systems can mitigate the risk of flaws being introduced and unnoticed during operations such as shipping, unloading and installation. Such testing systems give manufacturers the ability to test every bag and produce reports that document the testing procedure and results.

Flaws from a bag already installed in the tank, mixer or bioreactor can happen a few ways. A large, obvious leak, usually called a “gross leak” can occur from an unattached hose. There are many tubing elements that require connection during media prep, bioreactor setup, or transfer of inoculum or other transfers. On the other hand, a fine leak test needs to be able to spot a flaw so tiny that it could elude the naked eye. Both types of leaks threaten production time and supply, and pose significant financial risk for the manufacturer. In addition, in the case of vaccine production, leaks can pose a threat to operator safety.


Figure 1: Operators preparing a 3,000 L bag for a point-of-use integrity test.

IntegrIty testIng Methods VaryThere are two integrity testing methods on the market today: helium integrity testing and pressure decay testing.

Helium integrity testing takes the entire bag assembly and places it inside a sealed chamber, evacuates the air and introduces a measured quantity of helium into the bag. The vacuum pulled inside the chamber ensures that helium will escape through holes in the bag, and a mass spectrometer is then used to detect and quantify the helium.

Pressure decay testing is a tried-and-true industry standard [ASTM F2095-01] for testing flexible bags. The term “pressure decay testing” refers to a change of pressure inside a pressurized containment during a leak test. The test is an inflation test in which the bag is pressurized to a preset level. After the bag system has been stabilized, the decay in pressure over time is evaluated to determine if a leak is present. If the pressure is lost, then air has escaped from inside the bag, and a drop in pressure correlates to the size of the defect.

The advantage of pressure decay testing is that it ensures that no alternative gasses are introduced into the cleanroom, by using in-room air, and can detect leakage problems with a high degree of accuracy. Innovations in the flexibility and mobility of such technology have occurred recently, where mobile units are available that can be wheeled to the exact container for testing.

docuMentatIon and FlexIbIlIty KeyPressure Decay Detection tests should quickly be able to locate small leaks (between 100 microns and 1,000

microns) and confirm connection and setup of the bag system; fine leak detection tests will uniquely validate each tank and bag assembly. Very fine leak detection is possible and is de-pendent on the environment and the time allotted for the testing to occur.

The initial pressure decay approach should always include the purposeful comparison of intentionally flawed bags and non-flawed bags during the validation set-up procedure. A comparison of these tests measures the changes in pressure that occur.


ASI’S InSITE PrESSurE DEcAy SySTEm

According to ASI, its inSITE system has some special and useful characteris-

tics. The system, explains ASI, walks users through a validation set-up, which

then becomes unique to each bag and tank combination and is stored in

memory for later access. A wireless PC Operating system allows the user to

save, store and email testing results. Recorded results are available as PDFs,

and files can be emailed, printed and saved for future use. These documents

become part of the audit trail that accompanies the product being manufac-

tured, a feature that is highly valued by the manufacturers.

ASI says its system inflates to a specified pressure allowing the user to load

the bag more easily. For gross leak detection, users simply select the gross

leak test to find large defects and visible leaks. A gross leak detection test

will also indicate a loose tube or nozzle. Fine leak selection is similar. Users

can select the fine leak test to detect pinholes, small tears and leaks. Lastly,

inSITE testing can be applied to bags of virtually any tank size, although the

current maximum size is 3,000 Liters.

A consistent environment is required for each setup and test because any

variance in these conditions can affect the test results. The test is a pressure

test which makes it ultra-sensitive to changes in external pressure, tank size

and room temperature.

Another aspect to ask about when looking for pressure-decay integrity

systems for point-of-use is automatic inflation, which can assist operators in

loading bags with minimal human intervention, reducing operator handling

errors that can cause tears in the first place.

A liquid filling monitor is also available, which moderates internal pressure

within the bag for the purpose of monitoring over-fill. It works by regulating

the open/close position of the coaxial valve.

Single-use technology in biopharmaceutical production continues to grow,

and its move into downstream processing has pushed the focus on quality

testing of the technology in the same direction: downstream. In many ways,

it is heartening to see the partnerships taking place between manufacturer

and single-use suppliers to improve usability, flexibility and accuracy of

integrity testing. As the application of single-use technology continues to

move from upstream to downstream, the focus of testing will move in paral-

lel, and has put a spotlight on doing everything possible to ensure and docu-

ment quality in products that are so much closer to final production batch.

Pressure decay testing is up to the challenge.

It Is currently a very interesting and dynamic time for the endotoxin testing community, as highlighted at Lonza’s recent Global Endotoxin Testing Summit during which vendors, regulatory bodies, pharmaceutical manufacturers, and conservationists came together to share their thoughts and perspectives on some of the industry’s key issues. Some of the challenges being addressed at the summit and discussed in detail here include methods to overcome the issue of low endotoxin recovery (LER), the need for alterna-tive tests in order to safeguard lysate supply and conserve the horseshoe crab, a guide to validating these alternative assays and the move toward automated systems.

OvercOmIng lOw endOtOxIn recOveryLER is widely regarded as a real challenge for the endo-toxin testing community and a problem that must be overcome. As Ingo Spreitzer, deputy head of the Micro-bial Safety Department of the Paul-Ehrlich-Institute (PEI) and European Directorate for the Quality of Medicines and Healthcare (EDQM), whose group published the new European Pharmacopoeial (EP) Chapter 5.1.10, Bacterial Endotoxins Ph. Eur. Policy for Substances for Pharmaceu-tical Use, proposed, “LER is the most important issue in endotoxin testing today because it is affecting the testing of current products that are already on the market.”

LER occurs when various combinations of excipients used in biopharmaceutical production mask known amounts of endotoxin in undiluted samples. This can result in false negatives if added endotoxin is not adequately recovered and ultimately challenges the validity of these results.

While regulators, pharmaceutical manufacturers and test vendors are aware of the issue, there is still much debate concerning the mechanisms behind LER and how endotoxin masking might be overcome. Allen Burgenson,

U.S. Regulatory Affairs manager at Lonza, thinks, “LER is a new type of inhibition. We’ve seen inhibition before and we solved it. There are a number of methods by which LER can be overcome before you have to go into the chemistry of demasking. The issue of LER is manageable, and while I think it is an important technical problem, we do not necessarily have a public health problem.”

Alan Baines, UK Strategic Projects head at Lonza, suggested that, “…when considering new biological license applications, manufacturers should be aware of the potential issues with LER when using polysorbate in combination with citrate or phosphate buffers. Finding the right combination could side-step potential problems. For existing products, it is likely that additional sample treatment steps will be needed to overcome the masking effect, as changes to formulations are usually a much less attractive option.”

To overcome the masking effect, Johannes Reich, PhD student at the University of Regensburg, has been working in conjunction with Hyglos GmbH to gain a better understanding of the aggregation and interaction of lipopolysaccharides in endotoxin testing. His theory assumes that LER is the result of endotoxin aggregate breakdown into monomers, which are subsequently embedded in surfactant micelles. He proposes that this process is reversible and as such, endotoxin demasking will require adjustments in magnesium and calcium, pH and/or the addition of polyanionic dispersants such as Pyrosperse, in order to reassemble the aggregates to allow for sufficient endotoxin recovery.

However, demasking is still an active area of contention among some industry members as Kevin Williams, senior scientist for Endotoxin Detection at Lonza, believes, “…many people are resisting using the demasking protocol as they want to maintain the simplicity of the test. I can certainly understand.


Why LER is hERE to stay, thE nEEd to safEguaRd tEst suppLy, REvisiting thE dEfinition of aLtERnativE assays,

and moving toWaRd automation

BIOPHARMACEUTICALtEchnicaL REsouRcE guidE

InsIdE 2015

EndOTOxIn TEsTInG

PM1511_36_40_Endotoxin.indd 36 11/2/15 5:14 PM

However, you can’t maintain simplicity by denying that complexity exists. So what we hope to do is to inform and educate at least the manufacturers of biologics such as monoclonal antibodies about the importance of addressing LER, as these are life-saving drugs and it’s a significant and growing market area.”

This reluctance is understandable, as carrying out an investigation into LER could delay the release of new products and cause significant financial issues if a product cannot be released within a reasonable timeframe. This is a particular problem for biological products, as they often have a very short shelf-life and require a fast turnaround time.

Regulators can also add additional time pressures; if a product is tested and shown to display LER, manufacturers will need to overcome the issue within a given timeframe, as stipulated by the FDA (typically one year but this can vary). The manufacturing delays introduced by the need to overcome the issue will likely be significant. In addition, biological products for which no defined hold-time has been established will need to be tested as soon as possible. This may cause a back-up in QC testing, as products that

exhibit the signs of early or somewhat instantaneous LER will need to be pushed ahead of other products where a longer hold-time has been established. If no clear hold-time can be established during the development stage due to LER, significant time and money may need to be invested to uncover better formulations that exclude the excipients known to be associated with LER.

The threat of LER can also influence manufacturing efficiency and cost in other ways. For example, in some cases, manufacturers may feel the need to implement alternative testing strategies, such as the introduction of additional in-process analysis steps during the manufacturing stage, or even at different points in the process where LER is not yet a factor. Such changes to existing workflows can have significant operational and financial impacts. Lastly, the FDA requires extensive evaluation of the drug product regardless of whether LER is present, which could be time-consuming and costly.

Evidently, further investigation in this area will ensure a better understanding of the LER and the means by which this issue can be overcome in a timely and cost-effective manner.


Figure 1: The supply of LAL and TAL is reliant on several horseshoe crab spe-cies including Limulus polyphemus (shown here) on Pickering Beach, Delaware.

By Lakiya WimBish, manager, endotoxin detection, Lonza


THREATS TO NATURAL AMEBOCYTE LYSATE� e Limulus or Tachypleus Amebocyte Lysate (L/T-AL) assays are currently the most widely used bacterial endo-toxin testing (BET) methods. � e need for these tests is on the rise due to an increase in the demand for medici-nal products, including biopharmaceuticals, particularly as more countries become economically developed. All parenterally administered pharmaceuticals will inevita-bly need to be tested for bacterial endotoxins and as such arise in vaccine production could place strain on lysate resources if current habits remain unaltered.

� e supply of LAL and TAL is reliant on several horseshoe crab species namely, Limulus polyphemus (Figure 1) and Tachypleus gigas or Tachypleus tridentatus, respectively. � is is because when endotoxins come into contact with the blood of these crabs, a clotting cascade is activated. It is this mechanism that has been used for endotoxin testing since its commercialization in the 1970s.

As the need for the amebocyte lysate increases, so too does the need to protect the crab populations. In North America, this has meant that the Atlantic States Marine Fisheries Commission has implemented a state-by-state fishing quota and the conservation efforts of the Ecological Research and Development Group (ERDG) such as Just Flip ’em and Backyard Stewardship community horseshoe crab sanctuary (Figure 2) have been put in place to safeguard the native L. polyphemus populations.

However, in Asia a lack of regulation has meant a considerable reduction in indigenous T.gigas and T. tridentatus numbers. A collaborative e� ort from regulatory bodies, pharmaceutical industry, vendors, end-users and conservationists will aid in ensuring horseshoe crab populations are preserved. In addition, the development and adoption of alternative testing methods that do not rely on a potentially � nite animal resource could also help to achieve this.


Figure 2: Lonza’s Global Endotoxin Summit delegates taking part in the Just Flip ‘em® program to help save stranded crabs on Pickering Beach, Delaware, one of ERDG’s com-munity horseshoe crab sanctuaries.


AlternAtive endotoxin testing methodsAlternative methods, such as Lonza’s PyroGene recombinant Factor C (rFC) assay, use a synthetic form of Fac-tor C, the essential component of the endotoxin-activated clotting cascade (Figure 3). Not only do such alternatives negate the need for an animal resource, but also they offer several other benefits over the natural assays. These may in-clude ease-of-use, lot-to-lot consistency, statistically robust spike recovery and enhanced endotoxin specificity.

Despite these benefits, many are reluctant to use these alternatives. This is due to the fact that both the FDA USP <1225> and EP Chapter 5.1.10 stipulate additional validation steps to be conducted when using these methods. However, pharmacopeial members, like Ingo Spreitzerare keen to discuss how rFC-based tests are defined. “I hope to see increased usage of rFC in the field of endotoxin testing. This shouldn’t be too challenging in my opinion, as I don’t see a significant difference between the LAL assay prepared from crab and industry prepared rFC — both depend on Factor C.”

Furthermore, the validation procedure can be accomplished in 1-3 days and doesn’t require much additional effort compared to compendial methods. The process is simplified by the availability of documentation and well-structured protocols from test manufacturers that can help users generate sufficient data to meet the regulatory requirements. Allen Burgenson thinks, “We’ll need big players to adopt rFC so that others will follow and this will increase the chance of it being accepted by regulatory bodies,” if alternatives are to become common practice.

moving towArd AutomAted testing Automating the endotoxin testing process could help improve efficiency and manage the increase in demand. Alan Baines believes, “Automation of the preparation steps will be pos-sible. In fact, for large-scale users this has already been successful, but this is expensive for the application and out-of-scale with the need of the assay. Testing is moving from the QC laboratory to the manufactur-ing floor, with the hope that this will allow problems to be detected sooner and prevented at an earlier stage. This has had some limited success so far, but this could become much more prevalent over the next 10 years.”

Wolfgang Mutter, general manager of Hyglos GmBH, concurred saying, “If we have the technology I think we can manage this.” However, if the regulators do not account for the technological advances, this could mean that “…rather than using the

latest biochemistry, such as rFC, new automation processes will be designed using LAL reagents, even though they could soon become obsolete.” For this reason, it is imperative that the pharmacopeias be kept up-to-date on developments in endotoxin testing in order to ensure the guidelines for use are acknowledged in the compendia. As a result, this will increase the probability of these methods being taken into consideration when designing new instrumentation.

modifying phArmAcopeiAl guidelines New products challenge the current pharmacopeial guidelines. Ingo Spre-itzer envisages, “New types of prod-ucts are going to affect the future of endotoxin testing. I predict that we will need to develop a much more de-tailed and product-specific set of risk assessments in the future.” Therefore, in order to ensure the industry and


LAL Recombinant Factor CEndotoxin

FC FC

FC FC

ProclottingEnzyme

ClottingEnzyme

Substrate DetectableSignal

FGFG

Glucan

Endotoxin

rFC rFC

Substrate DetectableSignal

Figure 3: Endotoxin-activated clotting cascade comparing LAL assays and Pyrogene recombinant

Factor C Assay (Lonza).


regulators move forward in parallel, every stakeholder will need to be involved to ensure a rapid mutual progres-sion amongst the endotoxin testing community.

LOOKING TO THE FUTURE� e endotoxin testing community is increasingly aware of the imminent transformative period ahead. Hence, regulatory bodies, pharmaceutical manufacturers, re-agent vendors and horseshoe crab conservationists will need to work together to align goals and set clear objec-tives to ensure innovative methods, which improve upon current assays, are incorporated into the pharmacopeia and adopted in the QC laboratory. Change is inevitable throughout this process. � erefore, it is necessary to have a responsive system in place to ensure prompt implementation of alternative tests while still maintain-ing patient safety, which remains the utmost priority for the pharmaceutical industry.

Given the research currently underway to fully understand LER and to assess potential solutions, it is likely that the problem will soon be solved and without becoming a risk to human health. Endotoxin

testing may be improved upon if the industry can be encouraged to carry out the additional validation steps required by the regulators when using an alternative method, as these tests deliver comparable results yet o� er a number of additional bene� ts for the user in addition to reducing the strain on lysate supply and protecting the horseshoe crab populations.

Evidently, change is coming and the global endotoxin industry will need to adopt a collaborative approach to realize sustainable BET operations and ensure patient health and well-being remains at the forefront of all future endeavors.

ABOUT THE AUTHOR Lakiya Wimbish, product manager for Endotoxin Detection at Lonza is responsible for alternative methods like the PyroGene™ recombi-nant Factor C Assay, Testing Services and Rapid Microbial Detection platforms. She joined Lonza eight years ago as an Applications De-velopment Scientist for Rapid Microbial Detection platforms before transferring into her current marketing role. Prior to Lonza, she was a contractor for the United States Navy/Biological Defense Research Directorate and graduated from the University of Pennsylvania.

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Technician || Don R. || 4:38 PM

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