Q: Our company recently acquired several new production sites in Europe, Asia, and the Americas. As part of the integration process, we decided to harmonize our batch records. We appreciate that local regulations and differences regarding the type of production equipment we use may require some local adaptations and deviations from a standard template; however, we are faced with stiff opposition from many sites to change their batch record design. Can you advise on how best to convince everyone of the benefits of a harmonized template?


	
	A:  The integration you describe will without doubt require many changes to the documentation, and therefore, it is a sensible decision to think about harmonizing documents, such as batch records. You are correct that there will be differences in the equipment and the processes, even for the same product by the same synthetic method, but in different facilities. But, this in itself is not an impediment to creating a universal batch record template.

	It is important to consider why batch record templates differ so widely. First, the workforce will be used to different styles of documentation. How much or how little detail do they require to perform a task? It is not unusual to find a 10-page document used for a process in one location to extend to 50 pages for the exact same process elsewhere.

	Next, let us look at the style of the contents: Is it all text? Is there use of pictures or graphics? Is it all in a logical sequence? Is it in one language or in multiple languages? Does it require each page to be signed by five persons for each batch record, or is there just one signature page? All these styles exist, and they all are developed for specific reasons. It is thus important to understand these reasons in order to design a universally accepted template.

	Having the opportunity to completely redesign the batch record template provides a unique chance to build in as many safeguards from a data integrity perspective as possible. This includes removing any ambiguity regarding what must be recorded, by who, when, and how. For example, the instruction ‘add 100 liters 10% NaOH over 1 hour should have fields for entering the actual values that should look like this:

	This technique makes it clear to the operators what fields to complete and how to enter the values correctly. The use of symbols and colors is encouraged (e.g., to highlight critical steps, warn of potentially dangerous substances, etc.).

	This is also a superb opportunity to eliminate the ‘numeritis disease’ (i.e., the unnecessary and time-wasting use of highly complex numbering systems). Step 001 in the batch record should be followed by step 002, then step 003, etc. There is no need at all for having something like step 1.2.5.2.8a.

	Depending on the level of automation in the plants, you may be able to move from paper batch records to electronic batch records. The latter will provide a higher degree of data integrity as much fewer manual entries of data will be required. Thus, the standardization of the batch record can indirectly also drive standardization of the computerized systems in your plants.

	Now let us look at some indisputable benefits of having a standard batch record template rather than a free-for-all: 

		Reviewing batch records for continued compliance with the regulations is facilitated across sites, countries, and continents.

		Extracting information for or verifying concurrence with the submitted dossiers (e.g., for new drug applications, marketing authorization applications, variations, post-approval changes, etc.) is straightforward and simplified.

		Batch record review by the qualified person (as regulated in the European Union) or the quality unit (e.g., for the purpose of batch release or audits) is streamlined.

		Extracting information from the batch records for preparing annual product reviews (or product quality reviews), or for the purpose of benchmarking is effectively repeatable and possible.

	Every day a product can be released to the market earlier because of any of the above benefits can result in monetary benefits. And who is to dispute that advantage in your company?

	In summary, if the regulatory compliance benefits of a standardized batch record template aren’t compelling enough, monetary benefits gained by earlier release of drug product will no doubt make it a straightforward decision. 


	Vol. 31, No. 5
	May 2018
	Pages: 50, 49

	When referring to this article, please cite it as S. Schmitt, " Harmonization of Batch Records" 

Articles

Ask the Expert

Monetary benefits will outweigh the hassle of batch record harmonization, says Siegfried Schmitt, principal consultant at PAREXEL.

Harmonization of Batch Records

	Scott Gottlieb has seen a whirlwind of activity since taking the helm of FDA in May 2017. He blasted brand manufacturer “shenanigans” for blocking generic-drug development and cited “pernicious” rebating schemes that expose consumers to high out-of-pocket costs for medicines. To help mitigate the nation’s deadly prescription drug epidemic, he has backed policies to reduce opioid prescribing and to develop less addictive pain treatments. And to continue last year’s notable gains in bringing important new drugs and gene therapies to market, Gottlieb has promoted innovative clinical research methods and other strategies to make drug testing more efficient. 

 that he is revving up FDA efforts to encourage industry conversion to advanced manufacturing systems able to scale up quickly to address public health issues. New policies to ensure quality manufacturing can facilitate the development of competitive biosimilars and prevent shortages of critical medicines to protect public health. 

	These and other initiatives have quieted critics on all sides. Democrats initially feared an industry bias but have been impressed by the commissioner’s criticism of drug pricing and his campaign to reduce nicotine in cigarettes. Republicans hoping for a free-market deregulator admire his efforts to combat opioid abuse and his support for innovation to speed new medicines, devices, and diagnostics to patients. Certainly, many of Gottlieb’s initiatives are not new and reflect years of hard work by FDA’s professional staff. But vocal support from the commissioner has accelerated action on many fronts. 

	A clear achievement is a proposed $400-million boost in FDA’s budget for 2019, as compared to the administration’s plan to cut agency appropriations by $700 million a year ago. The commissioner has gained support for FDA in Congress, which helped enact crucial user fee reauthorizations last year and blocked the Department of Defense from taking control of approving new treatments for the military. FDA also negotiated some modifications in “right-to-try” legislation to lessen its erosion of the FDA approval process and maintain patient protections. 

	To convince the legislators to approve FDA’s new budget plan, Gottlieb outlined proposals for utilizing added resources (1, 2). Several initiatives advance the testing and production of new therapies, including greater use of real-world evidence and knowledge management systems to facilitate regulatory decisions, particularly for new treatments for rare diseases. 

	FDA also highlights the importance of modernizing drug manufacturing in proposing to spend $35 million to produce novel technologies, vaccines, and personalized medicines more reliably and at lower cost.  Gottlieb now sees a convergence in regulatory resources, industry frustration with traditional production methods, and wider availability of new technology to advance more reliable and flexible advanced and continuous manufacturing systems. 

	“We’re now at a tipping point,” says Gottlieb. The agency will develop further guidance and standards to reduce uncertainty for industry in adopting high-technology platforms. And more highly trained field investigators will inspect for quality and those aspects of manufacturing that create risks, Gottlieb explains, and move away from a checklist system for uncovering violations. Further innovation may come from FDA funding of advanced manufacturing R&D projects to assess new quality manufacturing and analytical methods (3). 

	This focus on quality manufacturing fits well with Trump administration efforts to encourage “re-domesticating some of the manufacturing that has moved overseas,” Gottlieb explains. He notes that high-quality, small-footprint manufacturing platforms have lower labor costs more suited to US operations. Advances in how FDA oversees medical device production similarly bolsters a “bring medtech manufacturing home” initiative that encourages firms to re-tool manufacturing processes in the United States. And streamlined oversight of software-based devices aims to lower the time and cost of market entry. 

	FDA also seeks to build the largely domestic pharmacy outsourcing industry through clearer manufacturing standards and policies. And more modern production methods for biologics are on the agenda to improve the agility, flexibility, and reliability of manufacturing processes for vaccines and cell and gene-based therapies. In the wake of this year’s severe influenza outbreak, Gottlieb has urged shifting from an egg-based to cellular system for seasonal flu vaccines, along with efforts to develop a universal influenza vaccine to provide multi-year protection, and ensure US access to vaccines to protect against a pandemic.  

	More advanced manufacturing methods also support more reliable production of biosimilars. Gottlieb plans to issue new guidance documents on reducing lot-to-lot variability over time for biologics by utilizing new tools better able to identify where lot variation raises potential risks to patients, along with more standard reference products that are easier to test and copy as biosimilars. 

	Despite a year of considerable success in broadening support for FDA initiatives and policies, the commissioner shows no sign of slowing down. He continues to tackle controversial issues, such as limits on flavored nicotine products, oversight of independent testing labs, and programs to limit food contamination outbreaks. The commissioner has emphasized the importance of promoting vaccination rates, despite continued opposition from vaccine deniers. And in another speech, he outlined plans to implement nutrition labeling standards and menu disclosures, which Gottlieb considers key to improving public health (4). 

	FDA also faces numerous deadlines for implementing key provisions of the 21st Century Cures legislation, including policies to support regenerative medicine and to speed the development of new cancer therapies, personalized medicines, and gene therapies. At the other end of the spectrum is a press for more efficient oversight and approval of over-the-counter medicines through a new user-fee program. And transparency remains a thorny issue, as FDA supports wider disclosure of data and analyses related to regulatory, safety, and enforcement decisions. Yet proposals for release of complete response letters remain on hold, as industry seeks to keep confidential certain regulatory decisions. 

	Combating the opioid epidemic is a prime challenge. While FDA supports the development of safer and more effective pain therapies and treatments for substance abuse and is re-examining the safety of abuse-resistant products, physicians are pushing back on proposals to limit opioid prescribing. FDA has gained added funds to expand its capacity to block imports of unlawful controlled substances at the border, and new legislation may strengthen its authority to require small-dose packaging of opioids and to remove from the market approved pain medicines found to raise safety issues. 

	Gottlieb plans to remain a visible advocate for lower drug prices, anticipating a continued roll-out of incremental changes to create a more competitive prescription drug market place. He has loudly criticized drug reimbursement and coverage policies for limiting consumer access to drugs, including a “rigged payment scheme” that blocks biosimilars, and suggested that FDA may be more flexible in setting standards for demonstrating product interchangeability (5). 

	The commissioner’s concerns about the high cost of medicines reflect his own experience as a physician and seeing ill patients “struggling very hard at the worst moments in their lives” to try to afford drugs that are “absolutely indicated for their disease.” He wants to be sure “that in my time here at FDA, I do something to address that.” 

	1. FDA, “Statement from FDA Commissioner Scott Gottlieb, MD, on Administration’s Request for New FDA Funding to Promote Innovation and Broaden Patient Access through Competition,” 

, Feb. 13, 2018. 
	2. FDA, Department of Health and Human Services Fiscal Year 2019, Food and Drug Administration, 

Justification of Estimates for Appropriations Committee

. 
	3. FDA, Agency Announcement, Solicitation Number: FDABAA-18-00123N, 

, Feb. 14, 2018, 
	4. S. Gottlieb, MD, “Reducing the Burden of Chronic Diseases,” 

, March 29, 2018.
	5. S. Gottlieb, MD, “Capturing the Benefits of Competition for Patients,” 

	When referring to this article, please cite it as J. Wechsler, "Gottlieb Tackles Tough Issues in First Year at FDA" 

Regulatory Beat

FDA’s commissioner addresses opioid abuse, drug costs, and manufacturing quality.

Gottlieb Tackles Tough Issues in First Year at FDA

This second installment in a three-part series on validation and technical transfer in the biopharmaceutical industry presents a generalized example that shows how a validation plan might be developed to support a process. While the example is not related to biopharmaceutical manufacture, it demonstrates various points to consider related to the inputs, the processing system, and the outputs that can be applied to biopharmaceutical processes and systems. The intent is to think outside the box and avoid terminology traps that hinder many validation efforts. 
	


, which appeared in the April 2018 issue of this publication, contained a brief history of validation and defined the terms process and validation to provide context (1). 

Let’s say one is about to open a coffee shop and wants to ensure its success. The process to be validated is coffee-brewing. The goal is to consistently produce good tasting coffee. For the sake of simplicity, no specialty coffee (e.g., latte, cappuccino) is considered and no cream, sugar, or flavoring is added to the brewed coffee. The process is described as the following:

The processing system is the coffee brewer and the coffee grinder.

The outputs are brewed coffee and process waste: coffee grounds and used filters.

The process seems simple enough, but to begin with the end in mind, it is important to define good-tasting coffee. A controlled, double-blind study should be conducted to determine which coffee the majority of tasters prefer to obtain a definition of “good-tasting coffee.” To have a meaningful result, the brewed coffee used in the study must be produced in some standardized way not only to achieve reproducible tasting results but to enable the ultimately chosen brewing process to be validated and to produce coffee equivalent to that used in the tasting study. The obvious analogy is a clinical trial followed by subsequent commercial-scale production of a biopharmaceutical product.

The process inputs are water and coffee; but what type of coffee is selected and how is it roasted and ground? Should the coffee be a blend, or should it be a single type? If a blend is desired, what types should be used and in what proportion? Should the coffee be sourced from various growing regions or should it be single-sourced? What level of roast should be used: light, medium, dark? How will the roasting be controlled? How will the beans be ground, and to what degree? Should there be a maximum time allowed between grinding and brewing? Will tap water be used, or should some form of processed or filtered water be considered? These decisions impact the process and must be carefully considered. Some process variables are more critical than others.

Even in this simple example, there are many factors to consider, and biopharmaceutical processing is much more complex. An Ishikawa (fishbone) diagram is a helpful tool for visualizing processes and process inputs. 
	

 is an example applied to coffee brewing.

Once the decisions have been made with respect to the coffee and water, supported by evidence from the tasting trials, the brewing process can be considered. Data from how the coffee used in the tasting studies was prepared serve as the basis for developing and validating the brewing process. Wherever possible, quantitative values should be established and documented so they can be used for process execution and further evaluation. Equipment make, type, model, and serial number should be documented.

The brewing process must be carefully assessed before validation can begin. What brewing process will be used-percolation, drip, vacuum, or French press? Assuming the coffee type and grind have been determined, what brewing ratio, coffee-to-water, will be used? How long will the brewing cycle be? How will it be timed? What water temperature will be used, and when and how will that temperature be measured and controlled? What, if any, type of filter is employed? How will the brewing equipment be cleaned and when? Will detergents be used? If so, what duration and type of rinsing will be used to remove detergent residues?

The coffee brewed for the tasting studies will have been prepared in some controlled manner using identifiable coffee type, roast, and grind, and processed in equipment that will serve as the basis for selecting equipment for the commercial brewing process. Once the choice of equipment has been finalized, the equipment must be qualified with respect to its operational parameters. What brew settings are available? Which ones have a critical impact on the taste of the brewed coffee? How reproducible are the settings, and how accurate? With respect to the coffee grinder, how is the fineness of the grind determined and set? How reproducible are the settings? What is the uniformity of the grind? Does it contain a high proportion of “fines” or large particles? What are the capacities of the brewer and grinder and do they match the expected coffee shop volume?
Finally, the process output must be examined and evaluated. Does the brewed coffee taste good? How will that be determined? Is it the same as the coffee chosen as a result of the taste testing? Are there any analytical methods that might provide confirmation? At what temperature should the coffee be held, and for how long? How should it be served, in a paper cup, foam cup, or china? Does the cup require insulation? Will take-out be available? If reusable, how will the cups be washed? Are coffee stains or detergent residue issues?
Once these variables have been defined, examined, and evaluated, the validation study can begin. A single validation protocol can cover the entire process or, more usefully, the process can be broken down into several manageable steps with individual protocols for each.

Validation protocols should describe the intended process, define the acceptance criteria, and set forth the procedures and tests that will be used to demonstrate that the process does what it is intended to do and results in an output that meets the predetermined acceptance criteria. Ideally, the protocol should be written by those most familiar with the process to be validated, with input from other organizational units as necessary and appropriate. Development, process engineering, production, and regulatory affairs departments should almost always be involved. Other departments that might have input are purchasing, warehousing, and compliance. The quality assurance department must be involved at all phases of protocol development and must approve the final protocol before validation begins.
	
Protocols fit two broad categories. Qualification protocols are used for process equipment, such as tanks, mills, piping systems, autoclaves, ion exchange units, chromatography columns, and stopper washers. Validation protocols are used for processes that employ the qualified equipment and for processes related to the equipment, such as cleaning and sterilization.

It is convenient to break down equipment qualification into several steps such as design, installation, and operational as described below for the coffee brewing example.

Tasting studies may have shown that customers preferred coffee produced by pouring hot water through ground coffee supported on a filter. The proportions of coffee and water as well as the coffee type and grind, filter type, the brewing time, and the temperature were known from the development studies used to support the tasting. Adequate design qualification used in equipment selection will ensure the commercial brewer and grinder will meet the process requirements established during development. Factors to be considered include materials of construction, ease of use, space requirements, utilities, and process interactions (e.g., compatibility, adsorption, and leachables), and cleaning and maintenance.

Once selected, the equipment is installed, ensuring that electrical and water supplies are available and adequate and that necessary operational and storage space for supplies is convenient and available. The shop must be set up and arranged to optimize workflow. Space and facilities for equipment cleaning must also be available. Processing settings and conditions must be checked and calibration of water temperature, flow rate controls, and timers must be accomplished and documented. Cleaning procedures must be performed and evaluated for effectiveness and any problems corrected.

The installed and qualified equipment may then be used in start-up and training exercises to ensure everything, including coffee shop staff, is ready for a successful opening day.

Validation of the coffee brewing process may take place during the operational phase of equipment qualification, although the validation studies extend backward and forward in time. Earlier activities include vendor qualification of the coffee supplier and roaster, qualification and validation of the water supply system, validation of the equipment cleaning processes, and any calibration programs and maintenance procedures. Later activities include periodic evaluations to ensure the brewing process is functioning as intended, evaluation of cleaning and maintenance procedures to ensure adequate frequency and effectiveness, and a review to determine whether any operational issues or employee training programs need to be adjusted.
	This good-tasting coffee example is intended to stimulate thinking about the important points to consider when developing and marketing a product that consistently meets customer expectations. Although the product in question, good-tasting coffee, is not a biopharmaceutical, the same validation principles apply. The validated process must be robust, consistent, and do what it is intended to do.

Part 3 of this series will discuss validation of a non-traditional biopharmaceutical process, lifecycle, and change management and offers a summarization of the benefits of well-conceived and executed process validation studies.

When referring to this article, please cite it as R. Madsen, "Understanding Validation and Technical Transfer, Part 2" 

Features

A validation plan developed to support a process unrelated to bio- pharmaceutical manufacture is applied to bio- pharmaceutical processes and systems.

Understanding Validation and Technical Transfer, Part 2

Upstream biopharmaceutical manufacturing has always depended on process measurements, because precise levels of nutrients and oxygen must be monitored closely to ensure cell culture viability and the health of the process. For many years, though, extending this approach into true process analytical technology (PAT) and using it to track and control processes was done mainly in the research lab.

	Recently, there has been a significant mindset change in the industry. Biopharmaceutical companies are starting to use PAT in more advanced development and even some manufacturing work, while methods are also moving downstream. Francisca F. Gouveia, a biopharmaceutical process specialist who is now working for a biopharmaceutical company, evaluated the industry’s progress in a PhD thesis written while she worked for 4Tune Engineering, a consulting company and software vendor based in Portugal, which she defended at the University of Copenhagen (1) in March 2018. 

	As she sees it, biopharmaceutical companies are now developing the mindset that will be needed to take PAT and advanced process control to the manufacturing area and to different areas of manufacturing. As she says, “PAT is not just sticking a probe into a bioreactor. A great deal of work is needed to make advanced process monitoring and control approaches feasible.” At this point, due to higher complexity of unit operations and production infrastructures, biopharma remains a step behind small-molecule manufacturing (where the methods have routinely been used in GMP facilities).

	One major challenge is developing a lifecycle approach to using PAT and advanced control that would allow these approaches to be used, from R&D through biopharmaceutical tech transfer, and manufacturing, she says. Ms. Gouveia and Jose C. Menezes, CEO and founder of 4Tune Engineering, shared trends they are seeing in biopharmaceutical process monitoring and control with 

:At the International Forum for Process Analytics and Control (IFPAC) conference in 2018, a record number of presentations addressed biopharma PAT and process control. Are more biomanufacturers adopting PAT and advanced control in biopharma?

:The initial use of PAT in bioprocessing was focused on monitoring specific culture attributes in upstream processing, with mid- or near-infrared (MIR or NIR) spectroscopies, or some transition analysis and performance studies with ultraviolet (UV) and NIR spectroscopies used in downstream processing. Those applications followed the experience and successes in pharma solid-dosage forms manufacturing. However, the low concentrations and/or aqueous matrices involved created several challenges, particularly for NIR spectroscopy, due to a lack of sensitivity and specificity.

	Monitoring calibration models could be built and used across lifecycle and process scales only if very detailed care was taken in designed experiments during calibration development (2) to avoid ‘indirect calibrations’ that can result when vibrational spectroscopies are used in bioprocessing.

	A second moment for PAT in biopharma involved moving from parameter monitoring to process state estimation and exploring control opportunities. Instead of putting effort into unspecific and insensitive methods pushed to their analytical limits, the multi-parametric character of all PAT methods was explored with multivariate analysis to provide a complete estimation of the bioprocess state over time (e.g., a process trajectory during an upstream cultivation), creating the opportunity in pharma to define guided sampling and end-point determination strategies. This involved most notably NIR and MIR spectroscopies and, more recently, Raman spectroscopy as well. There are accounts of 

and at-line under GMP conditions use of different spectroscopies (2,3).

	Currently, we are observing a trend toward connecting process condition-monitoring to accurate product quality-control during processing, by very specific techniques such as 

mass spectrometry (MS). The capability to use MS as a PAT, and aggregate multiple attributes that MS can very specifically measure, is a real breakthrough. IFPAC 2018 already showed this year several talks on MS-based multiple attribute methods (MAM), a new acronym being used by FDA’s Emerging Technology Team (ETT) to name the PAT use of these methods.

	The aims of optimization and control were present at earlier phases for PAT in biopharma, but today it is possible to monitor product quality attributes end-to-end (E2E) in upstream and downstream processing. Use of approaches such as MAM could open a completely new field for PAT used earlier in development for building. This approach would result in very fast process/product understanding, but more importantly, would support the process performance qualification (PPQ, Stage 2) and the entire commercial lifecycle (Stage 3).

: What obstacles remain to greater use of advanced monitoring and control in biopharma?

: Some of the obstacles are not technical at all, but organizational. Companies need to align different groups (e.g., the process engineers, analytical experts, regulatory departments) in efforts to leverage PAT and advanced process control. Some companies still have a disconnect between production  experts and those who work on statistics and data analysis. This approach does not facilitate data-driven thinking. 

	As I found while researching my thesis, people working in PAT at biopharmaceutical companies often have difficulty trying to take Raman or NIR spectroscopy out of the lab into development and manufacturing. Extending the lifecycle concept to PAT method development will be essential to ensure its fit for purpose during routine production.

	The right questions need to be asked: what is our problem statement, what do we want the PAT method to do, in what range, in the presence of what other substances (e.g., metabolites in cell culture), what technique will work best for a specific application, and what performance requirements [established in the International Council on Harmonization’s (ICH) Q2, the European Medicines Agency (EMA) Near-Infrared Spectroscopy NIRS guideline, and guidance from the US and EU pharmacopoeias], will be required for control purposes?

	Efforts taken early in development will pay off, and the PAT method will be robust even if there are changes in raw materials or in a specific process step. In general, more thought [to use of process monitoring and control] is needed earlier on. There’s a need to take knowledge of the process and use it to build a method, then to align the lifecycle of the method with that of the process through teamwork and collaboration.It’s much more than understanding chemometrics and spectroscopy. You need to understand the organization, its quality culture and the regulatory framework.

: Has the industry grown more comfortable with the concept of soft sensors?

: The use of soft sensors in bioprocessing is seeing a rebound from its promising inception in the mid-1990s. Today, they are being used across operations, making true the promises of quality by design (QbD).  In time, they may even permit the use of real-time release (RTR) in bioprocessing. As data management becomes more sophisticated, the possibility of retrieving and aggregating data from critical process parameters (CPPs) and critical quality attributes (CQAs) in real-time will allow CQAs to be estimated during processing for subsequent operations. That opens many possibilities for E2E optimization and feedforward control and will make QbD a reality in bioprocessing. We have developed a soft sensor applications for GMP biomanufacturing in which media components quality attributes are related to upstream yields or bulk product CQAs (e.g., stability) (4,5).

: Can you give an example of how soft sensors are being used to leverage data?

: In the usual commercial biopharma setup, you have a complex package of specs and very complex upstream and downstream unit operations. It can often be difficult to pinpoint which step(s) is/are responsible for quality results. Soft sensors can be effectively used to link processing steps using different data sources (e.g., online and offline process measurements, in-process quality measurements) to shifts in product quality. For example, chromatography data can provide a fingerprint of the product at a specific point in the process so that changes in peak shape can be used to better understand the underlying buffer preparation variability or to anticipate packing problems that might have been overlooked.

: In general, what progress are you seeing in the use of advanced process control and the use of predictive models?

: We see a significant change in how advanced control practices from other processing and systems engineering areas are today applied in biopharma. The realization that in bioprocessing there is one more control agent present (i.e., the biologic component used, such as bacteria or cells) took some time to accept. Feedback control has always been carried out based on extracellular measurements, specific sensors, and multiparametric ones (e.g., PAT).

	Effective advanced control must start early in the lifecycle by considering the process E2E: What are the CQAs, the CPPs available for establishing a control strategy?  This is a risk-management exercise that will make the knowledge about causality between CPPs and CQAs explicit. From this point on it will be clear where, when, which, and by how much each CPP should be set or changed to achieve a specific set of CQAs.

: Companies are becoming more open to the idea of predictive models, as they start to address data gathering and management. This issue often centers around the manufacturing execution system (MES). Commercial data-aggregation software packages can help companies develop the necessary models. This is true upstream, but we’re also seeing more advanced control move downstream to help better control yields and purification steps, and even to improve the management of plant and equipment.

: What is preventing a more unified approach to integrated continuous bioprocessing?

: Several companies are  working on end-to-end continuous biopharmaceutical processes, but the industry’s existing plants have a totally different facility design. A strong business case will be needed for taking this approach before much more can be done.

: Integrated bioprocessing presents specific challenges, compared to continuous small-molecule processes, in terms of PAT, controllability, and RTR. Over the next decade, plant modularization and new facility designs promise to move biopharm and small-molecule manufacturing closer to Industry 4.0 models.

	1. F. F. Gouveia, “Chemometrics and PAT Applications in the Pharma and Biopharma Industries,” PhD Thesis, University of Copenhagen, March 2018, SL grafik, Frederiksberg, Denmark, March 2018. 
	2. JC Menezes, “Process Analytical Technology and Quality by Design in Bioprocess Development and Manufacturing,” 

Industrial Biotechnology, in Comprehensive Biotechnology

, Vol.3, 2nd edition, Ed. A Moreira, Moo-Young Ed., (Elsevier, 2011).
	3. “Near-Infrared Spectroscopy in Laboratory and Process Analysis,” 

(Wiley, 2012) DOI:10.1002/9780470027318.a9361
	4. “Spectroscopic finger-printing of raw materials,” Hoffmann-La Roche AG, WO 2012/059520 A1. 
	5. “Method and system for preparing synthetic multicomponent biotechnological and chemical process samples,” Hoffmann-La Roche AG, WO/2015/097217. 


	Vol. 31, No. 5
	May 2018
	Pages: 42–45

	When referring to this article, please cite it as A. Shanley, "Leveraging Data for Better Biopharmaceutical Process Control" 

The need to improve and understand processes is moving PAT and more advanced control strategies beyond the lab into manufacturing and downstream applications.

Leveraging Data for Better Biopharmaceutical Process Control

	Trade shows are a good opportunity to assess where an industry stands on new technologies, ongoing challenges, and future opportunities. It also is a good time to assess general attitudes about prospects for the road ahead. As I write this, I am half way through three consecutive weeks of industry events, each with a unique market focus, revealing the potential of biopharma to make a difference in the lives of patients and the work that must be done to achieve that goal.

	Continuous manufacturing, which has gained momentum for small-molecule drugs with FDA approval of several therapies, was a popular discussion topic at INTERPHEX in New York, NY in mid-April. The strong interest is an indication that the pharma industry may be looking to consider advanced technologies that are common in other industries. In the biologics arena, the move to continuous manufacturing will be more difficult; experts on a panel hosted by BioPharm International magazine noted that while some segments of a bioprocess may have continuous operations, an end-to-end continuous process will be difficult to achieve.

	At CPhI North America in Philadelphia, PA, medical futurist Bertalan Mesko shared his vision of bringing science fiction to medical reality through the use of digital technologies and data management and identified actions that must be taken today to get the most out of future technologies. Smartphone-based monitoring, 3D printing of medications, drone delivery of medications to remote regions, use of blockchain for data security of drug products, and Internet-based monitoring of patient medical conditions in their homes are a few advances he identified.

	A first step to digital medicine was made when FDA approved the first digital medicine system, a drug-device combination product comprised of Otsuka Pharmaceutical’s oral aripiprazole tablets embedded with an ingestible event marker (IEM) sensor from Proteus Digital Health.

	Mesko, however, noted how the lack of doctors, lack of money, and lack of patient trust in medicine can hinder the acceptance of innovation for medical applications. New digital technologies will generate vast amounts of data that must be managed by artificial intelligence; some people fear the power of artificial intelligence, a hurdle that must be overcome, he said.

	The cost of new technologies may be high, creating a divide between those that can afford it and those that cannot, Mesko warned, and including the patient in the design of the medical advances-by asking them what they want-is crucial.

	Mesko also noted that technology is only part of the solution; people are needed to implement this vision. The lack of a trained, qualified workforce to operate bioprocessing facilities spurred a partnership between Philadelphia-based Thomas Jefferson University and the National Institute for Bioprocessing Research and Training (NIBRT) of Dublin, Ireland to establish the Jefferson Institute for Bioprocessing, the first education and training institute for biopharmaceutical processing in North America. The partnership was announced in February 2018; further details were provided by Mary Lynne Bercik, founder and CEO, GenZinnovation, and Ronald G. Kander, Dean, Kanbar College of Design, Engineering & Commerce Associate Provost for Applied Research at Jefferson.

	When operational in 2019, the Jefferson Institute for Bioprocessing is expected to serve 2500 people annually, including an academic program for bioprocessing engineering, from undergraduate through doctorate levels, industry training with the pharmaceutical companies, workforce training through community college partnerships, and bioprocessing certifications through regional university partnerships.

	When referring to this article, please cite it as R. Peters, " Key Ingredients to Healthcare’s Future,"

From the Editor

While technology promises advances for healthcare, a skilled workforce is needed to deliver on the potential. 

Key Ingredients to Healthcare’s Future

	Ultraviolet (UV) absorbance measurements provide a rapid and reliable method to determine protein concentrations. The National Institute of Standards and Technology (NIST) has developed 

as a pathlength standard for UV absorbance measurements for use with the new generation of microvolume spectrophotometers and short-pathlength cuvettes. Short pathlengths are used with high-concentration targets to ensure that absorbance values are within the optimal range. The short-pathlength instruments and cuvettes also reduce the required volumes to conserve valuable samples. The authors compared the results obtained with high-quality dual-beam spectrophotometers and short-pathlength cuvettes to the results obtained from a microvolume spectrophotometer and a microvolume plate reader. SRM 2082 can be used to accurately calculate pathlength values, thereby increasing the accuracy in subsequent measurements using the short-pathlength cuvettes and microvolume absorbance instruments. RM 8671 (reference material, the NISTmAb) can then be used to ensure the accuracy and reproducibility of protein concentration measurements by providing an industrially relevant reference material, a well-characterized monoclonal antibody.

	Submitted: Jan. 22, 2018
	Accepted: Feb. 16, 2018

is group leader bioassay methods, Kenneth.cole@nist.gov; Paul DeRose, Brian Lang, John Schiel, and Aaron Urbas are research chemists; Hua-Jun He and Erica V. Stein are research biologists; Evelyn Solis is summer student; and Steve Choquette is director, Office of Reference Materials-all are at NIST.

To whom all correspondence should be addressed.


	Vol. 31, Number 4
	April 2018
	Page: 22–34

	When referring to this article, please cite as K.D. Cole et. al, “NIST Spectroscopic Measurement Standards,” 

Peer-Reviewed Research

The National Institute of Standards and Technology (NIST) has developed Standard Reference Material (SRM) 2082 as a pathlength standard for UV absorbance measurements for use with the new generation of microvolume spectrophotometers and short-pathlength cuvettes.

NIST Spectroscopic Measurement Standards

There is general agreement in the biopharmaceutical industry that new manufacturing paradigms will be essential to tackling issues around the cost and timeliness of new drug development, particularly for complex biologic therapeutics. Process intensification is being pursued as a first step toward fully continuous manufacturing. A combination of business challenges, technology gaps, and regulatory uncertainties must first be overcome before continuous biomanufacturing (CB) becomes a commercial reality. Equipment suppliers, drug manufacturers, and regulators are working closely to address these issues.

	The potential benefits to implementing continuous processing range from economic to time savings to quality improvement. Process intensification, the forerunner of continuous manufacturing, is allowing drug manufacturers to achieve, in some cases, up to 75% reduction in cost of goods sold (COGS), according to Andrew Bulpin, head of process solutions for MilliporeSigma.

	There are a range of business hurdles, however; benefits vary with each bioprocess and require individual assessment. The historic standardization on fed-batch processes is one key challenge, according to Parrish Galliher, chief technology officer for upstream with GE Healthcare Life Sciences.

	In addition, he notes that the business risk for CB is substantially higher due to the 5-10-fold increased rate of raw material consumption under continuous upstream processing (perfusion-medium consumption), which presents a significantly higher financial risk in the event of a product-quality failure compared to batch or fed-batch processes. Conducting quality-by-design (QbD) studies and validation of critical parameters and process design spaces is also more complex, labor-intensive, and time-consuming due to the extended duration of continuous production campaigns. The cost of training can be higher as well; operators need to be able to run more complex processes 24–7 without mishap.

	Proof of scalability across upstream and downstream processing is another main hurdle, according to Peter Levison, executive director of business development at Pall Biotech. “Processes must satisfy both internal and external expectations from concept through to commercialization,” he says.

	“There are many unsubstantiated claims in the literature that the costs for CB are lower compared to current methods. On the other hand, users are beginning to report that perfusion media consumption is far higher for CB in the upstream, and in the downstream, buffer and resin reductions need to be balanced toward any increased capital or consumables costs compared to batch chromatography,” Galliher says. On the positive side, he does note that CB has the potential to improve product quality consistency in cases where variability in product quality is not acceptable.

	Levison stresses, too, that, “While investment may first seem like a financial hurdle, one of the most often overlooked points is the exceptional savings on the backend (even with higher costs on the front end), for the life of the process. Savings come from less human/operator intervention and investment, less cost in process critical resources like fluids, and fewer quality-control demands, which combined lead to improvements in productivity and process economics.”

	Duncan Low, previously with Amgen and currently principal at Claymore Biopharm, asserts that from a purely business perspective, there are in fact more incentives than hurdles, “unless you start stacking up uncertainty.” “You have to define the technical issues and identify the risks as for any project. You may ask if you want to start with a commercial molecule or a biosimilar, or a new molecule where the risk of clinical failure overshadows the whole assessment. You may also want to ask about regulatory acceptance, which you could argue is a business risk,” he observes.

	Much of the technology for CB is in a relatively advanced state (compared to that for cell and gene therapies, for example), and much of it has been implemented to varying degrees, Low argues. “CB is, however, broader in scope than continuous processing for small molecules in that it considers the entire process, involves biology as well as chemistry and physics, and can be performed in plastics rather than steel,” he comments.

	While suppliers have developed and demonstrated scalable platform technologies for end-to-end CB, there still remains some work to be completed with analytics and automation and control to secure the greatest benefits of improved product quality and safety, according to Levison. “The right level of automation and control has been a hurdle for drug manufacturers, regardless of process type, and is even more crucial for continuous processes because they are run in closed environments. There needs to be sensors and detectors that measure critical process parameters and critical quality attributes in real time, ideally in-line or at-line,” he comments.

	“Improvements are needed around sensor and process analytical technologies (PAT), as this would bring enhanced process monitoring and real-time release of the product,” agrees Galliher. Such sensors must be stable to operate in-line for weeks without drift or fouling.

	Advances in these technologies are also important in the drive to create and archive more data that prove continuous processing advantages. “Data are really the top technical gap,” Levison emphasizes. “There still remains a paucity of published experimental data and case studies to demonstrate that continuous processes work effectively and provide multiple advantages. Consequently, there has yet to be a strong enough record of commercialized drugs (small or large molecule) to model success from,” he states.

	Levison anticipates that the Internet of Things will play a significant role in how the industry will be looking to manage and drive progress based on data. Pall Biotech has also created a process development services lab to help customers overcome the perceived challenges in transitioning from batch to continuous processes, or to create new processes from scratch. “With this approach, it is possible for drug manufacturers to start to gather data with less investment up front,” he says.

	Indeed, for Low, the transparent and seamless integration of data between suppliers and manufacturers is desirable when it comes to addressing PAT and automation requirements for CB. Overall, he sees CB as offering “amazing opportunities” for biopharmaceutical manufacturing. “Analytics and process control is an area with significant opportunities to apply ground-breaking, disruptive experience from other industries in data gathering, manipulation and understanding, and machine learning. We are at the beginning of Industry 4.0, and industry groups are working to address the ramifications of the impact these developments will have on the pharma industry,” he explains.

	Regulatory authorities support the implementation of CB, and companies can work closely with different agencies from the process development stage. Limited regulatory precedent does exist for continuous upstream processing given that more than 15 biologic products manufactured using continuous upstream processing are on the market, according to Galliher. “There is still regulatory uncertainty in the downstream space, however, because no biologics produced continuously in the downstream [process] have yet been licensed for commercial manufacturing,” he says.

	In particular, regulatory uncertainty surrounding batch definitions for continuous processes remains. Bulpin points to two examples: demonstrating product equivalence for a perfusion process at day one through day 60 and ensuring virus validation in an integrated and continuous bioprocess. “In the former case, the cell-culture development team must express product with low variability and the purification development team must minimize the impact of variability in the cell-culture feed on the final profile of the purified product. Even if successful, it is not possible to produce a fully uniform product over the entire process time, so we must be able to define a level of functional equivalence that is acceptable to the regulators,” he says.

	For virus validation, which is a downstream operation, Bulpin says it is necessary to rethink the entire strategy for CB because for integrated and continuous processing, variability in the performance of one operation can have a ripple effect on several downstream steps. “This impact as well as changes in operating modes including mass loading, flow rates, and consumables re-use, must all be accounted for during virus inactivation and removal validation studies,” Bulpin observes.

	There are also questions about how to handle the traditional three batches during a performance qualification when working with 30-90 days processes, according to Galliher.

	“Until these types of questions are addressed, manufacturers have to consider performing QbD studies over the full extent of a continuous bioprocess campaign, driving up material costs, time for process development, and labor requirements,” Galliher says.

	Based on the process development and validation strategy for a product, a batch may be defined according to the mass of product produced, such as 2 kg of purified product equals one batch; or process time, for example, 24 hours of clarified cell culture harvest from a perfusion bioreactor; or as a number of process cycles typically in the downstream process, that is 50 cycles through a Protein A column on a multi-column capture step.

	“While regulators appear agnostic on which definition is used, determining the required data package to support the definition and successfully collect that data in a way that is transparent and defensible will be the critical step in timely approval of the process for commercial production,” Bulpin asserts. “Suppliers, biomanufacturers, and regulators must work together to build the regulatory framework for approval of next-generation processes,” he adds.

	The ultimate goal with CB is to perform integrated biomanufacturing, with upstream and downstream operations connected together so the process is running in continuous mode. Doing so brings additional complexities and hurdles, according to Galliher.

	First, liquid flow rates through all unit operations must be matched and controlled continuously to be in synchrony, so that no overflows or flow stoppages occur. The process controls for each of the unit operations must also be synchronized to maintain steady-state operations without mishap, which requires sensors to operate stably and reliably over extended periods of time.

	“It is increasingly important with CB to define process and control strategies and use in/at-line analysis and a step-wise approach to ensure control over each individual process step before verifying the complete process. Setting the design-space for integrated CB often starts with defining the design-space for one-unit operation at a time, followed by multivariate data analysis to define the complete process,” Galliher notes. He adds that reliable model-scale setups should be available, including those for the connections between unit operations, where process development and trouble-shooting can be performed.

	Sensors and automation controls are relevant to bioburden control as well, which is also essential throughout the duration of integrated continuous processes. Connection of the bioreactor with the clarification system presents particular challenges, according to Levison. “In fed-batch, there is less chance for bioburden contamination due to the relatively short time taken to harvest the cell culture (typically 2–8 hours). In the case of perfusion culture, however, where the user may be continuing this process for 20–60 days or even longer, there must be a closed system to maintain low bioburden; consequently the analytics, sensors, and controls become so much more important. The user needs to be able to ‘know’ what is going on during the entire process,” he states.

	Today, the industry is taking an evolutionary approach toward achieving integrated and continuous processes. “Process intensification, like multi-column chromatography or the implementation of single-pass tangential-flow filtration, has been a successful first step. We are now in the process of connecting operations like anion exchange and virus filtration into a single operation,” Bulpin says. “As we move toward connected and continuous processes, software must enable processing systems to communicate and integrate several operations in order to maintain process controls and product quality. Biomanufacturers are clamoring for this type of software and control platform,” he continues. “Based on the knowledge we are gaining in the earlier stages of this evolutionary path, we will innovate and develop software and automation capabilities that don’t yet exist to fully connect and integrate both upstream and downstream processes to enable continuous processing,” Bulpin asserts.

	Low agrees: “We must have a realistic appreciation of the issues that need to be addressed and try to tackle them. That will involve identifying the issues, defining them (regulatory, quality, technical, etc.), recruiting the appropriate subject matter experts, and working together to resolve them.”

	Given that continuous bioprocessing generally considers the generation of the active molecule as well as its purification and formulation, there are multiple issues where standards can facilitate implementation, according to Low, who also is an officer for ASTM International’s E55 Committee on Manufacture of Pharmaceutical and Biopharmaceutical Products, and vice-chairman of the Subcommittee E55.04 General Biopharmaceutical Products.

	A proposal for a new standard on continuous bioprocessing of biopharmaceuticals has been brought to the attention of the E55.04 Subcommittee and will be a focus of the group during 2018. Particular areas of interest, according to Low, include the stability of cell lines over multiple generations, the management of bioburden over extended periods of time under conditions that are conducive to growth, and the design of unit operations such as bind and elute chromatography and viral inactivation via low pH and/or detergent that require defined hold times. Because single-use technology provides many advantages--and has its own set of issues for which standards development is actively ongoing--its impact on continuous bioprocessing must also be considered.

	“Collaborating to develop standards in anticipation of the issues rather than reacting after the fact is going to be helpful to manufacturers, suppliers, regulators, and most importantly to patients,” Low asserts. “If the pharmaceutical community genuinely shares a passion for serving patients, we have to collaborate when we can advance common, non-competitive interests for patients in areas of safety, quality, and technology. Consensus standards are recognized by the US government, FDA, and international bodies as a format for capturing and sharing knowledge. Individual and corporate commitments ensure ongoing dialog and the ultimate quality of the finished product,” he adds.

	FDA reaffirms support for continuous processing

	In February 2018, FDA Commissioner Scott Gottlieb, MD, announced that the agency’s requested budget is intended to continue to fund its current programs at consistent levels (1). It also includes an additional $400 million to support planned initiatives “aimed at supporting new and ongoing efforts to foster more investment and innovation in the development of therapeutics and diagnostics,” including the movement toward continuous manufacturing as a means “to improve the agility, flexibility, cost, and robustness of manufacturing processes.”

	Gottlieb also commented in the statement: “Armed with a robust scientific understanding of the requirements and the impact of these advanced manufacturing technologies, the FDA can help industry make investments in these new technologies and grow these opportunities. By developing a science-based framework that includes the regulatory tools and guidance for how products developed in these systems will be evaluated, and by funding research, development, and testing of the enabling technologies, the agency can help reduce the cost and uncertainty of adopting these new manufacturing platforms. The FDA would lead stakeholders in the development of clear scientific standards, policy, and guidance to support the effective and efficient adoption of these new manufacturing platforms, including the new inspectional methods they’ll require.”

	There is a perception, according to Levison, that transitioning to continuous processing from batch is difficult, when it really is not. “While early adopters may have to work out some of the nuances, they also get the greatest advantage. Single-use technologies were initially viewed with skepticism but have gained acceptance and are now moving into a more mature phase; late adopters have had to play more catch up. At Pall Biotech, we are driven by the potential of CB and are happy to embrace early adopters and work with them to advance continuous bioprocessing,” he states.

	MilliporeSigma is also bullish about the future of CB. “We estimate that next-generation processing cuts down one-quarter of original cost, around $100/g to $25/g, and frees up capacity in the range of 25-93% for manufacturing of other molecules,” says Bulpin. He also notes that PAT offers the opportunity for easier and more cost-effective quality and process controls. “Through continuous and automated monitoring driven by an advanced software platform, we can eliminate the need for sampling and offline measurement in many cases. Instead, we will have the ability to make near real-time decisions and react quickly to control our processes and ensure product quality,” he observes.

	As a result, next-generation bioprocessing will have a significant impact on how biopharmaceutical manufacturers bring therapies to market, delivering them to patients faster and more cost-effectively than ever before, according to Bulpin. “We estimate that by 2025, next-generation bioprocessing will represent 20% of pipeline molecule revenue and will be a [$1.5-billion] €1.2-billion opportunity for life-science suppliers,” he concludes.

Statement from FDA Commissioner Scott Gottlieb, M.D., on Administration’s request for new FDA funding to promote innovation and broaden patient access through competition


	Vol. 31, No. 5
	May 2018
	Pages: 12–17

	When referring to this article, please cite it as C. Challener, "Managing Uncertainty in Continuous Biomanufacturing"

Cover Story

More published data and initial regulatory approvals are needed to drive adoption of continuous bio-manufacturing. 

Managing Uncertainty in Continuous Biomanufacturing

Drug products based on live cells have an inherent risk for viral contamination that could cause serious harm or death to patients. When applying for regulatory approval, a drug license holder must demonstrate that its proposed manufacturing process can remove or inactivate potential viral contaminants.

	Viral clearance studies assess the capability of a downstream process to remove or inactivate potential contaminants and are based on a scale-down model of a biopharmaceutical production process. The studies must be designed to evaluate potential viruses, be representative of the production process, meet regulatory requirements, and provide reportable data. In addition, the testing should be conducted under “worst-case” conditions.

	 “The scale-down process used in the spiking study must be representative of the full-scale process and care must be taken to demonstrate the validity of the scale-down model using appropriate model viruses,” says Kate Smith, principal scientist, global operational development services, MilliporeSigma. “The study should be carefully designed to ensure the capacity to remove or inactivate virus is not over-estimated, applying ‘worst-case’ parameters to individual steps, where known.”

	The key elements of a viral clearance validation are choice of process steps, viruses, points of sample withdrawal, and the correctness of scaling, says Gustav Gilljam, client project manager, Vironova Biosafety. “The process steps chosen must represent different mechanisms in virus inactivation/removal to be included. The viruses tested should include both enveloped and non-enveloped viruses, and both RNA and DNA viruses with different physical and chemical properties.” He also notes that the studies should be conducted under worst-case conditions and performed according to good laboratory practice.

	Developing a test protocol, including the selection of viruses, is crucial. The model viruses used, and the number of steps investigated for viral clearance capacity, should be related to the risk assessment and product-specific regulatory guidance, says Horst Ruppach, director, viral clearance and virology at Charles River. “Pre-tests like cytotoxicity and interference assays are essential to prove the validity of the assays used for viral quantification,” he explains. “The product- and step-specific adjustment of virus spiking, sample treatment, and assay sensitivity ensure the viral clearance potential can adequately be demonstrated.”

	Drug license holders often turn to contract testing laboratories for this specialized testing; planning and communication are key elements. “Studies should be planned enough in advance to allow time to determine the scope and essential parameters of the study, to obtain the necessary materials for the study, and to work with your testing partner to schedule the study,” says Katherine F. Bergmann, manager, viral safety and clearance services, Eurofins Lancaster Laboratories. “The key parameters that determine the scope of the study are the clinical stage and indication of the product and the nature and origin of the source material.”

	Viral clearance studies typically are conducted at two phases of product development. “The early-stage study demonstrates the general viral clearance capacity, while the late-stage study typically demonstrates the robustness of the clearance capacity,” says Ruppach. “The extent of both depends on the product type and the development phase.”

	While only one or two viruses and a minimum number of samples are tested in early clinical phase, says Bergmann, four or five viruses are typically tested for products approaching or in commercial manufacturing. “Additional samples are evaluated in order to determine mass balance,” she says. “In addition, expanded ranges of critical operating parameters may be evaluated, and column cleaning and carry-over must be evaluated.”

	In testing prior to Phase III, Gilljam notes, “Reduction of virus infectivity is the most important measure, but various methods to detect viral genome copies or physical particles could be a complement. The manufacturing limits of parameters in these steps that might have an impact on the virus reduction should be challenged in the virus validation studies prior to Phase III, to show the robustness of the steps.”

	Smith notes the key areas of viral safety testing. Raw materials and cell substrates must be characterized using molecular, 

 testing strategies, she says, and cell banks and end-of-production cells are tested to identify species of origin, confirm expression construct stability, and to demonstrate the absence of potential bacterial and viral contamination. “Additional routine bulk harvest testing and the viral clearance study complete the tripod of viral safety testing,” she says.

	The multi-step nature of bioprocesses-and the viruses themselves-present challenges to the development of viral clearance studies and limit their effectiveness.

	 “All steps in a viral clearance study must be orthogonal; they must clear virus by independent mechanisms,” says Bergmann. “For example, if one step inactivates virus due to low pH, then a second step that uses a low pH buffer may not also be included, since virus that escapes inactivation by one low pH step is likely to be resistant to a second low pH incubation. Achieving a satisfactory clearance level can be limited by the virus titer, by cytotoxicity, or by viral interference,” she explains. “These limitations can be addressed by careful study design to optimize the clearance available from each step.”

	The European Medicines Agency lists potential limitations in a guideline (1), notes Smith. “Test sample composition can limit assay sensitivity and reduction factors obtained where large dilutions are required to alleviate cytotoxic effect on indicator cell lines,” she says. “Virus spike quality can influence the operation of key steps; for example, higher purity virus spikes are required for virus reduction filters to minimize virus induced flux decay and achieve the target filter capacity.” International Council for Harmonization (ICH) Q5A (2) also lists limitations of viral clearance studies.

	Ruppach and Gilljam note that the use of virus models presents some limitations.  “Relevant viruses may be difficult or impossible to produce in high concentrations. Therefore, model viruses, preferably of the same genus or family, are used as substitutes,” says Gilljam.

	“Even though few model viruses represent the biophysical characteristics of a broad range of mammalian viruses of different virus families, they are still models prepared and kept under laboratory conditions. They do not perfectly mimic the characteristics of related wild-type viruses,” says Ruppach. “This is of specific concern for biopharmaceuticals directly isolated from human or animal tissues, like human plasma products. On the other hand, the laboratory model viruses have a great chance of contaminating bioreactors using continuous cell lines.”

	Gilljam identified other challenges. “Due to the volume tested in the viral clearance study and that a dilution of the sample is needed to avoid any cytotoxicity to the indicator cells and the interference with the ability of the indicator cells to be infected with the virus, it is not possible to analyze the entire volume for the presence of infectious virus,” he says. “There is always a lower limit of detection, so the virus infectivity may be greatly reduced, but never to zero. Not all viruses are known. We will find what we look for but may miss the unexpected.”

	The relevance of the model virus depends on the virus step analyzed, Ruppach notes. “Virus retentive filtration is based on size exclusion, and a model of a specific size will represent all viruses of the same or greater size. But removal with chromatography steps is based on the virus envelope characteristics, which can differ among viruses of the same virus family and even among different strains,” he explains.

	Another limiting factor is the relevance of the downscale model. “In some cases, it’s easy to downscale the manufacturing scale but in other cases a 1:1 downscale isn’t possible,” Ruppach says.

	As in other areas of biopharmaceutical development, a risk assessment can define potential risks of viral contamination-and the need for viral clearance-in different phases of a production process.

	Risk assessment defines the viruses of risk, the type of and how many model viruses should be analyzed in the viral clearance study, and the overall reduction needed, says Ruppach. “In general, a high and robust viral clearance capacity is a much more efficient measurement to reduce viral risk than any extensive viral testing program; in fact, it can significantly reduce the testing on viruses.”

	Assessments should consider the entire production process and any changes.

	The source of starting materials and raw materials used in production are of primary concern, says Bergmann, and a risk assessment identifies which viruses are likely to be contaminants and the levels of contamination that could potentially exist. “This analysis is relatively simple for biologicals produced in well-characterized cells in culture but can be much more complex for products derived from uncharacterized cells or from animal materials (e.g., tissue),” she said. “Understanding the risks of viral contamination leads to the choice of viruses selected for a study, as well as the level of virus clearance required, to assure a safe product.”

	Assessments should consider the entire production process and any changes. “The impact on the validity of the viral clearance data by changes to the process, such as facility, procedural, process, and raw materials must be assessed,” says Smith. “A detailed risk assessment covering all aspects of the manufacturing process demonstrates an understanding and control of the process and provides a framework to evaluate the impact of each change both on the affected unit operation and those following. An informed decision can then be made to determine the scope of revalidation required.”

	While the primary guidance documents-EMA/CHMP/BWP/268/95 and ICH 5QA-are 20 years old, they are still adequate for determining the background and principles for viral clearance, says Ruppach. There is space for adaptions based on the experiences made since the guidances were issued, he adds.

	Bergmann concurs and notes that while these guidance documents work well for monoclonal antibodies and therapeutic proteins, “use of the guidelines for novel types of products can be challenging” and revisions of regulatory guidance documents need to address these product types.

	Advances in production technology also can present complications for the viral clearance studies. “A lack of appropriate scale-down models and strategies to support changes in industry practices such as continuous processing can restrict the design of the viral clearance study,” Smith says. “As new markets open up to the industry, greater visibility of requirements supporting biosimilars, validation of continuous processes, and global submissions would be beneficial.”

Notes for Guidance on Virus Validation Studies: The Design, Contribution and Interpretation of Studies Validating the Inactivation and Removal of Viruses

, CHMP/BWP/268/95, London, Feb. 14, 1996.
	2. ICH, Q5A (R1) 

Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

	When referring to this article, please cite it as R. Peters, "Putting Viral Clearance Capabilities to the Test"

Process understanding and careful assessment of risks are essential in developing viral clearance programs. 

BioPharm International-05-01-2018