An emerging challenge for biotech companies is understanding the bigger picture: How should manufacturing facilities be configured to link together process technologies? Should plants be highly flexible or focus on process standardization? How would a disruptive new technology affect current supply chains, and how could it be implemented? Meeting the challenge requires a complete and detailed understanding of supply chains. Much current focus in process development is on improving operations, with limited consideration to how improvements affect “big picture” variables. Evaluating a portfolio of overlapping incremental improvements requires detailed understanding of a plant, biological variability’s effects, the impact of testing and quality control, and other issues. Berkeley’s Bioprocess Forum series addressed them in four meetings held in November and December of 2007.
Focus on Operational Issues
Supply chain issues and technology management are crucially important not just for reducing cost, but also ...
Today, there is much discussion regarding the promise of improved insight into bioprocess industry processes. Look to the pages of industry publications such as this one, and you’ll see that industry leaders in process measurement and control have begun to discuss openly the potential for simulating and modeling bioprocesses.
“Important opportunities such as the application of mass spectrometers, dissolved carbon dioxide probes, and inferential measurements of metabolic processes have come to fruition today opening the door to more advanced process analysis and control technologies,” says Greg McMillan with Emerson Process Management.
However, speak to such professionals for any length of time, and you’ll learn that unlike processes associated with petroleum manufacturing, for example, which have been modeled for nearly 40 years, biotechnology involves living processes, which are much more challenging to predict. But if the industry is going to improve its process reliability and product quality while red...
Downstream Processing
Product:
Cogent µScale tangential-flow filtration (TFF) system
Applications:
Downstream process development and low-volume sample preparation
Features:
The easy-to-use, semiautomated benchtop system has been designed to support TFF process development at the microscale using up to three Pellicon 3 88-cm
2
cassettes. With a low minimum working volume, the ability to operate at feed pressures up to 80 psig and very low pulsation, the system fully supports both scaling studies and low-volume ultrafiltration and diafiltration (UF/DF) work using the cassettes. It is ideal for purifying and concentrating MAbs, recombinant proteins, vaccines, gene therapy constructs, blood serum products, and other cell-derived components.
Contact Millipore
www.millipore.com
Fluid Processing
Product:
Standardized offering of M-7125 and M-7250 Microfluidizer high-shear fluid processors
Applications:
Cell disruption and nanoemulsions and nanodispersions
Features:
Six standardized configurations have ...
As single-use products are increasingly implemented, end-users are exploring applications, designing system approaches, assessing suitability and economics, and demanding expanded capabilities. Industry experts say that the single-use market is now moving into its next phase in which suppliers and developers are being challenged to not only “step up” and offer larger scale options, but also to provide additional downstream capabilities.
IBC’s 5th International Single-Use Applications for Biopharmaceutical Manufacturing conference will provide over two days of current knowledge and strategies to ensure maximum use and efficiency of single-use systems, while minimizing investments and increasing speed time to clinic. Conference delegates will explore and analyze the latest advancements being made in downstream processing and will hear industry assessments of the latest bioreactors and probes on the market, including fully disposable perfusion bioreactors. Attendees will gain a full range of market knowledge...
Regulatory bodies around the world expect downstream purification processes to demonstrate robust clearance of model adventitious viruses in time for execution of phase 3 clinical trials and product licensure (
1
,
2
,
3
). Model viruses selected for these studies should represent a diversity of viral physicochemical properties, and the clearance methods applied should include orthogonal mechanisms such as clearance based on size alongside chemical inactivation. Virus filtration is a critical unit operation used in numerous purification processes of monoclonal antibodies (MAbs), recombinant proteins, and plasma-derived biopharmaceuticals.
PRODUCT FOCUS:
ANTIBODIES AND OTHER RECOMBINANT PROTEINS
PROCESS FOCUS:
DOWNSTREAM PROCESSING
WHO SHOULD READ:
MANUFACTURING, PROCESS DEVELOPMENT, AND ANALYTICAL PERSONNEL
KEYWORDS:
VIRAL SAFETY, MMV/MVM, XMULV, FILTRATION, SCALE-UP
LEVEL:
INTERMEDIATE
Virus filtration unit operations have been shown to be scalable, robust, and reproducible (
4
,
5
). Initial sizin...
+5LUIS CARLOS TORRES (WWW.ISTOCKPHOTO.COM)
As one of its first initiatives, the BPSA Technology Committee conducted an initial review of referenced quality test methods and specifications currently applied to common components of single-use systems: filter capsules, films and containers, tubing, and connectors and fittings. Recognition of consensus quality test methods, referenced to established industry standards and regulatory bodies, can help guide users when making their selections and can facilitate qualification, validation, and use of single-use products. Ultimately they can serve to elevate and maintain the level of excellence across the single-use industry.
Component Quality Test Matrices
For each single-use system subcomponent class — whether filter capsules, films and containers, tubing, and connectors and fittings — BPSA member manufacturers identified consensus quality tests. The matrices describe test methods in common language and list consensus reference documents along with testing frequenc...
In vivo delivery of DNA-based biopharmaceutical agents encoding proteins of interest (“DNA drugs”) offers a means for the production of protein by target regions of tissue in a subject. This product class derives activity from an ability to induce sustained endogenous protein expression from recipients’ own cells. These unique characteristics are favorable for multiple applications, several of which are now in clinical testing.
Therapeutic Proteins:
DNA drugs encoding autologous therapeutic proteins could serve as an alternative to long-term therapy based on administration of recombinant protein-based drugs. By enabling sustained production and secretion of protein (lasting up to weeks or months) from a target tissue with just a single administration, DNA drugs exhibit potential advantages over the frequent injections required to achieve and maintain therapeutic levels of a protein of interest administered as a protein-based drug. Increased convenience and cost effectiveness come from a reduction in the ...
+1 The use of single-use components in the biopharmaceutical industry is not new. For more than a decade, a range of disposables have been available and commonly used — plastic film bioprocessing containers, microbial sampling bags, encapsulated filters, sterile connection devices, tubing, flasks, roller bottles and hollow-fiber membrane systems, to name a few. What began as a handful of individual components is now evolving into a category of preassembled, sterilized, and validated integrated disposable systems. The latest innovations to hit the market are 500-L to 2,000-L disposable bioreactors and cryogenic storage bags, further expanding the design space for single-use applications in biopharmaceutical manufacturing processes.
Over time, the biopharmaceutical industry’s level of comfort with single-use options has grown. Sales of disposable bags, containers, and tubing are increasing annually by 10–20%, according to a recent worldwide report surveying 187 biopharmaceutical manufacturers and contract manu...
A major goal of pharmaceutical development is to characterize pathways of chemical and physical instability and then to develop strategies to minimize them. Deamidation and oxidation are examples of the former, aggregation a result of the latter. The potential for the presence of multiple variants in protein-based pharmaceuticals highlights a need for analytical methods capable of reliably and accurately identifying and measuring those variants. The ideal analytical method would be sensitive, accurate, linear over a broad range, resistant to sample-matrix interference, capable of measuring all possible structural variants of a protein, and would allow for high throughput. Needless to say, such a method does not yet exist. So multiple methods are used to study the different characteristics of each protein.
PRODUCT FOCUS:
PROTEINS/PEPTIDES
PROCESS FOCUS:
DOWNSTREAM PROCESSING, FORMULATION DEVELOPMENT
WHO SHOULD READ:
ANALYTICAL, PROCESS DEVELOPMENT, FORMULATIONS, AND PRODUCT DEVELOPMENT PERSONNEL
KEYWORD...
+2 Figure 1:
SARTORIUS STEDIM BIOTECH (WWW.SARTORIUS-STEDIM.COM)
Determination of extractables and leachables for disposable manufacturing systems must be addressed as part of process validation when single-use technology is used. The idea that compounds leach into pharmaceutical formulations or process fluids (e.g., buffer solutions and bulk storage) from processing and storage materials is not new or even unique to plastics. All materials have extractables and potential leachables. When properly evaluated, these are easily addressed and rarely lead to disqualification of a disposable component. Ideally, processing methods and equipment are chosen early in the development lifecycle of a pharmaceutical product. The choice should be made by a dedicated team of scientists, quality assurance and/or regulatory affairs (QA/RA) representatives, and validation specialists working in partnership with component and system suppliers.
It is important first to understand the distinction between extractables and leachabl...
Virtually all aspects of the Chinese economy are booming, not the least of which is its pharmaceutical sector. Growing at 20% over the past five years, the $15 billion Chinese pharmaceutical market is predicted to become the world’s fifth largest by 2010 (
1
), making China an attractive place to do business for multinational pharmaceutical companies (MPCs). Rising living standards and improvements in China’s regulatory and technology infrastructure are the key drivers for this continued growth.
Although all segments of the Chinese pharmaceutical market are growing, the production of biogenerics and vaccines offers the greatest opportunities for Chinese manufacturers. This is the result of China’s strong generics manufacturing capabilities, significant cost advantage over Western manufacturers, and the fact that 17 million babies are born annually in China, each requiring vaccination. China’s vaccine market alone is worth $388 million, and it is growing at 15% per year (
2
). Looking at the broader biolog...
Single-use bioprocess systems can provide a range of environmental benefits beyond those of stainless steel systems. Although single-use systems may generate additional solid waste, benefits include reduction in the amount of water, chemicals, and energy required for cleaning and sanitizing as well as avoiding the labor-intensive cleaning processes required with stainless steel systems (
1
,
2
).
One of BPSA’s core activities is to educate users and develop guides on issues pertaining to single-use systems. The organization’s disposals subcommittee was chartered to establish a guide to address the issue of disposing of single-use bioprocess components and systems. The purpose of this introductory guide is to address the following questions:
This guide provides information to help concerned professionals and companies better understand the issue of single-use bioprocess component and system disposal.
Options for Disposal
When disposing of a large-scale system, a company may be dealing with an assembly of ...
Life-science companies that adopt “quality by design” (QbD) into their overall operations are expected to achieve the “desired state” of manufacturing. So concludes the Q10 document from the EMEA, US FDA, and the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (
1
). The ability to achieve an appropriate quality outcome must be designed into each manufacturing process rather than companies relying on final product testing. An increased focus on QbD ultimately requires manufacturers to make larger investments earlier in the life cycle of their products — during process development — well in advance of approved commercial operations. The goal is to develop a sound scientific basis for a manufacturing “control space” that accommodates a range of defined variability in commercial process materials and operations while continuing to produce desired product quality outcomes for bottom-line business benefits.
Today’s new regulatory environ...
Single-use bioprocess manufacturing systems increasingly are being implemented by the biopharmaceutical industry based on safety, time, and cost-reduction benefits. These disposable systems are used to process or contain fluids ranging from culture media, additives, and buffers, to bulk intermediates and final formulations. In many cases microbial control or sterility is required to ensure product purity and safety. Radiation sterilization is a common means of microbial control and sterilization applied to single-use systems. The standard methods for validating radiation sterilization are not widely understood in the pharmaceutical industry, which has historically relied on moist heat (steam) for sterilization of stainless steel bioprocess systems.
Under the auspices of The Society of the Plastics Industry, Inc. (SPI), the BPSA Technology Committee established a subcommittee to develop this guide to irradiation and sterilization of single-use bioprocess components and systems.
Scope, Purpose, and Backgrou...
Three major elements comprise validation projects in the biopharmaceutical industry: cost, schedule, and quality. If you can work within a budget, complete activities on time, and maintain regulatory-compliant documentation, then you significantly increase your chances for a successful validation project. Here we suggest ways you can improve these essential measurements with the help of a third-party validation team to achieve favorable outcomes.
Team Selection
The first key is building a validation team. Cohesion is critical for successful project management. All members must pull in the same direction and fully understand their colleagues’ concerns and responsibilities for a project to run smoothly.
The size of a validation group will depend on project scope. This can be determined by developing a preliminary project schedule and carefully evaluating the times at which activity levels will peak during the course of it. The scope of a project can also influence selection criteria used in determining and ...
When considering integration of single-use technologies (SUTs or disposables) into a manufacturing process and facility, a number of criteria should be satisfied. These criteria govern both selection and implementation. Each criterion should be established by due diligence in which end-user requirements and the operation setting are considered carefully.
Depending on a facility’s infrastructure and even a company’s business model, end users will define their criteria differently. Companies are driven to single-use technologies because of the simplicity and flexibility they impart to processes. But those are relative terms and depend on end-user requirements for proper interpretation. Simplicity is not an inherent characteristic of SUTs alone. At a contract manufacturer providing parenteral fill–finish services, end users (e.g., process engineers charged with technology transfer) must acknowledge that typically no appreciable amount of time will be allowed to design and subsequently optimize or develop a p...
