Quality by design (QbD) has changed the biopharmaceutical industry’s approach to chemistry, manufacturing, and controls at its core. And that’s changing how companies plan for and execute the life cycle of their products. New candidates entering development especially benefit from strategies implemented from the start. The 2012 BioProcess International Conference and Exhibition devotes a track on Tuesday and Wednesday (9–10 October 2012) to examining those strategies in the dawning age of biosimilars: from regulatory approaches and analytical innovation to involving partners the right way at the right time.
AUDIENCE: PRODUCT AND PROCESS DEVELOPMENT, BUSINESS DEVELOPMENT
KEYWORDS: OUTSOURCING, QBD, RISK, BIOSIMILARS, COMPARABILITY, PRODUCT AND PROCESS CHARACTERIZATION, TECHNOLOGY TRANSFER
TAKE-AWAY: CREATE MORE VALUE AND ENHANCE QUALITY FOR PRODUCTS AND PRODUCT CANDIDATES THROUGH THE LATEST STRATEGIES FOR PROCESS DESIGN, IMPLEMENTATION, AND CONTINUOUS IMPROVEMENTS.
Performance By Design
Product quality can be built into manufacturing processes through a performance-by-design approach. As Paul McCormac (senior manager of the biomanufacturing sciences group at Pfizer) explains, “The development of a product control strategy is not a new concept but should be the culmination of the product development life cycle.” He points to the “ICH quartet” (the Q8, Q9, Q10, and Q11 harmonized tripartite guidelines) along with FDA’s 2011 guidance on process validation as vitally important documents stressing the importance of a control strategy in the development life cycle of biopharmaceutical products.
That linkage can be achieved through structured risk assessment. On Tuesday morning, 9 October 2012, McCormac will discuss approaches to risk management (with examples from Pfizer) and how their output can help define a product control strategy. That same morning, Graham McCartney (technical services lead in biotechnology at Eli Lilly) will describe a life-cycle management case study from his company as well.
Kumar Dhanesekharan (associate director of process sciences and technology at Genzyme, a Sanofi company) goes into more detail on FDA’s process validation guidance in the same session. “The third validation stage describes a life-cycle approach,” he says, “to continually assure that the process remains in a state of control (the validated state) during commercial manufacture.” At the conference, he will describe strategies and approaches to implementing continuous monitoring and improvement consistent with QbD principles applied to earlier stages such as process design.
Process modeling can help companies do more at those early process stages, according to James Velez (senior process engineer in Merck’s global engineering services). With Miriam Monge (vice president of Biopharm Services Ltd.), he will examine the use of advanced process modeling tools to support critical decision making in the evaluation of innovative technologies. The Merck case study involves functionalized porous media chromatography platforms (both membrane and structured hydrogels). Forward-looking process modeling techniques help evaluate novel unit operations such as continuous porous media chromatography.
In the same Tuesday-morning session, Marjorie Shapiro (molecular and developmental immunology laboratory chief at FDA’s Division of Monoclonal Antibodies) provides some regulatory perspective. “Too often the quality submission is lacking data or clarity,” she cautions, “resulting in an IND hold, a delay in approval of a BLA or a postmarketing change.” Although clinical trial outcomes areuncertain, Shapiro says that “the quality of the therapeutic protein in that clinical trial should be under the complete control of the sponsor.” She will highlight roadblocks and speed bumps that can occur throughout a product’s life cycle.
And Melissa Perkins (senior director of drug product sciences at Human Genome Sciences) will provide an example related to the container–closure systems for parenteral products. “Selecting vial and stopper combinations with optimal fit can be challenging,” she says. “Issues during manufacturing can negatively impact process productivity and timelines, and proper closure integrity is of utmost importance.” Perkins will provide data to demonstrate such challenges and make recommendations for how to evaluate material attributes and dimensions when implementing control strategies.
Productct Life-Cycle Management Sessions
Monday, 8 October 2012 1:00–5:00 PM Symposium #1: Biosimilars: Defining Successful Development Strategies in an Evolving Regulatory Environment 1:00–5:00 PM Symposium #4: Regulatory Requirements in Preclinical CMC Development 1:00–5:00 PM Symposium #7: CMC Project Management Throughout the Product Development Life Cycle Tuesday, 9 October 2012 8:00 AM–12:15 PM Performance By Design: Mapping and Controlling Critical Quality Attributes 1:30–3:15 PM Process Innovation and Regulatory Submission Strategies 4:00–5:45 PM Keynote Presentations Wednesday, 10 October 2012 8:00 AM–12:00 PM Advancing the Science of Comparability: Cost-Effective Approaches for the Implementation of Process Change Through the Life Cycle
Regulatory Strategies and Innovation
Continuing the regulatory focus on Tuesday afternoon, two presenters will discuss considerations related to process and product innovation. Biotechnological innovation isn’t transformational, says Andrew Papas (regulatory affairs director of Becker & Associates Consulting’s pharmaceutical and biologics practice). Rather, it involves “implementation of a newer and better alternative and represents a change away from the norm.” But in a regulated biotech environment, he cautions, such advancements must be incremental and deliberate, requiring development time and supportive te
chnical data. “Whereas comparability is the cornerstone of implementing life-cycle changes,” Papas says, “a sound foundation of process and product knowledge facilitates regulatory agency approvals.” He will include examples in his presentation.
“Even though we work in a very regulated industry,” puts in Robert O’Hagan (director of quality operations at Abbott Bioresearch Center), “it doesn’t mean we can’t be innovative in our manufacturing environment, supply chain, and regulatory filings.” He plans to discuss tools and techniques that can foster an innovative environment, also providing examples demonstrating innovation in those three key areas.
Robert Boulanger (upstream process development manager at Protein Sciences Corporation) will follow them with a more detailed case of innovation. His company’s platform technology generates vaccines using the baculovirus expression vector system (BEVS). “PSC leverages a QbD-based process for large-scale production of vaccines in less than 50 days from identification of the target virus,” Boulanger reports. His case study focuses on rapid modification of a seasonal influenza vaccine for the 2012–2013 virus strain change.
Comparability and Biosimilars
Analytical technologies are one area that have seen (and continue to see) a great deal of innovation. In fact, it is the ability to characterize biologics that led to the biosimilar era that is now upon us. Several speakers will delve into the subject on Wednesday morning (10 October 2012).
“Changes to pharmaceutical processes or products may be implemented at any stage of development or postlicensure,” says Sarah Demmon (senior research scientist in bioproduct R&D at Eli Lilly), “and have the potential to impact product quality. Regardless of the nature of the change, quality assessments are always conducted to demonstrate comparability of pre- and postchange material.” Her talk will cover approaches to establishing analytical comparability of bioproduct drug substance and drug product solutions, including risk assessments, establishing acceptance criteria, and designing the appropriate stability studies.
So, are comparability and biosimilarity the same thing? Not really, says Stephen Hosselet (director of global analytical sciences at Amgen). “Biosimilarity between a follow-on biomolecule and its innovator counterpart relies upon many of the same principles as does the demonstration of comparability between pre- and postchange biotech products by an innovator company,” he explains. “However, there are important differences.” His Wednesday morning presentation will compare and contrast the two paradigms and show how QbD principles can be applied to drug development for both.
Joseph McClellan (director of Pfizer’s bioenhancement development unit) will follow up with the biosimilar developer’s perspective on understanding innovator products. Then consultant Emily Shacter (formerly chief of the FDA/CDER’s office of biotechnology products) will shine some light on the agency’sregulation of biosimilars for companies considering development of a biosimilar protein product for the US market. The FDA’s February 2012 draft guidance covers over-arching scientific considerations and provide specific analytical, nonclinical, and clinical approaches for demonstrating similarity to a US-licensed reference product. Shacter will offer insights into the overall approach, which emphasizes evaluation of molecular similarity.
Product Life-Cycle Management Symposia: Monday, 8 October 2012
Biosimilars: Defining Successful Development Strategies in an Evolving Regulatory Environment, cochaired by Thomas Stangler (biopharmaceutical development strategy and technology manager at Sandoz) and Thomas J. Vanden Boom (vice president of global biologics R&D for Hospira, Inc.)
With the emergence of significant new commercial partnerships and continued evolution of the global regulatory environment, the biosimilars sector continues to gain momentum. The global regulatory framework has seen recent advances: publication of the first three draft-guidance documents by the US Food and Drug Administration (FDA) in February 2012; new product-specific guidelines and an update to the overarching guideline for biosimilar medicinal products by the European Medicines Agency (EMA). Originator and follow-on companies are refining their strategies.
With international perspectives and presentations from Gillian Woolett (Avalere Health), Cyrus Karkaria (Lupin Ltd.), and Thomas Nikolai (Hospira Corp.), this symposium addresses questions such as the following: What does the emerging competitive landscape look like, and what will be the keys to success in this space? What technical and regulatory challenges are presented by alternative development and manufacturing strategies? What are the opportunities for innovation?
Regulatory Requirements in Preclinical CMC Development with Bruce K. Burnett (director of regulatory affairs at Duke University School of Medicine’s Translational Medicine Institute)
The instructor comprehensively overviews FDA regulatory requirements applicable to pharmaceutical research organizations during preclinical drug development through preparation of an investigational new drug (IND) application. Burnett will detail the chemistry, manufacturing, and controls (CMC) section of an IND application. He will include a product development timeline and address required preclinical studies, good laboratory and manufacturing practices (GLPs, GMPs), and regulatory compliance in outsourcing relationships.
CMC Project Management Throughout the Product Development Life Cycle cochaired by Seshu Tyagarajan (associate director of CMC project management for ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company) and Zahra Shahrokh (biotech product development consultant at ZDev Consulting)
Covering phase-dependent CMC activities and the role of CMC teams in integrating development plans and facilitating progress, talks cover different models for managing CMC projects that are tied to company resources, the number of products in progress, and their development phase(s). Offering best practices in CMC project management, this symposium addresses the process from discovery to commercialization with an strategic vision integrated through tactical implementation. After presentations — e.g., “CMC structure: One Size Does Not Fit All” and “CMC PM as a Career Path” — a panel discussion addresses topics of interest to both audience and speakers, from risk management to organizational structures and functional roles; managing in-licensed products, partnerships, and outsourcing; business processes, tools, and templates; and models for managing CMC activities throughout a product’s life cycle.
Discussion continues with Goran Valinger (technical support director for Hospira Zagreb), who provides some European perspective as well as the interesting extension of comparability to postapproval changes of biosimilar products. He says that the regulatory framework established for managing postapproval changes to originator biologic products applies to biosimilar products as well. “The foundation of this regulatory framework is a well-designed comparability exercise that compares the quality attributes of a biologic product before and after a change,” Valinger explains. He will present a comparability case study with unpublished data for a postapproval site and scale change.
Wednesday afternoon’s keynote presentation session features one talk on regulatory challenges for biologics, specifically in regard to biosimilars, characterization, and QbD. “Ensuring pharmaceutical performance is of critical importance to public health,” says Steven Kozlowski (director of FDA/CDER’s office of biote
chnology products). He says that QbD manufacturing and advances in analytical characterization can enhance pharmaceutical quality. “The appropriate characterization of protein products is also very important for the development of biosimilar biological products.” Kozlowski explains that, having recently published three draft guidances on biosimilars, the FDA wants to apply a risk-based totality-of-evidence approach to evaluating information submitted to support a biosimilarity claim.
You’ll hear Thomas Stangler (biopharmaceutical development strategy and technology manager at Sandoz) talking about biosimilars in several capacities at the BioProcess International Conference and Exhibition: cochairing a preconference symposium on Monday (see the “Symposia” box), participating in a thought-leadership panel on Thursday morning (with experts from Amgen, Hospira, Bristol-Myers Squibb, Lupin, Merck, Biologics Consulting Group, and CDER), and presenting a Tuesday afternoon keynote address.
If the primary goal in biosimilar development is to deliver products that are highly similar to originators, then comparable safety and efficacy must be demonstrated through extensive testing. He will discuss how QbD concepts help enable successful biosimilar product development. “In a systematic approach,” Stangler explains, “development targets are defined based on originator product data with the comparability exercise in mind. A science- and risk-based approach combined with product and process understanding enable [you] to set the right priorities throughout product development to finally achieve a highly similar product.”
Partnering for the Future
It’s now an accepted fact of bio-business life that companies partner with each other and with contract service providers to access other competencies and get their products to market as fast as possible. Most often, such collaborations involve large companies taking smaller companies under their wings or small-to-midsize companies engaging the services of a contract manufacturing, development, or research organization. But John Stubenrauch (Merck’s head of external commercialization and operations for biologics) reports in the same keynote session on a different kind of partnership.
Two big names in bioprocessing, MedImmune and Merck, have entered into a 15-year manufacturing capacity-sharing agreement that initially involves MedImmune’s Maryland facility for Merck’s bulk bioproduct manufacturing. “The agreement serves to grow MedImmune’s manufacturing capabilities,” says Stubenrauch, “while providing Merck with world-class manufacturing capability and capacity for its novel products and biosimilars pipeline. In this presentation, we will highlight both the deal structure and execution as an industry best practice.” The agreement allows for joint capacity planning and represents a strategic, long-range solution to biomanufacturing capacity. It’s not unusual for biopharmaceutical companies to share manufacturing capacity, Stubenrauch explains, but it’s less common for them to jointly plan for capacity use in one company’s facility. He will describe the program in further detail in his keynote address. Both companies are now exploring the suitability of Merck’s facilities for producing MedImmune’s microbial-based compounds, as well as other opportunities where their business strategies intersect.
Partnerships are increasingly providing many companies with access to new markets. “The expansion of biotechnology in the emerging markets comes at an inflection point for industry, governments, and patients,” says Matthew Walker
(Pfizer’s vice president of operations). “With expanding life expectancy, increasing per capita income, and significant unmet medical need, the allure for industry is clear. This is tempered, however, with concerns regarding intellectual property protection, an uncertain regulatory landscape, and limited biotechnology expertise.” Walker’s keynote presentation on Wednesday afternoon will explore those factors along with the need for effective partnerships to improve patient access and affordability.
A Tuesday afternoon thought-leadership forum will look closer at how CMOs fit in. Panelists from DSM Biologics, BioAtla, Boehringer Ingelheim, and Rentschler Biotechnologie will offer their perspectives and answer questions from the audience. Directly affecting product quality and value, optimization of drug substance and product development and manufacturing is key to biopharmaceutical success. These days, most biotech companies rely on some external partner(s). The discussion will center on critical issues such as when to start outsourcing, how to reduce associated risks while keeping early development costs down, and other crucial questions. No one has to go at it alone.
Cheryl Scott is senior technical editor of BioProcess International. Quotes not otherwise attributed are from presentation abstracts.