Biopharmaceutical manufacturers have often explored the idea of real-time process control and monitoring — but until relatively recently, few case studies were available to help put all the information together in a coherent plan for true product lifecycle management. Shifting from previous BPI Conference programs that included a “scale-up” track, this year’s lifecycle track will reflect how companies are being encouraged to view development, design, and manufacturing as a continuum rather than (more “traditionally”) as a set of discrete phases. And continuous improvement throughout a product’s lifecycle, including postlaunch activities, is an important goal of these new approaches.
Upstream and downstream processes still exist as separate operating units, but much development and design work is performed in parallel these days. Different functional departments within biopharmaceutical companies are communicating with one another in ways not encouraged (or facilitated) before. Software to operate and track manufacturing operations across an entire enterprise has increased in both interdepartmental accessibility and sophistication.
A large part of this evolving paradigm has been the establishment of design spaces within which allowable variability is determined for individual operations. Within those spaces, a company can make process changes while the process continues, which expedites development and helps control cost. Incorporating risk-management tools and other operational methods help ensure final product safety without reliance on testing. This new approach overall emphasizes the importance of process knowledge, identification of critical attributes, and development of tools to enable real-time monitoring and, potentially, product release.
Despite all the conference presentations and industry literature of the past few years, the industry has in many ways been “spinning its wheels” in learning how to put all these elements together into a coherent development, manufacturing, and regulatory package. Earlier design-space discussions were hard to grasp without a clear understanding of (and appropriate analytical tools for) defining critical quality attributes (CQAs). There was a lack of clarity about CQAs and specifications, as well as some confusion about how to define a design space experimentally and how to set proper controls. Companies with products already on the market realized that process changes could be more straightforward if they went back to assess and (with new tools) increase their process knowledge to establish design spaces retrospectively.
TRACK SPOTLIGHT: PRODUCT LIFECYCLE MANAGEMENT
Sessions taking place over the two full days of this track include case studies and presentations of so-far-unpublished data. Presenters will discuss strategies, technologies, and innovations related to
- Establishing a design space and developing robust process parameters
- Process control for real-time monitoring
- Use of design-of-experiments (DoE) for determining parameters
- Implementation and execution of quality-by-design and operational excellence
- Continuous process improvement, including use of QbD Principles for managing postapproval changes
Tuesday, September 21, 2010
8:00–11:45 AM: Process Design: Establishing Design Space and Robust Process Parameters
1:45–4:00 PM: Implementation and Execution
Wednesday, September 22, 2010
8:00 AM–12:00 PM: Continuous Process Improvement
Regulatory Modernization: FDA’s Desired State for Product Quality (Tuesday, 4:00 PM)
The Role of Biosimilars in Driving Innovation in the Biopharmaceutical Industry (Tuesday, 4:45 PM)
Sustainable Commercial Cell Culture Operations (Wednesday, 4:00 PM)
Finding a Home for Process and Product Development (Wednesday, 4:45 PM)
Complete information on the Product Lifecycle Management track can be found at www.ibclifesciences.com/bpi/product-lifecycle.xml.
As will be presented at the BioProcess International Conference in September, new ICH and FDA guidelines are now in place to facilitate such activities. Internal staffing and systems within the FDA are better able now to support science and risk-based quality review and inspections. Specific implementation programs have facilitated the embracing of new quality systems approaches for a growing number of companies. These include the Office of New Drug Quality Assessment (ONDQA) pilot program, CDER’s Office of Biotechnology Products (OBP) pilot program, and the Office of Generic Drugs question-based review program (OGD QbR). For example, the FDA quality-by-design (QbD) pilot program invited companies to submit chemistry, manufacturing, and controls (CMC) information demonstrating QbD to help the agency explore how to access submissions based on these new concepts. One question explores how much regulatory flexibility is needed to assess a company’s quality system — so it can indeed operate within the defined design-space parameters.
Although the keynote presentations function as plenary sessions, appealing to audiences in more than one track, four of them have specific relevance to product lifecycle approaches. They help emphasize the bigger-picture, far-reaching scope of such activities.
INTERVIEW: LEVERAGING FLEXIBILITY IN QBD
Peter Watler, PhD (chief technology officer, Hyde Engineering + Consulting Inc.) will be a panelist in “Leveraging Flexibility in QbD” beginning at 11:15 AM Tuesday, September 21.
BPI: The conference will offer several sessions about leveraging quality by design. What are some advantages of implementing QbD principles in biomanufacturing?
Watler: It is important for manufacturers to have a thorough understanding of how their products are manufactured, given they are administered to human beings and patient safety and product quality are of paramount importance. Using the techniques and principles of QbD enables us to thoroughly understand how our products are manufactured and institute better control of product quality.
BPI: Some the concerns in the industry are whether QbD will take investment in new technologies and how compatible these technologies will be with existing systems. Are there key technologies for building quality into a process?
Watler: To compete and keep current the “C” in “CGMP” requires manufacturers to continually invest and improve their manufacturing capabilities. Fortunately, the new technologies help lower costs by reducing variability and reducing operating expense. For example, disposables help reduce water and set-up expenses. New technologies can also increase capacity and streamline operations. Although there is some upfront investment to use these new technologies, there is a payback in being
more efficient and ultimately in reducing cost of goods. As for reducing the burden of QbD, manufacturers are realizing the need to continually update production techniques as standards rise and that implementing new technologies will lead to better consistency, fewer lot rejections, less scrapped product, higher yields, and higher success rates. All of these lead to lower cost of goods.
As an example of how investing in QbD techniques can improve product quality and reduce costs, about a year ago Biogen Idec received FDA approval for its TYSABRI process, which increased their yield four-fold. Imagine how a four-fold increase in yield would reduce your cost of goods. This is a great example of how using QbD to thoroughly understand a process enables regulatory flexibility to realize cost saving process improvements. However, the FDA has stressed that enhanced process control is the main driver for using QbD techniques. Nonetheless, if companies better understand the manufacturing processes, they will reap significant cost, compliance and regulatory benefits.
BPI: The session covers leveraging the flexibility of QbD. What does flexibility in QbD mean?
Watler: Some FDA regulators, such as Dr. Moheb Nasr, have spoken about using QbD techniques to understand how processes respond across a broad operating range. If you have this data and knowledge, then making process adjustments within these ranges will be straightforward. Regulators will have more confidence in evaluating your process, since fewer process performance questions will remain unanswered.
Regulatory Modernization: FDA’s Desired State for Product Quality will be presented by Helen N. Winkle (director, Office of Pharmaceutical Science, CDER, US FDA). QbD can streamline development and manufacturing for all biotechnology products, whether from innovators or manufacturers of biosimilars, helping the industry as a whole meet higher product quality standards. Facing competition from biosimilars, innovator companies can use QbD as a timely tool for bringing new, competitive products to the marketplace faster, more efficiently, and more affordably.
The discussion is important for both sides of this equation: QbD should help biosimilar makers streamline their processes from the get-go, and innovator companies can use it to implement process/product changes that may even extend their patent protection — or at least help some show how their brand-name version is “better” than the less expensive competition. Continuing this theme, the keynote presentation on The Role of Biosimilars in Driving Innovation in the Biopharmaceutical Industry will be presented by Thomas J. Vanden Boom, PhD (vice president, Global Biologics R&D, Hospira, Inc.).
In Sustainable Commercial Cell Culture Operations, W. Blair Okita, PhD (senior vice president, manufacturing sciences and technical operations, Genzyme Corporation) will focus on defining critical quality attributes (CQAs): one of the first elements in a product lifecycle approach and a key component of QbD. Maintaining performance, ensuring the currency of the technical foundation, and improving productivity and efficiency become the key challenges in designing a sustainable operation. As noted in Okita’s abstract, “Knowledge is perishable; establishing routine can maintain performance but inhibit improvement; and everything ages.” The audience will hear about systems that can support operations and bolster the productivity of people, processes, and infrastructure.
INTERVIEW WITH FEATURED PRESENTER
Helen Yang (technical operations, Abbott Bioesearch Center) will speak about “Humira Downstream Process: Challenges in Continuous Improvement and Technology Transfer,” at 4:00 PM on Tuesday, September 22.
BPI: How do scale and the multiple-facility production of a product affect the complexity of implementing quality by design principles in processing?
Yang: There are challenges in producing a product at various scales and at multiple facilities, but QbD is actually a good tool to guide technology transfer to these different scales and different facilities. Using a good understanding of the process based on QbD helps us in troubleshooting and targeting the root cause of many issues that may occur. In general when you have a technology transfer, you have to prove the process from facility to another, and in most cases that second facility is not designed for that particular product, which may have different equipment configurations and settings. Different equipment configurations could lead to different mass transfer profile during, for example, a chemical addition or other process. A good process understanding helps us to troubleshoot and determine whether a particular mixing condition is good enough to achieve a certain in-process product quality criteria. This is one of the commonly faced challenges during technology transfer.
BPI: What is the connection between process improvement and technology transfer?
Yang: As part of our process improvement work, we aim to enhance our process robustness and ensure consistent product quality. The more robust process you have, the easier the tech transfer process is. A robust process means it could tolerate different facility conditions and different process settings within the design space. The final goal is to produce a consistent product from various sites.
The fourth keynote of special relevance to the lifecycle track is Finding a Home for Process and Product Development. To compete in our cost-conscious world, the speaker urges the biotechnology industry to reinvent itself. Successful companies are redefining their organizational approaches to manufacturing technology and product development (and design) under a number of different organizational designs (OD). The presentation by S. Robert Adamson, PhD (Advance Biotech Consultants; former senior vice president for product and process development, Wyeth Biopharma) will address, through examples and guiding principles, how and where OD can enable game-changing outcomes.
Product Lifecycle Session Tracks
Process Design — Establishing Design Space and Robust Process Parameters: This session, chaired by Duncan Low (Amgen, Inc.), begins with a presentation by Justin McCue (Biogen Idec) addressing design-space strategies. Cenk Undey (Amgen Inc.) will talk about dealing with lot-to-lot variability in chromatography adsorbent properties and applying multivariate technology to find patterns in process data. Peter K. Watler (Hyde Engineering + Consulting Inc.) will show how mechanistic modeling can identify critical parameters and define an ICH/FDA Q8 compliant design space. And Martin Kane of Human Genome Sciences will show how general DOE concepts can help optimize biopharmaceutical product formulations. This session concludes with a presentation by Ali M. Afnan (Step Change Pharma, Inc.) and a panel discussion on leveraging the flexibility within QbD.
Implementation and Execution: In this session, chaired by Cenk Undey of Amgen, Inc., Vassia Tegouli will describe a strategy to implement QbD and offer lessons that Genentech learned by participating in the FDA QbD pilot program. Attendees will learn more about the role of PAT in operational excellence from Amgen’s F. Ceylan Erzen. A case study from Thomas Linden (Merck & Co., Inc.) will share how robust process parameters were developed for production of a therapeutic glycoprotein to prepare it for transfer to a CMO. That presentation will also discuss some relationships of process parameters to identify critical product quality attributes.
Continuous Process Improvement: Co-chairs Maninder Hora (Facet Biotech) and Ellen L. McCormick (Pfizer, Inc.) will oversee further exploration of the lifecycle approach. This session comprises case studies bas
ed on new, unpublished data. The session begins with a talk by Debbie O’Connor (Genentech, Inc.) about how supply demands, increased process knowledge, new technologies, regulatory standards, and manufacturing network additions all factor into deciding whether to make process changes. Process validation has also been profoundly affected by quality-systems approaches, so the audience will hear examples from Ciaran Brady (Human Genome Sciences Inc.) and Helen Yang (Abbott Bioresearch Center) on procedures and case studies for effective process monitoring — and learn more about identifying and making improvements. Additional case studies by Marc Better and R. Michael Boychyn (Amgen Inc.) and Robert Genduso (Biogen Idec) will look at process control and real-time monitoring, application of QbD to manage postapproval changes, and designing a robust contamination barrier for serum-containing products
QBD-AND PAT-RELATED ACRONYMS
AAPS American Association of Pharmaceutical Scientists
API Active pharmaceutical ingredient
ASTM American Society of Testing and Materials
AUC Analytical ultracentrifugation
CAPA Corrective and preventive action
CASSS California Separations Science Society
CD Circular dichroism
CER Carbon dioxide evolution rate
CMC Chemistry, manufacturing, and controls
COD Critical operating data
CPA Critical product attribute
CPP Critical process parameter
CQA Critical quality attribute
CQP Critical quality parameter
CQV Continuous quality verification
CPV Continuous process verification
CZE Capillary zone electrophoresis
DAE Differential and algebraic equations
DCS Distributed control system
DFSS Design for Six Sigma
DoE Design of experiment(s)
DO Dissolved oxygen
DSP Downstream processing
EBR Electronic batch record
EDMS Enterprise document management system
ELISA Enzyme-linked immunosorbent assay
EMS Enterprise manufacturing system
FDA United States Food and Drug Administration
FFF Field flow fractionation
FMEA Failure mode, effects analysis
FMECA Failure mode, effects and criticality analysis
FTA Fault tree analysis.
FT-IR Fourier transform infrared spectroscopy
GAMP Good automated manufacturing practice
GCP Good clinical practice
GEP Good engineering practice
GLP Good laboratory practice
GMP Good manufacturing practice
HACCP Hazard analysis and critical control points
HAZOP Hazard operability analysis
HCP Host cell protein
HIC Hydrophobic interaction chromatography
HPLC High performance liquid chromatography
ICH International Conference on Harmonisation
IEC Ion exchange chromatography
IEF Isoelectric focusing
IFPAC International Forum on Process Analysis and Control
ISA Instrument Society of America
ISPE International Society for Pharmaceutical Engineering
IVC Integral viable cells
KQI Key quality indicator
KPIKey performance indicator
KPP Key process parameter
LAL Limulus amebocyte lysate
LT Laboratory testing
LSL Lower specification limit
MA Membrane absorber
MALS Multi-angle light scattering
MES Manufacturing execution system
MF Micro filtration
MPC Model predictive control
MS Mass spectrometry
MSX Methionine sulphoxamine
NFF Normal flow filtration
NIR Near infrared
NMR Nuclear magnetic resonance
OEE Overall equipment effectiveness
Op Ex Operational excellence
OUR Oxygen uptake rate
PAC Process analytical chemistry
PAI Preapproval inspection or productivity improvement appraisal
PAR Proven acceptable range
PAT Process analytical technology
PCA Principal components analysis
PCR Polymerase chain reaction
PDA Parenteral Drug Association
PFD Process flow diagram
PHA Preliminary hazard analysis
PLS Partial least squares or projection to latent structures
PTM Posttranslational modifications
PV Process validation
QA Quality assurance
QbD Quality by design
QC Quality control
q-PCR Quantitative polymerase chain reaction
QRM Quality risk management
RC Respiration coefficient
ROI Return on investment
RPC Reverse-phase chromatography
RTR Real-time release
SB Systems biology
SDS-PAGE Sodium-dodecyl sulfate polyacrylamide gel electrophoresis
SEC Size-exclusion chromatography
SOP Standard operating procedure
SPC Statistical process control
TFF Tangential flow filtration
UF Ultra filtration
USL Upper specification limit
USP United States Pharmacopeia
CP Process capability
CPK Process capability index
QpSpecific production rate
s Standard deviation
Source: Julian C, Whitford W. Hitchhiker’s Guide to Bioprocess Design. Process Design: Harmonizing the Concepts of QbD, PAT, and Systems Biology. BioProcess Int. 6(1) 2008: S52–S59; www.bioprocessintl.com/journal/supplements/2008/March/Hitchhikers-Guide-to-Bioprocess-Design-183952 (supplement glossary).
S. Anne Montgomery is editor in chief of BioProcess International.