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SCIENTIFIC OPPORTUNITIES THROUGH QUALITY BY DESIGN
T IMOTHY J.W ATSON AND R OGER N OSAL
Global CMC,Pfizer,Inc.,Groton,CT,USA
Quality by design(QbD)is about understanding the relation-ships between the patient’s needs and the desired product attributes by ensuring that all process attributes and para-meters that are functionally related to safety and efficacy are consistently met.The value of prospectively developing enhanced product knowledge and process understanding can significantly minimize patient risk.The application of QbD principles also strengthens the balance between continued product improvements,technical innovation,business needs, and regulatory oversight.A QbD approach can rve as the foundation that links rearch and development,manufactur-ing,and regulatory conformance through a fundamental common language that is bad on a science and risk-bad principles.
For decades,much of the activity in quality and quality management focud on compliance rather than utilizing a fundamental understanding of the science behind process understanding.Business practices
adapted to procedures and focud on minimizing regulatory risk.The implementation of new technology was not typically part of a strategy becau oversight for novel technology was not precedented. Extremely risky and high attrition rates of rearch programs, unlike other industries,coupled with the lack of global regulatory harmonization fostered a minimalist paradigm and,significantly challenged investments in new technolo-gies and using modern methodologies for development.In the1990s the u of PAT started to gain interest in pharma-ceutical manufacturing;however,it was primarily ud for business purpos and not riously considered for regulatory purpos.Describing to regulatory authorities a comprehen-sive view of process understanding was generally avoided for fear of being held accountable to incread scrutiny and higher standards.
In August2002,the FDA launched their GMPs for the twenty-first century initiative in partial respon to aca-demics and consultants who criticized the pharmaceutical industry for not manufacturing to the highest standards. Companies were encouraged to u risk-bad asssments, in particular when identifying product quality attributes, and adopt integrated quality systems that operated through-out the lifecycle of a product.This movement toward science-bad regulations has not been limited to the United States as en by the guidance provided by The International Conference on H
armonization(ICH).Thus,quality by design for the pharmaceutical industry evolved from a conceptual approach that envisioned an efficient,agile,flexible ctor that reliably produces high-quality drug products without extensive oversight[1].Guidance for QbD was crafted through the ICH process to what is now con-sidered the“QbD trio”;ICH Q8,Q9,and Q10(ICH Q11for drug substance in progress).This movement away from prescriptive development programs has become an exciting and empowering platform for chemists,scientists,formu-lators,and engineers.While many elements associated with QbD,such as risk asssments,design of experiments (DoE),operational control strategies,etc.,have been em-ployed well before the adoption of the ICH guidelines, application was frequently not systematic,concerted or prospective,but rather retrospective in respon to issues or problems encountered during development or after com-mercial launch.Conquently,companies were reluctant to pursue a QbD approach or introduce supplemental studies
Chemical Engineering in the Pharmaceutical Industry:R&D to Manufacturing Edited by David J.am Ende
CopyrightÓ2011John Wiley&Sons,Inc.
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on process capability for fear of unnecessarily increasing regulatory“requirements”and potentially delaying regula-tory approvals.
QbD begins with a prospective vision that accepts and builds upon a science and risk-bad platform with a com-mitment to maintain focus on the patient.It starts with the establishment of a quality target product profile(QTPP)that provides an inventory of expectations or“product attributes”required to ensure patient safety and efficacy and product quality.Using the QTPP,relationships between product attributes and the sources for meeting tho attributes can be derived from drug product and drug substance platforms to establish a holistic understanding of how attributes are linked to patients needs,and how the attributes are functionally related through the entire manufacturing process.Ensuring patient safety and efficacy is not about“what measures we apply”to maintain the QTPP,it is about“how we develop”process understanding to establish the appropriate design and control elements of a process.The approach is predicated on executing a rigorous risk management exerci to determine “what we need and what we have”to demonstrate that quality is consistently met.It is about identifying the relationship between each attribute and its functional relationship to manufacturing variables and consistently controlling the relationships.
It is generally recognized that the three fundamental concepts of QbD are design space,control strat
egy,and criticality;where design space and control strategy are the deliverable outcomes from a systematic application of risk and science-bad asssments,analys,experiments,tech-nical innovation,and control.The development of design spaces and control strategies is a symbiotic relationship that encompass all of the concepts contained within the chap-ters of this book.In adopting a QbD approach and applying the science and risk-bad principles to asss quality attri-butes and process parameters,design space can be created to describe the boundaries within which unit operations of a manufacturing process may operate.In esnce,design space can demonstrate control of variables that may impact a critical quality attribute,and a control strategy can be estab-lished parametrically to as the resulting design modate design space.For example,a combination of well-space boundaries and real-time relea testing can effectively demonstrate and confirm control and rve as the basis for relea of the product without the need for specific end-product testing. Therefore,where the risk is understood and the verity and probability of impact are controllable,the demonstration of process control through the creation of design space could conceivably reduce the need to perform in-process testing as well.Continuous formal verification to demonstrate process capability in accordance with well-grounded design space criteria could rve as the basis for product relea to a specification derived largely from critical quality attributes (Figure5.1).
Scientists who embrace an enhance approach to devel-opment should consider the types of questions: .How is prior knowledge substantiated,how can internal and external knowledge be ud to leverage more accurate risk asssments?
.What level of detail is required to justify risk asssments?
.How should design space be prented and conveyed to demonstrate quality assurance?
.How can modeling be ud to justify commercial manufacturing process changes?
.How should the control strategy connect drug product and drug substance quality attributes to process para-meters and material attributes?
.Is there an attenuation of regulatory latitude for post-approval optimization and continual
improvement?
FIGURE5.1General outline of approach to application of quality by design.Source:EfPIA
QbD WG.
68SCIENTIFIC OPPORTUNITIES THROUGH QUALITY BY DESIGN
In addition,there are many general process that can be adapted to sketch out a general procedure for any team of subject matter experts to adapt a science and risk-bad approach.One example is given are Figure 5.2.A Common thread that runs through all varieties of QbD applications is repeated risk asssment of process parameters and material attributes and their connectivity to the QTTP;adoption of an an iterative approach to risk and experimental data evalua-tion;creative experimental design to understand parameter interaction in a multivariate process;establishment of a well grounded design space and control strategy that ensures safety and quality.Finally,transparency in the interpretation and prentation of data and its justification for process design must meet the standards for peer review and “pass the red face test”for regulatory authorities.There are many options for implementing QbD.However the fundamental conceptual elements of the risk and science-bad approach have emerged as relatively consistent within the industry.With appropriate s
cientific justification and consistent ap-plication most options are acceptable.Far from suppressing progress,the refinement of the meaning,application and implementation of QbD has stimulated regulatory authorities and industry to pursue clarification.As a result,subquent progress has improved the consistent application and value of the concepts.
The intrinsic advantages of investing in enhanced process understanding increas confidence and assurance of product quality.Tangible benefits,for example,reductions in manufacturing costs associated with improved efficiencies and innovations,reduction in manufacturing recalls,and failures or extraneous investigations attributed to uncertainty,are largely realized over the lifecycle of a product.
The fundamental scientific premi derived from the application and implementation of Quality by Design prin-ciples that attracts scientific support from every discipline across this industry is driven by a common passion to develop improve process understanding and product knowledge.The movement away from prescriptive and in many cas retro-spective development approaches has become an exciting and empowering platform for chemists,scientists,formula-tors,and engineers.QbD has also played an instrumental role in establishing the value and importance of cross-functional,scientific relationships in pharmaceutical development through proactively developin
g and understanding process and formulations.Perhaps,most importantly,the application of a QbD approach and investment in robust Pharmaceutical Quality Systems are expected to reduce unexpected variabil-ity in manufacturing process and unanticipated failures in product quality,thereby improving quality assurance of products.
ACKNOWLEDGMENT
Robert Baum from Pfizer for sharing his knowledge and thoughts on the historical perspective on QbD.REFERENCES
1.Woodcock J,M.D.October 5,2005.
2.Watson TJN,Nosal R,am Ende D,Bronk K,Mustakis J,O’Connor G,Santa Maria CL.J.Pharmaceut.Innovation 2007;2(3-4):71.公司罚款
咳嗽治疗Analytical control strategy API critical specifications Intermediate specs (ICH Q6A,Q3A,Q3C)
Pha I, II, III
API risk asssment (ICH Q9)
Multivariate designs, process modeling,
Data analysis, parameter control
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strategy
(PARs, NORs, EoFs)
梦见喝白酒Asssment of criticality
design space completed A顶的形近字
公务员考试条件
B
D
E
G in flow equipment, upts, etc.
F
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criticality for the CTD
H
Workflow for the Drug Substance Development of the
Illustrative Example
FIGURE 5.2Small example of drug substance workflow for QbD.
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