Quality by Design is the modern approach for quality of pharmaceuticals. This paper gives idea about the Pharmaceutical Quality by Design (QbD) and describes use of Quality by Design to ensure quality of Pharmaceuticals. The Quality by Design is described and some of its elements identified. Process parameters and quality attributes are identified for each unit operation. Benefits,opportunities and steps involved in Quality by Design of Pharmaceutical products are described. The aim of the pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Quality cannot be tested into products but quality should be built in by design. It includes the Quality target product profile, critical quality attributes and key aspects of Quality by Design. It also gives comparison between product quality by end product testing and product quality by Quality by Design. The foundation of Quality by Design is ICH Guidelines. It is based on the ICH Guidelines Q8 for pharmaceutical development, Q9 for quality risk management, Q10 for pharmaceutical quality systems. It also gives application of Quality by Design in pharmaceutical development and manufacturing of pharmaceuticals.
INTRODUCTION:- The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls. Information from pharmaceutical development studies can be a basis for quality risk management. It is important to recognize that quality cannot be tested into products; i.e., quality should be built in by design. Changes in formulation and manufacturing processes during development and lifecycle management should be looked upon as opportunities to gain additional knowledge and further support establishment of the design space. Similarly, inclusion of relevant knowledge gained from experiments giving unexpected results can also be useful. Design space is proposed by the applicant and is subject to regulatory assessment and approval. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. In all cases, the product should be designed to meet patients’ needs and the intended product performance. Strategies for product development vary from company to company and from product to product. The approach can also vary and should be outlined in the submission. An applicant might choose either an empirical approach or a more systematic approach to product development, or a combination of both. A more systematic approach to development (also defined as quality by design) can include, for example, incorporation of prior knowledge, results of studies using design of experiments, use of quality risk management, and use of knowledge management (ICH Q10) throughout the lifecycle of the product. Such a systematic approach can enhance achieving the desired quality of the product and help the regulators to better understand a company’s strategy. Product and process understanding can be updated with the knowledge gained over the product lifecycle.
- Product is designed to meet patient needs and performance requirements.
- Process is designed to consistently meet product quality attributes.
- Impact of starting raw materials and process parameters on product quality is understood.
- Critical sources of process variability are identified and controlled.
- The process is continually monitored and updated to allow for consistent quality over time.
Definition [ICH Q 8(R1)]:- A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.
Definition [FDA PAT Guidelines, Sept. 2004]:- A system for designing, analyzing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of new and in-process materials and processes, with the goal of ensuring final product safety. The concept of “Quality by Design” (QbD) was defined as an approach which covers a better scientific understanding of critical process and product qualities,designing controls and tests based on the scientific limits of understanding during the development phase and using the knowledge obtained during the life-cycle of the product to work on a constant improvement environment. QbD describes a pharmaceutical development approach referring to formulation design and development and manufacturing processes to maintain the prescribed product quality. Guidelines and mathematical models are used to ensure the establishment and use of the knowledge on the subject in an independent and integrated way.
Benefits of QBD
- QbD is good Business.
- Eliminate batch failures.
- Minimize deviations and costly investigations.
- Avoid regulatory compliance problems.
- Organizational learning is an investment in the future.
- QbD is good Science.
- Better development decisions.
- Empowerment of technical staff.
- Efficient, agile, flexible system.
- Increase manufacturing efficiency, reduce costs and project rejections and waste.
- Build scientific knowledge base for all products.
- Better interact with industry on science issues.
- Ensure consistent information.
- Incorporate risk management.
STEPS INVOLVED IN QUALITY BY DESIGN PRODUCTS7-9
STEPS INVOLVED IN QUALITY BY DESIGN PRODUCTS
- Development of new molecular entity
- Preclinical study
- Nonclinical study
- Clinical Study
- Scale up
- Submission for market Approval
- Design Space
- Process Analytical Technology
- Real time Quality Control
- Control Strategy
- Risk based decision
- Continuous Improvement
- Product performance
Seven steps of quality by design start up plan
- Hire an independent Quality by design expert.
- Audit your organization and process with the expert conducting a gape analysis.
- Hold a basic quality by design workshop with all your personal.
- Review the expert’s report and recommendation.
- Draft an implementation plan, timelines and estimated costs.
- Assign the resources (or contract out).
- Retain the independent expert as your “Project Assurance” advisor.
QbD BY PHARMACEUTICALS
Even though the pharmaceutical industry has focus on quality, it has failed to keep up with other industries in terms of manufacturing efficiency and productivity.
Current scenario in the Pharmaceutical Industry:
- Cost of revalidation
- Off‐line analysis for in‐process ‐ need based
- Product specifications as primary means of control
- Unpredictable Scale‐up issues
- Inability to understand failures
Systematic approach to development:
- That begins with predefined objectives
- Emphasizes products and process understanding
- Process control
- PAT:- Process Analytical TechnologyCRITICAL QUALITY ATTRIBUTES:-
- It is necessary to identify the quality attributes that are critical, i.e. those defining purity, potency and surrogate for Bioavailability Criticality etc. It is based on the impact of quality attribute/ parameter on the safety, efficacy & quality (manufacturability) of theproduct.
- Establish a link between CPP & CQAs: Identification of attribute or parameters that can be used as a surrogate for clinical safety & efficacy (important to patient).
- Manufacturability is also an attribute (important to business) that is critical to quality.
- The level of criticality may differ for an API manufacturing process relative to a drug product manufacturing process.
- API is one component of a drug product and one step further away from the patient continuum of Criticality. Several levels of criticality may be used to describe multiple levels of risk.
- As attribute or parameter boundaries approach edges of failure, the level of critically increased with the risk.
- Certain Key Aspects of QBD
- The Target Product Quality Profile (TPQP):- Target Product Quality Profile (TPQP) is a tool for setting the strategic foundation for drug development “planning with the end in mind.” More recently an expanded use of the TPP in development planning, clinical and commercial decision making, regulatory agency interactions, and risk management has started to evolve.
- Drug Substance and Excipient Properties:- To consistently achieve the drug-product quality specified in the label, the drug substance needs to be thoroughly characterized with respect to its physical, chemical, biological, and mechanical properties such as solubility, polymorphism, stability, particle size, and flow properties.
- Formulation Design and Development:- Not all prototype formulations can be evaluated in human subjects, which mean that developing sensitive in vitro dissolution methods is crucial to an effective development
- Manufacturing Process Design and Development:- Process development and formulation design cannot be separated because a formulation cannot become a product without a prescribed process. Process design is the initial stage of process development, in which an outline of the commercial manufacturing processes is documented, including the intended scales of manufacturing. The outline should include all the factors that need to be considered for the design of the process, including facility, equipment, material transfer, and manufacturing variables. Other factors to consider during process development are the QTPP and CQAs.
Product quality by end product testing vs QbD17,18:- Comparison is shown between product qualities by end product testing vs. quality by design.
- Successful adoption
- Regulatory flexibility to accommodate quality by design submissions.
- Common dossier accepted worldwide by regulatory agencies.
- Post-approval changes within pre-defined design space can be implemented with regulatory flexibility.
- Laws and processes in place to protect intellectual property (IP).
- Designed to consistently meet desired product quality
- Design space concept
- Experimentally defined process operating space based on scientific principles.
- Critical process parameters identified.
- Critical – impact product quality.
- Space – operating range yielding acceptable product Space.
- Critical process parameters are consistently controlled.
- Product of process is always desired quality Product.
- End product testing might be reduced.
Designed to facilitate continuous improvement
- Process control strategy: control of the process.
- Performance and continuous process improvement.
- Real-time process feedback Process improvements within design space Knowledge builds with experience. Leverage information/new technologies to improve process efficiency. Key opportunity to continuously improve the process. E.g. increased supply, more efficiency.
APPLICATIONS OF QBD
- Quality by design (QbD) – a comprehensive systematic approach to pharmaceutical development and manufacturing:- Advancement in the pharmaceutical development and manufacturing by Qbd can be explained against traditional approach.
- In Pharmaceutical Development:- To design a quality product and a manufacturing process to consistently deliver the intended performance of the productBENEFITS OF IMPLEMENTING QBD FOR FDA
- Enhances scientific foundation for review
- Provides for better coordination across review, compliance and inspection
- Improves information in regulatory submissions
- Provides for better consistency
- Improves quality of review (establishing a QMS for CMC)
- Provides for more flexibility in decision making
- Ensures decisions made on science and not on empirical information
- Involves various disciplines in decision making
- Uses resources to address higher risksBenefits to Industry
- Ensures better design of products with less problems in manufacturing
- Reduces number of manufacturing supplements required for post market changes –rely on process and risk understanding and risk mitigation
- Allows for implementation of new technology to improve manufacturing without regulatory scrutiny
- Allows for possible reduction in overall costs of manufacturing –less waste
- Ensures less hassle during review –reduced deficiencies –quicker approvals
- Improves interaction with FDA –deal on a science level instead of on a process level
- Allows for continuous improvements in products and manufacturing process.
Quality target product profile for the ANDA product:- The Quality Target Product Profile (QTPP) is “a prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product.” The QTPP is an essential element of a QbD approach and forms the basis of design for the development of the product. For ANDAs, the target should be defined early in development based on the properties of the drug substance (DS), characterization of the RLD product and consideration of the RLD label and intended patient population. By beginning with the end in mind, the result of development is a robust formulation and manufacturing process with an acceptable control strategy that ensures the performance of the drug product.
A critical quality attribute (CQA) is “a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” The identification of a CQA from the QTPP is based on the severity of harm to a patient should the product fall outside the acceptable range for that attribute. All quality attributes are target elements of the drug product and should be achieved through a good quality
management system, appropriate formulation/process design and development. From the perspective of pharmaceutical development, we only investigate the subset of CQAs of the drug product that also have a high potential to be impacted by the formulation or process variables. Our investigation culminates in an appropriate control strategy.
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