An Overview on Quality by Design
Harshal D. Patil*, Chandrabhan B Patil*, Vikas V. Patil, Pankaj S. Patil
Department of Pharmaceutical Quality Assurance,
Kisan Vidya Prasarak Sanstha’s Institute of Pharmaceutical Education, Boradi 425428
*Corresponding Author E-mail: chandrabhanpatil123@gmail.com, Harshalpatil27896@gmail.com
ABSTRACT:
Quality by Design (QbD) has as a new concept for the development of high-quality pharmaceutical products. It is an essential component of the modern approach to pharmaceutical quality. QbD is the best way to build quality into all pharmaceutical products, but it poses a significant challenge to the pharmaceutical industry, whose processes are time-bound, despite inherent process and material variability. Throughout the design and development of a product, it is critical to define the desired product performance profile [Target Product Profile (TPP), Target Product Quality Profile (TPQP)] and identify critical quality attributed to the product (CQA). Applications of QbD to pharmaceutical processes (formulation development) and analytical development are briefly discussed. A standardized pharmaceutical quality system that is applicable throughout the product's lifecycle and emphasizes an integrated approach to risk management and science should be developed, resulting in better quality medicines for patients.ICH documents such as ICH Q8, i.e. Pharmaceutical development; ICH Q9, i.e. Quality Risk Management; ICH Q10, i.e. Pharmaceutical Quality Systems, and FDA's Process Analytical Technology (PAT) were referred to in order to ensure drug product quality. QbD allows formulation and manufacturing variables to be properly understood and controlled.
KEYWORDS: Quality by Design, ICH, GMP, TPQP.Control strategy, Design space.
INTRODUCTION:
The basic concept of QBD is “The Quality cannot be tested into the product, but it should be built into it.” The design space is defined as a manufacturing area of the product including Equipment, Material, and Operators and Manufacturing Conditions. The design space should be well defined prior to regulatory approval. Working with design space is not considered as a change, but working out of design space is considered as a change. Different variables are monitored for their effect of product quality when the manufacturing is done out of design space.
All these variables are assessed and conclusions will be drawn which serves as a tool to QBD. All these data are included in the regulatory submission dossier the pharmaceutical product.
formulation can be developed based on the data obtained from product development studies. The process variables that are emerged during development stages will serve as a source for QRM. Before conducting the development studies, the QTPPs of the product must be determined and having the final product quality in mind and evaluation is performed to obtain the desired quality of product. The QTPP of product includes design space, specifications and manufacturing controls. Quality by design (QBD) is a concept that promulgates a core message that quality should its characteristics and understanding of the process by which the product is manufactured.1
Definition of Quality by Design (QBD)1–4:
As per ICH Q8 (R1) guideline: QbD is 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. As per FDA PAT guidelines: QbD is 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 process will impact on the quality of the product safety.
Pharmaceutical Quality By Design Objective.1,2,5,6:
1. To achieve meaningful product quality specifications that is based on clinical performance.
2. To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control.
3. To increase product development and manufacturing efficiencies.
4. To enhance root cause analysis and post approval change management.
5. To ensure the quality products.
6. From this knowledge and data process measurement and desired attributes may be constructed.
7. Experimental study would be viewed as positive performance testing of the model ability through Design space.
8. Ensures combination of product and process knowledge gained during development.
Benefits of QBD5,6,28
1. QBD is good Business
2. Eliminate batch failures
3. Minimize deviations and costly investigations
4. Avoid regulatory compliance problems
5. Organizational learning is an investment in the future
6. QBD is good Science
7. Better development decisions
8. Empowerment of technical staff
Opportunities2,9:
· 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 COD
Advantages of QBD10,11,12:
1. It involves both the patient safety as well as efficacy of the product.
2. The scientific understanding of the process involved in the manufacturing of the product can be done easily.
3. It includes both product design as well as process development.
4. The science based risk assessment can be carried out by this approach.
5. It is a robust process.
6. Design space concept avoids the post-approval modification which may cause to pay a high price for any of the firm.
7. Less batch failure.
8. More efficient and effective control of change.
9. Return on investment / cost savings.It increases the efficiency of pharmaceutical manufacturing processes.
10. It minimizes high penalties and drug recalls.
11. It provides more efficiency for regulatory oversight.
12. It updates regulatory processes and postapproval manufacturing changes.
13. Improves information in regulatory submissions.
14. Regulatory flexibility.
15. Reduces Product Variability.
Application Of QBD13:
The basic concept of QBD is “The quality is tested into the product, but it should be built into it.” During development of analytical methods, same QBD principle can be applied to the development of analytical method. Various quality and statistical tools and methods, such as statistical designs and experiments, multivariate statistics, statistical quality control have been comprised in QBD. The main goal for changing from quality by testing is to accelerate the understanding of the product such that product quality, processes efficacy, and regulatory flexibility can be attained.
Fig. no. 1 Application of QbD
1. Pharmaceutical Development:
To design a quality product and a manufacturing process to consistently deliver the intended performance of the product.
2. QbD in CMC Review Process:
· Science-based assessment
· Restructured organization and reorganized staff –premarket staff and post-market
· CMC Pilot
· Lessons learned
· Evaluation of information
· Implementation of PMP
3. Office of New Drug Quality Assessment (ONDQA):
· Science-based assessment
· Restructured organization and reorganized staff –premarket staff and post market
· CMC Pilot
· A number of applications submitted
· Lessons learned
· Evaluation of information
· Implementation of PMP
4. Office of Generic Drugs (OGD):
· QbD contains the important scientific and regulatory review questions
· Evaluate whether a product is of high quality
· Determine the level of risk associated with the manufacture and design of this product
· 416 applications received using QbD by June 2007
· Successful in ensuring that questions address issuesregarding QbD
5. Office of Biotechnology Products:
· Have more complex products
· Already doing some aspects of QbD
· In process of preparing to accept applications using QbD
· Beginning a pilot for biotech products for QbD –usingmainly comparability protocols
· Also implementing Q8, Q9 and Q10
Elements Of QBD5,14–16:
In a pharmaceutical QBD approach to product Development, an applicant identifies characteristics that are critical to quality from the patient’s perspective, translates them into the drug product critical quality attributes (CQAs), and establishes the relationship between formulation/manufacturing variables and CQAs to consistently deliver a drug product with such CQAs to the patient order to address GMP's limitations, the FDA introduced cGMP in the year 2002.According to cGMP, the focus on "software" throughout the production phase, especially at the managerial level, precisely defines the transparency of workers. The ICH Q8 framework defines QbD as a systematic approach for development, which begins from predefined targets and emphasizes process and product evaluation with tracking, based on validated quality and process risk assessment. CQAs were identified based on the initial screening studies and literature review. Risk assessment was then employed during development to identify possibly high risk input and process parameters to conclude the required variables that would be investigated. Risk ranking was determined based on the screening studies, current knowledge and the ICH Q9 risk management guidelines. The CPPs were assessed against CQAs using risk assessment tool. For each input and process attribute a risk rank was made based on the impact on the final product quality. Identification ofCQAs ofthe final product were determined also according to risk assessment anticipating a failure ofthe product ifCQAs were not met. Risk ranking was categorized as low, medium and high. Risks ranked as low were not included as independent factor, while those with medium and high risk rank were considered as independent factors and used in the DOE study.
Fig. No. 2 Elements of QbD
Different elements of pharmaceutical development include:16
Determination of critical quality attributes (CQAs)
Critical process parameters
Risk assessment
DesignControl strategy
Design Space
1)The Target Product Quality Profile (TPQP)7,17–19
The Target Product Quality Profile (TPQP) is a tool for laying the strategic groundwork for drug development, or "planning with the end goal in mind. "A natural extension of the Target Product Profile for product quality – Quality characteristics (attributes) that the drug product should have in order to deliver the therapeutic benefit promised on the label guide in order to establish formulation strategy and keep the formulation effort focused and efficient. A drug product that is designed, developed, and manufactured in accordance with the Quality Target Product Profile, with specifications (such as dissolution/release acceptance criteria) that are consistent with the product's desired in vivo performance.
2)Critical Quality Attributes20–22
The foundation of QbD is a thorough understanding of the molecule itself. Because of the various post-translational modifications that can and have been observed, bimolecular are quite heterogeneous. These modifications are caused by glycosylation, oxidation, deamidation, labile site cleavage, aggregation, and phosphorylation. A pharmaceutical manufacturing process is typically made up of a series of unit operations that work together to create the desired product. A unit operation is a discrete activity involving physical changes such as mixing, milling, granulating, drying, compaction, and coating. A process is designed based on these properties, and qualitative and quantitative attributes of raw material are investigated to meet objectives set in TPQP.
3)Design And Control Strategy17,18,23
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 design of experiment (DOE) approach, process variables are first ‘screened’ to determine which are important to the outcome (excipients type, percentage, disintegration time (DT) etc. Second step is the ‘optimization’, when the best settings for the important variables are determined. Process design is that the initial stage of process development where an overview of the commercial manufacturing processes is identified on paper, including the intended scales of manufacturing. This could include all the factors that require to be considered for the planning of the process, including facility, equipment, material transfer, and manufacturing variables. a risk assessment approach, it is possible to establish a control strategy for product attributes that assures high quality through process and/or testing control The Attribute Testing Strategy [ATS] tools were designed to identify quality attributes that required process and/or testing controls
4)Risk Assessment2,24–26
Risk assessment is a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. Risk assessment is the linkages between material attributes and process parameters. It is performed during the lifecycle of the product to identify the critical material attributes and critical process parameters. An initial risk assessment is attempted to recognize probable interactions between drug, excipients, different unit operations and important attributes. Risk based compliance is a principal FDA strategy in its current Good Manufacturing Practice (cGMP) for the 21stcentury. ICHQ9 guidance document introduced the idea of quality risk management for evaluating, supervising, transmission and assessing risks to the quality of drugs over the product life cycle. During risk assessment, the critical quality attributes. (CQAs) that could vary with a change in the manufacturing operations are identified. CQAs are physical, chemical, biological or microbiological attributes or characteristics that should be within a relevant threshold or radius to attain product quality17. CQAs may be properties of thepure drug, excipients, intermediates (in-process materials) and/or drug product
5) Design Space10,27,28
The ICH Q8 (R2) defines the design space as to ensure the quality of the product. The design space is defined as the multidimensional combination and interaction of the input variables and process parameters to provide assurance of the quality .This definition arises from early ICH Q8 drafts where design space was defined as “the established range of process parameters that has been demonstrated to provide assurance of quality”. A design space is either described in terms of ranges of material attributes and process parameters or using complex mathematical relationships. The Design Space is linked to criticality through the results of risk assessment, which determines the associated CQAs and CPPs. It describes the multivariate functional relationships between CQAs and the CPPs that impact them, and should include their linkage to or across unit operations.
Fig. No. 3 Steps to Design space
Step Involved In Quality By Design Product2, 5, 27
1. Development of new molecular entity
· Preclinical study
· Nonclinical study
· Clinical Study
· Scale up
· Submission for market Approval
2. Manufacturing
· Design Space
· Process Analytical Technology
· Real time Quality Control
3. Control Strategy
· Risk based decision
· Continuous Improvement
· Product performance Seven
Fig No. 4 Step involved quality by Design Product
Seven steps of quality by design start up plan2
1. Hire an independent Quality by design expert.
2. Audit your organization and process with the expert conducting a gape analysis.
3. Hold a basic quality by design workshop with all your personal.
4. Review the expert’s report and recommendation.
5. Draft an implementation plan, timelines and estimated costs.
6. Assign the resources (or contract out).
7. Retain the independent expert as your “Project Assurance” advisor.
ICH Guidelines For QBD (ICH guideline Q8, 2012; ICH guideline Q10, 2012; ICH guideline Q9, 2012; ICH guidelines, 2012)14,18,29–34:
The underlying principles of QbD i.e. science- and risk-based product development, risk assessment, lifecycle approach and method design are explained in the quality guidelines of international conference on harmonization i.e. ICH Q8 Pharmaceutical Development, ICHQ9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System. ICH Q10 describes one comprehensive model for an effective pharmaceutical quality system that is based on International Standards Organization (ISO) quality concepts, includes applicable Good Manufacturing Practice (GMP) regulations and complements ICH Q8 “Pharmaceutical Development” and ICH Q9 “Quality Risk Management. International Council for Harmonization (ICH) Q8, Q9, and Q10, and current guidance documents, current good manufacturing procedures (cGMP), food and drug administration (FDA), currently, the principles of QbD have gained popularity for several interventions in drug discovery in the twenty-first century.The introduction of ICH Q9 states that: “…the protection of the patient by managing the risk to quality should be considered of prime importance”. The QTPP provides an understanding of what will ensure the quality, safety and efficacy of a specific product.
1. Quality by Design relative to ICH:
· Concepts aligned
· Design Space
· Key to understanding
· Process robustness
· Design of Experiments (DOE)
· Quality management Quality management Critical Concept:
2. Design Space:
Multidimensional combination with interactions Multidimensional interactions put variables (e.g. raw material attributes) and process parameters.
· Demonstrated to provide assurance of quality
· Defined by applicant and reviewed by regulator
· Defined regulator
· Once design space is approved, regulatory post approval change requirements will be simplified
· Approval Inside vs. outside design space inside space
· Regulatory flexibility to operate within the design space Regulatory space.
ICH Q8: Pharmaceutical Development:
The QBD concept came with the release of the ICH Q8 guideline ‘Pharmaceutical Development’ in November 2004. This guideline reached ‘step 4’ – recommendation for adoption by the regulatory agencies party to the ICH – in November 2005. A further annex to the guideline, intended to clarify the concepts in the original guideline, was re- leased for public consultation in November 2007 and reached step 4 in November 2008. It should be emphasized that theICH Q8 guideline provides guidance on the suggested contents of the Pharmaceutical Development section of the Common Technical Document.ICH Q8 (R2) guidelines do not discuss analytical method development in correlation with design space; however it is understood that the concept can be applied to analytical design space and continuous improvement in method
ICH Q9: Quality Risk Management:
ICH Q9 ‘Quality Risk Management’ was released at approximately the same time as ICH Q8 and ICH Q10, and needs to be considered as part of the over- arching QbD guidance released by regulatory agencies. The purpose of ICH Q9 was to offer a systematic approach to quality risk management.It provided guid- ance on the principles and some of the tools of quality risk management for use by both regulators and industry in managing drug substances and drug products.
ICH Q10: Pharmaceutical Quality System:
ICH Q10 reached ‘step 4’ in 2008 and described a model of an effective quality system for a pharmaceutical company. This model was intended to complement ICH Q8 and Q9 and defines the ICH expectations for management responsibilities in a pharmaceutical company.
The Pharmaceutical Quality System described had four key elements:
· A process performance and product quality monitoring system;
· A corrective action and preventive action system;
· A change management system;
· Management review of process performance and product quality.
ICH Q11: Development and Manufacture of Drug Substances:
Dealing with the manufacture of Drug Substances, ICH Q11 ‘Development and Manufacture of Drug Substances (Chemical and Biotechnological/Biological entities)’ was released for public consultation in May 2011 and reached step 4 in May 2012. Importantly for biological and biotechnological products this guideline stated that most of the CQAs of a biologically derived drug product are associated with the drug substance and, thus, are a direct result of the design of the drug substance or its manufacturing process.
CONCLUSION:
Quality by design is an essential part of the modern approach to pharmaceutical quality. This paper clarifies the use of QbD including. Accentuation on the significance of the Target Product Quality Profile in articulating a quantitative execution focus for QbD. Quality by design (QbD) is proposed to develop process knowledge and it is based on existing guidance and reference documents. QbD is quality system that builds on past and sets the potential regulatory expectations. QbD becomes important in the area of pharmaceutical processes like drug development, formulations, analytical methods and biopharmaceuticals. The major reason behind adoption of QbD is the regulatory requirements. Pharmaceutical industry requires a regulatory compliance to get their product official for marketing. The QbD is a cost-effective time-saving strategy that uses PAT, risk assessment, and DoE as tools to understand raw materials and process parameters. A QbD approach for analytical methods that include risk assessment, robustness testing, and ruggedness testing is much more rigorous than ICH validation requirements.
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Received on 12.10.2022 Modified on 16.11.2022
Accepted on 05.12.2022 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2023; 13(1):49-55.
DOI: 10.52711/2231-5659.2023.00009