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Abstract

Quality is one of the fundamental criteria in addition to safety and efficacy for any entity to be qualified and approved as a drug. For ensuring consistency of performance of pharmaceutical products and systems, the recent emphasis has been on building the “quality” rather than merely testing it. This philosophy forms the basis of Quality by Design (QbD). This initiative intended to modernize the FDAs regulation of pharmaceutical quality, and establish a new regulatory framework focused on QbD risk management, and quality system. The initiative challenged industry to look beyond quality by testing (QbT) for ensuring product quality and performance. The entire pharmaceutical product development strategy is based upon the TPQP. It is this parameter which determines the design and extent of development. TPQP is the performance based quality attribute that a product should possess in order to meet TPP. Life cycle management is a control strategy used for implementation of design space in commercial stage. CMM is final step in AQbD life cycle; it is a continuous process of sharing knowledge gained during development and implementation of design space. This includes results of risk assessments, assumptions based on prior knowledge, statistical design considerations, and bridge between the design space, MODR, control strategy, CQA, and ATP. Once a method validation is completed, method can be used for routine purpose and continuous method performance can be monitored. This can be performed by using control charts or tracking system suitability data, method related investigations, and so forth. CMM allows the analyst to proactively identify and address any out-of-trend performance. Advantages and Recommendations.

Keywords

Quality by design , HPLC , Quality Risk management

Introduction

High?performance liquid  chromatography  (HPLC)(8?12),  particularly Reversed  Phase  HPLC  (RP?HPLC), is the most popular analytical technique  in  the  pharmaceutical  industry.  The  quality  of  HPLC methods has become increasingly important in a qbd environment.For  the  purpose  of  qbd  for  HPLC  methods,  robustness  and ruggedness  should  be  verified  early  in  the  method  development stage  to  ensure  method  performance  over  the  lifetime  of  theproduct.  Otherwise,  if  a  non?robust  or  non?rugged  method  is adapted,  significant  time  and  resource  may  be  required  to Redevelop, revalidate and retransfer analytical methods.According to literature survey, there are quite a few publications on HPLC  method  development  strategy  but  the  method  development approaches  for  RP?HPLC  specifically  focused  on  pharmaceutical development in a qbd environment have not been widely discussed.Therefore,  there  is  an  unmet  need  to  develop  a  systematic  HPLC method  development  approach  for  pharmaceutical development using qbd principles to ensure the quality of the method throughout the product lifecycle .(1) In past few decades, pharmaceutical companies had spend an Enormous amount of resources in their unflagging efforts to assure Quality, achieve regulatory compliance, and produce drugs as cost-Effectively as possible. Consequently, they employ advance Processes and technologies that entail a great deal of scientific Sophistication and operational complexity. However, such effort Lacks comprehensive, rationale based understanding of these Complex processes, associated critical variables and strategies to Control these variables, which is pivotal in assuring quality of the Product. Little emphasis is paid to identify the root cause of Manufacturing failures. Furthermore, no rationale-based approach Is followed to predict the effects of scale-up on the final product. This has led to a gap between product quality attributes and Their clinical performances, forcing regulatory authorities to set Stringent specifications and guidelines for approval of drug Products. In order to overcome these roadblocks, in 2002, us food and drug Administration (FDA) had announced a new initiative-Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century, intended to modernize the FDAs regulation in regards to pharmaceutical manufacturing and product quality. The initiative challenged industry to look beyond quality by testing (QbT) for ensuring product quality and performance. Additionally, International Conference on Harmonization (ICH) Q8 guideline was published in May 2006 for pharmaceutical product development, and has been complemented by the ICH Q9 on Quality Risk Management and ICH Q10 for a Pharmaceutical Quality System. These guidelines emphasize quality by design (QbD), a science- based approach for designing formulations and manufacturing processes in order to ensure predefined product quality objectives. The fundamental assumption underlying QbD is that the quality of the product can be assured only if critical sources of variability is understood and is suitably mitigated or controlled within a defined design space .(2) Along with safety and efficacy, quality is a prerequisite for any substance to be certified and authorised as a drug. Building "quality" rather than just evaluating pharmaceutical items and systems has become more important in order to guarantee consistency in their performance. The foundation of Quality by Design (QbD) is this philosophy. As stated in ICH guidance Q8(R2), QbD is "a systematic approach to pharmaceutical development, based on sound science and quality risk management, that begins with predefined objectives and emphasises product and process understanding and process control Building "quality" rather than just evaluating pharmaceutical items and systems has become more important in order to guarantee consistency in their performance. The foundation of Quality by Design (QbD) is this philosophy. As stated in ICH guidance Q8(R2), QbD is "a systematic approach to pharmaceutical development, based on sound science and quality risk management, that begins with predefined objectives and emphasises product and process understanding and process control The foundation of Quality by Design (QbD) is this philosophy. As stated in ICH guidance Q8(R2), QbD is "a systematic approach to pharmaceutical development, based on sound science and quality risk management, that begins with predefined objectives and emphasises product and process understanding and process control ."[1]. The core concepts of QbD are process design appropriateness and process performance comprehension for the intended product performance. A key component of the entire plan is continual improvement, which is predicated on the understanding of the process. With an emphasis on scientific knowledge building, superior design, performance demonstration, Quality Risk Assessment (QRM), Design of Experiments (DoE), Process Analytical Technology (PAT) tools, continuous improvement and learning, and life-cycle management, the concept moves towards a "desired state" with "regulatory flexibility." A QbD-based progression's building blocks are illustrated graphically in Figure 1.(3)



       
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The ICH Q8 guideline, which asserts that "quality cannot be tested into products, i.e., quality should be built in by design," made reference to the idea of QbD. A systematic approach to development that starts wih predetermined objectives and stresses understanding of the product and process as well as process control, based on good science and quality risk management, is what is meant to be understood by ICH Q8 QbD. [7].  QbD encompasses designing and developing formulations and manufacturing processes which ensures predefined product specifications. In 2002, the FDA announced a new initiative (cGMP for the 21st Century: A Risk based Approach) [1].

 This initiative intended to modernize the FDAs regulation of pharmaceutical quality, and establish a new regulatory framework focused on QbD risk management, and quality system. The initiative challenged industry to look beyond quality by testing (QbT) for ensuring product quality and performance. An important part of QbD is to understand how process and formulation parameters affect the product characteristics and subsequent optimization of these parameters should be identified in order to monitor these parameters online in the production process.                          This paper discusses the pharmaceutical quality by design and describes how it can be used to ensure pharmaceutical quality with emphasis on solid oral dosage forms of small molecules. The pharmaceutical industry works hard to develop, manufacture, and bring to market new drugs and to comply with regulatory requirements to demonstrate that the drugs are safe and effective. A new approach to drug development could increase efficiencies, provide regulatory relief and flexibility, and offer important business benefits throughout the product’s life cycle.                                                 This article explores the processes used in developing a market formulation and requisite supportive data, particularly in light of the industry’s current movement toward submissions based on quality by design (QbD). It outlines activities that should be performed early in the drug development process before initiating manufacturing and attempting market entry .(4)

The pharmaceutical industry works hard to develop, manufacture, and bring to market new drugs and to comply with regulatory requirements to demonstrate that the drugs are safe and effective. A new approach to drug development could increase efficiencies, provide regulatory relief and flexibility, and offer important business benefits throughout the product’s life cycle.                                      This article explores the processes used in developing a market formulation and requisite supportive data, particularly in light of the industry’s current movement toward submissions based on quality by design (QbD). It outlines activities that should be performed early in the drug development process before initiating manufacturing and attempting market

entry. The Food and Drug Administration (FDA) Office of Generic Drugs (OGD) has developed a question based review (QbR) for its chemistry, manufacturing and controls (CMC) evaluation of Abbreviated New Drug Applications (ANDAs). QbR is a new quality attributes. It is a concrete and practical implementation of some underlying concepts and principles outlined by the FDA’s Pharmaceutical CGMPs for the twentyfirst century and quality by design (QbD)

initiatives (4)

Definition

Quality by Design:

 QbD is a systematic approach that helps in the development of the pharmaceutical product by improving the quality. It begins with the predefined objectives and process understanding and process control, based on sound science and quality risk management

Design:

 This refers to the plan or sequence for the construction of an object.

Advantages of QbD

  • It involves both the patient safety as well as efficacy of the product.
  • The scientific understanding of the process involved in the manufacturing of the product can be done easily.
  • It includes both product design as well as process development.
  • The science based risk assessment can be carried out by this approach.
  • It is a robust process.(9)

KEY ELEMENTS OF QUALITY BY DESIGN:



       
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  1. Target product quality profile

The entire pharmaceutical product development strategy is based upon the TPQP. It is this parameter which determines the design and extent of development. TPQP is the performance-based quality attribute that a product should possess in order to meet TPP. TPQP translates TPP into quantitative tests, for example, assay, impurities, content uniformity, dissolution, bioequivalence, stability, etc. Tests which are vital to the performance of dosage form vis-à-vis meeting therapeutic objectives are included in this section.

  1. Design and development of product

The physico-chemical and pharmacological properties of the active pharmaceutical ingredient

(API) determine the critical attributes for pharmaceutical development. The objectives of the product development program using QbD are to achieve desired patient requirements and to identify attributes that drug product should possess to exert intended therapeutic response. The product development must invariably be systematic, scientific, and risk-based to accomplish these predefined objectives. Experience component is an add-on value at various stages to this holistic approach. A strong and thorough understanding of a product and its manufacturing process helps in identifying CQA, which must be controlled to reproducibly produce desired product.(5)

  1. Control Strategy and Risk Assessment:

Control strategy  is a planned set of controls, derived from analyte nature and MODR understanding. Method control strategy can be established based on the complete statistical data collected during the DoE and MODR stages as discussed above. Using this statistical experimental data, correlations can be drawn between method and analyte attributes for the ability to meet ATP criteria. Control strategy will resolve the method parameters inconsistency (e.g., reagent grade, instrument brand or type, and column type). Method control strategy does not appear dramatically different under the AQbD approach when compared to the traditional approach. However, method controls are established based on CQA, DoE, and MODR experimental data to ensure a stronger link between the method purpose and performance.

D. AQbD Method Validation:

AQbD [14–23] method validation approach is the validation of analytical method over a range of

different API batches. It uses both DoE and MODR knowledge for designing method validation for all kinds of API manufacturing changes without revalidation. The approach provides the required ICH validation elements as well as information on interactions, measurement

uncertainty, control strategy, and continuous improvement. This approach requires fewer resources than the traditional validation approach without compromising quality.(8)

Steps for Pharmaceutical QbD implementation As a general rule, the practical implementation of QbD in the development of new pharmaceutical products can go through the following steps:

  1. Define the desired performances of the product and identify the QTPPs;
  2. Identification of the CQAs;
  3. Identification of possible CMAs and CPPs;
  4. Setup and execution of DoE to link CMAs and CPPs to CQAs and get enough information of how these parameters impact QTPP. Thereafter, a process Design Space should be defined, leading to an end product with desired QTPP;
  5. Identify and control the sources of variability from the raw materials and the manufacturing process; 6. Continually monitor and improve the manufacturing process to assure consistent product quality(7)

Comparison between QbD  and QbT



       
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  Figure 2 : comparison between Qbt (a) and Qbd (b).(Qbt - quality by test ; Qbd : Quality by design ;QTPP : Quality target product profile ;CQA : Critical quality attributes; CMA :  critical material attributes ; CPP : critical process parameters ; DOE: Design of experiments


Application of QBD approach in pharmaceutical development :

  1. Lessons learned and future opportunities:

An integrated set of simple risk assessment tools was designed to connect product and process knowledge to a rational control system and post-approval management plan. Conservative assumptions and limits were built into the tools and minimize the risk to patients and ensuring product quality. There is significant value in the application of these tools as they form the basis for a balanced and transparent discussion of risk and risk management for both the manufacturer and the regulating health.

  1. Roche/Genentech QbD concept

Quality risk management is one foundation of the enhanced approach. Structured risk assessments are performed at several stages of product and process development to identify risks and harms and to prioritize development activities. Cross functional expertise contributes to the risk assessments and ensures that the evaluation is performed considering different perspectives. Some of the risk assessment tools applied were based on those presented in the A-Mab Case Study and further developed.(6)

Continuous Method Monitoring (CMM) and Continual Improvement

Life cycle management is a control strategy used for implementation of design space in commercial stage. CMM is final step in AQbD life cycle; it is a continuous process of sharing knowledge gained during development and implementation of design space. This includes results of risk assessments, assumptions based on prior knowledge, statistical design considerations, and bridge between the design space, MODR, control strategy, CQA, and ATP. Once a method validation is completed, method can be used for routine purpose and continuous method performance can be monitored. This can be performed by using control charts or tracking system suitability data, method related investigations, and so forth. CMM allows the analyst to proactively identify and address any out-of-trend performance. Advantages and Recommendations. AQbD is an approach that moves away from reactive troubleshooting to proactive failure reduction. The type and extent of the risk assessment depends on the stage of the project in the development timeline. AQbD success rate depends on right approach, planning, tools usage, and performance of work in a suitable time. Applying the appropriate risk assessment tools at the right time could lead to prevention of method failures and better understanding on the design space and control strategy.

Regulatory Perspective of QbD :

  • Regulatory bodies now strongly emphasize QbD alone rather than only “Quality by Testing” or “Quality by Chance”. Analytical procedures are a crucial component of the control plan concerning the pharmaceutical quality system (ICH Q 10 recommendations).
  • Analytical QbD will be implemented in the manufacturing process to guarantee predetermined performance and product quality as a control technique7 .

 ICH guidelines and QBD

 The ICH guidelines provide clear definitions of QbD principles: Q8 (R1): pharmaceutical development, Q9: quality risk management, and Q10: pharmaceutical quality system.

 Stages in QBD vs AQBD

 Analytical QbD implementation follows a similar method to that of product QbD. Initially, the target measurement for implementing AQbD is dependent on the product file in the form of the ATP (analytical target profile) and CQA (ATP is the analogue of QTPP in product design).A comparison between QBD and AQBD is given in Table 1.

Implementation AQBD Analytical Target Profile (ATP)

 ATP specifies the objective of the development of analytical methods. The definition of ATP, recently offered by PhRMA and EFPIA, is as follows: “ATP is a declaration that describes the method’s goal and is used to guide method selection, design, and development activities.” Following regulatory authorities’ approval of the ATP statement, ATP is a crucial AQbD characteristic that enables increased improvement of analytical techniques and their selection. While the examples above are mostly focused on directly measurably and changeable technique parameters, the ATP should ideally cover all important aspects of method performance.

Analytical Method Performance Characteristics:

 These are specified to satisfy the requirements of the analytical target profile. For chromatographic separations, USP and ICH have published numerous validation factors and are regarded as method performance characteristics. Accuracy, specificity, linearity, precision, detection limit, and quantification limit are these parameters. Robustness and range.

 Selection of Analytical Techniques

 The chosen analytical methodology must meet the validation requirements of ICH8 as well as the required method performance specified in Adenosine triphosphate (ATP).

 Risk Assessment

The parameters that affect the ATP are identified by risk assessment as the essential method variables. Following the identification of the technique, AQbD concentrates on developing the method and includes a thorough evaluation of the risks related to variability, such as analytical techniques, instrument settings, measurement and methodology parameters, sample properties, sample preparation, and ambient factors. The ICH Q9 guideline must be followed in the risk assessment strategy: Risks to the quality over the product lifecycle are assessed, controlled, communicated, and reviewed using a systematic approach22.

Design of Experiments:

 Method operable design region (MODR) can be formed in the method development phase, which could serve as a source for reliable and affordable methods, in compliance with the requirement of ICH Q8 recommendations, regarding “design space” in product development. DoE implementation during the method development phase necessitates a deep comprehension of input variable selection and output reaction. The following are the components of DoE in the AQbD technique.

Screening

 Screening allows for the exclusion of qualitative input characteristics. It lists the different critical method parameters (CMP) that should be considered during the optimization studies. The CMP that has to be regulated or subjected to DOE approaches in MODR optimization should be separated as a result of the screening studies. Optimization Quantitative metrics for critical methods in variables (i.e., CMP) can be introduced at this point either directly from risk assessment or through screening. It provides a basis for comprehending the scientific connection between the quantities of input variables (CMP) and responses at the output, which will significantly.(10)

Reference

  1. Bhatt DA, Rane SI. QbD approach to analytical RP-HPLC method development and its validation. International Journal of Pharmacy and Pharmaceutical Sciences. 2011;3(1):179-87.
  2. Jain S. Quality by design (QBD): A comprehensive understanding of implementation and challenges in pharmaceuticals development. Int. J. Pharm. Pharm. Sci. 2014;6:29-35.
  3. Bhutani H, Kurmi M, Singh S, Beg S, Singh B. Quality by design (QbD) in analytical sciences: an overview. Quality Assurance. 2004 Sep;3:39-45.
  4. Patil AS, Pethe AM. Quality by Design (QbD): A new concept for development of quality pharmaceuticals. International journal of pharmaceutical quality assurance. 2013 Apr;4(2):13-9.
  5. Pramod K, Tahir MA, Charoo NA, Ansari SH, Ali J. Pharmaceutical product development: A quality by design approach. International journal of pharmaceutical investigation. 2016 Jul;6(3):129.
  6. Finkler C, Krummen L. Introduction to the application of QbD principles for the development of monoclonal antibodies. Biologicals. 2016 Sep 1;44(5):282-90.
  7. Zhang L, Mao S. Application of quality by design in the current drug development. Asian journal of pharmaceutical sciences. 2017 Jan 1;12(1):1-8.
  8. Jayagopal B, Shivashankar M. Analytical quality by design–a legitimate paradigm for pharmaceutical analytical method development and validation. Mechanics, Materials Science & Engineering Journal. 2017 Apr 10;9.
  9. Raman NV, Mallu UR, Bapatu HR. Analytical quality by design approach to test method development and validation in drug substance manufacturing. Journal of chemistry. 2015 Jan 1;2015.
  10. Mohurle MS, MDA JA, DD RC, Kurian MJ, Bais G. Quality by Design (QbD): An Emerging Trend in Improving Quality and Development of Pharmaceuticals. Saudi J Med Pharm Sci. 2019 Dec;5(12):1132-8

Reference

  1. Bhatt DA, Rane SI. QbD approach to analytical RP-HPLC method development and its validation. International Journal of Pharmacy and Pharmaceutical Sciences. 2011;3(1):179-87.
  2. Jain S. Quality by design (QBD): A comprehensive understanding of implementation and challenges in pharmaceuticals development. Int. J. Pharm. Pharm. Sci. 2014;6:29-35.
  3. Bhutani H, Kurmi M, Singh S, Beg S, Singh B. Quality by design (QbD) in analytical sciences: an overview. Quality Assurance. 2004 Sep;3:39-45.
  4. Patil AS, Pethe AM. Quality by Design (QbD): A new concept for development of quality pharmaceuticals. International journal of pharmaceutical quality assurance. 2013 Apr;4(2):13-9.
  5. Pramod K, Tahir MA, Charoo NA, Ansari SH, Ali J. Pharmaceutical product development: A quality by design approach. International journal of pharmaceutical investigation. 2016 Jul;6(3):129.
  6. Finkler C, Krummen L. Introduction to the application of QbD principles for the development of monoclonal antibodies. Biologicals. 2016 Sep 1;44(5):282-90.
  7. Zhang L, Mao S. Application of quality by design in the current drug development. Asian journal of pharmaceutical sciences. 2017 Jan 1;12(1):1-8.
  8. Jayagopal B, Shivashankar M. Analytical quality by design–a legitimate paradigm for pharmaceutical analytical method development and validation. Mechanics, Materials Science & Engineering Journal. 2017 Apr 10;9.
  9. Raman NV, Mallu UR, Bapatu HR. Analytical quality by design approach to test method development and validation in drug substance manufacturing. Journal of chemistry. 2015 Jan 1;2015.
  10. Mohurle MS, MDA JA, DD RC, Kurian MJ, Bais G. Quality by Design (QbD): An Emerging Trend in Improving Quality and Development of Pharmaceuticals. Saudi J Med Pharm Sci. 2019 Dec;5(12):1132-8

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Nirwan Harshada
Corresponding author

SND College Of Pharmacy Babhulgaon Yeola

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Udawant Pratiksha
Co-author

SND College Of Pharmacy Babhulgaon Yeola

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Darade Ramdas
Co-author

SND College Of Pharmacy Babhulgaon Yeola

Nirwan Harshada , Udawant Pratiksha , Darade Ramdas, QbD Apporach Progress In Pharmacetical Method Development And Validation, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 6, 91-99. https://doi.org/10.5281/zenodo.11442589

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