Bridging Science and Regulation : The Evolution of QbD in Drug Development

Quality is the principle that necessity has to be realized as long as the product has not been distributed and only then should the funding of the project be allowed.¹ It is an interesting phenomenon indeed, to me, that business people will first simply declare what type of quality they want to produce and then only develop those features in their items which will help them produce the carefully chosen product lines and which production lines will always produce the similar products, i.e., in other words, only through the use of supplier warranties.² The present situation is such that the QbD concept, the invincible mode of quality by design (QbD) and the one that will replace it, the "Quality by Design (QbD)," designs [no-combinator hypo]Quality by Design is the scientific, proactive, statistical, risk-based approach that keeps pace with new technologies or capability improvement and allows the development of inventions and introduction of them to market, which is called QbD (fig. 1), and it refers to the use of a particular method and process control in the one that is mentioned, and the goods and/or services are the only ones that are of good quality] ³. The QbD methods are displayed in Figure 1. "In line with the FDA's current drug quality system ideology 'quality cannot be tested into products; it should be built-in or should be by design,' the ICH Q8 guideline describes Quality by Design as a scientific method that is a system-driven development that allowing predetermined goals and process understanding and process control not only based on sound science but also quality risk management'.⁴ How formulation and process characteristics affect product quality and maintain it in the desired state for the entire shelf life will be discussed, quality-by-design (QbD). The initial procession is to figure out the approved requirements for both matrices since QbD commences with the definition of the necessary product attributes. The quality attributes, which ensure product labelling that matches TPP on the technology side, are the centre of QTPP.⁵ After the QTTP has been defined, the next step is to find the factors that influence the QTPP and to discover those that make the QTPP possible. These are the product's critical quality attributes or CQAs.

1.1 Advantages of QbD

• It provides an increased level of trust about the genuineness of medicine production that helps    thus the quality of pharmaceutical products.
• Through This, the pharma industry gets end-to-end optimization of costs and benefits.
• The use of the strategy by the sponsors is the one that assures the approval of the drug product to be commercialized and by submitting on the market.⁶
• This is by explaining that the sponsor knows and is confident in the control strategy for the product to be approved and marketed later.
• A better understanding of the subject matter and the process itself.
• Experiments that make use of the different variables.
• It assists the validation, commercialization, and scale of processing to be transparent, rational, and predictable.
• Feeding innovation with new drugs for non-communicable conditions.
• The design flexibility in the process.⁷

2. STEPS IN QUALITY BY DESIGN ^8,12

• Quality target product profile (QTPP)
• Target product profile
• Critical quality attributes (CQA)
• Risk assessment
• Development of experimental design
• Design Space (DS)
• control Strategy

2.1 Quality target product profile (QTPP)

To get top-notch products, the patients' good health and safety of drugs should be specified by following the production requirements. Quality of a target product profile (QTPP) is a possible representation of a drug product's attributes and also is its key determinant of drug product quality.¹³ A decision has previously been established for the practical application of the methodology QbD. It is the QBD mechanism's central point of IT. The efficacy, impurities, stability, methods, and other parameters are regulated.¹⁴ A QTPP, a producer, can design a dosage form with the therapeutic action of the drug, drug release time, and reliability being the most important purposes. For example, the drug product's QTPP is made of a semi-solid dosage form.¹⁵

• Stability
• Solubility
• Consistency
• Emulsifying and suspending properties
• Assay
• Solvent properties
• Dose strength
• Administration route

The process of patient report submission is for QTPP purposes exclusively. E.g.: 1) Quality Target Product Profile (QTPP) includes tablet hardness and friability validations.¹⁶ However, these are not "QTPP" operations. Although the particle size of a resulting suspension is mostly dependent on these [the solid/liquid volume ratio and the syntax of operation], the QTPP here includes particle size as these properties.¹⁷

2.2 Target product profile

The target quality is communicated through the desired "profile" of the drug that is to be used in treating a specific ailment or disease in a target product profile (TPP). TPPs are areas that include information such as the target populations, the medicine's intended use, trademarks, and other qualities like safety and efficacy.¹⁸ The development of new products is supported by profiles. TTP (or the Target Product Profile), a vital document, is the one that the F and D administration receives to get more details on the drug development process. A TPP is designed to make sure that the manufacturer's development of the drug is efficient and that all the necessary data is available for evaluating the medicine's economic potential.¹⁹ Explaining the general purpose of the drug along with the current stage of progress at the time is the purpose of this paragraph The TPP for communication between the FDA and the manufacturer. The TPP in previous years had been a vehicle for interaction between the FDA and the drug maker. The TPP is communication between the FDA and the manufacturer.²⁰ The TPP consists of drug labels' portions that form connections between particular concepts and drug development activities. A TPP should continuously be up to date with the latest facts and developments concerning the phase of the drug's clinical development as it is a dynamic document. The document must also be updated frequently.²¹

2.3 Critical Quality Attributes [CQA]

A Critical Quality Attribute is a set of quality criteria that need to be fulfilled so that the product would have good quality. They also include some of the QTPP characteristics. Chemical, Physical, Microbiological, Biological properties can be assessed as being CQA.²² The three validation procedures are the processing design, the process validation, and the ongoing process validation. The CQA is identified in the process design stage are discussed here. The associated topics listed above are not sufficient in assuming the importance of CQAs.²³

The following elements are essential to identifying CQAs.

1) Depends on the attributes of the final product.

2) Pharmacopeia and regulatory quality standards.

3) Criticality degree of each of the identified quality attributes.

But some can be less critical (or not critical at all), and some can be more critical.²⁴ That is why it is required to determine the Critical Quality Attributes and then the Quality Risk Management process will be used to evaluate them. Employees with experience in such a field as well as previous knowledge are required for the risk grading evaluation.

                                          Fig1. ICH guideline and QbD

2.4 Risk assessment

Risk assessment is the activity of recognizing dangers and evaluating of risks associated with these dangers. To help officials arrive at the best solution during the risk management process, its risk will sort data. The basic pillar of the risk management concept is the analysis of risks: others are the control and review.²⁵ Risk control is both the use of control and the making of the best decisions. It can be used to reduce the threat to a level that is possible to control. Risk management is thus the best strategy for redeeming risks in the future.²⁶ Risk communication is an activity that is conducted between concerned parties like the industry, the patient, the company, the supporting regulatory body, etc. to use it as an important component of risk management. Risk communication at any stage of risk management is important to maintain. Its termination might be buried in complexities.²⁷ The content, among other quality criteria, incorporates the nature of risk, i.e., what has been, what is the risk, if any, and what is the situation now, the treatment, and control. Risk identification, risk analysis, and risk evaluation are the three components of risk management.²⁸ Hedging facts with historical data, theoretical analysis, overall performance, etc. are among the methodologies used to identify risk.

The ICH Q9 however, suggests the risk assessment tools: ²⁹

• Risk ranking and filtering Initial hazard analysis [IHA]
• Critical control point and hazard analysis.
• Failure mode effect analysis [FMEA]
• Hazard probability analysis.
• Failure mode, effects, and criticality analysis [FMECA]

2.5 Design of experiment (DoE)

Risk assessment should be performed before the design of the experiment is committed. In the context of "design of experiments," or DoE, we are talking about the use of a step-by-step structured methodology to figure out where each element affecting a procedure stands in the scheme of things.³⁰ Pharmaceutical scientists can also systematically manipulate the system inputs that DoE software offers using DoE which is a great procedure. The basic ingredients to a perfect design are an elaborate plan and the production process in an efficient way. Mechanistic-based research and DoE studies are working together to advance our knowledge of products and how they are produced.³¹ Performing DoE is an effective way of visualizing how the inputs and outputs of processes are related. It can also help define the Design Space, CMAs, CPPs, and the best possible conditions. It is logical to utilize DoE to develop a Design Space for multivariate studies. The term Design Space as used here by ICH Q8 Quality System Development refers to the whole combination of inputs (e.g. material quality) and process parameters (pp). These were the factors that we used in our study that indicated that the final product was of good quality as per what ICH Q8 has characterized the Design of Space   Reports indicates that confirming changes are within acceptable Design Space will not require companies to file supplements with the FDA to expand (e.g. increase) the acceptance criteria. Since the QbD project was made public, many studies have been carried out on drug delivery systems as presented in Table 1. The near future broader use of DoE will result in highly efficient research accompanied by improved quality of the products. DoE is effective even in the research and development of other dosage formulations and unit operations, besides injectables. ^32-37

2.6 Design Space (DS)

Under ICH Q8(R2), the term design space is defined as "the multidimensional amalgamation and interrelation of input variables and process parameters that have been substantiated to guarantee quality assurance. One time the CQAs, CMAs, and CPPs are all arranged, a design space can be occupied. The design space is a collection of CQA, CMA, and CPP variables that the product can be among to meet the QTPP's prescribed requirements.³⁸ In some cases, several criteria or many different parameters of one can be run to find the design space. The design space is a part of the repertoire or the described space that the output cancels the requirements or the acceptance criteria. Therefore, making a design space means assuring quality which proves that the product is all safety, identity, purity, and strength requirements compliant. The CMAs and CPPs cannot be treated as changes if they generate CQAs, which are within the limits of the design space. ³⁹ The generation of the design space would make it possible for the engineers to specify the range of experimental input variations to be used in the development of a process that is dependable and robust. The design space may encompass the operational area or control space so that the output will remain within the internal target range. The need for PCC that is assumed for the post-approval change process results in the situation when one has to work outside the design space.⁴⁰ However, the aftermath clarity enhancement is not perceived as a change, if the work happens within the design space after the FDA clearance.

2.7 Control Strategy

A control strategy is the fundamental concept of the control strategy which is laid out by the different parameters that were reviewed in the design development process. It has three levels:

? Level 1: The automatic engineering control monitors the CQAs. This high-compliant level is labour saving, and the automatic adjustment of the product quality standards is guaranteed. Class III prioritizes real-time release testing over end-product testing as it enhances the quality assurance of the goods. For real-time release testing, a process analytical approach is used.⁴¹

? Level 2: This activity will not only reduce the number of tests done on the final product but also allow an understanding of how variation affects the products. This minimizes product testing. It comprises significant process parameters and quality qualities.⁴²

? Level 3: The usual level of control is the medicine development area, which is typical in pharmaceutical sectors. This stage is mainly about performing the test on the result. Even a minor alteration is disclosed under the regulatory process because of the restricted categorization of variables, lack of information, stringent CMAs and CPPs, and incomprehensive understanding of their relationships with CQAs. A composite of level 1 and level 2 is the current practice being followed at this moment. For example, a plan for a microbiologically, manufacturing, quality, and contamination control strategy must be implemented to produce a sterility product.

 The control plan includes the following points:

• The required process parameters and the material properties are regulated.
• Real-time release testing and end-product testing.
• The main focus for utilizing this software is tracking alternations in the code throughout the project.                      
• The management of vital unit functions is done according to risk (evaluation level).⁴³

 3. Application of QBD ⁴⁴

? To check whether the final product meets the expected standards.

? To give space for creative ideas.

? To support ongoing development.

3.1 Benefits of implementing QBD for FDA ^45-47

Enriches information in regulatory submissions -

? Supports greater consistency.

? More coherent.

? Enriches the quality of the review (applying a QMS for CMC)

? Enhances the aspect of making decisions beyond the norm.

? Affirms that decisions are rooted in research rather than in your common knowledge.

? Combines various specializations in making a decision.

3.2 Benefits to industry

• Guarantees perfect product design with fewer contingent problems during manufacturing.⁴⁸
• Enables the use of new technologies to increase manufacturing without the need for regulatory actors; it is dependent on process and risk understanding and risk mitigation to shorten the number of manufacturing supplements that are required for post-market adjustments to be made.⁴⁹
• Means less hassle during the review - less flaws - quicker turnaround - also enables potential cost savings in production - less wastage.⁵⁰

4. Conclusion

Quality by design (QbD) is a key instrument of the pharmaceutical field which has a long-standing broad usage in the business environment of today. Due to this fact, ICH has invented rules for how QbD has to be applied to the everyday practice of the business. Not enough papers have been produced to deal with the pros and cons of applying QbD to each use case. So here, an attempt is made to join QBD models down with clear and specific experimental methods of the topic. The principal objective of a well-defined method, development is to be able to establish a reliable technique that is capable of consistently producing data that meets the set of demanded criteria and runs within the set of clients with a high degree of confidence. It is not only employed to develop the method but also to assess the capability of the analytical process. If we are trying to recognize the dependencies, we need to look at the potential components (inputs) and main analytical reactions investigated throughout the method development process. A method akin to the one in ICH Q8 and Q9 for process development, which is also focused on finding critical analytical variables, is employed. A corporate knowledge repository should be set up to support the collection, review, and addition of the most important information in the future so that the process can be improved by using the learned lessons. (Here, reference to) a particular technology being considered as well as other similar techniques being applied to different products are needed. The repository, which is based on the principles laid down in the ICH Q10 draft, will satisfy the need for method change control as well as its improvement during its lifecycle. A QbD approach supported by a risk-assessed change control system took over so that instead of just applying ICH validation and analytical technology transfer, one could check if a proposed technology could perform well via risk assessment hence the need for continuous improvement. An in-depth risk assessment is needed each time the technique is switched. In the event of change discovery, a method assessment is performed. Such as by making it have the ability to drive the method's identified design space expansion.

Compliance with ethical standards

Acknowledgments

A special thanks to Dr. Velenti Chauhan for her endless support and guidance provided during the completion of this review article.

Funding

This research did not receive any grants from funding agencies in the public or private sectors. Disclosure of Conflict of Interest

No conflict of interest to be declared.

5. Reference:

1. 1. Mishra SM, Rohera BD. “An integrated, quality by design (QbD) approach for design, development and optimization of orally disintegrating tablet formulation of carbamazepine”. Pharmaceutical development and technology. 2017 Oct 3;22(7):889-903.
   2. Syed SM, More RI. Quality by design: An approach for formulation development. Inventi Rapid: Pharm Analysis & Quality Assurance. 2020; 1:1-6.
   3. Soni S, Sahu P, Dikkatwar MS. Quality by Design: Modern Approach In Pharmaceutics for Quality Pharmaceuticals. Journal of Pharmaceutical Negative Results. 2023 Jul 1;14(3).
   4. Grangeia HB, Silva C, Simões SP, Reis MS. “Quality by design in pharmaceutical manufacturing: A systematic review of current status, challenges and future perspectives”. European journal of pharmaceutics and Biopharmaceutics. 2020 Feb 1; 147:19-37.
   5. Rawal M, Singh A, Amiji MM. “Quality-by-design concepts to improve nanotechnology-based drug development”. Pharmaceutical research. 2019 Nov;36(11):153.
   6. Simoes A, Veiga F, Vitorino C, Figueiras A.” A tutorial for developing a topical cream formulation based on the quality by design approach”. Journal of pharmaceutical sciences. 2018 Oct 1;107(10):2653-62.
   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. Waghule T, Dabholkar N, Gorantla S, Rapalli VK, Saha RN, Singhvi G. “Quality by design (QbD) in the formulation and optimization of liquid crystalline nanoparticles (LCNPs): A risk based industrial approach”. Biomedicine & Pharmacotherapy. 2021 Sep 1; 141:111940.
   9. Sangshetti JN, Zaheer Z, Mahaparale PR, Chitlange SS. “Quality by design (QbD) in pharmaceuticals”. Unique Publication, Aurangabad. 2015;20.
   10. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, Woodcock J. “Understanding pharmaceutical quality by design”. The AAPS journal. 2014 Jul; 16:771-83.
   11. Soni S, Sahu P, Dikkatwar MS. “Quality by Design: Modern Approach in Pharmaceutics for Quality Pharmaceuticals”. Journal of Pharmaceutical Negative Results. 2023 Jul 1;14(3).
   12. Gandhi A, Roy C. “Quality by design (QbD) in pharmaceutical industry: Tools, perspectives and challenges”. Pharma Tutor. 2016 Nov 1;4(11):12-20.
   13. Ganesh S. Continuous Pharmaceutical Manufacturing: Systems Integration for Process Operations Management (Doctoral dissertation, Purdue University).
   14. Nadpara NP, Thumar RV, Kalola VN, Patel PB. “Quality by design (QBD): A complete review”. Int J Pharm Sci Rev Res. 2012 Oct;17(2):20-8.
   15. Rathore AS, Winkle H. “Quality by design for biopharmaceuticals”. Nature biotechnology. 2009 Jan;27(1):26-34.
   16. Lionberger RA, Lee SL, Lee L, Raw A, Yu LX. “Quality by design: concepts for ANDAs”. The AAPS journal. 2008 Jun; 10:268-76.
   17. Kamboj SU, Chopra SH. “Quality by design (QBD) in pharmaceutical industry”. Int J Curr Pharm Rev Res. 2015; 6:142-8.
   18. Stagner WC, Haware RV. “QbD innovation through advances in PAT, data analysis methodologies, and material characterization”. AAPS Pharm SciTech. 2019 Oct; 20:1-2.
   19. Ferreira AP, Gamble JF, Leane MM, Park H, Olusanmi D, Tobyn M. Enhanced Understanding of pharmaceutical materials through advanced characterisation and analysis. Aaps Pharmscitech. 2018 Nov; 19:3462-80.
   20. Ibrahim A, Kothari BH, Fahmy R, Hoag SW. “Prediction of dissolution of sustained release coated ciprofloxacin beads using near-infrared spectroscopy and process parameters: a data fusion approach”. AAPS PharmSciTech. 2019 Aug; 20:1-9.
   21. Djuris J, Ibric S, ?uri? Z. “Quality by design in the pharmaceutical development”. In Computer-aided applications in pharmaceutical technology 2024 Jan 1 (pp. 1-21). Woodhead Publishing.
   22. Patil AS, Pethe AM. “Quality by design (QbD): A new concept for development of quality pharmaceuticals”. Int J Pharm Qual Assur. 2013 Apr;4(2):13-9.
   23. Guerra AC, Glassey J. “Machine learning in biopharmaceutical manufacturing”. European pharmaceutical review. 2018;23(4):62-5.
   24. Yu LX. “Pharmaceutical quality by design: product and process development, understanding, and control”. Pharmaceutical research. 2008 Apr; 25:781-91.
   25. Khan MM, Sangshetti J, Khan Z, Mumtaaz A. “Application of QbD in Method Development of Stavudine”. World Journal of Pharmaceutical Research. 2020 Jul 12;9(10):874-906.
   26. Kelley B, Cromwell M, Jerkins J. “Integration of QbD risk assessment tools and overall risk management”. Biologicals. 2016 Sep 1;44(5):341-51.
   27. 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.
   28. Soni S, Sahu P, Dikkatwar MS. “Quality by Design: Modern Approach in Pharmaceutics for Quality Pharmaceuticals”. Journal of Pharmaceutical Negative Results. 2023 Jul 1;14(3).
   29. Fukuda IM, Pinto CF, Moreira CD, Saviano AM, Lourenço FR. “Design of experiments (DoE) applied to pharmaceutical and analytical quality by design (QbD)”. Brazilian journal of pharmaceutical sciences. 2018 Nov 8;54: e01006.
   30. Schweitzer M, Pohl M, Hanna-Brown M, Nethercote P, Borman P, Hansen G, Smith K, Larew J. “Implications and opportunities of applying QbD principles to analytical measurements”. Pharmaceutical Technology. 2010 Feb 2;34(2):52-9.
   31. Patil AS, Pethe AM. “Quality by design (QbD): A new concept for development of quality pharmaceuticals”. Int J Pharm Quali Assur. 2013 Apr;4(2):13-9.
   32. Kepert JF, Cromwell M, Engler N, Finkler C, Gellermann G, Gennaro L, Harris R, Iverson R, Kelley B, Krummen L, McKnight N. “Establishing a control system using QbD principles”. Biologicals. 2016 Sep 1;44(5):319-31.
   33. Yu LX. “Pharmaceutical quality by design: product and process development, understanding, and control”. Pharmaceutical research. 2008 Apr;25 :781-91.
   34. Joshi AN, Rajput AI, Verma PR, Srivastava SP, Sharma UT, Mishra SU. “Quality by Design-A tool for pharmaceutical industry that has no near end”. Int. J. Pharm. Res. 2021 Jul 1;13(3):77-85.
   35. Rathore AS. “Roadmap for implementation of quality by design (QbD) for biotechnology products”. Trends in biotechnology. 2009 Sep 1;27(9):546-53.
   36. Tomba E, Foco P, Bezzo F, et al. “Latent variable modeling to assist the implementation of quality-by-design paradigms in pharmaceutical development and manufacturing: a review”. Int J Pharm 2013;457(1):283–297.
   37. International Conference on Harmonization (ICH). Guidance for industry: Q9 quality risk management, ICH harmonised tripartite guideline, step 4. 2005.
   38. Kumar S, Gokhale R, Burgess DJ. “Quality by design approach to spray drying processing of crystalline nanosuspensions”. Int J Pharm 2014;464(1–2):234–242.
   39. Patil H, Feng X, Ye X, Majumdar S, Repka MA. “Continuous production of fenofibrate solid lipid nanoparticles by hot-melt extrusion technology: a systematic study based on a quality by design approach”. The AAPS journal. 2015 Jan; 17:194-205.
   40. 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.
   41. Gawade A, Chemate S, Kuchekar A. “Research and Reviews”: Journal of Pharmacy and Pharmaceutical Sciences.
   42. Patil AS, Pethe AM. “Quality by design (QbD): A new concept for development of quality pharmaceuticals”. Int J Pharm Qual Assur. 2013 Apr;4(2):13-9.
   43. Nagar M, Panwar KS, Chopra VS, Bala I, Trivedi P. “Quality by design: A systematic approach to pharmaceutical development”. Der Pharmacia Lettre. 2010;2(2):111-30.
   44. Kumar VP, Gupta NV. “A review on quality by design approach (QBD) for pharmaceuticals”. Int. J. Drug Dev. Res. 2015;7(1):52-60.
   45. Wu H, White M, Khan MA. “Quality-by-Design (QbD): An integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and process design space development”. International journal of pharmaceutics. 2011 Feb 28;405(1-2):63-78.
   46. Pandey AP, Karande KP, Sonawane RO, Deshmukh PK. “Applying quality by design (QbD) concept for fabrication of chitosan coated nanoliposomes”. Journal of liposome research. 2014 Mar 1;24(1):37-52.
   47. Troiano G, Nolan J, Parsons D, Van Geen Hoven C, Zale S. “A quality by design approach to developing and manufacturing polymeric nanoparticle drug products”. The AAPS journal. 2016 Nov;18(6):1354-65.
   48. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, Woodcock J. “Understanding pharmaceutical quality by design”. The AAPS journal. 2014 Jul; 16:771-83.
   49. Ingvarsson PT, Yang M, Mulvad H, Nielsen HM, Rantanen J, Foged C. “Engineering of an inhalable DDA/TDB liposomal adjuvant: a quality-by-design approach towards optimization of the spray drying process”. Pharmaceutical research. 2013 Nov; 30:2772-84.
   50. Shah RB, Zidan AS, Funck T, Tawakkul MA, Nguenpho A, Khan MA. “Quality by design: characterization of self-nano-emulsified drug delivery systems (SNEDDs) using ultrasonic resonator technology”. International Journal of Pharmaceutics. 2007 Aug 16;341(1-2):189-94.