Anwar Khan*, Sabir Alam, Rupa Gupta, Rizwanul Hasan, Mohini Chaurasia, Mohsin Ali Khan
Department of Medicine, ERA Medical University and Hospital, Sarfarazganj, Lucknow
Received: 03-Oct-2022, Manuscript No. DD-22-76418; Editor assigned: 05-Oct-2022, PreQC No. DD-22-76418 (PQ); Reviewed: 19-Oct-2022, QC No. DD-22-76418; Revised: 16-Jan-2023, Manuscript No. DD-22-76418 (R); Published: 25-Jan-2023, DOI: 10.4172/DD.07.1.001
Citation: Khan A, et al. Quality by Design-A Trending Aspect for Pharmaceutical Product Development. RRJ Drug Deliv.2023;7:001.
Copyright: © 2023 Khan A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Regulatory bodies are now a days concerned with the safety, efficacy and quality of the pharmaceutical drug products. Quality is first priority of all regulatory bodies, it is at high priority for triple P factor (patient, pharmacist and physician). It serves as a linkage between pharmaceutical ind ustries and regulatory authorities for designing, manufacturing and consistently delivering safe and efficient product.
It mainly focuses on fabricating and designing formulations and manufacturing processes to ensure predefined product quality. It is base d on the ICH guidelines Q8 for pharmaceutical development, Q9 for quality risk management, Q10 for pharmaceutical quality systems. Some of the important effective elements of QbD are to define the target profile that what is the requirement of pharmacist, physician and patient (TPP -QTPP) and then measuring the criticality for achieving that target (CQA), and analyzing the risk assessment of variables associated with materials and cont rolling processes to produce consistent quality over time. The objective of this review is to discuss the concept of quality by design and describe its application in pharmaceutical product development.
Quality by Design (QbD); Quality Target Product Profile (QTPP); Critical Quality Attribute (CQA); Design of Experiment (DOE); Process Analytical Technique (PAT); Design space; Control space
Regulatory bodies and pharmaceutical industries are constantly working to enhance the quality, safety and efficacy of the products that are directl y linked to patients’ health. But due to manufacturing failure, cost effectiveness, finished product quality control failure, scale up issues and regulatory demand has become a major challenge for the researcher and the industries, because of these kind of failure regulatory bodies have started focusing and demand pharmaceutical product development in QbD manner so that the products will be stage wise evaluated and all the high risk materials and processes will be assessed and mitigated for successful development it has therefore reduces the chances of failure [1].
Though depending blindly on finished product quality control test as if in traditional method QbD checks product at each and every level so that the root cause analysis is easy and the success rate would be high. The concept of QbD was first advocated by USFDA and in the ICH Q8 guidance, which states that “quality cannot be tested into products, i.e., quality should be built in by design”.
QbD is a systematic approach for robust product development, it is the quality system for managing a product’s lifecycle and regulatory expectation intended to increase process and product understanding an d thereby decrease patient risk. It begins with predefined objective and emphasizes product and process understanding using design of experiment, design space and managing its outcome to the safer range [ 2 ] .
The initiation of quality has been started in 1979-P. Crosby’s who believe that quality is free in 1986 Motorola develops six sigma for reducing defects and improving quality and therefore customer compliance, in 1987 -FDA’s first guideline on process validation has been implemented, in 1988-US DoD implements total quality management, in 1991-J. Juran has given Quality by Design: The new steps for planning quality into goods and services, finally in 2005 ICH guideline QbD related drafts appear ICH Q8-11 and at last in 2008-FDA’s guidance for industry process validation a general principles and practices was given (Figure 1) [3 - 6] .
Principles of quality by design:
•Risk and knowledge based decisions.
•Systematic approach for process development.
•Continuous improvement leads to “capable” processes.
ICH role in quality by design ICH implemented 4 guidelines for maintain quality of pharmaceutical product development.
•Q8: Pharmaceutical development (Nov 2005).
•Q9: Quality risk management (Nov 2005).
•Q10: Pharmaceutical quality system (June 2008).
•Q11: Development and manufacture of drug substances (May 2012).
Figure 1: Voice of consumers.
Objective of QbD
•To increase process capability and reduce product variability and defects, by enhansing product and processdesign, understanding, and control.
•To achieve meaningful product quality specifications based on clinical performance.
•To increase product development and manufacturing efficiencies.
•To enhance root cause analysis and post approval change management [7].
•It is applicable in both drug product and drug substances.
•To reduce the failure and improve the outcome of the product.
•Working range can be obtaining working within that would leads to no change in quality of product.
•To increase manufacturing efficiency, reduce costs and project rejections and waste.
Advantages of QbD
•QbD helps in providing safer, quality, and efficient drug product.
•QbD help in safer and faster drug development.
•The QbD approach sets production team up for success by providing a clear and comprehensiveunderstanding of the parameters involved in the development process and how they work together. This deepunderstanding helps teams assess risk and act accordingly significantly reducing the likelihood of failure [8].
•It provides proper understanding of critical process parameter and critical material attributes and their effecton final quality of drug product.
•Using QbD helps companies achieve greater batch to batch consistency and reduces batch to batch variation.
•The QbD approach builds quality into the manufacturing process by designing, and controlling the critical parameters.
•It provides in between checkpoints for in process evaluation of the product so that the root cause analysis iseasy.
Key elements of QbD9: Quality by Design is a scientific risk based holistic and proactive approach to pharmaceutical product development by improving its quality. It involves the designing and planning of a drug product and process before actual experiment (Table 1 and Figure 2) [9].
| Phase 1 | Define phase | Defining the targets or the objective of drug product development, these targets or objective should be achieved to ensure desired quality of the drug product required for safety and efficacy. |
| Phase 2 | Measure phase | Measuring the critical quality attributes out of Quality Attributes (QA’s) because deviation or out of specification of CQA’s will have definite impact on safety and efficacy of customer or patient. |
| Phase 3 | Analyse phase | Identifying Critical Process Parameter (CPP’s)and Critical Material Attributes (CMA’s) and further analyzing risk factors through SIPOC, RRMA, FMEA, ANOVA |
| Phase 4 | Improve phase | Designing design of experiment and developing and verifying design space. It can be done by first screening of experiments and then optimization of experiments. |
| Phase 5 | Control phase | Implementation of control strategy and control critical factors with control space and continue improvement. From DoE and design space, control space for each and every CMA’s and CPP’s are proposed for future commercial manufacturing batches so that no out of specification or batch failure is possible. |
Table 1. Steps involved in QbD based product development.
Figure 2: Chronological order of QbD based product development.
Identifying a Quality Target Product Profile (QTPP): Defining the Quality Target Product Profile (QTPP) as it relates to quality, safety and efficacy, considering e.g., the route of administration, dosage strength, container closure system, Therapeutic moiety release, strength, and stability. It is a prospective summary of the ideal quality characteristics of the drug product taking into account of safety and efficacy) will be defined based upon voice of patient (Table 2).
Basically, it is an element for setting the target for drug product development. QTTP is worldwide used in development planning, setting up of target. Clinical strategies and commercial outcome, regulatory requirement, and risk management [10-16].
| QTPP elements | Target | ||
|---|---|---|---|
| Solid | Liquid | Parenteral | |
| Dosage form | Uncoated, coated, scored | Solution, suspension, emulsion | Injection |
| Dosage design | Immediate release, modified release etc. | Immediate release formula | Immediate release formula |
| Route of administration | Oral | Oral, topical | Parenteral |
| Dosage strength | X mg | X mg/ml | X mg/ml |
| Drug product quality attribute | Must meet the same compendia or other applicable reference standard (identity, assay, purity, quality) | ||
| Packaging | HDPE, blister, strip to protect from heat moisture, light and microbial attack to achieve target shelf life. | HDPE plastic container Al closure to protect from heat moisture, light and microbial attack. | USP type I glass vial with neoprene rubber closure and Al seal to protect product from heat, moisture, oxygen, light and microbial attack |
| Pharmaco-kinetics | Should meet fasting and fed bioequivalence limit (80-125) when compared to reference product. | Solution bioequivalence study can be waived of in case of solution, suspension should follow bioequivalence limit (80-125) with reference product, emulsion rate of penetration, rate of drug release and extent of absorption should be comparable with reference product. | Bioequivalence study can be waived as it is directly administered into systemic circulation and release of the drug substance from product solution is self-evident. |
| Stability and shelf life | At least 24 moth of shelf life is required equivalent or better than reference product. | At least 12 month of shelf life is required at room temperature or better than reference and 28 days of in-use shelf life at room temperature in case of emulsion | At least 6 months of long term shelf life is required at proposed condition and 28 days of in use shelf life is required for multidose |
| Patient acceptance and patient compliance | Should have suitable colour, flavour, and can be easily administered or applied. | Should have suitable colour, flavour, and can be easily administered or applied. | Can be easily administered similar with reference product to achieve desired patient compliance. |
Table 2. These are examples of final quality targets that the product should always have in order to satisfy customer compliance. Some of the elements of QTPP.
The main thing to acknowledge is that QTPP should only include target or target reflecting quality, not the critical parameter for determination of specification [ 1 7] .
Critical Quality Attribute (CQA’s): “A property or characteristic that when controlled within a defined limit, range, or distribution ensures the desired product quality" (Figure 3).
Figure 3: Steps involve in product development.
CQA’s are the physical, chemical, biological or microbiological property that should be within an appropriate limit, range or specification in order to ensure the desired product quality [18].
It is important to identify the quality attributes that are critical, i.e., those defining purity, potency and surrogate for efficacy (Figure 4 and Table 3). It is based on the impact of quality attribute on the safety, efficacy and quality of the product. If the drug product contains a polymorphism that is having direct impact on dissolution and bioavailability then it should be specified so as to provide proper bioavailability and efficacy [19].
•Potential CQAs are derived from the QTPP and guide product and process development.
•CQAs are identified by quality risk management and experimentation to determine the effect of variation onproduct quality.
Figure 4: Impact of CQAs.
| Substance quality attributes | Product quality attributes | Is this a CQA’s? |
|---|---|---|
| Particle size | Identification | Yes |
| Solid state | Assay | |
| Organic impurity | Impurity | |
| Inorganic impurity | Uniformity of Dosage (UOD) | |
| Residual solvent class | Disintegration/Dissolution | |
| Water content | Water content | |
| Assay | Residual solvent | |
| Hygroscopicity | Microbial limit |
Table 3. Determination of critical quality attributes.
Risk assessment: Identification of critical material attributes and critical process parameters. Risk assessment is an important element used in quality risk management that can aid in identifying which critical material attributes and critical process parameters potentially have a significant impact on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained [20].
The evaluation of the quality risk should be based on the both scientific knowledge as well as therapeutic benefit to the patient. Independent formulation variable and independent process variable likely to have impact on in process or finished product CQA’s can be analyzed based upon preliminary experiments or prototype fabrication.
It can be further divided into 3 phases (Figure 5).
Figure 5: Phases of risk assessment.
Identification of critical process parameter: Process parameter which have a significant impact on critical quality attribute, whose variation will directly impact the quality of the finished product. CPPs are responsible for ensuring the CQAs and it is identified from a list of potent ial CPPs using risk assessment.
It is a measurable input material attribute or output material attribute of a process step that should be controlled to achieve the desired product quality as well as process uniformity.
Further CPP’s can be classified into 2 types:
•Critical parameter: A realistic variation in parameter can cause the product to fail to achieve CQA’s and QTPP.
•Non-critical parameter: No failure in QTPP determined the within the potential operating space and nointeractions with other parameters in the established suitable range (Table 4).
| S. No | Manufacturing process step | Input processing parameter | Output quality attributes |
|---|---|---|---|
| 1 | Co-sifting | Screen size mill type sifting speed | Particle size distribution flow ability powder bulk density |
| 2 | Wet granulation | Impeller speed chopper speed dry mixing time kneading time binder addition/spraying time amperage reading | Granule PSD flow ability |
| 3 | Drying | Inlet air volume inlet air temperature fill volume filter type/shaking time | Granule PSD loss on drying |
| 4 | Sizing | Mill type clade orientation oscillation speed screen size | Granule PSD flow ability granule assay granule uniformity |
| 5 | Blending | Blender type Fill volume order of addition rotation speed and time | Blend assay blend uniformity BD/TD flow ability compressibility index |
| 6 | Compression | Turret speed feed frame paddle speed feeder fill depth precompression force main compression force ejection force hopper design | Appearance, dimension, weight variation hardness, assay, related substance related solvent disintegration dissolution |
| 7 | Coating | Inlet air volume inlet temperature exhaust air volume exhaust temperature time spray pattern spray rate atomization air pressure |
Table 4. Some of the critical process parameter during tablet formulation.
Qualitative risk base matrix analysis: Can be further divide into 3 categories (Tables 5 and 6).
| Low risk | Broadly acceptable risk |
| Medium risk | Risk may be acceptable, may or may not impact product quality. |
| High risk | Risk is unacceptable, will have significant impact on quality |
Table 5. Qualitative risk base matrix analysis.
| Probability | Severity | Detectability | Score |
|---|---|---|---|
| Very unlikely | Minor | Always detected | 1 |
| Relatively less | Low | Regularly detected | 2 |
| Occasional | Moderate | Likely not detected | 3 |
| Repeatedly high | High | Normally not detected | 4 |
| Almost inevitable | Hazardous | Absolute uncertainty | 5 |
| Risk priority number more than 25 seeks critical attention prevent from further product failure. | |||
Table 6. Quantitative risk Failure Mode Effect Analysis (FMEA).
Process parameters based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained.
Design space: Multidimensional combination of and interaction of input variables (material attributes) and process parameters that have been demonstrated to provide quality assurance. (Multidimensional combination of factors) is developed, where all the desired responses simultaneously met.
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. It provides assurance of quality of the product.
Design space can be established by the implementation of design of experiment. It is the systematic series of experiments in which purposeful changes are made to input factors for screening and optimization of CMA’s and CPPs with respect to CQA’s (Figures 6 and 7). Methods for presenting design space included graphs (surface response curves and contour plots), linear combination of parameter ranges, equations, and models.
Figure 6: Steps for design of experiment.
Figure 7: Design space for fluidized bed granulator.
Development of process analytical technique: Process Analytical Technology (PAT) has been defined by the Food and Drug Administration (FDA) “as a method to design, analyses, and control pharmaceutical manufacturing processes through the measurement of Critical Process Parameters (CPP) which affect Critical Quality Attributes (CQA). The framework has two components: (a) A set of scientific principles and tools supporting innovation. (b) A strategy for regulatory implementation that will accommodate innovation.
PAT is the system for designing, analyzing, and controlling manufacturing through timely measurements of CQAs and CMAs with the goal of ensuring finished product quality through 3 phases (Table 7 and Figure 8).
| Design | CMAs and CPPs are optimised with respect to CQAs at lab scale developmental level with at line/off line analyzer. |
| Analysis | Exhibit scale data are analyzed by inline/online analyzers and compared with at line/offline data. |
| Control | According to the ranges specified in control strategy, controller are used at manufacturing scale for continuously attaining acceptable ranges of CMAs / CPPs to achieve desired in process/finished process CQAs. |
Table 7. Phases of process analytical technique.
Figure 8: Working of process analytical technique.
Implementation of control strategy
As per ICH guideline Q10 control strategy can be defined as planned set of controls, derived from current product material and process understanding, that assures process performance and product quality. For finalizing of control strategy (planned set of controls), each and individual CMA’s and CPPs are reviewed with respect to their past, present and future prospective.
The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in process controls, finished product specifications, and the associated methods and frequency of monitoring and control (Tables 8 and 9 and Figure 9).
| Past | Present | Future |
|---|---|---|
| Ranges studied at lab scale or R&D scale | Range studied at pilot scale/exhibit scale | Ranges proposed for commercial scale. |
Table 8. Levels of control strategy.
In order to ensure batch to batch uniformity in evaluation parameter and quality and performance of the finished drug product during commercialization process.
| Control strategy for critical material attributes | |||||
|---|---|---|---|---|---|
| Factor | CMAs | Range at lab scale | Range at pilot or exhibit | Proposal for commercial batches | Control strategy |
| Active pharmaceutical ingredient | |||||
| Particle size distribution | D10 D50 D90 |
NMT 5 µm NMT 10 µm NMT 15 µm | NMT 5 µm NMT 10 µm NMT 15 µm | NMT 5 µm NMT 10 µm NMT 15 µm | To ensure batch to batch uniformity in BU, CU, dissolution, bioavailability |
| Inactive ingredient critical material attribute | |||||
| Magnesium stearate | Level specific surface areal | 0.5-1.5 w/w 10-15 m2/g |
0.75-1.25 w/w 10-15 m2/g |
0.80-1.20 w/w 10-15 m2/g |
To ensure proper lubrication and smooth compression and ejection force. |
| Critical process parameter for fluidized bed granulator | |||||
| Fluidized Bed Granulator (FBG) | Spray rate | 4.0-8.0 g/min | 3.5–6.0 g/min | 4.0-5.0 g/min | To ensure batch to batch uniformity in, PSD, BD to provide better flow ability, disintegration as well as moisture content of granules. |
| Atomisation air pressure | 1-3 bar | 1.5-3.5 bar | 2-4 bar | ||
| Critical process parameter for tablet compression machine | |||||
| Compression machine | Compression force | 2.0-6.0 kN | 3.0-5.0 kN | 3.5-4.5 kN | Uniformity hardness, weight and disintegration to ensure friability, cu, dissolution |
| Turret speed | 10-40 rpm | 10-30 rpm | 15-25 rpm | ||
Table 9. Some of examples explaining control strategies.
Figure 9: Quality by design for product development.
QbD is emerging to an important element providing significance for quality improvement. The objective of quality by design method in pharmaceutical product development is to formulate a reliable method that gives assurance of the ultimate quality and efficacy of the product and minimizes batch to batch variation or inconsistency and to reduce errors.
Implementation of quality by design at materials and processing method will provide a quality based effective and robust product. Production improvements to Manufacturers with significantly reduced batch failures and regulatory bodies will have greater confidence in the robust quality of products.
QbD is emerging into a promising scientific tool in quality affirmation in pharmaceutical industry. Which provides a safe operating range that assures or provide confidence for batch to batch consistency, quality, safety and efficacy and mitigate the lengthy step of scale up post approval changes? QbD successfully provide a layout or the path from initial defining objective and finally successfully commercializing the product.
The authors have no conflicts of interest regarding this review article.
Mr. Anwar khan, Mr Rizwanul hasan, Mrs Rupa Gupta was involved in the collecting, organizing of the data, reviewing, and editing of the manuscript. Dr. Sabir alam and Dr Mohini chaurasia was involved in the study analysis, drafting, reviewing article, and Mr Mohsin ali khan was involve in editing the manuscript.
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