ABOUT AUTHORS:
Ghodke Deepa.V*, Dr.Bhusnure O.G1, Kulkarni Aditi. A2
*Department Of Quality Assurance in M .Pharmacy
1Department Of Medicinal chemistry
Maharashtra College of Pharmacy, Nilanga, Dist –Latur 413 512
*ghodke.deepa@gmail.com
ABSTRACT
Quality by design (QbD) encompasses designing and developing formulations and manufacturing processes which ensures predefined product specifications. ICH Q8 defines quality as “The suitability of a drug either substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity. “Quality by Design” 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. Quality by Design is a systematic scientific approach to development and design of products and processes illustrated and facilitated through the establishment of the Design Space. Quality means fitness for intended use. Pharmaceutical quality refers to product free of contamination and reproducibly delivers the therapeutic benefit promised in the label to the consumer.Many pharmaceutical implement the quality by design system to obtain the high level of assurance of the product, for increasing the efficiency of manufacturing product & to reduce manufacturing cost and product rejection, the main aim of this is to design robust process.
REFERENCE ID: PHARMATUTOR-ART-1868
INTRODUCTION[1-5]
The FDA publication defined Quality by Design as:
- Developing a product to meet predefined product quality, safety and efficacy
- Designing a manufacturing process to meet predefined product quality, safety and efficacy
The use of QbD principles during product development provides opportunities to facilitate innovation and continual improvement throughout the product lifecycle, compared to traditional approaches hence it is systematic way to product and process development. QbD principles increase process knowledge and product understanding, often through the application of new technologies such as PAT or modeling. The increased process knowledge and product understanding resulting from QbD can increase the efficiency of manufacturing processes; reduce product recalls and compliance actions, resulting in cost savings for pharmaceutical companies. By reducing uncertainty and risk, QbD can allow industry and regulators to focus their resources in the most critical areas. Because much more process understanding has been demonstrated and expressed in the dossier, QbD filings also can help facilitate CMC reviews and GMP inspections by the regulators and decrease the number of post-approval regulatory submissions required to make process changes. QbD can also facilitate the use of innovative technologies and promote the use of new approaches to perform process validation, such as continuous quality verification.
NEED OF QBD[6]
- Higher level of assurance of product quality
- Cost saving and efficiency for industry and regulators
- Facilitate innovation to address unmet medical needs
- Increase efficiency of manufacturing process and reduce manufacturing cost and product rejects
- Minimize/eliminate potential compliance actions, costly penalties and recalls
- Enhance opportunities for first cycle approval
- Streamline post approval manufacturing changes and regulatory processes
- More focused PAI and post approval cGMP inspections
- Opportunities for continual improvement
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The main objectives of Quality by Design
- To facilitate innovation and continuous improvement throughout the product lifecycle
- To provide regulatory flexibility for specification setting and post-approval changes
- To streamline the submission and review processes
ELEMENT OF THE QBD
1.Define Target Product Quality Profile
2.Identify Critical Quality Attributes, Process Parameters, and Sources of Variability
3.Design Product and Manufacturing Processes
4.Control Manufacturing Processes to Produce Consistent Quality over Time
5.Risk assessment & risk control
6.Process Design and Development
Define Target Product Quality Profile (TPQP)
The target product profile (TPP) has been defined as a “prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to ensure that the desired quality, and thus the safety and efficacy, of a drug product is realized”. This includes dosage form and route of administration, dosage form strength(s), therapeutic moiety release or delivery and pharmacokinetic characteristics (e.g., dissolution and Excipients meeting specification Unit operation with fixed process parameters In process specification Finished product aerodynamic performance) appropriate to the drug product dosage form being developed and drug product quality criteria (e.g., sterility and purity) appropriate for the intended marketed product .The Target Product Quality Profile (TPQP) is a term that is a natural extension of TPP for product quality. It is the quality characteristics that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised in the label. The TPQP guides formulation scientists to establish formulation strategies and keep formulation efforts focused and efficient.TPQP is related to identity, assay, dosage form, purity, stability in the label .
Identify Critical Quality Attributes, Process Parameters, And Sources Of Variability:
A pharmaceutical manufacturing process is usually comprised of a series of unit operations to produce the desired product. A unit operation is a discrete activity that involves physical changes, such as mixing, milling, granulation, drying, compaction, and coating A physical, chemical or microbiological property or characteristic of an input or output material is defined as an attribute. Process parameters include the type of equipment and equipment settings, batch size, operating conditions (e.g., time, temperature, pressure, pH, and speed), and environmental conditions such as moisture The quality and quantity of drug substance and excipients are considered as attributes of raw materials. To demonstrate the reproducibility and consistency of a process, process capability should be studied. Process capability is a statistical measure of the inherent process variability for a given characteristic. The most widely accepted formula for process capability is six sigma. Process capability index19 is the value of the tolerance specified for a particular characteristic divided by the process capability, which is defined as follows
Upper limit of specification –lower limit of specification
Process capability index (CpK) = ----------------------------------
standard deviation
If the CpK value is significantly greater than one, the process is deemed capable. If the process capability is low, Strong recommends an iterative five step procedure to progressively reduce the variability of the process.
These five steps are:
1. Define: The intended improvement should be clearly stated. This may be defined as material attributes. Should be measured to see if they are out of specification the out of specification data should be analyzed and used to the sigma level of the process.
2. Measure: The critical product performance attributes
3. Analyze: When the sigma level is below the target, steps should be taken to increase it, starting by identifying the most significant causes of the excessive variability.
4.Improve: The process should be redesigned and/or process controls should be incorporated to eliminate or attenuate the significant root causes of variance.
5. Control: The improved manufacturing process should be evaluated and maintained.
Design Product and Manufacturing Process
In order to design and develop a robust generic product that has the desirable TPQP, a product development scientist must give serious consideration to the biopharmaceutical properties of the drug substance. These biopharmaceutical properties include physical, chemical, and biological properties. Physical properties include physical description (particle size, shape, and distribution), polymorphism, aqueous solubility as function of pH, hygroscopicity, and melting points. Pharmaceutical solid polymorphism, for example, has received much attention recently. Its impact on product quality and performance has been discussed in recent review articles. Chemical properties include pKa, chemical stability in solid state and in solution as well as photolytic and oxidative stability while biological properties include partition coefficient, membrane permeability, and/or oral bioavailability. Biopharmaceutical properties should be assessed for every form for which there is an interest in development and every form that can potentially be created during processing (e.g., hydrates, anhydrates) or in vivo (e.g., less soluble salts, polymorphic forms, hydrates). The investigation of these properties is termed preformulation in pharmaceutical science.
The goal of preformulation studies is to determine the appropriate salt and polymorphic form of drug substance evaluate and understand its critical properties, and generate a thorough understanding of the material’s stability under various processing and in vivo conditions, leading to an optimal drug delivery system. Pharmaceutical preformulation studies need to be conducted routinely to appropriately align dosage form components and processing with drug substance and performance criteria. Mechanical properties, though not often studied in detail, can have a profound impact on solid dosage form development and processing. A sound understanding of mechanical properties of the drug and excipients can be useful in developing a processing method such as granulation or direct compression, rationally selecting excipients whose properties can compensate for the properties of the drug substance, and helping assess critical material attributes and root cause analysis during process scale-up or failure. Pharmaceutical materials can be elastic, plastic, viscoelastic, hard, soft, tough, or brittle. There exist various methods in the literature to evaluate these mechanical properties. The knowledge of mechanical properties of the drug and excipients are expected to play a more significant role in product design and development in the future. Drug-excipient compatibility has been identified as one of the most frustrating, troubling, and perplexing formulation challenges. Despite the fact that excipients can alter stability and bioavailability of drugs, the general principles of selecting suitable excipients for dosage forms are not well defined, and excipients are often selected without systematic drug-excipient compatibility testing. To avoid costly material wastage and time delays, ICH Q8 recommends drug-excipient compatibility studies to gain early prediction of drug-excipient compatibility. Systematic drug-excipient compatibility studies offer several advantages: minimizing unexpected stability problems which usually lead to increases in time and cost; maximizing the stability of a formulation; and enhancing understanding of drug-excipient interactions that can help with root cause analysis if stability problems occur. Despite its significance, however, there is no universally accepted way to conduct drug-excipient compatibility studies in this evolving area. One method is thermal analysis, where a physical property of a substance (e.g., melting point) and/or reaction products is measured as a function of temperature while the substance is subject to a controlled temperature program. Another method utilizes isothermal stress. This method typically involves storing the drug-excipient blends or compacts with or without moisture at elevated temperature and determining drug content or degradation product formation as a function of time. Both methods can be used together to evaluate the compatibility of drugs with the selected excipients.
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Control Manufacturing Processes To Produce Consistent Quality Over Time
This means that manufacturers have knowledge of the operating range as well as the proven range of critical raw material attributes and process parameters. The operating range is defined as the upper and/or lower limits for raw material attributes and process parameter values between which the attribute and parameter are routinely controlled during production in order to assure reproducibility. The proven range 20 is defined as the upper and/or lower limits for process parameter values between which the parameter is known to produce a high quality product that delivers the therapeutic benefit claimed on the label. The proven range can be established based on historical and/or experimental data. It can also be established based on scientific and operational judgment and expertise .Within the QbD, design space21 is defined as then multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide quality assurance
Risk Assessments
Several applications in the CMC pilot included risk assessments, especially for the drug product by linking input and process variables to CQAs. Tools used in the risk assessment included the Ishikawa or fishbone diagram, failure mode effect analysis (FMEA), and Pareto analysis. An Ishikawa or fishbone diagram is used to identify all potential variables, such as raw materials, compression parameters, and environmental factors, which can have an impact on a particular CQA, such as tablet hardness. A FMEA can then be used to rank the variables based on risk (i.e., a combination of probability, severity, and detectability) and to select the process parameters with higher risks for further studies to gain greater understanding of their effects on CQAs. A multidisciplinary team based on prior knowledge and experiments amasses the risk assessment. “It isimportant to provide a systematic risk analysis of how raw materials, process steps, and process parameters affect product quality,” One of the points to consider in risk assessment, is to provide an explanation when citing prior experience as the basis for assigning risk. The risk assessment that leads to the development of a comprehensive control strategy to reduce risk to product quality should be described, and the risk reduction and control should be discussed for changes that occur inside or outside the design space, “Risk assessment can provide increased assurance to quality,” because “process variability is identified and its linkage to product CQAs is understood; process and product controls reduce the impact of variability; and quality product will continue to be made when movement within the design space occurs in the future.” A risk assessment also is important for effective communication between FDA and industry and for intra company communication (such as between research/development and manufacturing and among multiple manufacturing sites), “And within FDA, risk assessment allows for a dialogue between pre-and post-marketing review functions and among review, compliance, and field inspection staffs.
Process Design And Development
Strictly speaking, process and product design and development cannot be separated since a formulation cannot become a product without a process. Process design is the initial stage of process development where an outline of the commercial manufacturing processes is identified on paper, including the intended scales of manufacturing. This should include all the factors that need to be considered for the design 22 of the process, including facility, equipment, material transfer, and manufacturing variables other factors to consider for process design are the target product quality profiles. Depending upon the product being developed, type of process, and process knowledge the development scientists have, it may be necessary to conduct preliminary feasibility studies before completing the process design and development. The selection of type of process depends upon the product design and the properties of the materials.
CONCLUSION
Ensures robust commercial manufacturing methods for consistent production of quality drugs.reduce product recalls and compliance actions, resulting in cost savings for pharmaceutical companies. Ensures the consumers that therapeutic equivalent generics are manufactured every single time. Offers the agency that quality applications are submitted to improve the review efficiency and to reduce the application approval times. QbD methodology helps in identifying and justifying target product profiles, product and process understanding.Helps in continuous improvement. There is a need for vigorous and well funded research programs to develop new pharmaceutical manufacturing platforms.
REFERENCE
1. FDA Guidance for Industry –Analytical Procedures and Method Validation, Chemistry, Manufacturing, and Controls Documentation, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), August 2000.
2. International Conference on Harmonization Quality Guidelines Q2(R1), Validation of Analytical Procedures, Text and Methodology, Parent guideline dated 27 Oct 1994, Complementary guideline on methodology dated 6 Nov 1996, incorporated November 2005.
3. US Food and Drug Administration. Guidance for Industry. PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance. Pharmaceutical cGMPs. Rockville, MD, 2004 Sept., 1–21.
4. ICH Q8 (R1), 2008b. Pharmaceutical Development. Part I: Pharmaceutical Development, a. And Part II: Annex to Pharmaceutical Development,MEDIA4986.pdf.
5. “Quality by Design (QbD) – A Modern System Approach to Pharmaceutical Development and Manufacturing – FDA Perspective” Moheb M. Nasr
6. A New Pharmaceutical Quality Assessment System (PQAS) for the 21st Century, AAPS Workshop October 2010
7. Woodcock J. Pharmaceutical quality in the 21st Century—an integrated systems approach, December 16, 2009.
8. Joshi Y, LoBrutto R, Serajuddins ATM. Industry opinion of regulatory influence: the initiative on pharmaceutical cGMPs for the 21st century. Journal of Process Analytical Technology July/August 2010.
9. Nasr MM. A New Pharmaceutical Quality Assessment System (PQAS) for the 21st Century, AAPS Workshop October 2010.
10. QbD Principles to be implemented in future FDA guidance; DIA Dispatch, Oct. 28, 2010.
11. Yu, LX. Implementation of quality by design: question Based Review, DIA Meeting, June 2010.
12. Chen C. Implementation of ICH Q8 and QbD—an FDA Perspective, Pharma Forum Yokohama.
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