Opportunities and challenges to implementing Quality by Design ...

Original Article

Opportunities and challenges to implementing Quality by Design approach in generic drug development Received (in revised form): 28th August 2009

Ramaji K. Varu received his MS (Pharmacy) from the Department of Pharmaceutical Analysis at the National Institute of Pharmaceutical Education and Research (NIPER) in Hyderabad, India. His dissertation work was on ‘Quality by Design in generic product development: Opportunitites and challenges’. Currently, he is working with Biocon Limited in RND (Research and Development) as a scientist in Bangalore, India.

Amit Khanna has an M.Pharm and a PhD (Pharmacy), and has over 9 years experience in drug development, quality assurance and regulatory affairs. Currently, he is working with Novartis Healthcare (P) Ltd. in global regulatory affairs (chemistry, manufacturing and controls) as a group head in Hyderabad, India.

ABSTRACT This article presents an overview of the implementation of key elements (Target Product Profile, Critical Quality Attributes, design space and control strategy) of Quality by Design (QbD) – a systemic approach in the case of generic drugs. The basis for this concept is that advanced understanding of variables affecting generic drug (product) quality, either obtained through historical operation or demonstrated through process modelling, justifies the replacement of the traditional process targets with acceptable operational ranges. This article also describes the steps involved in the development of generic drugs, steps through which the QbD concept can be applied, and the opportunities for and challenges to implementing QbD in generic drug development. Journal of Generic Medicines (2010) 7, 60–73. doi:10.1057/jgm.2009.37; published online 17 November 2009 Keywords: Quality by Design (QbD); Target Product Profile (TPP); Critical Quality Attributes (CQAs); design space; control strategy; Process Analytical Technology (PAT)

INTRODUCTION Traditionally, pharmaceutical development has focused on the delivery of the product

Correspondence: Ramaji K.Varu Pharmaceutical Analysis, IDPL research centre, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, Andhra Pradesh, India E-mails: [email protected]; [email protected]

to the next phase of clinical study, and thus formulation design has tended to be iterative and empirical.1 The regulatory framework surrounding the manufacture of pharmaceutical products ensures patient safety through the use of well-defined parameters governed by a change control process, which places a significant burden on industries when changes to the parameters

© 2010 Macmillan Publishers Ltd. 1741-1343 Journal of Generic Medicines Vol. 7, 1, 60–73

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Opportunities and challenges of Quality by Design

are required during the product’s life cycle. As a consequence, it is difficult to implement a continuous improvement culture. At the same time, regulatory authorities have recognized that more controls are needed for drug manufacturing processes to ensure efficiencies and better focus on regulatory decisions, but it has seemed that there is a tendency to require a supplemental application for every manufacturing change. One result of this more stringent regulatory environment has been a dramatic increase in the number of manufacturing supplement applications. In 2007, for example, the US Food and Drug Association (FDA) received a total of 5000 supplements for new drug applications (NDAs), biological license applications (BLAs) and abbreviated new drug applications (ANDAs). The data required in both original applications and supplements were focused mainly on chemistry, without providing consideration of other important aspects of the manufacturing, such as engineering.2 Traditionally, the data have not included information about product development. However, under the new Quality by Design (QbD) paradigm it will be possible to use valuable knowledge and data from product development studies to create a design space within which continuous improvement can be implemented, but in which the burden for the management of change control lies within industry without the need to seek further regulatory approval.1 In the methodology section below, we describe a general scheme for implementation of QbD principles in generic drug development. We conclude by outlining some opportunities for and challenges to implementing the QbD concept in generic drug development.

LITERATURE AND HISTORICAL PERSPECTIVE At the International Conference on Harmonization (ICH) meeting of July 2003,

industries and regulators agreed on a vision encouraging ‘Quality by Design’. QbD is intended to facilitate innovation and continuous improvement throughout the product life cycle. Through the sharing of process and product understanding with the authorities, applicants obtain enhanced regulatory flexibility (for example, specification setting and testing, reduction of post approval submissions), and potentially expedite the review and approval of marketing authorizations.3 In a 2004 perspective article,4 Janet Woodcock (Director for the Centre for Drug Evaluation and Research) described the problems and limitations of the current definition of pharmaceutical quality, and suggested that the concept of the pharmaceutical quality should be recast in terms of risk. She noted (and recently reiterated5) that the lack of observable connection between critical product attributes and clinical performance is a persistent roadblock to establishing an effective, risk-based definition of pharmaceutical quality. Woodcock defined pharmaceutical quality as a product that is free of contamination and reproducibly delivers to the consumer the therapeutic benefit promised on the label.6 The FDA’s report on critical path opportunities for generic drugs states that ‘under the QbD paradigm, quality is built into the final product by understanding and controlling formulation and manufacturing variables: testing is used to confirm the quality of product’.3 In 2005, the FDA began a pilot programme that enables participating firms to submit chemistry, manufacturing and controls (CMC) information demonstrating application of QbD, using the quality overall summary (QOS) format.7 The CMC pilot project provides a mechanism for the FDA and industry to cooperate on strategies for the implementation of the ICH Q8 and Q9 guidelines and the FDA’s Process Analytical Technology (PAT) guidance. According to a recent interview with Dr Chi-Van


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Chen, Deputy Director of the Office of New Drug Quality Assessment, considerable diversity was observed in the QbD, and the concept of design space is approached by industry participants.7 Relevant documents from the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Q8,8 Pharmaceutical Development, along with ICH Q9,9 Quality Risk Management, and ICH Q10,10 Pharmaceutical Quality Systems, indicate on an abstract level how QbD acts to ensure drug product quality.

QbD AND ITS ELEMENTS QbD means ‘building in quality from the development phase and throughout a product’s life cycle’ or ‘designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains predefined quality at the end of the manufacturing process’.11 QbD includes the following elements: 1. 2. 3. 4.

Target Product Profile (TPP); Critical Quality Attributes (CQAs); Design space; and Control strategy.

Target Product Profile TPP is generally accepted as a tool for setting the strategic foundation for drug development ‘planning with the end in mind’. More recently, an expanded use of the TPP in development planning, clinical and commercial decision making, regulatory agency interactions and risk management has started to evolve. The target profile is a summary of the drug development programme described in the context of prescribing information goals.12 TPP has also been defined as a ‘prospective and dynamic summary of the quality characteristics of a drug product that ideally will be achieved to evolve the desired quality and thus the

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safety and efficacy, of a drug product is realized’.13 It can play a central role in the entire drug discovery and development process, in the following ways: 1. 2. 3. 4.

Effective optimization of a drug candidate; Decision making within an organization; Design of clinical research strategies; and Constructive communication with regulatory authorities.

TPP links drug development activities to specific statements intended for inclusion in the drug’s label. It also guides formulation scientists to establish formulation strategies and keep the formulation effort focused and efficient. For example, a typical TPP of oral suspension would include the following: • • • • • • • • • • • • • • • •

Dosage form; Route of administration; Dosage form strength; Oral suspension characteristics; Identity; Assay and uniformity; Purity/impurity profiling; Stability; Dissolution; Pharmacological category; Indication; Contraindication; Adverse reaction; Precaution; Overdose; and Drug abuse and dependence

The TPP of a generic drug can be readily determined from the Reference Listed Drug because a generic must contain the same active ingredients as the original formulation. According to the FDA, generic drugs are identical or bioequivalent to the brand name counterpart with respect to pharmacokinetic and pharmacodynamic properties. By extension, therefore, generics are identical in dose, strength, route of administration, safety, efficacy and intended use.



Critical Quality Attribute A Critical Quality Attribute (CQA) is a physical, chemical, biological or microbiological property or characteristic that should be controlled within an appropriate limit, range or distribution to ensure the desired product quality. CQAs are generally associated with drug substance, excipients, intermediates and drug product.14 Drug product CQAs include the properties that impart the desired quality, safety and efficacy. CQAs of solid oral dosage forms are typically those aspects affecting product purity, potency, stability and drug release. CQAs for other delivery systems can additionally include more product-specific aspects, such as aerodynamic properties for inhaled products, sterility for parenterals and adhesive force for transdermal patches. For drug substances or intermediates, the CQAs can additionally include those properties (for example, particle size distribution, bulk density) that affect downstream processability.14 A list of typical CQAs for oral suspension is mentioned below: • Particle size and particle size distribution; • Density of drug substance and dispersion medium; • Particle shape; • Polymorphic form; • Content uniformity; • Dissolution; • Order of addition of ingredients; • Viscosity (concentration of suspending agent); • pH of suspension; • Zeta potential of the drug substance; and • Quality and quantity of the drug substance and excipients. Identification of CQAs is carried out through the risk assessment as per the ICH Q9 guidance.15

Design space Process development results in the definition and approval of a ‘Control Space’ within

the universe of possibilities about a process called a ‘Knowledge Space’. The approved manufacturing process can be carried out within the Control Space to produce material that meets the required specifications for identity, potency, quality, safety and so on. As the product matures in its life cycle, scale-up, economic and/or other factors necessitate changes in the control scheme for the process, moving it from Control Space 1 to Control Space 2. The scientific basis for Control Space 2 is usually developed out of necessity to cope with process shortcomings long after the original process development work has been conducted. The process needs to be reviewed and approved by the regulatory authorities before it can be carried out commercially in the new Control Space. This can be a costly and inefficient process because it can trigger the need for newer/ additional studies and a long gestation period. Furthermore, many of the expert resources that developed and gained approval for Control Space 1 have moved on by the time Control Space 2 is needed or implemented16 (Figure 1). Design space is defined in the ICH Q8 guidelines (November 2007) as ‘the multidimensional and interaction of input variables (for example, material attributes) and process parameters that have been demonstrated to provide assurance of quality’. The definition itself is not self-expanding, and needs further elaboration by industry and regulators before it can be implemented in daily practice. A design space for a certain product proposed by the applicant is subject to regulatory assessment and approval. Figure 2 shows that one of the key outcomes of the ICH Q8 process is that working within a design space is not considered a regulatory change. Only movement out of a design space is considered to be a change, and would normally initiate a regulatory post-approval change process. A large number of workshop sessions will enable industry participants and regulatory representatives from around the world to


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Control space 1

Control space 2

the commercial scale. The design space is dependent upon the equipment and design principle and batch size.12

Control strategy Knowledge space

Control space 1

Control space 2

Design space

Knowledge space

Figure 1: Representation of Control Space 1 and Control Space 2, which are subparts of design space.

A control strategy is designed to consistently ensure product quality. Control strategy describes and justifies how in-process controls and the controls of input materials (drug substance and excipients), the container closure system, intermediates, and end products contribute to the final product quality. These controls should be based on product, formulation and process understanding, and should include, at a minimum, control of the critical parameters and attributes.14 Control strategy is also defined as ‘a planned set of controls, derived from current product and process understanding that assures process performance and product quality’.17 The control strategy can include the following elements: procedural controls, in-process controls, lot release testing, process monitoring, characterization testing, compatibility testing and stability testing.2

PAT: SUPPORTIVE TOOL FOR QBD IMPLEMENTATION

Figure 2: Representation of design space, including acceptable range and operating range to provide regulatory flexibility and continuous improvement.

discuss the pros and cons of design space concepts and to achieve a greater mutual understanding of how such design space can be constructed, submitted in application and reviewed, together with the potential for regulatory flexibility.3 The design space for generic drugs can likely be established in small-scale batches using design of experiments and prior knowledge, and may need to be verified on

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PAT is defined as a system for analysing and controlling manufacturing through timely measurements (that is, during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.18 PAT is a tool that allows enhanced control of the manufacturing process and can improve process understanding, and thus facilitates building quality into products and the development of a design space. ICH Q9 (Quality Risk Management) provides an approach and a selection of tools that can be used to manage risks associated with these processes.18 The goal of PAT is to support principles of QbD that emphasize fundamental process understanding and control focus to maximize process efficiency. There will be a shift from



lab-based end-product quality testing to better formulation and process design, leading potentially to more in-line, online or at-line testing.19 The main PAT tools are as follows:18 1. Multivariate data acquisition and analysis. 2. Modern process analyzers or process analytical chemistry tools.

company must show that the generic drug is ‘bioequivalent’ to the branded drug, must have full documentation of the generic drug’s chemistry and manufacturing steps, and the generic drug maintains stability as labelled before it can be sold. The raw materials and the finished product must meet pharmacopoeial specifications, if these have been set.29

For example,

QbD: Generic drug development process and roadblocks

1. laser diffraction as a PAT tool for spray drying;20 2. mass spectrometry as a PAT tool for bulk drying process;21 3. Near Infra Red spectroscopy and Raman spectroscopy as PAT tools for measurement of coating on modified release tablets;22 and 4. HPLC as a PAT tool for measurement of %RSD (Relative Standard Deviation) in blend uniformity.22

The difference between QbD for NDA and ANDA products is most apparent in the first step of the process. For an NDA, the TPP is under development, whereas for the ANDA product the TPP is well established by the labelling and clinical studies conducted to support the approval of the reference product.6 The steps of the generic drug development process and at which step QbD can be applied are as follow:30

CURRENT APPROACH VERSUS QbD APPROACH TO PRODUCT DEVELOPMENT14, 23–27 Table 1 shows an overview of the current approach and QbD approach to product development.

METHODOLOGY Generic drugs A generic drug is a cost-effective alternative to a branded drug whose patent has expired. The original manufacturer receives a patent on his invention to prevent others from using it. Once the patent expires, other manufacturers may produce and sell the drug. These manufacturers usually sell the drug under its common or generic name.28 An approved generic drug must have the same active ingredient(s), labelled strength, dosage form, quality, performance, intended use, route of administration and labelling as that of the approved brand name drug. The drug

Characterization of the reference product This includes full details regarding proof of the compound’s structure. Roadblocks: Complex reference product, natural source origin, polydisperse mixture and complex supramolecular structure. To make a generic product, the ANDA sponsor may need better characterization than the originator.

Design of generic product and process Figures 3 and 4 give the general overview of the generic product development pathways using the current approach and QbD approach, respectively. Roadblocks: Identification of CQAs of a dosage form and establishment of a design space using selected parameters or variants.


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Table 1: Comparison of current approach and Quality by Design approach for product development Current approach

Quality by Design approach

Empirical approach to setting specification to fit available data

Systemic, relating mechanistic understanding of input material attributes and process parameters to drug product critical quality attributes (CQAs) Clinical linkage always assured Establishment of design space

Clinical linkage (safety and efficacy) not always assured Negotiation to set specification because of limited data and lack of systemic approach to product development Specifications may not be reflective of the ‘true’ product quality, sometimes out of specification result leading to • non-compliance and subsequent investigations; • product quarantine/delays or recall from the market depending upon situation; • drug shortage in the market in certain cases. Developmental research often conducted one variable at a time Regulatory hurdle for continuous improvement Multiple chemistry, manufacturing and controls (CMC) review cycle Manufacturing processes are fixed or ‘frozen process’, discourage changes Validation of manufacturing process is primarily based on initial full-scale batches Focus on optimization and reproducibility of the manufacturing process Product specifications are primary means of control Product specifications are based on batch data available at time of registration Control strategy by testing and inspection Life cycle management of product quality is reactive (problem solving and corrective action) to problems and to Out of Specifications (OOS), post-approval changes needed Use of statistical process control unit method is limited Root cause analysis: • In most cases, root cause analysis is unknown. • Poor understanding of observed variability such as product-related variability. Formulation component Manufacturing process Operator • Measurement system variability. Analytical methods (eg USP calibrator table) Dissolution apparatus • Drug development effort with poor or lack of understanding. Raw material properties Effect of formulation component’s properties on manufacturing processes (unit operations) Effect of manufacturing on CQAs of the drug product Causal link between critical material attributes of formulation component (API, excipients) and CQAs of the drug product Associated risks to product quality Off-line analysis of process control In-process tests primary for go/no-go decisions

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An approved design space is always reflective of ‘true’ product quality

Multivariate experiments to understand product and process Regulatory scrutiny adjusted to process understanding, continuous improvement allowed within design space Single CMC review cycle and risk-based specifications Manufacturing processes are flexible, cover a wide range and allow changes Life cycle approach to validation of manufacturing process and continuous verification Focus on robustness and control strategy of the manufacturing process Product specifications are part of the overall quality summary Product specifications are based on desired product performance with relevant supportive data Risk-based control strategy, real time release possible means control strategy by designing/control strategy by online testing/analysis Life cycle management of product quality by preventive action

Use of statistical process control unit method is predominant Process Analytical Technology (PAT) tools utilized in pharmaceutical development

Process operations are tracked and treated to support continual improvement efforts after approval PAT tools utilized in process control with appropriate feed forward and feedback control



Chemical and physical characterization of drug

Preformulation study of the drug

Drug substance formulation Excipients

Drug product with desired features

Generic drug must be bioequivalent to that of the pioneer drug

Frozen manufacturing process

Pivotal biobatch Scaling up Post approval changes require regulatory permission

Licensing of the drug product Marketing of product

Figure 3: Generic drug development pathways using the current approach to product development.

Figure 5 shows an example of how QbD can be helpful in the identification of CQAs in the case of the oral suspension dosage form.

QbD for bio-equivalence study (Figure 6): QbD tools to aid in the design and manufacture of bioequivalence product:

Pivotal bio batch

• Formulation modelling • Dissolution and in vivo–in vitro correlation

Bioequivalence study Roadblocks: Bioequivalence for systemic or locally acting drugs; expensive, extensive or unpredictable bioequivalence tests; many companies do not develop products that need clinical end point bioequivalence study.

Commercial product manufacture Roadblocks: Problems on scale-up, wasted commercial batches, cannot meet specifications, process variability, sometimes sponsor may


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Chemical and physical characterization of drug

Preformulation study of the drug

Establishment of design space with selected variables (formulation design space) Drug substance

Formulation design Excipients Drug product with desired features

Generic drug must be bioequivalent to that of the pioneer drug Quality by Design for dissolution and IVIVC study

Manufacturing process with continuous improvement within an approved design space (using PAT tools) Pivotal biobatch Scaling up During post approval changes QbD provides flexible regulatory approach to change site, scale, process condition, process type, excipient grade etc. within an approved design space Licensing of the drug product No need to take regulatory authorities permission if change is made within the design space Marketing of product

Figure 4: Generic drug development pathways using the Quality by Design approach to product development.

need to reformulate product or revise process. A control strategy, an element of QbD, is what a generic sponsor uses to ensure

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consistent quality as they scale up their process from the exhibit batch presented in the ANDA to commercial product manufacturing.6



Raw material

Manufacturing

Final product

Product Performance

Particle size distribution, Zeta potential and Wetting property of drug substance

Sedimentation rate

Cacking

Redispersibility measurement

API level

HPLC assay or UV spectroscopy assay

Clinical safety and efficacy

Identity, strength and purity

Density of dispersion as well as drug particles uniformity of dispersion of drug through the medium

Electrokinetics and wetting property of drug particle

Temperature control and pH control of dispersion medium Stability of API and excipients

Blending time

Drug substance impurity

Degradant level

HPLC impurities

Stability study

Anti microbial effectiveness Consistency of Suspension

Quality and quantity of excipients Particle size

Drug substance particle size Viscosity of vehicle

Critical material attributes of drug substance and excipients

Critical process parameters

Dissolution test

Bioavailability

Redispersibility

Critical material attributes of drug product

Target product quality profile

Target product profile described on the label

Critical Quality Attributes

Figure 5: An illustration of oral suspension dosage form that shows how under QbD the identification of critical process parameters and critical material attributes is linked to the TPP that represents clinical safety and efficacy.

OPPORTUNITIES The following are the opportunities for generic drug and new drug development that will arise by implementing the QbD approach.23,31,32 • Opportunities for industry and regulators to jointly achieve a more comprehensive understanding of what is meant by design space; • Opportunities for discussion on how design space can be established and submitted for both new and existing products; • Understanding of how quality risk management can be used to develop a design space;

• Identification of scientific expectations that need to be fulfilled for the successful implementation of regulatory flexibility; • QbD provides opportunities for facilitating continuous improvement throughout the product life cycle and contributes a better understanding of scientific and risk-based regulatory submissions and reviews, thereby maintaining high quality. • We can establish a greater degree of understanding of material attributes and manufacturing processes and their control within our company and with the regulatory authorities;


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Drug release from product

In vitro dissolution study

IVIVC and QbD

Plasma concentration

In vivo plasma concentration study

Site of action

Effect

Figure 6: Bioequivalence study for systemically acting drug.

• Design space facilitates understanding of difference between the manufacturing process used to make the drug product for pivotal clinical trials/stability studies versus the commercial product; • QbD provides potential opportunities for risk-based regulatory decisions (reviews and inspections); • QbD facilitates manufacturing process improvement without further regulatory review (staying within a design space) and may reduce post-approval submissions; • QbD provides potential opportunities for real-time quality control and reduction of the end point (QC) release testing; and • Opportunities to obtain the following benefits from QbD: ° Reduced batch failure rates, reduced final product testing and lower batch release costs; ° Lower operating costs from fewer failures and deviation investigations; ° Increased predictability of manufacturing output and quality; ° Reduced raw material and finished product inventory costs; ° Faster technology transfer between development and manufacturing;

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° Faster regulatory approval of new product ° ° ° ° ° °

° ° ° °

°

°

applications and process changes; Fewer and shorter regulatory inspections of manufacturing site; Provides for better coordination across review, compliance and inspection; Provides for better consistency; Improves quality of review; Provides more flexibility in decision making; Ensures that decisions are based on scientific rather than empirical information; Involves various disciplines in decision making; Uses maximum resources to address higher risks; Ensures better design of the products with fewer problems in manufacturing; Allows for the implementation of new technology to improve manufacturing without regulatory scrutiny; Ensures less complication during review, so that reduced deficiencies and quicker approval is possible; Improves interaction with regulatory authorities at a scientific level instead of a process level;



° Allows for a better understanding of

how active pharmaceutical ingredients and excipients affect manufacturing; ° Relates manufacturing to clinical during design; and ° Provides a better overall business model. • PAT benefits are as follows:19 ° Possibilities of introducing ‘real-time release’; ° Reduction of cycle time; ° Improved product quality; ° Use of ‘state-of-the-art’ technologies in manufacturing; ° Guaranteed quality level (‘unit to unit’); ° Reduced documentation; ° Risk mitigation; ° Real-time data acquisition and integration; ° Knowledge management; ° Reduction in complaints and recalls; and ° Opportunities for interdisciplinary communication and for bridging the gap between the R&D, manufacturing, Quality Assurance (QA), Quality Control (QC) and IT departments.

CHALLENGES The following are the challenges to generic drug and new drug development in implementing the QbD approach.23,26,27,31,33 • Expectations for QbD-based submissions while addressing traditional requirements; • Training is also a major challenge, and therefore regulatory authorities and industry should conduct the training programme for the implementation of the QbD concept; • Establishing appropriate/expected level of detail in regulatory submissions (types and extent of data in future CMC submissions); • Achieving regulatory flexibility while assuring product quality; • Establishing balance between QbD-based versus traditional demonstration of quality; • Sharing proprietary information with regulatory groups; • Different strategies/approaches to accommodate diversity of drug products: ° Small chemicals versus large biological

° Oral solids versus complex/novel dosage

forms ° Drug versus combination products;

• A potential regulatory strategy – CMC Regulatory Agreement; • Lack of understanding and trust; • Associated costs to implement QbD into product development and manufacturing unit operations (business and marketing decisions); • Different regulatory processes (BLA, NDA, ANDA, follow-on and so on) and associated regulatory practices and culture; • Integration of review and inspection; • Workload; • Resources for assessment; and • Cultural changes needed in industry and FDA.

DISCUSSION At present, demand for generic drugs in the market is increasing day by day, and on 4 February 2006 Marc Kaufman (Washington Post staff writer) stated that ‘The Food and Drug Administration has a backlog of more than 800 to bring new generic products to the market – reported to be an all time high’.34 Furthermore, generic drugs save consumers $8–10 billion yearly.29 Therefore, to allow more generic drugs onto the market as early as possible and to assure the quality of generics throughout the product life cycle, it is important to implement the QbD concept, along with PAT, for generic drug development because it ensures better design of products with fewer problems in manufacturing, reduces the number of the manufacturing supplements required for post-market changes, reduces the product approval time, reduces the total cost of the product, decreases the rate of failure of the batches, decreases end product testing costs and provides a better overall business model. Implementation of QbD will also be helpful for the industries and regulatory authorities to achieve the goal of modernization of product quality. To facilitate QbD implementation


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in generic drug development, there should be strong links, mutual understanding, trust and a good relationship between regulatory authorities and industries. Furthermore, to adopt the QbD culture in generic drug development, industries should develop the culture of sharing all information with regulatory authorities, and regulatory authorities should develop the culture of trust, and should give encouragement to industries for continuous improvement in product quality during the life cycle of the product. Better understanding and control of pharmaceutical process are greatly needed, as well as the development of advanced measurement tools and data analysis methods. QbD and PAT implementation is the solution for this.

SUMMARY AND CONCLUSION This article describes the concept of QbD and its implementation in generic drug development. QbD, along with PAT, provides better knowledge of raw materials, manufacturing parameters and their impact on finished product quality. This will result in more robust processes, better products and huge cost savings in manufacturing. Therefore, we can conclude that QbD is a concept that will provide better opportunities for ANDA sponsors to get generic drugs onto the market faster, and will also be helpful in maintaining the quality of a drug product throughout its life cycle.

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