Short review on Quality by design: A new Era of Pharmaceutical drug development

The purpose of present article is to discuss the concept of pharmaceutical Quality by Design (QbD) and describe how it can be help to ensure pharmaceutical quality. Quality by design is an essential part of the modern approach to pharmaceutical quality. The elements of quality by design are examined and a consistent nomenclature for quality by design, critical quality attribute, critical process parameter, critical material attribute, and control strategy is proposed. The use of QbD was contrasted with the evaluation of product quality by testing alone. The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include defining target product quality profile, designing product and manufacturing processes, identifying critical quality attributes, process parameters, and sources of variability & controlling manufacturing processes to produce consistent quality over time. Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. *Corresponding author, Mailing address: Gupta Anuj* E-mail: [email protected] Article History:-----------------------Date of Submission: 06-06-2012 Date of Acceptance: 18-06-2012 Conflict of Interest: NIL Source of Support: NONE R e v i e w P a p e r C o v e r e d i n I n d e x C o p e r n i c u s w i t h I C V a l u e 4 .6 8 f o r 2 0 1 0 Int. J. Drug Dev. & Res., July-September 2012, 4 (3): 19-26 Covered in Scopus & Embase, Elsevier 19 levels by sorting, reworking, and so on to prevent defective product leaving the factory [1]. During the heydays of the pharmaceutical industry, there was lesser focus on the yields, number of defects, etc., and the quality organizations of the companies were more focused on compliance based on inspection of the final products. Traditional development focused on the formulation and the delivery of the product to the next phase of the clinical studies. Most of the formulation development tended to be iterative and empirically designed. Thus, changes were driven by the need to modify the process during scale-up or due to the formulation failing to meet the desired shelf life of the product. During phase 3, changes were kept to a minimum to avoid the need for expensive bioequivalence studies to bridge between the Clinical Trial Material (CTM) and the commercial product. Thus, manufacturing processes were fixed and the quality of the product was measured by end product testing (commonly referred to as quality by testing). In this case, quality is not built in to the product and is achieved by end product testing. This approach is inefficient and does not facilitate continual improvement. In the past, there also existed a notion that the regulatory processes and requirements prohibited manufacturing enhancements, which in turn prevented the modernization of the pharmaceutical industry. The initiation of the cGMPs for the 21st Century Initiative [2] and the publication of the Process Analytical Technology (PAT) guidance [3] in 2004 by the FDA paved the way for the modernization of the pharmaceutical industry. In July 2003, the experts from the three regional grouping (USA, EU, and Japan) working on the Quality Topics within ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) created a vision for the future pharmaceutical quality system (Figure 1). This vision recognizes that regulatory agencies will also benefit from this initiative as it will enable them to prioritize and allocate resources more efficiently, and patients will also benefit from improved access to medicines and an enhanced assurance of quality. Figure 1: ICH vision for the future pharmaceutical quality system “Quality by design (QbD),” although a new concept to the pharmaceutical industry, is a tried and tested concept that has been in existence for quite a few years and has been extensively applied in the automotive, the semiconductor, and the petrochemical industry. The concept of building quality into products has been extensively documented by Deming and Juran. The common theme of the various initiatives is “planning for quality,” that is, building quality into the products compared to the traditional paradigm of testing the product to ensure quality. The Juran trilogy concept identifies quality planning, quality control, and quality improvement as three fundamental aspects of quality planning [4]. Quality planning is the process of identifying the needs of the customer and designing the product and the process to meet the needs of the customer. 2.0 ENABLERS OF QUALITY BY DESIGN Knowledge management and quality risk management are two of the primary enablers of QbD. They play a critical role both in development and in the implementation of QbD. They are instrumental in achieving product realization, establishing and maintaining a state of control, and lastly facilitating continual improvement [5]. A brief description of the R e v i e w P a p e r C o v e r e d i n I n d e x C o p e r n i c u s w i t h I C V a l u e 4 .6 8 f o r 2 0 1 0 Gupta Anuj* et al: Short review on Quality by design: A new Era of Pharmaceutical drug development Int. J. Drug Dev. & Res., July-September 2012, 4 (3): 19-26 Covered in Scopus & Embase, Elsevier 20 two enablers and their utility is provided in the following sections. 2.1 Quality Risk Management Quality risk management (QRM) is a key enabler for the development and application of QbD. During development, it enables resources to be focused on the perceived critical areas that affect product and process. It is one of the tools that provide a proactive approach to identifying, scientifically evaluating, and controlling potential risks to quality. It also facilitates continual improvement in the product and process performance throughout the product life cycle. 2.2 Knowledge Management Product and process knowledge management is an essential component of quality by design and must be managed from development through the commercial life of the product, including discontinuation. It is a systematic approach to acquiring, analyzing, storing, and disseminating information related to products, processes, and components. This also emphasizes on a transparency of information from development to commercial and vice versa. Prior knowledge comprises previous experience and understanding of what has been successful or unsuccessful, and recognition of issues, problems, or risks that may occur and need to be addressed. Examples of prior knowledge include the following: Knowledge gained about the drug substance and/or drug product from early development work Knowledge of the properties of materials and components used in other products and the variability of associated physicochemical and functional properties .Knowledge from related products, manufacturing processes, test methods, equipment, systems, and so on Knowledge from previous product and process development projects, both successful and unsuccessful Knowledge from the published scientific literature Experience from the manufacture and testing of related dosage forms and products, including deviations, customer complaints, etc. Prior knowledge, be it from the literature, experience with prior compounds/processes that are similar provides the basis for the initial risk assessments and influences a number of decisions that are made. Therefore, a good understanding of the documentation relating to prior knowledge referenced in risk assessments and DoEs is a must for the success of QbD. 3.0 ELEMENTS OF QUALITY BY DESIGN ICH Q8(R2): Pharmaceutical Development discusses the various elements of quality by design. These in combination with the enablers form the fundamental basis for the QbD approach to development. Figure 2 provides a pictorial representation of the typical elements of QbD. This section describes the various elements in detail and provides examples of the elements for controlled release (CR) products. Figure 2: Elements of quality by design R e v i e w P a p e r C o v e r e d i n I n d e x C o p e r n i c u s w i t h I C V a l u e 4 .6 8 f o r 2 0 1 0 Gupta Anuj* et al: Short review on Quality by design: A new Era of Pharmaceutical drug development Int. J. Drug Dev. & Res., July-September 2012, 4 (3): 19-26 Covered in Scopus & Embase, Elsevier 21 3.1. Identifying a Quality Target Product Profile (QTPP): The quality target product profile (QTPP) as defined in ICH Q8(R1) [6, 7] is a summary of the quality characteristics or attributes of a drug product that ideally will be achieved and thereby ensure the safety and efficacy of a drug product. The QTPP forms the basis of design for the development of the product and is developed with the end in mind. It is both prospective, that is, it describes the goals for the development team, and dynamic, that is, the QTPP may be updated or revised at various stages of development as new information is obtained during the development process. The FDA has published a guidance defining the Target Product Profile (TPP) [8], that focuses on the consumer (patient) and the desired product label. The QTPP is a subset of the TPP and is more oriented towards the chemistry, manufacturing and controls (CMC) aspects of development. 3.2. Identification of Critical Quality Attributes Pharmaceutical development consists of product and process design and development. The TPP provides the basis for the ideal dosage form. While designing a product and process, it is may be important to focus on the clinical performance, manufacturability, and global acceptability of the drug product. In the QbD paradigm, it is imperative that the manufacturing process is capable of accommodating typical variability in the inputs, resulting in a product that always meets the requirements of the QTPP. 3.2.1. Critical Quality Attributes (CQA): A critical quality attribute as defined by ICH Q8(R2) is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with raw materials (drug substance, excipients), intermediates (in-process materials), and drug product. Drug product CQAs derived from the QTPP are used to guide the product and process development. Drug product CQAs are the properties that are important for product performance, that is, the desired quality, safety, and efficacy. Depending on the CR dosage form, these may include the aspects affecting the purity, potency, stability, drug release, microbiological quality, and so on. CQAs can also include those properties of a raw material that may affect drug product performance or manufacturability. An example of this would be drug substance particle size distribution (PSD) or bulk density that may influence the flow of a granulation and therefore the manufacturability of the drug product. Similarly, the dissolution from a controlled release dosage form is dependent on the particle size of the polymer and the hardness of tablet. In this example, PSD and hardness can be designated as CQA’s. They are also commonly referred to as critical material attributes (CMA). Table 1. Table 1: Example of QTPP for a Typical Oral Controlled Release Summary Quality Target Product Profile and Identification of Critical Quality Attributes for a Typical Oral Controlled Release Product Quality Attribute Target Criticality Dosage form Dosage form could be matrix tablet, maximum weight XX mg Potency Dosage form label claim Dosing One tablet per dose, once daily Pharmacokinetics For example, controlled release over a period of 12 or 24 hr Related to dissolution Appearance Dosage form description Critical Identity Positive for drug name Critical Assay 95.0-105.0% Critical Impurities List specified impurities with appropriate limit; unspecified impurities with limit; total impurities with limit Critical Water Current limit (eg., NMT 1.0%) Critical/Not critical depending on API sensitivity to moisture Content Uniformity Meets USP/EP/other pharmacopoeia Critical Hardness NLT X SCU (preferred for film coating) for a tablet For example, can be critical if related to dissolution Friability Current limit (eg., NMT 1.0%) Dissolution Conforms to USP (eg., use a 5 point profile or NLT 10% in 0.1 N HCl for enteric coated tablets) Typically critical Microbiology If testing required, meets harmonized ICH criteria Critical only if drug product supports microbial growth R e v i e w P a p e r C o v e r e d i n I n d e x C o p e r n i c u s w i t h I C V a l u e 4 .6 8 f o r 2 0 1 0 Gupta Anuj* et al: Short review on Quality by design: A new Era of Pharmaceutical drug development Int. J. Drug Dev. & Res., July-September 2012, 4 (3): 19-26 Covered in Scopus & Embase, Elsevier 22 3.2.2. Quality Attributes Important to the Performance of the Drug Product: From a clinical perspective, safety and efficacy (product performance) is of prime importance. Thus, for an oral CR product, it is important to consider attributes that are potential surrogate(s) for performance. This may be drug dissolution/release, potency, polymer concentration, polymer viscosity, glass transition temperature (Tg) of composite, etc., or any other attribute that can either be substituted for drug release or clinical design space. 3.3. Quality Risk Assessment: A key objective of risk assessment in pharmaceutical development is to identify which material attributes and process parameters affect the drug product CQAs, that is, to understand and predict sources of variability in the manufacturing process so that an appropriate control strategy can be implemented to ensure that the CQAs are within the desired requirements. The identification of critical process parameters (CPP) and critical material attributes is an iterative process and occurs throughout development. During the initial phases of development, prior knowledge serves as the primary basis for the designation as there is not sufficient process/product understanding on the product under development. Therefore, the risks identified at the initial phases are perceived risks and as further process/product understanding is gained, the actual risks become clearer and a control strategy can be better defined. The risk assessment tools used in earlier phases of development therefore tend to be more qualitative and serve as a means to prioritize the experimentation. Typical tools used include risk ranking and filtering, input–process–output diagrams, Ishikawa diagram, and so on. Risk filtering and ranking is a tool for comparing and ranking risks. Risk ranking of complex systems typically requires evaluation of multiple diverse quantitative and qualitative factors for each risk. The tool involves breaking down a basic risk question into as many components as needed to capture factors involved in the risk. These factors are combined into a single relative risk score that can then be used for ranking risks. Table 2 is a typical example of risk filter that is used in early development to prioritize parameters/attributes with higher risk. This is typically qualitative in nature. Table 2: Example of risk filter during initial drug development Initial risk assessment DP QRA, showing the impact of critical parameters/attributes/process and its impact on the CQA Critical parameters factors