QbD (Quality by Design) Has industry benefited from this? WHITE PAPER.

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1 WHITE PAPER

2 There are many facets to engineering for a healthier world. It is important to understand what surrounds us today and look into what we believe will surround us tomorrow. This article is planning to bring the big misunderstanding the Pharmaceutical Industry has about the nature of new trends in pharmaceutical development and manufacturing: the concept known as Quality by Design (QbD), it also discusses some of the interesting angles on this new concept. Current views on the implementation of QbD in the development of Generic Drugs are also captured in this article in an attempt to give a broad picture on current practices and what to expect in future. This article emphasizes the importance of TPP, TPQP, and CQA in QbD for pharmaceutical development. Identification of CMAs, CPPs provide links to product quality. Control strategy and design space are implementation of QbD elements into practice. Presently the QbD is becoming essential approach to the pharmaceutical quality. The Big Misunderstanding As in the old tale of the blind men touching different parts of an elephant and then producing conflicting experiences, a part is taken for the whole, and the unity that permeates all of the parts of the elephant in its entirety remains unseen. Similarly misconceptions about the nature of Quality by Design (QbD) add up to a fragmented understanding. Many of you have heard about QbD, but what and why QbD when there are so many other frameworks and tools that are available? To put it simple, QbD is about focusing on the product and the patient from the outset. Understanding the quality risks of a pharmaceutical product to the patients - and then systematically tracing back into what is critical. Initially, what is critical about the product and then what is critical in the raw materials and in the manufacturing processes. QbD is not only about development There is a tendency in the pharmaceutical industry towards using QbD to develop medicines in a smarter and cost-effective way, but QbD is not only about development it has far wider applications. The main reason for the sluggishness in implementing QbD by the industry is all about the regulatory fear of not getting the product approved by the health authorities, but the fact is that the industry itself is responsible for the bottleneck. In 2004 the FDA had released Process Analytical Technology (PAT) - A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, since then its importance has been discussed. QbD is not only an integral part of PAT but in fact include PAT under the larger principle of designed quality. Further, the FDA made it clear from the beginning that the goal of PAT is not the technological automation of process control, but comprehensive process understanding, as the PAT guidance says, a process is generally considered well understood when all critical sources of variability are identified and explained. As the PAT initiative and the concept of designed-in quality appeared at first to be focused on drug development, the misconception arose that QbD was also primarily for use in developing drugs and the manufacturing processes that would be used to produce them. But the FDA also encouraged improved process understanding and continuous improvement of manufacturing processes for products already in the market. 02

3 QbD applies to all phases of the product life cycle: drug development, scale-up, manufacturing of both new and marketed products and technology transfer of processes and products to other sites. In drug development, for example, the potential of design space understanding leading to robust manufacturing processes is perhaps the most widely understood aspect of QbD. But QbD offers a further advantage here, because development usually takes place over a long period of time and often involves many people; it can sometimes result in misunderstandings, errors, and redundant activity. QbD keeps an understanding of design space at the forefront of development efforts, providing the coherence and continuity that trial and error approaches lack. QbD can also help maintain lifetime development the continued gathering of data after a product is already in production. Because only a limited amount of data accumulates during initial development, additional data, framed by the product s design space, can be helpful in deepening process understanding and continually improving the process. In January 2011, the FDA published a new guideline on process validation that builds on the concept of QbD. It is already being enforced by FDA investigators during inspections. However, with or without the new process validation requirements, QbD is a new manufacturing paradigm in the pharmaceutical industry. But when we shred away all the hype, we see that the concept has been around in other industries for many years. Other industries have done it without any regulatory involvement, simply because it makes good business sense. Today many business benefits that these industries have enjoyed for years are becoming available to pharmaceutical companies. QbD is here. It is time for the industry to remove the blinkers. An Overview of Quality by Design for Generic Drugs. The regulatory agencies (USA, European Union and Japan) have made significant progress in implementing the concept of Quality by Design into its pre-market processes. ICH guidelines Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System) provide guidance for manufacturers to apply Quality by Design into their own operations. Pharmaceutical Quality by Design (QbD) is defined as designing and developing formulations and manufacturing processes to ensure predetermined product quality. Quality cannot be tested into products; it must be built into products. Quality by Design assures in-vitro product performance which provides assurance of in-vivo product performance. Description: Tools of Quality by Design Design of experiments (DoE) Risk Assessment Process Analytical Technology (PAT) Quality by Design is important because In product and process development for ANDAs Quality by Design (QbD) is becoming the most critical component. It is highly recommended to use the QbD approaches as part of product and process development strategies The importance of QbD approaches during the technical review of an ANDA is increasing day by day, so it is essential for the generic industry to understand the expectation of Office of Generic Drugs 03

4 The main objective of the generic pharmaceutical industry is ensuring the product quality. The generic industry follows the same concepts and principles set by the FDA incorporating the concept of "Quality of Design" as core content in production and manufacturing. QbD is important for generic manufacturers who continue to produce high quality medicines for all consumers. Quality is built into a product with a thorough understanding of the process by which it is developed and manufactured, and an intense responsiveness of both the risks involved in manufacturing the product and the best ways to decrease those risks. QbD provides the scientific structure to know all critical aspects of a drug formulation and manufacturing process. QbD enables to reproduce the highest quality product from batch to batch and year to year. Design goals: The following flow chart describes overview of Quality by Design Overview of Quality by Design Labeled Use Safety and Efficacy Knowledge Space Define Target Product Quality Profile Design Formulation Design Process Identify Critical Material Attributes and Critical Process Parameters Establish Control Strategy Monitor and Update Process TARGET DESIGN IMPLEMENTATION The variation between QbD for NDAs and ANDAs are at target product profile step i.e. for NDAs, TPP is under development whereas for ANDAs, the TPP is well reputable by the labeling and clinical studies conducted to support the approval of the reference product. Target Product Profile (TPP): The purpose of a TPP is to provide a format for discussions between a sponsor and the FDA that can be used throughout the drug development process, from pre-investigational new drug application (pre-ind) or investigational new drug application (IND) phases of drug development through post-marketing programs to pursue new indications or other substantial changes in labeling. The TPP embodies the notion of beginning with the goal in mind. That is, the sponsor specifies the labeling concepts that are the goals of the drug development program, documents the specific studies intended to support the labeling concepts, 04

5 and then uses the TPP to assist in a constructive dialogue with the FDA. The ideal version of what the sponsor would like to claim in labeling guides the design, conduct, and analysis of clinical trials to maximize the efficiency of the development program. Ideally, the final version of the TPP will be similar to the annotated draft labeling submitted with a new drug application (NDA) TPP provides a statement of the overall intent of the drug development program and gives the information about the drug at a particular time in development. The pharmaceutical development contains identification of attributes that are critical to the quality of the drug product, taking into consideration intended usage and route of administration through the TPP. The generic version and its reference product would expect to have the same TPP. At the laboratory scale the quality attributes of product manufacturing will be evaluated by the relevant ANDA sponsor can confirm the productive formulation. ANDA sponsors agree that a formulation design space would be valuable to industry if appropriate regulatory flexibility is granted. Process design is the first stage of process development which contains documentation of commercial scale manufacturing process and scale up of manufacturing. The main factors considered for the process design and process development are facility, material transfer, manufacturing variations, equipment, QTPP and CQA. Preliminary feasibility studies may be necessary to conduct before completing the process development, it is depending upon the type of product development, type of process, and process knowledge. Physicochemical properties of the materials and excipients may influence the type of process Target Product Quality Profile (TPQP): Pharmaceutical scientists had further translated the qualitative TPP into Target Product Quality Profile (TPQP) for further use in a Quality by Design Process. TPQP is a quantitative alternative aspect of clinical safety and efficacy that can be used to design and optimize a formulation and manufacturing process. TPQP contains only patient relevant product information, it does not contain any specifications, it contains tests like stability, bioequivalence etc. which are not carried out for every batch. Critical Quality Attributes (CQA): Determination of CQA is the next step after developing a QTPP in drug product development. CQA is appropriate for attributes of the drug product. CQA are the physical, chemical, biological or microbiological properties or characteristics, which should be within the limit range distribution to ensure the desired product quality. CQA includes product attributes that alter by changes to process parameters or formulation variables during pharmaceutical development that directly related to the safety and efficacy of the drug product. Any change in QTPP or CQAs, will directly impact on the product development report. Identification of critical process parameters (CPPs) and critical material attributes (CMAs): Manufacturing processes of pharmaceuticals contains a series of unit operations to produce the desired quality products. Material attributes are physicochemical or microbiological properties or characteristics of input or output materials. The output of the process depends on the process parameters and input material attributes. Process parameters include type of equipment settings, operating and environmental conditions (time, temperature, pressure, ph, speed and moisture). In-Process-Robustness studies are evaluated by effect of variations in process parameters and input material attributes. The limit on CMAs and CPPs are either scale independent (Design space) or scale dependent (Multivariate experiments). The process robustness studies are risk based because more studies are performed with complex products and fewer studies are performed with simple low risk dosage forms. Risk assessment and design space: By performing risk assessment prior to the pharmaceutical development manufacturer has to decide which study to be conducted. By knowing which variables are critical and which are not by study results, it can guide the establishment of the control strategy for in process, raw material and final testing. Design space is a multidimensional combination and interaction of material attributes and process parameters which provides assurance of quality. Design space is a living document, which should be reviewed periodically as a part of quality 05

6 system. Any change out of design space would be considered as a regulatory post approval change. Design space determined at the development level may not be relevant to the commercial process. Therefore design space verification is essential at commercial scale. Scale up and control strategy: Scale up is mainly based on general rule of thumb & trial and error approaches. During the scale up process, the process parameters vary but not the material attributes. Scale up with QbD can avoid the higher risk. Control strategy defines in ICH Q8 (R1), specifically control strategy includes Control of input material attributes (Critical Material Attributes) Controls for unit operations (CPPs and Process end points) Product specifications In-process real time release testing In-monitoring program for verifying multivariate prediction model Conclusion: Quality Saves Life: Quality assurance of pharmaceuticals is a major public health challenge, particularly in the light of growing cross-border health issues and the international dimensions of trade. The pharmaceutical industry and its regulators are strongly focused on all quality issues because at the end of the day, drugs often make the difference between life and death. It is therefore crucial that patients can trust the producers of their medicine. The approach to quality management in the pharmaceutical industry has to change. And the industry should see the advantages that other industries have enjoyed for years of developing much more advanced and cost-effective quality techniques. For the pharmaceutical industry, Quality by Design is not only about adjusting to a new set of requirements - it is an opportunity to import modern quality management techniques and use them for more cost-effective manufacturing and quality management. Reach us at: consulting@makrocare.com 06