Conventional Medicine and Quality by Design - Essay Example

?Quality by Design The Conventional method of practicing medicine refers to the practice of allopathic medicine that uses pharmacologically active agents and physical interventions to treat and suppress symptoms or pathophysiologic processing of diseases or conditions. It was started by Samuel Hahnemann (1755-1843) a haemopath in 1810. Although allopathic medicine was rejected as a term by mainstream physicians it was adopted by alternative medicine advocates to refer to conventional medicine. With the term allopathy which also means “other than the disease” Hahnemann intended to point out how physicians with conventional training employed therapeutic approaches that in his view merely treated symptoms and failed to address the disharmony produced by underlying diseases. Haemopaths saw such symptomatic treatments as “opposites treating opposites” and believed these conventional methods were harmful to patients (Dalmaso, 2008). Therefore, Conventional medicine was used to refer to a system of medicine that combats diseases by using remedies that produce effects in a healthy subject that are different from the effects produced by the disease to be treated. As used by homeopaths, allopathy has always referred to the principle of curing disease by administering substances that produce other symptoms when given to a healthy human than the symptoms produced by a disease. For example, part of conventional treatment for fever may include the use of a drug which reduces the fever while also including a drug such as an antibiotic that attacks the cause of the fever such as a bacterial infection. Many conventional medical treatments do not however fit to be allopathy as they seek to prevent illness or remove the cause of an illness by acting on the etiology of disease (Rathore & Winkle, 2009). Due to these evidences the conventional method of medicine preparation faded away as it was traditional and replaced by Quality by Design (QbD). The QbD is a systemic approach to pharmaceutical development whereby it involves designing and developing formulations and manufacturing processes to ensure predefined product quality. An example of QbD method includes granulation among other processes. Some of the questions by design elements include; defining target product quality profile; designing product and manufacturing processes; and identifying critical quality attributes, process parameters, and sources of variability. By using QbD, pharmaceutical quality is assured by understanding and controlling formulation, manufacturing variables and product testing which confirms the product quality. Implementation of QbD enables transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment. According to Borman (2007), quality by design is a systematic approach to drug development which begins with predefined objectives and uses science and risk management approach to gain product and process understanding and ultimately process control. The concept of QbD can be extended to analytical methods and mandates to definition of a goal for the method and emphasizes thorough evaluation scouting of alternative methods in a systematic way to obtain optimal method performance. Candidate methods are then carefully assessed in a structured manner for risks and are challenged to determine if robustness and ruggedness criteria are satisfied. The main goal of QbD is to embed quality into pharmaceutical products to ultimately protect patients’ safety. Drug development using the principles of QbD emphasizes a systematic approach atarting with predefined objectives and applying scientific understanding and risk management approaches. Two concepts are applied in QbD which where by the first concept is design space which generally involves the identification of critical attributes for the input materials, the process and the final product. Applications of traditional analytical methods in Qbd process development show that most QbD applications have not focused on the analytical methods but instead have been implemented in the context of the overall pharmaceutical manufacturing process with emphasis placed on the process understanding gained by application of QbD principles and in some cases the development of a design space and control strategy for a process. When enough information is collected, process analytical technologies can ultimately lead to real time release testing (RTRT) wherein end-products analytical testing is no longer necessary to ensure product quality as the real time information gathered already provides a guarantee that the product is acceptable (Sun, Liu & Kord, 2010). Methodological aspects of QbD Beyond the use of traditional analytical methods in QbD application its possible to apply QbD principles to the development of the analytical methods. QbD approach can lead to better analytical methods and can positively impact the broader QbD aspect of drug development since the data from these methods underpin much of the QbD process. QbD can also be approached in a different way which involves the definition of an analytical target profile (ATP), a set of criteria of the method but without specifying it (Borman 2007). By using material, process, and product attributes as input, the ATP thus defines the analytical variable to be measured for example the level of a specified impurity, as well as the performance characteristics to be obtained by this measurement for example accuracy, precision, and range. The ATP provides a link between the eventual analytical method and the chemical or formulation methods. A process that can be chemically defined for example the need for a particular analytical method to measure impurities at a certain level can be defined in an ATP. Throughout the development lifecycle, a host of methods can be developed to meet the ATP. Equally, Dalmaso (2008) believes that a relatively efficient method that achieves the initial ATP can be developed near the product launch. The principle motivating factor behind the ATP approach is the desire to gain flexibility in the method used to perform testing and avoid costly post-approval changes to the registered analytical methods that require proactive discussions with regular controls. Otherwise under this as generic scenario, each method that meets the ATP would be appropriately validated and documented but would not require changes to the registered method, as only the ATP would be registered. The analytical method development adopts the principles of QbD to build quality into the method during development rather than test the method after development. Because of this the actual method development process for an analytical QbD method should follow a structural approach. Traditional analytical method development can incorporate some structural aspects, but often is applied in a reactionary manner to address issues experienced (Larew 2010). Some of the methods for development under QbD include: Goal of the method According to Sun, Liu and Kord (2010), the goals and intent of the method to be developed must be clearly defined at the outset, if the method is to comply with QbD principle of predefined objectives. Beginning with a method goal also helps to emphasize the need for product and process understanding. A number of factors such patient safety, product efficacy, and quality requirements as well as prior knowledge of similar drug compounds on the market must be taken into consideration for the development of a method goal. The operational intent of the method and end user needs must also be considered, including instrumentation capacities at future testing laboratories, geographical location and climate of the laboratories and potential constraints on access to chemical reagents reacting. The method goal concept can be illustrated using high performance liquid chromatography ( HPLC) as an example API is generally to separate and quantify the main compound and the critical quality attribute (CQA) impurities that may impact the quality of the drug product. Method performance criteria must be achieved based on regulatory requirements such as specificity, linearity, accuracy, precision, sensitivity, robustness and ruggedness. Determination of certified quality auditor impurities is a key objective of the high performance liquid chromatography (HPLC) separation, analytical chemists generally work closely with other functions to asses the manufacturing process starting materials, active pharmaceutical ingredient(API), and drug product to identify process related impurities and degradation products. Clear identification of the markers for the impurities are are generally required. Background information is collected prior to starting experimental method development activities, including physicochemical characteristics such as pKa, ultraviolet (UV) chromospheres, solubility, and chemical stability (Li, Terfloth & Kord, 2009). Operational intent of the method is referred to as the operational factors taking into account the actual laboratory environments in which the methods will be used, including factors such as the typical temperature and humidity in the laboratory, reagent availability and requests from quality control laboratory staff. Scouting and evaluation According to Li et al (2009), the use of detailed flowcharts and decision trees to aid the analyst in deciding among the options should be adopted during method scouting immediately the method goal is in hand. Even though it is possible to capture all knowledge about a technique in such a format, it is possible to capture many important points frequently encountered during method development for many of the techniques of interests, such as HPLC. Flowcharts and decision trees seek to combine traditional knowledge of best practices in an analytical discipline with current state of the art approaches to method development. By using these tools, the scouting and evaluation of methods then follows a systematic experimental approach design. This approach can be augmented by automation and the scouting experiments are followed by optimization of chromatographic performance using simulation software, wherein experimental data from scouting experiments are entered into the software, which then simulates and predicts separations for a very large number of chromatographic conditions based on the limited data set obtained in the scouting experiments (Schweitzer et al 2010). Experimental data and predicted separations provide a comprehensive database that assists with method understanding, optimization, selection and can be used to evaluate and implement future changes to the method for example if a particular impurity is no longer relevant to the process. Selection and risk assessment After systematic method scouting and evaluation, methods that best meet the method goal can be selected for risk assessment. The risk assessment ruggedness and robustness testing supersede the identification and prioritization of risks in a structured fashion. In some cases, the risk assessment process can be conducted without identification of any significant risks once the primary method has been identified by scouting and evaluation. Nevertheless, a precautionary action should be availed in case potential problems are indicated in the assessment of the primary method. However, Rathore, AS & Winkle, H 2009) deduce that if well-chosen desirable method attributes are overlooked over the final method selected against, the reliability of the selected method should be guaranteed. Through limiting the amount of work necessary to demonstrate ruggedness and robustness and the number of controls that must be fixed, the consideration will have factored in the risk assessment for the method. Control strategy According to Yu (2008), the control strategy is an important QbD feature of an analytical method, because it assures that the method is performing as intended on a routine basis. When implementing a method control strategy several factors can be identified as a result of risk assessment activities. If the risk assessment activities indicate that the overall understanding of method performance can be improved, and the risk to obtaining reliable data is high and difficult to manage, a more appropriate method may be needed. The method control strategy can be defined if the risks are low and well managed, which generally consists of appropriate system suitability criteria to manage risk and ensure the method delivers the desirable method attributes. After method development, method validation is a key activity that traditionally occurs. Validation exercise is typically a separate activity, removed from development which occurs only once. Conclusion Although the field is in its infancy, the outcome of science- and risk-based approaches will ensure optimal performance and reliability of methods and the data generated. Importance of the outcome of a successful QbD analytical method development is that its robust, rugged and that it will likely be useful for many years with few problems. The field of analytical QbD is likely to continue to develop within pharmaceutical industry as favorable results have already been realized from its application. The most common benefit includes methods that are more robust and rugged and thus survive the challenges of long-term usage by quality control and manufacturing laboratories with a decreased likelihood of failing. The approaches published to date emphasize the structured development of a method through sound decision-making obtained from scouting and evaluation of methods. The knowledge built up during the development of complex methods (such as HPLC methods for impurity profile) is used to select methods that meet pre-defined, stringent performance criteria and goals. These methods are then thoroughly assessed for risk, amended and optimized as appropriate, and challenged with performance-stretching tests before being released for use in other laboratories. The development of analytical QbD hinges on continued investment by industry members, and the avoidance of generic methods except in cases where such methods and associated risks are already well-understood. Reference list Borman, P, Nethercote, P, Chatfield, M, Thompson, D, and Truman, K 2007, The application of quality by design to analytical methods, Pharm Tech, vol. 31, pp. 142–152. Dalmaso, G. 2008. Product Real Time Release for the Micro-bial Critical Quality Attribute Using QbD Approach. American Pharmacology Review, no. 11, vol. 3, pp. 10-16. Li, Y, Terfloth, GJ, & Kord, AS 2009, A Systematic Approach to RP-HPLC Method Development in a Pharmaceutical QbD Environment, American Pharmacology Review, vol. 12, no. 4, pp. 87–95 . Rathore, AS & Winkle, H 2009, Quality by Design for pharmaceuticals: International Regulatory perspective and approach, Nature Biotechnol, vol. 27, pp. 26–34. Schweitzer, MG, Pohl, M, Hanna-Brown, M, Nethercote, P, Borman, P, Hansen, G, Smith, K, Larew, J 2010, Implications and opportunities of applying QbD principles to analytical measurements, Pharm Tech, vol. 34, pp. 52–59. Sun, M, Liu, DQ & Kord, AS 2010, “A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities“, Organic Process Research & Development, vol. 14, pp. 977-985. Yu, L 2008, Pharmaceutical quality by design: product and process development, understanding and control, Pharmacology Research, vol. 25, pp. 781–791. Read More