Why Validation Is Important In Manufacturing Of Drugs - Essay Example

Summary Validation is required for the manufacture of a medicinal product since this enhances the quality of a medicinal product manufactured. Validation comes from a variety of methods. Use of quality management systems is one of the ways of ensuring the validity of a medicinal product since this ensures that the accreditation procedures have been followed to the latter. The V model is another avenue of enhancing validation of a medicinal product since it stipulates the specifications upon which requirements are measured and evaluated. They will further be discussed in the introduction and discussion of this report. Medicinal products are affected by manufacturing facility used in its synthesis. Enteral, parenteral and topical are the different techniques used in drug administration. These forms of drug administration influence the type of tests that should be done on medicinal products. There are guidelines proposed in the good management practices, which define quality control, equipment and facility requirement for manufacture of medicinal products. Different countries have come up with a harmonized GMP while WHO developed GMP which are used in most developing countries. Introduction Medicinal Product Terms According to European Medicines Agency (2000, p.2), a drug substance is defined as an active ingredient intended to accomplish a pharmacological activity or a direct effect on the treatment, prevention of disease, diagnosis, cure, mitigation, or to influence the function or structure of the human body. However, European Medicines Agency (2000, p.2) explains that drug substances do not include intermediates used in the manufacture of such ingredients. A drug substance is affected by the manufacturing facility used in its synthesis where Balogh and Corbin (2005, p. 56) observe that drugs produced in facilities that do not compile with good manufacturing practices may have toxic materials which may be introduced by unclean air or low-quality water. In addition, cross-contamination may happen to other chemicals being used in the facility. Viruses and bacteria may also contaminate drug substances where they could be introduced by operators working in the manufacturing facility. A drug product refers to a finished dosage form such as capsule, tablet, or solution that contains a drug substance. A drug product is a dosage of the final primary packaging intended for marketing. Packaging is important to protect the drug product from adverse external influences that can change the properties of the product as observed by Bhat (2000, p 3). Packaging is also used to help in the identification of the product and protect the drug product from physical damage. There are various techniques applied to the drug administration. (Lees, Cunningham and Elliott, 2004, p. 396) explains that drug administration via the gastrointestinal tract also referred to as enteral or enteric administration. This form of administration includes drug administration through either the mouth or rectum where the drug does into the intestines. Parenteral drug administration is where the drug is administered by other routes other than the digestive system. This can be either through intravenous, intra-arterial, intramuscular, or intracerebral. On the other hand, topical administration is when a substance is applied directly to the place where the action is required. Good Manufacturing Practices (GMP) To ensure the efficacy and the safety of drug products consumed, pharmaceutical companies are required to observe some manufacturing practices. Good manufacturing practices are defined as the ways and systems that pharmaceutical companies need to adapt to in manufacturing, quality assurance, manufacturing and quality systems testing of drugs, diagnostics reagents, medical devices, and foods. GMPs set out guidelines on the aspects that can have an effect on production and testing of the quality of a product. Different countries have legislated different GMPs guidelines but the basic principles of GMP include; the requirement that the manufacturing processes should be clearly defined and controlled. Moreover, any changes to the manufacturing process of drugs must be evaluated and validated to prevent any negative impact on the quality of drugs. GMP calls for the documentation of drug manufacturing process and instructions and procedures must be written clearly. In addition, records of manufacture must be filed to allow for the tracing of the drug history and a system must be put in place to enable recall of drugs from the market. World Health Organization (WHO) has developed GMP guideline which is used in pharmaceutical industry in more than a hundred countries world over mostly in developing nations. The countries within the European Union and America’s Food and Drug administration follow similar GMP as those developed by WHO. In the UK, the Medicines Act of 1968 contains most aspects of GMP, in what is commonly referred to as the Orange Guide. Medicines and HealthCare Products Regulatory Agency is the organization charged with the responsibility of enforcing GMP in the UK. Countries have come together to harmonize the GMP and in 1999, there was the publication by International Conference on Harmonization (ICH) of GMPs for Active Pharmaceutical Ingredients as explained by Balogh and Corbin (2005, p. 56). These guidelines are currently used in countries that are signatory to the ICH. Quality Management Systems Quality management entails factors that are necessary to be fulfilled by a product and their fulfillment and lack thereof determines the quality of the medicinal product developed. Quality management systems ensure that manufacturing practices are followed to the later in the design and development of a medicinal product. Consequently, quality management ensures that there was a clear specification of operations of control taken into consideration in manufacturing the medicinal product. In addition, quality management systems ensure the responsibilities of the managers are specified clearly and that adequate arrangements have been put in place for the packaging and supply of manufactured medicinal products (EudraLex, 2005, p. 1). Also, quality management ensures that correct procedures are followed in the checking and processing of finished medicinal products. Moreover, quality management places sanctions against the sale of medicinal products prior to the certification by a qualified medical practitioner. The quality management system also outlines the storage, distribution, and handling of the medicinal products to ensure that their quality is maintained prior to their expiry dates (EudraLex, 2005, p. 1). ISO 9001 is referred to as the genesis of accreditation of manufactures and all other specialized accreditation facilities stemmed from ISO 9001. ISO 13485 is an example of a certification accrediting quality management system that is awarded to manufacturers of medical devices. It is evidence that the particular manufacturer adheres to the quality assurance programs prescribed and includes the design, installation, manufacturing, servicing, and control. This is required for manufactures of medicinal products since through this accreditation; they are allowed to affix the accreditation number with their products. This enhances consumer satisfaction as customers regard accredited facilities as providing valid and certified products (Management System Certification, p. 1). Validation and the V Model The V model is a model that has been accepted universally. It is known as a V model since it assumes a letter V by comparing the activities on the right side with requirements specified for the particular activity on the left side. Any medicinal manufacturing company is entitled to come up with a V model that is modeled to verify that the design in each stage in verification and validation goes as per the set down requirement. Application of the V model in the manufacture of a medicinal product enhances the validity of a product as it means that all the requirements in the manufacture of the product have been adhered to the latter (Deshpande, 2008, p. 1). The V model commences with the user requirement specifications. This can be compared with a top-bottom approach whereby the design of a medicinal product commences form the needs of the user. It is designed to suit the specifications of the user and this appears on the right side of the V model. This is compared with the performance qualifications. It is aimed at ensuring that the medicinal product performs as per the requirements specified on the right side of the V model (Deshpande, 2008, p. 1). Functional specifications follow the user specifications. This entails that the role of the medicinal product is outlined at this juncture. The category of the medicinal product; analgesic, anesthesia, the anti-inflammatory is specified. The drug manufactured should meet the functions which it was designed to accomplish. The functional specification is compared with the operational qualifications. This ensures that the operations are encompassed into the functions of the medicinal products. The operations qualifications ensure that the function of the drug meets its optimal qualifications and does not produce effects not designated for the manufacture purposes (Deshpande, 2008, p. 1). The design specification is the final component in the V model. Design precedes the implementation phase entailing the utilization of the medicinal product by the prescribed users. This entails that the V model needs to specify how the medicinal product following its manufacture will reach the targeted audience and remain viable. It includes the packaging design, transportation design, storage design and dispatch design. On the left side, it is compared with the installation qualification. This ensures that the designs meet the qualifications prescribed for the medicinal products and hence enhancing the validity of the medicinal product manufactured (Deshpande, 2008, p.1). Discussion Product Quality Attributes and Process Parameters for medicinal products There are critical assessments that are required to validate all new drug substances. According to European Medicines Agency (2000, p.24), a description of the drug substance outlining the state, and color of the new substance should be provided. Any changes during the storage of any characteristic are then investigated and the appropriate action taken. European Medicines Agency (2000, p.2) further explains that specific identification testing should be conducted for the new substance which may be done by use of various technologies such as infrared spectroscopy. To validate the suitability of the drug substance, it is important to carry out assay which is a procedure to determine the stability of the new drug substance. Lastly, ICH Guidelines calls for tests to be run to determine the presence of any impurities in the drug substance. New drugs also require to be validated before they can be supplied. A description of the new drug product includes a qualitative statement on the size, shape, and color of the new product. The new product is evaluated for any changes during its storage. European Medicines Agency (2000, p.23) asserts that the new drug product requires an identification to establish its identity. Similar procedures as those used for drug substances are used. Assay and impurity tests are also conducted for all new drug products. According to European Medicines Agency (2000, p.26), there may be other specific tests carried out on the case of cases for new drug substances and products. For new drug substances physiochemical properties which include melting point, the pH and refractive index may be conducted. The particle size of the drug substance may also be conducted for substances intended to be used in suspension or solid drug product. This is because particle size can have a significant effect on dissolution, stability, and bioavailability of the substance. Water content test is also crucial for drug substances known to be degraded by water or are hygroscopic. Further, microbial tests are conducted to determine the total count of aerobic micro-organisms. Given the varying drug administration techniques, drugs products are validated using different tests. For tablets and hard capsules, it is important to carry out dissolution tests to determine the release of drug substance from the drug as observed by European Medicines Agency (2000, p.26). The hardness of the drug tested. For oral liquids, uniformity of the dosage, pH, and microbial tests need to be done. It is also critical to carry out redispersibility tests to determine whether shaking will allow for redistribution of oral suspensions that settle after storage. Specific tests for parenteral drugs include; tests on the uniformity of the dosage, pH, sterility, endotoxins, particulate matter and water content. Moreover, tests on antioxidant preservative content, antimicrobial preservative content and reconstruction time have to be carried out. GMP Compliance Efficiencies To ensure compliance of pharmaceutical companies with GMP, regulator authorities carry have to carry out an inspection of their manufacturing facilities. This is conducted to ensure that medicinal products are manufactured in a safe environment and where the products cannot be contaminated by externals micro-organisms and chemicals to ensure the safety of the drug user. In addition, regulatory authorities carry out an inspection to help in assuring the efficacy of the medicinal product when consumed. The inspection is aimed to give the drugs a clean bill for various uses. There are different GMPs developed by EU for the manufacture of drug substance and those of dealing with finished products. All finished products require process validation as one of the GMPs. Validation is defined as the process of providing documented evidence that the process achieved all it intended to do. Process validation satisfies that the manufacturing method is accurate, specific and be reproduced. CFR 211deals with the current manufacturing practices for finished pharmaceuticals where it outlines packaging and labeling requirements, handling and distribution procedures and records and reporting. CFR 211 also specifies the buildings, facilities, and equipment. ICH Q7, on the other hand, deals with the manufacture of drug substances. The guideline deals with practices dealt with by CFR 211. The practice calls for inspection of packaging materials, facilities and buildings as observed from ICH Expert Working group (2000, p. 5). In addition, laboratory testing of substances and return of unsuitable drug substances materials. Key enablers for a Quality Management System Quality management has evolved to be a continuous process and not a fixed process carried out at the end of a month or trading period as was applied before. This continuous evaluation entails appraisal of systems as feedback is provided for correction and improvement purposes. For quality management to be effective, the key players involved are broadly classified into: structure, process and the outcome (Carman, et al. 2010, p. 283). The structure in quality management system applied in the manufacture of a medicinal product entails the organization heads and the manufacturing company as a whole. This entails the building which should be accredited for the manufacture of the medicinal product for the product to be valid. Consequently, the structure entails the opinion holders of the manufacturing company encompassing the leaders who should be qualified to supervise the manufacture of the medicinal product (Carman, et al. 2010, p.283). The process is the period between conception and output of a finished product. A successful quality management system is anchored on valid processes employed in the manufacture of the medicinal product. This entails the machinery used in the manufacture, they should be valid. Also, the staff deployed for the manufacture purposes should be qualified and the materials used for the manufacture of the medicinal product should be quality materials. The process is an essential key player for the success of a quality management system as it is the core of the whole quality and validity of the medicinal product (Carman, et al. 2010, p. 283). The outcome is the final medicinal product generated following the interplay of the process and the structure. The effectiveness and efficiency of the medicinal product determine the success of the quality management system. This is since it is a symbol of complete quality having been implemented throughout the manufacture of the medicinal product hence making the product fit for the consumption of the product. This affirms the quality management system of the organization among the consumers increasing the credibility of the medicinal product (Carman, et al. 2010, p. 283). Cost Effective Validation Prior to carrying out a validation exercise, it is important for a medicinal manufacturing company to carry out a cost feasibility study. This is aimed at comparing the benefits of a validation program with the demerits and the cost incurred in the validation program. This is achieved through gathering adequate information prior to carrying out a validation study. This will give the manufacturer adequate information as pertains to the best decisions that will give him the best possible outcome. Through this, the manufacturer of medicinal products develops subject matter expertise since he is able to know what ventures generate the best outcomes and those that lead to massive losses (Ruggles, 2005, p. 90). Consequently, cost-effective validation can be achieved through having a variety of designs and methods to choose from. Through this, the manufacturer is able to able to have a wide decision base and hence select the alternative that gives him the best returns and cost least. Also, the medicinal manufacturer should aim at selecting a design that delivers information and products to the customers in the most time and cost-effective manner. This calls for the need of a wide base of research that leads to the manufacturer having a wide base knowledge on the most cost-effective validation method (Ruggles, 2005, p. 90). Cost effective validation is also enhanced by risk-based decision making. This is encompassed in strategic management whereby the manager takes greater risks, expecting greater benefits in future. It means that for a cost-effective validation of a medicinal manufacturing company, the manager needs to carry out a SWOT analysis. This entails the manager evaluating his strengths and comparing them with his weaknesses. The manufacturer also needs to use his opportunities and mitigate his threats and hence have a cost-effective validation process. Once a manufacturer of a medicinal product is aware of his internal and external environment, he is able to come up with business ideas that will lead to a more cost-effective validation (Ruggles, 2005, p. 90). Conclusion Validation is an important aspect of ensuring the quality of a product. The manufacture of a medicinal product is a very sensitive process since it entails a final product consumed by human beings. The quality management system is an avenue that can be employed by a medicinal manufacturing company to enhance the validity of its medicinal product. This is since the organization has to meet the accreditation means stipulated by the quality management system like ISO 13485. The V model is another measure of validity that compares specifications with the delineated requirements. This ensures that the medicine manufacturing company adheres to the requirement in the design and final conception of a medicinal product. In response to the question in this paper, validation of the manufacture of a medicinal product is important as it enhances and assures the consumer of the quality of the medicinal product. In the manufacture of medicinal products, different guidelines have been developed to ensure the safety and efficacy of these substances. Different countries have come up GMPs to control the pharmaceutical industry. In addition, there has been a move to harmonize GMP with International Conference on Harmonization and WHO coming up with guidelines being used in many countries. References Balogh, M. & Corbin, V 2005, 'Taming the Regulatory Beast: Regulation vs Functionalism', Pharmaceutical Technology Europe, vol. 17, no. 3, pp. 55–58. Bhat, J. M 2000, ‘Role of Packaging material on Pharmaceutical Product stability’ pp. 1-10 accessed 23 January, 2011 Carman, J, Shortell, S, Foster, R, Hughes, E, Boerstler, H, O’Brien, J, and O’Connor, E “Keys for successful implementation of total quality management in hospitals” Health Care Management Review: 2010: 35 (4): pp 283- 293. Deshpande, G, “V Model & Validation Process- in the Pharmaceutical Industry- FDA perspective” SAP AG, 2008: 1-8. 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