=~ Institute of Good Manufacturing Practices India Global accredited training & certification provider Conferred with QUALITY COUNCIL OF INDIA (QCI) - D.L. SHAH NATIONAL QUALITY AWARD & ASSOCHAM Services Excellence Award 2017 Trusted by organizations & training participants in over 30 countries ‘Training | Certification | Edueation | Research New Delhi | Noida | Vadodara STUDY RESOURCES Module: 5 {Intended only for the personal and confidential use the designated recipients] YeAdvisory Board Kindly view the website links [Link]/[Link]! to know about advisory board of the Institute. All rights reserved. No part of this study material can be reproduced or transmitted in any form or by any means whatsoever without express written permission from Institute of Good Manufacturing Practices India (IGMP!) Icme1 1119, H-Block, Sector 63, NOIDA, Delhi National Capital Region (NCR), Pin Code 201307, India. Phone: +91 8387838177, +91 8130924488, 0120-2427175 E-mail: infoo@[Link]‘TABLE OF CONTENTS Pharmaceutical Regulatory Affairs (Module 5) Quality Assurance and Drug Regulations, ICH and WHO guidelines Contents: "Quality Assurance = Quality Control = Need of Quality Assurance * Principles of Quality Assurance = Elements of Quality Assurance * Quality Management a. Principles b. Responsibilities of the Quality Unit(s) c. Responsibility for Production Activities d. Internal Audits (Self Inspection) e. Product Quality Review = Total Quality Management = The Plan, Do, Check, Act (PDCA) Cycle Of TQM © Stability testing: ICH and WHO guidelines © ICH guidelines * Stability testing of new drug substances and products * Stability testing: Photostability testing of new drug substances and products * Stability testing of new dosage forms = Bracketing and matrixing designs for stability testing of new drug substances and products "Evaluation of stability data © WHO stability guidelines © [Link] Part 211.166: Stability testing For feedback:info@[Link]QUALITY ASSURANCE Quality is a measure of excellence or a state of being free from defects, deficiencies and significant variations. itis the central aspect of a product that is determined by the consumer and includes attributes such as safety, reliability, serviceability, and attractability. Product quality is constantly changing to meet changing consumer demands. A perception of high quality or that Which is above expectations can help to create high brand loyalty and in turn helps create brand equity for the company. It is brought about by strict and consistent commitment to certain standards that achieve uniformity of a product in order to satisfy specific customer or user requirements, ISO 8402-1986 standarddefines quality as "the totality of features and characteristics of a product or service that bears its ability to satisfy stated or implied needs." Most of the organizations have a product Quality Assurance and Quality Control department that monitors outgoing products for consumer acceptability Quality Assurance (QA) is defined as a procedure or set of procedures intended to ensure that a product or service under development meets specified requirements. It is the activity of providing evidence needed to ensure that activities are being performed effectively So as to provide enough confidence that a product or service will satisfy the given requirements for quality. It refers to administrative and procedural activities implemented in a system so ‘that requirements and goals for a product, service or activity will be fulfilled. Quality Assurance is a concept used in developing products and services where it checks whether a product or service being developed is meeting specified requirements. Many companies have a separate department devoted to quality assurance. A quality assurance system is said to increase customer confidence and a company's credibility, to improve work processes and efficiency, and to enable a company to better compete with others. Quality assurance systems emphasize catching defects before they get into the final product. For those in the UK, the MHRA definition of Quality Assurance is as follows: “It is the sum total of the organized arrangements made with the objective of ensuring that medicinal products or services are of the quality required for ‘their intended purpose.” The pharmaceutical industry is one of the most regulated activity sectors, where regulation includes specific quality systems such as good laboratory practice (GLP), good clinical practice (GCP) and good manufacture practice (GMP). The principles of many of these practices mainly cover the formal quality aspects of a procedure and do not evaluate the technical aspects in depth. The challenge is, therefore, to develop quality systems, compatible with various principles, that not only cover formal quality items, but also ensure good scientific and technical performance. An implementation process focused on real quality improvement is the best way to achieve this objective. Every ‘government allocates a substantial proportion of its total health budget to medicines. This proportion tends to be greatest in developing countries, where it may exceed 40%. Without assurance that these medicines are relevant to priority health needs and that they meet acceptable standards of quality, safety and efficacy, any health service is evidently compromised, In order to manufacture products of high quality at the right cost, the manufacturing processes must be controlled. This gives birth to a set of specifications, procedures and tests for checking the ‘manufacturing processes (QA plan). This QA plan should normally guarantee that quality products are manufactured. The next step is to apply the same specification process to the quality assurance system itself in order to be sure that the QA plan is regularly and adequately reviewed. In other words, a quality assurance plan should be designed for the whole company. QAis focused on planning, documenting and agreeing on a set of guidelines that are necessary to assure quality. The ‘typical outcomes of the QA planning activities are quality plans, inspection and test plans, the selection of defect, tracking tools and the training of people in the selected methods and processes. The purpose of QA is to prevent defects from entering into the solution in the first place. In other words, QA is a pro-active management practice that is used to assure a stated level of quality. Undertaking QA at the beginning of a project is a key tool to mitigate the risks that have been identified during the specification phases. Communication plays a pivotal role in managing project risk, and is crucial for realizing effective Quality Assurance. Part of any risk mitigation strategy is the clear ‘communication of both the risks, and their associated remedies to the team or teams involved in the project. While many groups which audit, provide advice and assist with inspection facilitation have the name “Clinical Quality “Assurance”, this term is slightly misleading as all members of the organization are responsible for quality. The quality level of the work is set when the work is done, and cannot be increased retrospectively during an audit. For feedback:info@[Link]History Quality Assurance Systems were first widely introduced during World War Il. There was need to tighten controls on industry output, particularly in the military industry. These were initially just inspection and testing, and relied on catching the defects at the end of the process. As the demand for better quality and more reliable products and services increased, the quality systems evolved to become the ISO 9000 series. These now rely on “Prevention is better than Cure”, and are applicable to all industries. Standards In 1987 respected industry representatives from around the globe assisted International Standards Organization (150) to develop the ISO 9000 series of quality system standards. These systems have been recognized and are in use in over 90 countries including the United Kingdom and the European Community. The two most commonly used standards in the ISO 9000 series are ISO 9001 and ISO 9002. © 180 9001 sets out the requirements to be met by the Quality System when a business is involved in design, development, production, installation and/or servicing, © 150 9002 sets out the requirements of the Quality system when a business is involved in development, production, installation and/or servicing, It can be seen that the only difference between the two standards is the "Design’ element. ‘The quality assurance department under the leadership of a Quality Assurance Manager will ensure the following: ‘© Appropriate global and affiliate-specific quality documents (company policies including quality policy and quality management plan, standard operating procedures (SOPs), working instructions, conventions, guidelines, forms, templates, logs, tabs, and labels) are determined, developed and implemented. * Personnel involved are, and remain, properly qualified and trained for job roles for which they are made responsible. The training will include new staff induction, ongoing quality awareness training including training in applicable SOPs and other quality documents, training for changing roles within and between functional units, and training resulting from an analysis of needs including the results of audits and regulatory inspections, top management reviews and employee appraisals. Further education and additional training needs should be constantly assessed by the Company, ‘+ All activities are conducted according to Company quality standards, current guidelines, and all applicable local, national, regional and international legal, ethical and regulatory requirements as defined in the quality documents, to meet with Company quality objectives and customer requirements. ‘+A system is putin place to track all global and affiliate-specific quality documents and to maintain an up-to- date overall inventory of all historical and effective quality documents. ‘* Personnel will have written job descriptions which will clearly define their roles and responsi processes and SOPs which they have to follow. ‘+ Asystem is put in place to initiate and maintain a personal file on each employee, containing his/her current curriculum vitae, job description, education and training records and personal and professional development plan, ‘+ An auditing function, independent of the operational units and the quality control system, is created to plan, conduct, and report internal and external audits and to support and monitor their close-out via appropriate corrective actions and preventive actions (CAPA) plan. The effectiveness of the corrective and the preventive actions must be assessed. + A system is put in place to oversee customer audits, regulatory inspections and Company Ccertifications/accreditations as applicable. ‘+ Assystem is put in place to a) share audit and regulatory inspection findings and learning with the relevant functional units and top management, b) promote auditing-in-tandem, and cross-pollination of auditors, c) track all internal and external audits, customer audits and regulatory inspections, and d) track status of findings (open, closed or pending) made during audits and regulatory inspections. ‘+ Liaison is maintained with functional units, affiliates, and human resources for continued personal and professional development (basic and advanced knowledge-based and skill-based training and retraining) of ‘employees worldwide, + Liaison is maintained with and between functional units and affiliates to promote standardization, improve ‘communication, and to enhance efficiency of quality systems through cooperation. ‘+ All functional units and affiliates are kept up-to-date with various established and emerging local, national, regional and international legal, ethical and regulatory standards. Continual quality improvement initiatives (adoption of industry best practices, implementation and monitoring of key performance indicators, and internal and external benchmarking) are identified, implemented and monitored via the Plan-Do~Check-Act (P-D-C-A) cycle. ‘+ Persons responsible for the quality assurance system are available in an advisory role to employees ‘worldwide on matters related to the quality systems and regulatory compliance. ies, and the [Link] For feedback:info@[Link]QUALITY CONTROL ‘The term quality control refers to the sum of all procedures undertaken to ensure the identity and purity of @ particular pharmaceutical. Such procedures may range from the performance of simple chemical experiments which determine the identity and screening for the presence of particular pharmaceutical substance (thin layer chromatography, infrared spectroscopy, etc.], to more complicated requirements of pharmacopoeial monographs. Activities extend to the area of quality control laboratories (good laboratory management practices, models, e.g. for certificate of analysis and lists of laboratory equipment), and an external assessment scheme. Quality control (QC) is a process by which entities review the quality of all factors involved in production. Quality Control is concerned with ‘sampling, specifications and testing as well as the organization, documentation and release (approval) procedures Which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Thus, QC is a reactive management practice by which quality is gauged and monitored, and QC includes all operational techniques and activities used to fulfill requirements for quality. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of quality control from production is considered fundamental to the satisfactory operation of quality control, It is an essential operation of the healthcare industry. It is a procedure or set of procedures intended to ensure that a manufactured product or performed service adheres to a defined set of {quality criteria or meets the requirements of the client or customer. The basic goal of this process is to ensure that the products or services that are provided meet specific requirements and characteristics, such as being dependable, satisfactory, safe etc. ‘A major aspect of quality control is the establishment of well-defined controls. These controls help standardize both production and reactions to quality issues. Controls include product inspection, where every product is examined before the product is sold into the external market. Limiting room for error by specifying which production activities are to be completed by which personnel reduces the chance that employees will be involved in tasks for which they do not have adequate training. It is important for an organization to agree on what the meanings of Quality Assurance (QA) and Quality Control (QC). Both form an integral part of the organization's quality management plan, and the effectiveness of delivery teams relies on the differences being well understood. ‘The difference is that QA is process oriented and QC is product oriented. ‘= Quality Assurance makes sure you are doing the right things, the right way. ‘© Quality Control makes sure the results of what you've done are what you expected. Quality Assurance attempts to improve and stabilize production (and associated processes) to avoid, or at least minimize, issues which led to the defect(s) in the first place whereas Quality Control emphasizes testing of products to uncover defects and reporting to management who make the decision to allow or deny product release. Quality Assurance (QA): refers to planned and systematic production processes that provide confidence in 2 product's suitability for its intended purpose. Itis a set of activities intended to ensure that products (goods and/or services) satisfy customer requirements in a systematic, reliable fashion. Quality Control (QC): Quality control emphasizes testing and blocking the release of defective products, quality assurance is about improving and stabilizing production and associated processes to avoid or at least minimize issues that led to the defects in the first place. ‘Quality assurance is proactive and takes control before the issue occurs. It is done proactively to determine the bug/issue at the phase of origin itself. Whereas quality control is reactive, itis testing which is carried out after the activity/phase is completed. Hence here any issue found will result in rework which is much costlier to fix. Assurance starts right from the beginning of the process; itis an attitude of the person who is operating that process, exactly knowing the process parameters, its variation and impact of its variation. Assurance means failure prevention. Quality Assurance means maintaining the process parameters within standard deviation limits to achieve the desired quality product. ‘Quality control is a method based on statistical tools, comes at the end of the process, where we identify the product deviation range from its desired parameters. Quality Assurance is a part of GMP (Good Manufacturing Practices) whereas Quality Control is part of the Quality management system, focused on fulfilling quality requirements and is only a part of the overall Quality assurance package. It’s about checking at the end of a development process (e.g. - a design activity] that we have built quality into the products and we have achieved this through our methods. For feedback:info@[Link]Quality begins with the Quality Assurance Department (QA), who sets the quality standards. QA’s main focus Is to verify that proper quality control is being maintained throughout the manufacturing process by setting individual specifications for all materials and formulas. This requires quite a bit of research to ensure that the proper specifications are set at meaningful levels for active ingredients, marker compounds (components of a raw material which may not be active ingredients, but do positively identify the material) and levels of undesirable compounds that may be found in that material. Quality continues in the Quality Control Department (QC). Here, the main objective is to maintain quality by testing and monitoring that proper procedures are followed by Purchasing, Receiving, and Production. QC performs the tests necessary to ensure that each ingredient and product meets the standards set forth by QA. Product performance is measured and evaluated before, during, and after each ‘manufacturing operation. The results are compared to previous data, reference standards and QA specifications. ‘These results are then reported to the company’s regulatory personnel. ‘The differences between Quality Assurance and Quality Control can be summarized as follows: aa ac Definition: Ais a set of activities for QCis a set of activities for ensuring quality in the processes ensuring quality in products. The by which products are developed. _ activities focus on identifying. defects in the actual products produced. Focus on: QAaims to prevent defects with a QCaims to identify (and correct) focus on the process used to defects in the finished product. make the product. Itis @ Quality control, therefore, is a proactive quality process. reactive process. Goal: The goal of QA is to improve The goal of QCis to identify Statistical Techniques: development and test processes s0 that defects do not arise when the product is being developed. Statistical Tools & Techniques can be applied in both QA & QC. When they are applied to processes (process inputs & operational parameters), they are called Statistical Process Control (SPC); & it becomes the part of defects after a product is developed and before it's released. When statistical tools & techniques are applied to finished products (process outputs), they are called as Statistical Quality Control (SQC) & comes under QC. OA What: Prevention of quality problems ‘The activities or techniques used through planned and systematic to achieve and maintain the ‘activities including product quality, process and documentation, service, How: Establish a good quality Finding & eliminating sources of management system andthe quality problems through tools & assessment of ts adequacy & equipment so that customer's conformance audit of the requirements are continually met. ‘operation system & the review of the system itself. Example: Verification is an example of QA _Validation/Software Testing is an ‘example of QC Responsibility: Everyone on the team involved in. Quality control is usually the developing the product is responsibilty of a specific team For feedback:info@[Link]responsible for quality assurance. that tests the product for defects NEED OF QUALITY ASSURANCE Quality assurance helps to ensure the consistency of quality of the goods or services that are supplied and the satisfaction of manufacturers as well as customers. Customer satisfaction leads to repeat business, customer referrals, increased sales and profits. A quality assurance system eliminates defective products and continuously evaluates the process to improve products and services. Quality assurance can result in a consistently reliable product or service, Increased reliability in the end product results in customer satisfaction and brand loyalty. Companies with reliable quality gain a favorable reputation in the industry. In many industries, particularly the pharmaceuticals sector, the strict regulatory requirements and the challenges of staying competitive in a fast changing environment are not only increasing the pressure on sales, production and administrative functions, but also on quality assurance department. By optimizing process reliability and efficiency, quality assurance can bring about speedy and effective operational performance which still observes all statutory requirements. Employee ‘morale is higher in a company using a quality assurance system, since the organization is more likely to run well, and actively seeks methods for improvement, according to the National Institute of Accountants. For example, a system Of quality assurance, such as Total Quality Management, involves employees in the process of quality improvement. Employees become stakeholders in the organization and its success. Improved employee morale results in less absenteeism and turnover among workers. Quality assurance is largely in interest of the manufacturer also as it minimizes the risk of loss which may be caused if products are not produced with a quality and standard which meets the specifications necessary for its intended use. Such products may not get market approval and may even cause penalty to the manufacturer. ‘A company is legally bound to produce quality products. Compliance with the guidelines which ensures quality is @ necessary condition for market authorization without which a company cannot sell its products in the market. FDA and other regulatory bodies conduct inspections to ensure quality so that products of standard and uniform quality are produced and provided to the customers. The QA team is now expected to keep control of quality, costs, reliability and speed, while also complying with regulations, If this is to be achieved, quality assurance must become a proactive process which ensures that product, manufactured adheres to specific standards. Thus, Quality Assurance serves as a passport to success by assisting the Company to achieve high-quality processes, procedures, systems, and people, with eventual high-quality products and services and enhancement of the following: Customer satisfaction, and therefore, customer loyalty and repeat business and referral; ‘Timely registration of drugs by eliminating waste and the need for rework; Operational results such as revenue, profitability, market share and export opportunities; Alignment of processes with achievement of better results; Understanding and motivation of employees toward the Company quality policy and business objectives, as ‘well as participation in continual quality improvement initiatives; and ‘+ Confidence of interested parties in the effectiveness and efficiency of the Company as demonstrated by the financial and social gains from Company performance and reputation. PRINCIPLES OF QUALITY ASSURANCE The Quality Assurance principles are based on the ISO 9001 standard and are intended to be used by senior Quality Managers to run a business based on continual improvement and quality assurance. = Customer Focus: The customer is always the most important factor for any business, which is why organizations need to understand current and future customer needs and aim to surpass expectations. Quality assurance relies on researching and understanding the customer's needs and ensuring that the organizations objectives are in line with those expectations. A quality management system needs to be in place to manage customer relationships and communicate those needs across the organization. + Leadership: Quality assurance principles also suggest that an organization needs leadership in order to have purpose and direction. Quality assurance relies on a business having a clear vision of the future ~ @ vision which should consider the needs of all relevant parties including customers, directions, employees, local info@[Link] [Link] For feedbaclcommunity etc. Good leadership within an organization should establish trust and remove fear, whilst encouraging and recognizing employee's contributions. + Involvement of people: /An organization needs to be able to put quality management training into practice. People at all levels of the business need to be motivated, committed and fully involved in the organization, This principle of quality assurance involves people evaluating their own performance and identifying their constraints, as well as actively seeking opportunities. ‘+ Process approach: ISO 9001 training encourages that in order to achieve a desired result, resources and activities should be managed as a process. The process should focus on resources, methods and materials which affect the key activities within a business. In order to maintain quality assurance within a service or product, risks, consequences, the impact on customers and suppliers and other relevant parties should be continuously evaluated. ‘System approach to management: Quality assurance training demonstrates how to create a structured system which is designed to achieve the organizations aims and objectives using the most effective and efficient methods. Quality management system training should provide a better understanding of the roles and responsibilities necessary for achieving those objectives and should be continually improved by evaluating and measuring its performance. * Continual improvement: Another quality assurance principle is that continual improvement should always be an objective for any business. To maintain quality assurance, it is essential to provide people with the necessary tools and knowledge for continual improvement. Continual improvement of products, processes and systems should be promoted as an objective for every employee throughout all levels in the organization. ‘+ Factual approach to decision making: This quality assurance principle simply ensures that decisions are based on analyzed data and information. To comply with this quality management standard, data and information should be accurate and reliable, accessible to those who need it and analyzed using valid methods, © Mutually beneficial supplier relationships: The Quality management standard ISO 9001 encourages ‘organizations to create mutually beneficial relationships with its suppliers. These mutually beneficial relationships allow the organization to benefit from optimized costs and resources, clear and open ‘communication and being able to share knowledge and plans on market changes and consumer expectations. ELEMENTS OF QUALITY ASSURANCE LEGAL BASE Drug quality assessment and assurance should have an adequate legal framework forming an integral part of general drug legislation. All regulatory and technical elements of quality assessment and assurance require the provision of legal powers to undertake these activities and to prescribe norms. The enabling legislation should provide the necessary authority to develop particular regulations in connection with quality assurance during the manufacture, importation and distribution of pharmaceutical products and, in some cases, pharmaceutical raw materials Additional regulations governing the practice of pharmacy, which form part of health legislation, may also be relevant here. The responsibility for the development of guides, norms, and administrative regulations may frequently be assigned to a drug control agency, Wide differences in legal approaches exist between countries according to whether the administrative structure is centralized or decentralized. It is, however, possible in the case of a decentralized system to establish legislation that permits the sharing of responsibility, and the coordination of all activities in the quality assessment of pharmaceutical supply systems. REGULATORY ELEMENTS General The regulatory elements of a quality assessment system include a central administrative entity, inspection services and drug quality control laboratories. For feedback:info@[Link]Regulatory implementation of quality assessment requires a legal base, as mentioned, giving authority to a designated agency to establish and enforce quality requirements throughout the manufacturing and distribution processes. {At the manufacturing stage, the alm is to ensure that all manufacturers, whether local or foreign, comply with good ‘manufacturing practices. At the distribution level, the aim is to ensure that the quality of all pharmaceutical products, particularly imported items, has been properly assessed and that adequate control exists over the transport, storage and rotation of supplies, including the conditions in customs, premises, warehouses, and other places in which the products are stored before reaching the final user. This also includes procedures for the recall, if necessary, of unsatisfactory products. Governmental drug control agencies To facilitate adequate national control of pharmaceutical supply systems, authority should be vested in a ministry which is responsible for health matters. This would permit the establishment of a drug control agency and the development of administrative and regulatory procedures for the control of pharmaceuticals such as drug notification, authorization or registration and for the carrying out of adequate drug quality surveillance. ‘Administrative and regulatory procedures based on notification, authorization or registration must provide an adequate definition or specification for each drug. To perform drug quality surveillance, the agency needs expert staff whose training is consistent with their responsibilities. For the quality surveillance of manufacturing operations the expertise required is comparable to that described in “Good practices in the manufacture and quality control of drugs”. Inspection, sampling and analysis of pharmaceutical products on the market, supplemented by information from other sources (manufacturer, distributor, other regulatory agencies and advisers, and investigations of reported defects) provide the basis for action to minimize health hazards due to poor-quality products. Study of the consolidated information provides guidance for priorities in future activities. To perform adequately its tasks on drug quality surveillance a fully developed agency should be supported by inspection and laboratory services. Where resources are adequate, there are advantages in uniting these services in the same organization; otherwise they must be closely coordinated to maximize the efficiency of the surveillance procedures. In countries with decentralized systems of administration the agency may be located at a central point, or it may be structured to comprise centrally coordinated regional components. ‘The term “agency’ is capable of wide interpretation, but in the present context itis intended primarily to designate the centre of authority for drug control activities without regard to the size of the administrative organization, Alternative regulatory procedures may exist and the type and extent of control exercised will determine the resources required. Inspection services ‘The inspection services act as the field arm of an agency by verifying that all elements within the pharmaceutical supply system comply with the regulations and that data submitted to the agency are factual. Verification by inspection includes assessment of manufacturing and distributing firms, as well as retail and dispensing outlets such ‘as pharmacies and hospitals. There is scope for international cooperation in the field of inspection services. Drug quality control laboratory ‘A governmental drug control laboratory carries out tests and assays required to establish whether drugs conform to the specifications claimed for them. Such a laboratory may also carry out investigations on new or improved analytical methods. Its type and size will be determined by a number of factors. These include the nature of the pharmaceutical supply system, the extent of local drug production and the quantum of pharmaceutical imports, and, in addition, the availability of support from other laboratories involved in drug quality testing. Under certain circumstances it might be useful for a group of countries to pool their efforts towards the creation of a regional control laboratory. In other circumstances, a fully established national drug control laboratory can serve neighboring countries, TECHNICAL ELEMENTS Quality specifications ‘Quality specifications comprise a set of properly selected standards with associated methods of analysis that may be sed to assess the integrity of drugs (including dosage forms) and starting materials. Adequate specifications for a [Link] For feedback:info@igmpparticular drug in its dosage forms for identity, purity, strength, performance and other characteristics are necessary to assure that all batches of the drug are of uniform quality. Quality can then be achieved by strict adherence to the specifications. In the course of drug evaluation for registration, tentative dosage form specifications are developed when clinical studies have proceeded sufficiently to suggest that the dosage form is an acceptable one. They are reviewed as further experience in drug manufacture is gained. This question was discussed in Annex 5 of the twenty-fifth report of the Expert Committee on Specifications for Pharmaceutical Preparations. Quality specifications may be either public or undisclosed in nature. The public specifications are usually contained in a pharmacopoeial monograph and are stated in terms that permit objective evaluation of product quality, not only by the manufacturer but by other interested parties also. ‘A pharmacopoeia normally includes the general methodology of testing, monographs on pharmaceutical raw ‘materials, including active and inactive ingredients of pharmaceutical products, and in many cases monographs on dosage forms. A number of national pharmacopoeias are kept up to date by periodic revision. Pharmacopoeias may also be issued through the joint effort of a group of countries. The European Pharmacopoeia and the Compendium Medicamentorum are recent examples of such endeavors. The International Pharmacopoeia Is issued by the World Health Organization. Plurinational pharmacopoeias and the International Pharmacopoeia serve to make more uniform test methodology and specifications for a particular product. There are many specifications that either are contained in an application for an authorization or registration or exist, as the manufacturer's own specifications, which are not generally subject to public disclosure. Interested parties ‘must therefore depend on the licensing authorities or the manufacturer for assurance that these specifications are adequate and are being met. Such assurance is mentioned in the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce through its provision concerning batch certificates to be Provided by the manufacturer. Analytical criteria for judging drug quality, which relate to the identity, purity and strength of drugs and to the performance of dosage forms, the selection of such criteria for pharmacopoeial monographs and for manufacturer's, specifications, and the relation between these two sets of quality requirements were reviewed in Annex 1 of the ‘twenty-sixth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. The selection of methods and procedures used in specifications must be based on their utility for the purpose of quality assurance of pharmaceuticals, and progress in the development of new analytical tools requires a periodic review of the methodology. In establishing specifications full account must also be taken of various technical and ‘economic constraints. Basic tests ‘Simplified tests (basic tests) may serve in specific circumstances for verifying the identity of a drug and ascertaining the absence of gross degradation or contamination. They may be especially useful in situations in which well- equipped laboratories do not exist and in which full examination of drug quality according to procedures requiring special skills and equipment is not feasible. When a product fails the basic tests, it should not be used until its quality is established by a full analytical examination. Various aspects of the problem of the development and application of such tests are discussed in Annex 2 of the twenty-sixth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations, Requirements for good manufacturing practices ‘The quality of pharmaceutical products depends on the correct performance of all manufacturing operations and ‘must be builtin from the beginning of the manufacturing process. The principles for quality control procedures that should be applied to drug manufacturing practices are designated “Good practices in the manufacture and quality control of drugs”. These principles are general guides which, whenever necessary, may be adapted to meet national needs, provided the established standards of drug quality are still achieved. Manufacturing establishments with a limited product line need only utilize the relevant parts of the requirements. ‘The requirements for good manufacturing practice indicate that the documents relating to manufacturing procedures should contain, among other necessary information, the data concerning each starting material, as well as detailed instructions for and precautions to be taken in the manufacture of the drug. If modifications due to changes in the equipment for processing or to the use of alternative types of ingredients are introduced, their influence on the quality, including the performance, of dosage forms has to be adequately evaluated, [Link] For feedback:info@[Link]10 Quality Management ‘The holder of a Manufacturing Authorization must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorization and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers and by the distributors. In the pharmaceutical industry at large, quality management is usually defined as the aspect of management function that determines and implements the “quality policy’, i.e. the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are: © an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources; and ‘© systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality. The totality of these actions is termed “quality assurance”. Within an organization, quality assurance serves as a management tool. In contractual situations, quality assurance also serves to generate confidence in the supplier. The concepts of quality assurance, GMP and quality control are interrelated aspects of quality management. ‘Quality Assurance (QA) QA is 3 wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. itis the sum total of the organized arrangements made with the objective of ensuring that pharmaceutical products are of the quality required for their intended use. QA, therefore, incorporates GMP and other factors such as product design and development. ‘The system of QA appropriate for the manufacture of pharmaceutical products should ensure that: (a) pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP); {b) production and control operations are clearly specified in a written form and GMP requirements are adopted; {c) managerial responsibilities are clearly specified in job descriptions; (d) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials; (e) all necessary controls on starting materials, intermediate products, and bulk products and other in-process Controls, calibrations, and validations are carried out; (f) the finished product is correctly processed and checked, according to the defined procedures; (g) pharmaceutical products are not sold or supplied before the authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing uthorization and any other regulations relevant to the production, control and release of pharmaceutical products; {h) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored by the ‘manufacturer, distributed, and subsequently handled so that quality is maintained throughout their shelf-life; (i) there is a’ procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the QA system; ()) deviations are reported, investigated and recorded; (k) there is a system for approving changes that may have an impact on product quality; (i) regular evaluations of the quality of pharmaceutical products should be conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement; and (m) there is a system for quality risk management (QRM). Qui Management A. Principles Quality should be the responsibilty of all persons involved in manufacturing. Each manufacturer should establish, document, and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel. The system for managing quality should encompass the organizational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended ‘specifications for quality and purity. All quality-related activities should be defined and documented. There should be a quality unit(s) that is independent of production and that fulfills both quality assurance and quality control responsibilities. The quality unit can be in the form of separate QA and QC units or a Single individual or group, depending upon the size and structure of the organization. The persons authorized to release intermediates and APIs should be specified. All quality-related activities should be recorded at the time they are performed. Any deviation from established procedures should be documented and explained. Critical deviations should be investigated, and the investigation and its conclusions should be documented. No materials should be released or used before the satisfactory completion of evaluation by the quality unit(s) unless there are appropriate systems in place to allow for such use (e.g., release under quarantine or the use of raw materials or intermediates pending completion of evaluation). Procedures should exist for notifying responsible management in a timely [Link] For feedback:info@[Link]u manner of regulatory inspections, serious GMP deficiencies, product defects and related actions (e.g., quality- related complaints, recalls, and regulatory actions). B. Responsibilities of the Qual The quality unit(s) should be involved in all quality-related matters. The quality unit(s) should review and approve all appropriate quality-related documents. The main responsibilities of the independent quality unit(s) should not be delegated. These responsibilities should be described in writing and should include, but not necessarily be limited to: ‘© Releasing or rejecting all APIs. Releasing or rejecting intermediates for use outside the control of the ‘manufacturing company ‘Establishing a system to release or reject raw materials, intermediates, packaging, and labeling materials. * Reviewing completed batch production and laboratory control records of critical process steps before release of the API for distribution ‘Making sure that critical deviations are investigated and resolved Approving all specifications and master production instructions Approving all procedures affecting the quality of intermediates or APIs Making sure that internal audits (self-inspections) are performed Approving intermediate and API contract manufacturers ‘Approving changes that potentially affect intermediate or API quality Reviewing and approving validation protocols and reports Making sure that quality-related complaints are investigated and resolved Making sure that effective systems are used for maintaining and calibrating critical equipment Making sure that materials are appropriately tested and the results are reported Making sure that there is stability data to support retest or expiry dates and storage conditions on APIS and/or intermediates, where appropriate ‘© Performing product quality reviews C. Responsibility for Production Activities The responsibility for production activities should be described in writing and should include, but not necessarily be limited to: ‘© Preparing, reviewing, approving, and distributing the instructions for the production of intermediates or ‘APIs according to written procedures ‘© Producing APIs and, when appropriate, intermediates according to pre-approved instructions Reviewing all production batch records and ensuring that these are completed and signed © Making sure that all production deviations are reported and evaluated and that critical deviations are investigated and the conclusions are recorded ‘Making sure that production facilities are clean and, when appropriate, disinfected ‘Making sure that the necessary calibrations are performed and records kept ‘Making sure that the premises and equipment are maintained and records kept ‘Making sure that validation protocols and reports are reviewed and approved Evaluating proposed changes in product, process or equipment Making sure that new and, when appropriate, modified facilities and equipment are qualified D. Internal Audits (Self Inspection) To verify compliance with the principles of GMP for APIs, regular internal audits should be performed in accordance with an approved schedule. Audit findings and corrective actions should be documented and brought to the attention of responsible management of the firm. Agreed corrective actions should be completed in a timely and effective manner. E. Product Quality Review Regular quality-reviews of APIs should be conducted with the objective of verifying the consistency of the process. Such reviews should normally be conducted and documented annually and should include at least: * Areview of critical in-process control and critical API test results A review of all batches that falled to meet established specification(s) ‘A review of all critical deviations or non conformances and related investigations ‘A review of any changes carried out to the processes or analytical methods; ‘A review of results of the stability monitoring program ‘A review ofall quality-related returns, complaints and recalls * _Areview of adequacy of corrective actions The results of this review should be evaluated and an assessment made of whether corrective action or any revalidation should be undertaken. Reasons for such corrective action should be documented. Agreed corrective actions should be completed in a timely and effective manner. Benefits of Quality Systems ind www For feedback:info@[Link]12 ‘The importance of properly established and managed quality control and quality assurance systems with their integral well-written SOPs and other quality documents for the achievement of Company business objectives cannot be ignored. They serve as a passport to success by assisting the Company to achieve high-quality processes, procedures, systems, and people, with eventual high-quality products and services and enhancement of the Following: '* Customer satisfaction, and therefore, customer loyalty and repeat business and referral; Timely registration of drugs by eliminating waste and the need for rework; Operational results such as revenue, profitability, market share and export opportunities; Alignment of processes with achievement of better results; Understanding and motivation of employees toward the Company quality policy and business objectives, as well as participation in continual quality improvement initiatives; and © Confidence of interested parties in the effectiveness and efficiency of the Company as demonstrated by the financial and social gains from Company performance and reputation. Total Quality Management Definition Total Quality Management (TQM) has been defined as an integrated organizational effort designed to improve quality at every level. The process to produce a perfect product by a series of measures requiring an organized effort by the entire company to prevent or eliminate errors at every stage in production is called Total Quality Management, According to International Organization for standards defined TQM as, “TQM is a management approach for an organization, centered on quality, based on the participation of all its members and aiming at long-term success through customer satisfaction and benefits to all members of the organization and to the society. Therefore, total quality management (TQM) means: 1. Satisfying customers first time, every time; 2: Enabling the employees to solve problems and eliminate wastage; 3. A style of working, a culture more than a management technique, 4. Philosophy of continuous improvement, never ending, only achievable by/or through people. British Quality Association offers three alternative definitions of TM: 1. The first focuses on soft quality characteristics and may be defined as ‘integrative management’ concept for continuously improving the quality of good/services delivered through the participation of all levels and functions. 2. The second focus on ‘hard’ production/operation management type of view involving less discretion for employees. it may be defined as a ‘set of techniques and procedures used to reduce or eliminate variation from a production/process or service delivery system in order to improve efficiency, reliability and quality. Br The third definition is a mixture of hard and soft comprising 3 features and obsession with quality, need for a Scientific approach and the view that all employees are involved in this process, TOM is the way of managing for the future, and is far wider in its application than just assuring product or service quality ~ it is a way of managing people and business processes to ensure complete customer satisfaction at every stage, internally and externally. TOM, combined with effective leadership, results in an organization doing the right ‘things right, first time. Total Quality Management (TOM) is an approach that seeks to improve quality and performance which will meet or exceed customer expectations. This can be achieved by integrating all quality-related functions and processes throughout the company. TOM looks at the overall quality measures used by a company including managing quality design and development, quality control and maintenance, quality improvement, and quality assurance. TOM takes into account all quality measures taken at all levels and involving all company employees. Concept of TAM The pharmaceutical industry, as a vital segment of the health care system conducts research, manufacturing and marketing of pharmaceuticals and biological products and medicinal devices used for the diagnosis and treatment of diseases, The poor qualities of medicines are not only a health hazard, but also waste of money for both government and individual consumers. Therefore, the maintenance of quality with continuous improvement in facilities is very important in pharmaceutical industries. The pursuit of quality being approached through the concept of total quality management (TOM) system which is aimed at prevention of defects rather than detection of defects. The concept of total quality management refers to the process to produce a perfect product by a series of measures requiring an organized effort by the entire company to prevent or eliminate errors at every stage in production. Although the responsibilities for assuring product quality belong primarily to quality assurance personnel, it involves many department and disciplines within a pharmaceutical company. To be effective, it must be supported by a team effort. Quality must be built into a pharmaceutical product during product and process design and itis influenced by ‘the physical plant design, space, ventilation, cleanliness and sanitation during routine production. The assurance of quality of the product depends on more than just proper sampling and adequate testing of various components and finished dosage forms (products). Prime responsibility of maintaining the product quality during production rests with the manufacturing department. Quality assurance personnel must establish control or check points to monitor the quality of the product as itis processed and up to completion of manufacturing. This begins with raw materials [Link] For feedback:info@[Link]13 and component testing and includes in-process packaging, labeling and finished product testing as well as batch auditing and stability monitoring. Origin of TAM Total quality management has evolved from the quality assurance methods that were first developed around the time of the First World War. The war effort led to large scale manufacturing efforts that often produced poor quality. To help correct this, quality inspectors were introduced on the production line to ensure that the level of failures due to quality was minimized. After the First World War, quality inspection became more commonplace in manufacturing environments and thi led to the introduction of Statistical Quality Control (SQC), a theory developed by Dr. W. Edwards Deming, This, quality method provided a statistical method of quality based on sampling. Where it was not possible to inspect every item, a sample was tested for quality. The theory of SQC was based on the notion that a variation in the production’ process leads to variation in the end product. If the variation in the process could be removed this would lead to a higher level of quality in the end product. After World War Two, the industrial manufacturers in Japan produced poor quality items. Ina response to this, the Japanese Union of Scientists and Engineers invited Dr. Deming to train engineers in quality processes. By the 1950's quality control was an integral part of Japanese manufacturing and was adopted by all levels of workers within an organization By the 1970's the notion of total quality was being discussed. This was seen as company-wide quality control that involves all employees from top management to the workers, in quality control. In the next decade more non- Japanese companies were introducing quality management procedures that based on the results seen in Japan. The new wave of quality control became known as Total Quality Management, which was used to describe the many ‘quality-focused strategies and techniques that became the center of focus for the quality movement. Objectives of TAM + Process improvement Defect prevention Priority of effort Developing cause-effect relationships Measuring system capacity Developing improvement checklist and check forms Helping teams make better decisions Developing operational definitions Separating trivial from significant needs Observing behavior changes over a period of time TOM revolves around Commitment by Senior Management and all employees Effective strategy, vision, mission and goals, Customer/ Supplier relationships Communication Tools and techniques for improvement Team work Primary Elements of TOM Total quality management can be summarized as a management system for a customer-focused organization that involves all employees in continual improvement. It uses strategy, data, and effective communications to integrate the quality discipline into the culture and activities of the organization. TOM is a real and meaningful effort by an ‘organization to change its whole approach to business to make quality a guiding factor is everything the organization does. The major ingredients in TOM are: ‘© Customer-focused. It is important to identify the organization’s customers. The customer ultimately determines the level of quality. No matter what an organization does to foster quality improvement— training employees, integrating quality into the design process, upgrading computers or software, or buying new measuring tools—the customer determines whether the efforts were worthwhile. External customers, ‘consume the organization's product or service. Internal customers are employees who receive the output of other employees. * Total employee involvement. All employees participate in working toward common goals. Total employee commitment can only be obtained after management has provided the proper environment. High- performance work systems integrate continuous improvement efforts with normal business operations. Self-managed work teams are one form of empowerment. Since the quality is considered the job of all ‘employees, employees should be involved in quality initiatives. Front line employees are likely to have the closest contact with external customers and thus can make the most valuable contribution to quality. Therefore, employees must have the authority to innovate and improve quality. ‘+ Process-centered. A fundamental part of TOM is 2 focus on process thinking. A process is a series of steps that take inputs from suppliers (internal or external) and transforms them into outputs that are delivered to [Link] For feedback:info@[Link]