Quality Management System including the Quality management and certification

Concept of Quality, Total Quality Management, Quality by Design, Six Sigma concept, Out of Specification, Change control, Introduction to ISO 9000 Series of quality system standards, ISO 14000,NABL, GLP

1. Quality Management System

2. Quality Management System (QMS) is an important aspect for the pharmaceutical industry for maintaining the quality and safety for their products and services. QMS relies on the regulations and guidelines to maintain the effective quality in pharmaceutical industries. According to US FDA, the international harmonized guidance is intended to assist pharmaceutical manufacturers by describing a model for an effective quality management system for the pharmaceutical industry. This guidance is referred as ICH (International Council for Harmonization) guideline. Quality: Quality can be defined according to US FDA as; "A measure of a product's or service's ability to satisfy the customer's stated or implied needs

3. Basics of quality management system Quality word oriented from Latin word ‘Qualitus’ it means General excellence OR distinctive feature. Quality a standard of how good something is as measured against other similar things( by OXFORD dictionary). If we try to analyze definition some common words like... 1.Standard 2. Measurement 3. Goodness 4. comparison Most simple definition of quality is ‘fitness for use’ The customer or user is at focus. if customer or user is happy and satisfied with our product or service then product or service is called good quality.

4. It must be remember that the quality is not the job of only a single person or single department but, it is responsibility of whole organization. Quality of Product and service is measurable, managerial, technological and stastical feature of organization. Dimensions of Quality Performance Feature Reliability Perceived quality Aesthetics Durability Conformance serviceability

5. Quality Assurance (QA): According to WHO, QA is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality assurance therefore incorporates GMP and other factors. including those outside the scope of this guide such as product design and development. Quality Control (QC): QC is that part of GMP concerned with sampling, specification, testing, documentation and release procedures which ensure that the necessary and relevant tests are performed and the product is released for use only after ascertaining its quality.

6. Scope of Pharmaceutical QMS: 1.Pharmaceutical Development: Drug substance development. Formulation development (including container/closure system) Manufacture of investigational products. Delivery system development (where relevant). Manufacturing process development and scale-up. Analytical method development. 2. Technology Transfer: New product transfers during development through manufacturing. Transfers within or between manufacturing and testing sites for marketed products.

7. 3. Commercial Manufacturing: Acquisition and control of materials. Provision of facilities, utilities and equipment Production (including packaging and labeling). Quality control and assurance. ICH Guidelines: ICH guideline is intended for bringing together the regulatory authorities and pharmaceutical industries together for the discussion of the scientific and technical aspects of drug registration. It is divided into four categories (QSEM): Q: Quality guidelines: It includes stability, impurities testing, GMP. S: Safety guidelines: It includes carcinogenicity, genotoxicity. reprotoxicity. E: Efficacy guidelines: It includes clinical, pharmacogenomics. M:Multidisciplinary guidelines: It includes medical dictionary for regulatory activities, electronic standards, non-clinical safety studies, common technical document (CTD).

8. QSEM

9. 1.Quality Guidelines: Harmonization achievements in the quality area include pivotal milestones such as the conduct of stability studies defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quantity based on good manufacturing practice (GMP) risk management. It includes the following guidelines:

10. 2.Safety Guidelines: ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity.

11. 3.Efficacy Guidelines: It is concerned with the design, conduct, safety and reporting of clinical trials.

12. 4.Multidisciplinary Guidelines: Some highlights of this guideline are:

13. Sources of Quality Variation: 1.Materials: (a) Variations among suppliers of same substances. (b) Variations among batches from same suppliers. (c) Variations within a batch. 2. Machines: (a) Variation of equipment of same process. (b) Difference in adjustments of equipment. (c) Aging of machines and improper care. 3. Methods: (a) Wrong procedure. (b) Inadequate procedure. (c) Negligence in procedure by chance. 4. Personnel: (a) Improper working conditions. (b) Inadequate training and understanding. (c) Lack of interest and emotional upheavals. (d) Dishonesty fatigue and carelessness.

14. Control of Quality Variation: The mistakes can be controlled, minimized or eliminated by material control, packaging control and GMP variations can be controlled when Quality Control, Quality Function and Quality Assurance work side by side. Controlling each and every step of process can control variations. Control can be divided into: 1.Material control 2. Manufacturing practice control 3. Packaging control 4. Distribution control

15. Total Quality Management (TQM)

16. Total Quality Management (TQM) Introduction: Total –Made up of the whole (or) Complete. Quality –Degree of Excellence a product or service provides to the customer in present and future. Management –Act, art, or manner of handling, controlling, directing, etc. TQM is the art of managing the whole to achieve excellence Definition: "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 society." Or Total Quality Management(TQM) is a management strategy aimed at embedding awareness of quality in all organizational processes.

17. TQM requires that the company maintain this quality standard in all aspects of its business. This requires ensuring that things are done right the first time and that defects and waste are eliminated from operations. Characteristics : Technological strength, hardness, Time – oriented, Reliability, maintainability – availability Contractual Guarantee.

18. GOAL OF TQM

19. Six basic concepts of TQM: 1. A committed and involved management to provide long term top – to – bottom organization support. 2. An unwavering focus on the customer, both internally and externally. 3. Effective involvement and utilization of the entire work force. 4. Continuous improvement of the business and production 5. Treating suppliers of the business and production process. 6. Establishing the performance measures

20. 6C’S of TQM

21. Total Quality Management and Continuous Improvement: TQM is the management process used to make continuous improvements to all functions. TQM represents an ongoing, continuous commitment to improvement. The foundation of total quality is a management philosophy that supports meeting customer requirements through continuous improvement

22. Quality Cost: Prevention Cost – Planning, Document, Control, Training. Appraisal cost – inspection test installation Calibration, Depreciation, Reports & Rejects. Internal Failure Cost – Scraps, Repair Rework, Design Changes, Defect Failure Analysis, Retests & Re-Inspection, Downgrading, Down Time. External Failure Cost – Complaints, Goodwill, & Replacement, Guarantee & Warranty, Compensation, Recall, Loss of Sales, Seconds Sales.

23. Benefits of Quality: Improved quality. Employee participation. Less migration of employee Team work. Internal external customer satisfaction. Productivity with connectivity. Profitability & increase market share.

24. QUALITY by DESIGN (QbD)

25. QUALITY BY DESIGN (QbD): Introduction: Pharmaceutical industries always rely on the continuous improvement in safety, quality and efficacy of the products. The pharmaceutical products are intended for the patient care. So, the priority is enhanced therapeutic benefits and absence of impurities. Therefore, the product should be designed to meet patients needs and the intended product performance. The product quality and performance are regulated by finished product testing, with understanding of the process and critical process parameters

26. The US FDA (Food and Drug Administration) has adopted the principles of QbD in the development manufacturing and regulation of pharmaceutical products. ICH guidelines also focus on the principles of QbD through its guidelines mentioned as ICH Q8 (R2) Pharmaceutical Development, ICH Q9 (Quality Risk Management), ICH Q10 (Pharmaceutical Quality System) and ICH Q11 (Development and manufacture of drug substances). According to US FDA and ICH Q8 (R2) the QbD is a systematic approach to development which includes the prior knowledge of product and process understanding based on the results of studies using design of experiments, use of quality risk management and use of knowledge management.

27. Objectives of QbD: The main objectives of QbD are as follows: 1. Increasing manufacturing efficiency. 2. Increasing the efficiency in product development. 3. Enhancement of product quality and performances to meet patients needs. 4.Increase in process capability. 5. Avoidance of regulatory compliances. 6. Incorporation of risk management. 7. Reduction in production costs and waste. 8. Reduction in product variability, defects and rejections.

28. The main outcomes of QbD are as follows: 1.Maintenance of product quality to meet expected clinical performances. 2. Maintenance of product quality by efficient manufacturing and formulation process. Elements of QbD: The following elements can be included in the study of QbD 1.QTPP (Quality Target Product Profile): This profile is related to quality, safety and efficacy. 2. CQA: (Critical Quality Attributes): The study of CQAs helps in the study and controlling of the product characteristics that have impact on product quality. 3. Determination of CQAs of drug substances, excipients, etc. and the selection of the excipients to attain the desired drug quality. 4. Suitable manufacturing process selection. 5. Risk assessment: CMAs (Critical Material Attributes)and CPPs (Critical Process Parameters) 6. Defining a control strategy.

29. Quality Target Product Profile (QTPP): It includes: 1.Dosage forms, route of administration, delivery systems. 2.Strength of doses. 3.Container closure system. 4.Pharmacokinetic properties. 5.Drug product quality criteria. Critical Quality Attributes (CQA) : CQA is related with drug substance, excipients, intermediates (in-process materials) and drug product. CQA is a physical, chemical, biological or microbiological property (should be within an appropriate limit, range, or distribution) to ensure the desired product quality.

30. Risk Assessment: CMAs (Critical Material Attributes) and CPPs (Critical Process Parameters) : Risk assessment, a science- based method or process, is used in QRM (Quality Risk Management, mentioned in ICH Q9). This assessment identifies materials attributes and process parameters effectively that have an effect on product CQAs. This process is utilized in prior pharmaceutical development process which makes available more information and knowledge about the development process. Based on prior knowledge and initial experimental data, risk assessment method helps to identify and rank different parameters like process, equipment's and input materials with potential that have an impact on product quality.

31. Control Strategy: The pharmaceutical product should be produced with required quality in consistent fashion and the control strategy ensures this. It includes the following elements: 1.Control of input material attributes viz, drug substance, excipients, packaging materials, considering their utilization and effect on product quality. 2. Product specifications. 3 Controls of unit operations that have a role to maintain the product quality. The operations may Include granulation, drying, degradation, particle size distribution etc. 4. In-process testing. 5. Finished product testing. 6. Testing of products at every stage at regular intervals (Monitoring program).

32. Design Space product Life Cycle Management Continuous Improvement Target product Profile (TPP) Quality Target Product Profile (QTPP) Risk Assessments CQAs, CMA, CPP Control Strategy Quality by Design ( QbD )

33. SIX SIGMA CONCEPT

34. Six sigma Six sigma is a business statistical Strategy. Is to identifying defects and removing them from the process of products to improve quality. A defect is defined as any process output that does not meet customer specifications. Statistical measure to objectively evaluate processes. History: The Six sigma was founded by Motorola in the 1970s. Out of senior executive Art Sundry's criticism of Motorola’s bad quality. They founded a connection between increases in quality and decreases in costs of production. Bill Smith, “Father of six sigma” introduce this quality improvement Methodology to Motorola

35. Definition : Quality management program developed by Motorola in the 1980s. Management philosophy focused on business process improvements to: Eliminate waste, rework, and mistakes Increase customer satisfaction Increase profitability and competitiveness

36. DMADV DMAIC Define Measure Analyze Improve Control Define Measure Analyze Design Verify Six Sigma Methods

37. DMAIV Explanation Define: company must identify the customer and which type of a product and hope from it. These are analyze by using flow cause/effect diagrams, check sheets, pare to analysis. Measure: company will collect the baseline data to determine where the process stands as compare to where it needs to be. And also see the critical to quality characteristics an estimate current process capability. Then find out the current sigma level according to those identified characteristic that are mostly important to the customer.

38. Analyze: this shows the amount of improvement necessary to make the Critical to quality characteristics the best in the industry. For this phase company use some descriptive statistical methods like mean, mode, median…etc. Improve: Implement the suggested improvements in this phase And also test possible solutions to the process problem. Collect data from the all possible solutions and test them on a small scale and run a cost/benefit analysis of implementing the solution. Then choose the best solution and create a plan for implement the solution. Control : measures are implemented to ensure improvements are maintained. To monitor the process improvements, basically use tools like statistically process control charts. These charts have three limits, the center line for the average. Monitor the process to ensure that the process is in the control limits.

39. Improvement cycle – PDCA cycle

40. DMADV Explanation This method is also called DFSS (Design For Six Sigma) and have five phases. Define design goals that are consistent with customer demands and the enterprise strategy. Measure and identify CTQs (characteristics that are Critical To Quality), product capabilities, production process capability, and risks. Analyze to develop and design alternatives, create a high-level design and evaluate design Design details, optimize the design, and plan for design verification. This phase may require simulations. Verify the design, set up pilot runs, implement the production process and hand it over to the process owner(s).

41. Statistical view of Six Sigma

42. Implementing Roles Executive Leadership (CEO and other top level managers) Champions (act as the leaders of black belts. And also ) Master Black Belts (chosen by champions, give their full effort to six sigma. Help to champions and guide the Black belts and green belts). Black belts (working under Master Black Belts, they are applying six sigma to specific projects).

43. Implementing Methodologies

44. Six Sigma Companies

45. Focus of Six Sigma Accelerating fast breakthrough performance. Significant financial results in 4-8 months. Ensuring Six Sigma is an extension of the Corporate culture, not the program of the month. Criticisms There is nothing new. It only proves defects and defectives counts offer measurable results. It is corrective action system rather than taking a preventive and proactive approach to problems. It is merely about appraisal system and that appraisal programs aren’t useful. In appraisals are great tools for identifying and tracking improvements, which is critical to any project. Critics have suggested that Six Sigma did not bring quality improvement in all the organizations where it was implemented. It depends on the tools

46. INTRODUCTION TO ISO 9000

47. International Organization for standardization (ISO) A network of national standardization bodies from over 160 countries with Nigeria inclusive. Based in Geneva Switzerland. Standard Organization of Nigeria (SON) is a Technical Committee (TC) in ISO, meaning participates fully developing ISO standards. ISO management standards Selected standards that companies can be certified for :- Occupational Health and Safety Assessment Series (OHSAS) ISO 9001 Quality ISO 22000 Food safety ISO 22301 Business continuity ISO 20000 IT services ISO 14001 Environment OHSAS 18001 Health & Safety ISO 28000 Supply chain Security ISO 27001 Information security

48. ISO 9001:2008 (QMS)basic principles Principle 1 – Customer focus Principle 2 – Leadership Principle 3 – Involvement of people Principle 4 – Process approach Principle 5 – System approach to management Principle 6 – Continual improvement Principle 7 – Factual approach to decision making Principle 8 –Mutually beneficial supplier relationships .

49. Principle 1 - Customer focus Pragmatically, a quality product centers on meeting customers current and future requirements in the needed form, time and place in synchrony with the company’s policies and objectives. Customer satisfaction Employee’s responsibility Management responsibility Customer requirements QMS

50. Principle 2 – Leadership Applications Benefits Perfect understanding of the More enthusiastic workers. organization short and Increased employee loyalty long term goals and objectives. Effective communication system Setting realistic and is enabled practicable targets. Make the needs of all stakeholders a focal point. Maintain a trustful work ambience and not a fearful environment. Positive contributions must be encouraged

51. Principle 3 - Involvement of the people Applications Benefits A sense of belonging should be Employees shows more commitment created in people that has direct & towards achieving organization indirect link with the company. goals and objectives People should be made to understand Innovation and creativity within the that their opinion counts. organization People openly discussing People show more interest problems & issues. in continuous improvement. People identifying constraints to their performance .

52. Principle 4 - Process Approach : Input Output Customers (and other interested parties) Customers (and other interested parties) Management responsibility Resource management Product realization Measurement, analysis and improvement Requirement s Satisfaction Continual improvement of the quality management system. Management responsibility Product Realization Measurement analysis & Improvement Resource management Continual improvement of the Quality Management system Customers (and other interested parties ) Customers (and other interested parties ) In put Out put Requirements Satisfaction

53. Principle 5 - System Approach to Management System = combinations of entities (processes)that works dependently and interrelated with each other and becomes a culture over a period of time. Management responsibility Measurement, analysis and improvement Product realization Resource management System. Management responsibility Measurement analysis & Improvement Product realization Resource management System

54. Principle 6- Factual approach to decision : making How? Benefits Conducting frequent market survey Prevents impulsive decision making & market intelligence. that could dissatisfy majority of the customers. Customer dissatisfactions be treated generically, Only informed decisions will be made generically. sequel to extensive market survey to generate valid information. Ensuring that data and information are An increased ability to demonstrate the sufficiently accurate and reliable effectiveness of past decisions through reference to factual records Making data accessible to those who need it Analyzing data and information using valid methods Increased ability to review, challenge and change opinions and decisions Making decisions and taking action based on factual analysis, balanced with experience and intuition.

55. Principle 7 - Mutually Beneficial Supplier Relationships Relationships Benefits Establishing relationships that balance Increased ability to create value for both parties short-term gains with long-term considerations. Pooling of expertise & resources. Flexibility and speed of joint response With partners. to changing market or customer needs and expectation Identifying and selecting key suppliers. Optimization of costs and resources. Clear and open communication Sharing information and future plans. Establishing joint development and improvement activities Inspiring, encouraging and recognizing improvements & achievements by suppliers.

56. Conclusion All discussed principles are the core attributes on which ISO 9001:2008 are based upon, and it is therefore imperative that to meet up with International standards, we should strive to align our operations with these principles to foster a better competitive advantage both on local and international front. 10 Clues 1.Scope 1. Planning 2. Normative references 2. Support 3. Terms and definition 3. Operations 4. Context of organization 4. Performance 5. Leadership Evaluation 5. Improvement

57. I SO 14000 OVERVIEW

58. Why was ISO 14000 revised? It was due for revision, ISO requires that all management system standards undergo periodic revision. To enhance compatibility with ISO 9001:2000 Revision allows opportunity to clarify requirements in the 1996 version and incorporate needed changes. ISO 14001:2004 General Requirements The organization shall establish, document, implement, maintain and continually improve an environmental management system in accordance with the requirements of this International Standard and determine how it will fulfill these requirements. Scope The organization shall define and document the scope of its environmental management system.

59. Environmental Policy ISO 14001: 2004 Top management shall define the organization's environmental policy and ensure that, within the defined scope of its environmental management system, it: a)is appropriate to the nature, scale and environmental impacts of its activities, products and services, b) includes a commitment to continual improvement and prevention of pollution,

60. ISO 14001: 2004 a)includes a commitment to comply with applicable legal requirements and with other requirements to which the organization subscribes which relate to its environmental aspects, b)provides the framework for setting and reviewing environmental objectives ISO 14001: 2004 a)is documented, implemented and maintained b)is communicated to all persons working for or on behalf of the organization . c)is available to the public

61. ISO 14001: 2004 The organization shall establish, implement and maintain a procedure(s) a) to identify the environmental aspects of its activities, products and services within the defined scope of the environmental management system that it can control and those that it can influence taking into account planned or new developments, or new or modified activities products b) to determine those aspects that have or can have significant impact(s) on the environment (i.e. significant environmental aspects). The organization shall document this information and keep it up to date. The organization shall ensure that the significant environmental aspects are taken into account in establishing, implementing and maintaining its environmental management system.

62. Objectives, targets and programme(s) The organization shall establish, implement and maintain documented environmental objectives and targets, at relevant functions and levels within the organization. The objectives and targets shall be measurable, where practicable, and consistent with the environmental policy, including the commitments to prevention of pollution, to compliance with applicable legal requirements and with other requirements to which the organization subscribes, and to continual improvement. When establishing and reviewing its objectives and targets, an organization shall take into account the legal requirements and other requirements to which the organization subscribes, and its significant environmental aspects. It shall also consider its technological options, its financial, operational and business requirements, and the views of interested parties

63. Resources, roles, responsibility and authority Management shall ensure the availability of resources essential to establish, implement, maintain and improve the environmental management system. Resources include human resources and specialized skills, organizational infrastructure, technology and financial resources. Roles, responsibilities and authorities shall be defined, documented and communicated in order to facilitate effective environmental management. The organization's top management shall appoint a specific management representative(s) who, irrespective of other responsibilities, shall have defined roles, responsibilities and authority for a) ensuring that an environmental management system is established, implemented and maintained in accordance with the requirements of this International Standard, reporting to top management on the performance of the environmental management system for review, including recommendations for improvement.

64. Communication With regard to its environmental aspects and environmental management system, the organization shall establish, implement and maintain a procedure(s) for a) internal communication among the various levels and functions of the organization, b) receiving, documenting and responding to relevant communication from external interested parties. c) The organization shall decide whether to communicate externally about its significant environmental aspects, and shall document its decision. d) If the decision is to communicate, the organization shall establish and implement a method(s) for this external communication.

65. Documentation The environmental management system documentation shall include a) the environmental policy, objectives and targets, b) description of the scope of the environmental management system, c) description of the main elements of the environmental management system and their interaction, and reference to related documents, d) documents, including records, required by this International Standard, and e) documents, including records, determined by the organization to be necessary to ensure the effective planning, operation and control of processes that relate to its significant environmental aspects.

66. Internal audit Audit programme(s) shall be planned, established, implemented and maintained by the organization, taking into consideration the environmental importance of the operation(s) concerned and the results of previous audits. Audit procedure(s) shall be established, implemented and maintained that address the responsibilities and requirements for planning and conducting audits, reporting results and retaining associated records, — the determination of audit criteria, scope, frequency and methods. Selection of auditors and conduct of audits shall ensure objectivity and the impartiality of the

67. NABL Accreditation NATIONAL ACCREDATION BOARD FOR TESTING AND CALIBRATION LABORATORIES (NABL)

68. What is NABL ? NABL specifies the general requirements for the competence to carry out tests and calibrations, including sampling. It covers testing and calibration performed using standard methods, non-standard methods, and laboratory-developed methods. National Accreditation Board for Testing and Calibration Laboratories (NABL) is an autonomous body under Department of Science & Technology, Government of India, and is registered under the Societies Act. NABL has been established with the objective to provide Government, Industry and Society in general with a scheme for third- party assessment of the quality and technical competence of testing and calibration laboratories. Government of India has authorized NABL as the sole accreditation body for Testing and Calibration laboratories. In order to achieve this objective, NABL provides laboratory accreditation services to laboratories that are performing tests / calibrations in accordance with NABL criteria based on internationally accepted standard for laboratory accreditation ISO.

69. CONCEPT: The concept of Laboratory Accreditation was developed to provide a means for third- party certification of the competence of laboratories to perform specific type(s) of testing and calibration. Laboratory Accreditation provides formal recognition of competent laboratories, thus providing a ready means for customers to find reliable testing and calibration services in order to meet their demands. Laboratory Accreditation enhances customer confidence in accepting testing / calibration reports issued by accredited laboratories. The globalization of Indian economy and the liberalization policies initiated by the Government in reducing trade barriers and providing greater thrust to exports makes it imperative for Accredited.

70. Benefits of Accreditation: Potential increase in business due to enhanced customer confidence and satisfaction. Savings in terms of time and money due to reduction or elimination of the need for re- testing . Better control of laboratory operations and feedback to laboratories as to whether they have sound Quality Assurance System and Increase of confidence in Testing / Calibration data and personnel performing work. Customers can search and identify the laboratories accredited by NABL for their specific requirements from the directory of Accredited Laboratories. Users of accredited laboratories will enjoy greater access for their products, in both domestic and international markets, when tested by accredited laboratories.

71. Types of Laboratory can seek Accreditation: Laboratories undertaking any sort of testing or calibration in the specified fields. Private or government laboratories. Small operations to large multi-field laboratories. Site facilities, temporary field operations and mobile laboratories.

72. CALIBRATION LABORATORIES MEDICAL LABORATORIES PROFICIENCY TESTING PROVIDERS REFERENCE MATERIAL PRODUCERS Biological Chemical Electrical Electronics Fluid-Flow Mechanical Non-Destructive Testing Photometry Radiological Thermal Forensic Electro-Technical Mechanical Fluid Flow Thermal & Optical Radiological Clinical Biochemistry Clinical Pathology Hematology & Immunohematology Microbiology & Serology Histopathology Cytopathology Genetics Nuclear Medicine (in- vitro tests only) Testing Calibration Medical Inspection Chemical Composition Biological & Clinical Properties Physical Properties Engineering Properties Miscellaneous Properties TESTING LABORATORIES

73. 10 Step Approach To Accreditation Awareness Training Quality Policy & Objectives Finalization Gap Analysis Documentation / Process Design Documentation / Process Implementation Internal Audit Management Review Meeting Shadow Audit Corrective –Preventive Actions Final Certification Audit Step 1: Awareness Training 100 Separate training sessions for top management, middle management and junior level management. Creates a motivating environment throughout the organization for ISO 17025 implementation.

74. Step 2: Quality Policy & Objectives Work shop with top management on development of quality policy. Work shop with top management and middle level functional management on development of quality objectives Step 3: Gap Analysis Understanding of all the operations of the organization. Development of process map for the activities of the organization. Comparing existing operations with requirements of ISO 17025:2005 standard. Step 4: Documentation / Process Design Quality Manual Functional Procedures Work Instructions System Procedures Formats

75. Step 5: Documentation / Process Implementation Work–shop on process / document implementation as per ISO 17025 requirements. Departmental / Individual assistance in implementing the new processes / documents. Step 6: Internal Audit Internal Audit Training & Examination (Optional). Successful employees carry out internal audit of the organization covering all the departments and operations. Suggest corrective and preventive actions for improvements in each of the audited departments. Step 7: Management Review Meeting Quality Policy & Objectives Results of internal audit Results of supplier evaluation Results of customer complaints Results of customer feedback etc.

76. Step 8: Shadow Audit It is a final certification audit. Finds degree of compliance with ISO 17025 standard. Gives an idea to the employees about the conduct of the final certification audit. Step 9: Corrective – Preventive Actions On the basis of shadow audit conducted in the last step, all the non-conformities will be assigned corrective and preventive actions. A check will ensure that all the points are closed and the organization is ready for the final certification audit. Step 10: Final Certification Audit Upon completion of various stages of accreditation audit, the audit, your organization will be awarded accreditation.

77. OUT OF SPECIFICATIONS (OOS)

78. Out of Specifications (OOS): Introduction:- When an analytical or test result of any batch or material is out of prescribed and predetermined limits or specifications, it is called as OOS. OOS may be raised in the case of stability testing, analysis of in-process, test of raw materials, intermediates and finished goods (API). Investigation for OOS may be performed while getting any unacceptable and questionable results.

79. Identification of OOS: Reports of Laboratory Investigation:- This investigation is conducted when OOS is found in analysis. The main purpose of obtaining OOS reports is to find out the source of the results which fall outside the specifications. In this initial investigation, all the results should be recorded and well documented. The data should be conveyed and forwarded to quality control department, so that full scale analysis can be performed.

80. Responsibility of Analyst and Supervisor:- An analyst has the primary responsibility for the laboratory testing results. He should have sound knowledge about the principle, primary requirements and process of the investigations. The accurate and precise results are expected, if any wrong results are found that should be informed to concern superior department and assessment should be initiated with immediate effect. The supervisor of the laboratory should discuss the problems and the malfunctioned result with the analyst. He should verify the followed correct procedure and knowledge of the analyst.

81. He should overlook the following points: 1. Raw data of the result. 2. Calculations of the result. 3. Proper functioning of instruments. 4. Procedure performed by the analyst. 5. Quality parameters of solvent's, reagents, standard solutions. 6. Knowledge of the analyst regarding investigation. 7. Method validation and evaluation of performance. 8. Preservation of the results obtained.

82. Identification of OOS: Reports of FuIl- Scale Investigation: When an initial analysis does not confirm the errors caused by OOS result from lab investigations, full scale investigations with proper design should be performed. The identification of the source of the errors and the action taken for the correctness are the main objectives of this investigation. The following are the important aspects of OOS results identification with respect to full scale investigation. 1. Review of manufacturing, production and sampling. 2. Review of lab investigation result. 3. Supplementary laboratory testing procedure.

83. Review of Manufacturing, Production and Sampling:- To find out the OOS results, review of manufacturing, production and sampling is very important. The errors and problems should be investigated and identified. The documents and records of manufacturing and production should be reviewed. The investigations should be reviewed through a well-documented manner.

84. Review of Lab Investigation Results:- It contains the following information: Cause of the investigation. Review and summary of manufacturing process (which may have identified as malfunctioned or cause of OOS results). Review of previous results to find out the possible causes of OOS results. Review of documented records to analyze the possible factors of wrong results. The actions taken to correct the process.

85. Supplementary Laboratory Testing Procedure: To investigate OOS results in full scale, additional laboratory testing may be performed. This includes Re-testing and Re-sampling. In Re-testing, a portion of original samples are tested again according to the standard procedures. The results are kept in a well documented manner. This process helps to find out the problems encountered due to error in instruments, process, dilution or sample handling. In Re-sampling, a specimen is collected from any additional units from original sample or a new sample is prepared from the same batch and analyzed further.

86. Analysis of Investigated Results:- The reported results should be analyzed and interpreted to find out the possible, probable and actual causes of OOS results. Some possibilities are discussed below: OOS Results Investigation reports Laboratory Investigation Full Scale Investigation Identification of factors of OOS results in Batch/Lot YES Batch Rejection Analysis of Investigated Results

87. OOS Results Investigation reports Laboratory Investigation Full Scale Investigation Identification of factors of OOS results in Batch/Lot Batch Rejection Release of Batch Causes not Identified Non-conformation of OOS results Testing for other Batch/Lot Identification of factor OOS results Proper follow up of laboratory investigations Failure of initial OOS results in Lab results Analysis of Investigated Results

88. CHANGE CONTROL

89. Change Control:- Introduction:- In pharmaceutical industry change control is an important part of quality assurance. The changes proposed and made in any procedure or process should be reviewed, established, documented and approved by the concerned authorities. Change control is the system to implement this approved change to confirm the regulatory requirements. Definition:- Change control can be defined as a formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.

90. Function: Any change in manufacturing process. equipment, materials used that may cause alteration in product quality should be validated. The main functions of change control are: 1. Identification of the changes made. 2. Review of the change. 3. Approval of the change. 4. Validating the changes which can alter the product quality, regulatory or GMP requirements. 5. Analysis of the change and monitoring of the impact of change

91. Area of Change: 1. Manufacture: Following changes are concerned: Raw materials, Equipment's, Process/parameters, Testing/validation procedures, Packaging materials, Cleaning process 2. Quality control and quality assurance: Following changes are considered: Quality testing parameters, Sampling size, Validation process, Specifications of raw materials, intermediates and final product, Documentation, Standard operating procedures (SOPs).

92. 3. Research and development: It includes the change in:- Manufacturing process (any addition of elimination of steps), Raw materials (any addition of omission of the product ) Specifications of raw materials, intermediates and final product, Quantitative aspects of raw materials and finished products, Manufacturing conditions and storage conditions, Testing/validation procedures. 4. Engineering: Equipment used, Validation of the equipment, Parts of equipment, Working and design layout, Software/ Hardware or Change in any program.

93. 5.Marketing: Written Procedures & Documentation: Procedures in writing should be kept at the proper place to describe the changes made related to the materials, equipment and method of manufacturing or testing conditions or any other change that can affect the quality of the product. Standard operating procedure (SOP) and records of change control documents are required for the documentation. The Change Control Form (CCF) is an important documentation part of change control. It contains the form related to initiate department for the proposed change, proposed change details, comments from QA Head, category of the changes, supportive documents, management review form and assessment of CCF.

94. GOOD LABORATORY PRACTICE (GLP)

95. GLP (Good Laboratory Practice) :- Introduction:- GLP was introduced for the non-clinical safety studies in 1976. In late 90's this practice along with OECD (Organization for Economic Co-operation and Development) was accepted as industry standards. GLP has been introduced due to the poor and dishonest practice in laboratory in the early 70's. The poor lab practices include wrong calibration of equipments, inaccurate test systems and accounts. In 1983, Industrial Bio Test Laboratory (1952-1978) of New York was found guilty as it provided wrong and inaccurate research data to the Government. The company provided fake, fabricated and concealed data of the tests on rodents involving Trichlorobanilide (deodorant soap additives), Naprosyn (arthritis drug), Sencor (Herbicide) and Nemacur (Pesticide).

96. Definition: - According to Valcarcel M., GLP is a set of rules, operating procedures and practices established by an organization to ensure the quality and accurate results in a laboratory practice. In this practice, the given organization sets the principles and the laboratory works are planned, operated, overlooked and reported. Fundamentals of GLP: Resources: It includes the following: 1.Organization and Management: Management has the overall responsibility for the implementation of both good science and good organization within their institutions. Good science includes proper definition of experimental design, knowledge of scientific principles, documentation of experimental and environmental variables, complete evaluation of the results and reporting of results. Whereas, good organization should provide proper planning of studies, qualified skilled personnel, adequate facilities, infrastructures, proper conduction of studies and verification process for the study results

97. 2. Personnel: The detailed records should be maintained for every individual staff of the institution. The records include the detail curriculum vitae, training records and their job descriptions. These records should meet the GLP requirements and these are maintained to establish that every staff has the competence, education, experience and training to perform the tests. 3. Availability of Facilities: Adequate facilities with state-of-the-art infrastructure should be provided by the institution and management to ensure the validation of the studies. The cleaning, maintenance and documents of the site plan should satisfy the guidelines. 4. Availability of Equipments: Adequate equipments must be available for the study in the organization. The suitability of the equipment and calibrated instruments should be provided by the management.

98. C. Characterization:- It includes: 1. Test Items: It may be an active ingredient for a medicine, a pesticide, a food additive, a vaccine, an industrially used chemical, a biomass or an extraction from plants. These items are characterized by analytical profile like chemical identification test, solubility, stability etc. The test items should be stored properly to avoid the contamination. 2. Test Systems: The test systems could be the animals, bacteria, cells, organs and plants. Sometimes they may be analytical equipments also. The test systems should be handled in such a way that it must comply with the GLP guidelines and with the national animal welfare law.

99. C. Rules:- 1. Study Protocols: The study plan or protocol describes how the study is designed and how it is to be conducted. The plan should include the expected time frame of the study. 2. Written Procedures: Written procedures are often known as SOPs (Standard Operating Procedures). SOPs provide the instructions how each technical procedure should be performed, how to ensure the sound organization of the study, environmental variables and data.

100. D. Results :- It includes raw data, final reports and data archiving. 1. Raw Data: The original record and the data needed for the reconstruction should be recorded. The raw data should include 'what‘ was done, 'how' it was done, 'when’ the work was done and ’who’ performed the work. The recorded data should clarify the process by which it is generated and should confirm the process has been performed as per the guidelines and SOPs. 2. Final Results: Final results are the responsibility of the study director. These results should describe the study accurately and the scientific interpretation. The results should reflect accurately the raw data. The review and audit of these reports should be done. All accepted changes in the results approved by the reviewer should be incorporated before the finalization of the results.

101. 3 Archives: Archiving is a safe depositing of all information. It is considered to be a center for the compilation and distribution of summary documents. The archiving of document helps the reconstruction of studies performed earlier. E. Quality Assurance: The requirement of the quality assurance is to validate the experimental results. Quality assurance unit (QAU) or simply QA must review all phases of preclinical research, organization framework, staff documents, study procedures and SOPs. The internal audits and inspections should be performed by the QA officers. The QA performs the study-based audit, facility and systems-based inspection and process-based inspections.

102. GLP Principles:- GLP principles are set of organizational requirements. GLP is a regulation covering the quality management of non-clinical safety studies. The aim of the regulation is to encourage scientists to organize and perform their studies in a way which promotes the quality and validity of the test data. GLP deals with the following issues: The facility provided by the organization. Efficient and trained personnel. Quality of validated equipment and reagents. Predetermined study design. SOPs, process validation and test procedures. Correctness of the results. Quality assurance laboratory (QAL) and Quality assurance program (QAP). Recorded and documented results and their storage. The organizations should fulfill all the criteria to provide all the facilities for the good practice in laboratory. The personnel should have enough knowledge about the principles and working of the practices. In the elements of GLP, SOP is an important part with respect to quality assurance. To maintain the productivity of the result, a well documented SOP is required; moreover, the personnel should have complete information mentioned in SOPs.

103. SOPs define the complete process flow and work steps which help to achieve the accurate and precised results. Validated modern equipments and adequate facilities should be provided by the organization to maintain the good practice in laboratory. The complete specifications and storage of reagents and materials should be provided. QA laboratory should have the proper test procedures (physical, chemical and biological) and characterized data for both the test and reference materials. Quality assurance unit (QAU) bears the responsibility to assure the GLP and this unit is attached with QAL and QAP. The audit of the laboratory and verification of the quality parameters are the major responsibilities of the QAU. The reported study results should be stored and retained with well documented manner.

104. Aim of GLP:- 1. GLP helps to reduce the number of false negatives arising from the studies. False negative result for a toxicity study falsely intimated that the test item is not toxic, but in real the item is toxic. 2. GLP also helps to reduce the chance of false positives. In the case of a non-clinical safety study, the results wrongly predict that the test item is toxic, when really it is not. 3. GLP promotes international recognition of study data. When studies are performed according to OECD GLP principles, then the acceptability and reliability of the data are recognized in the international level by the OECD member states.

105. Thank you