(IPC LOGO, WHO LOGO & CDSCO)

GUIDANCE MANUAL FOR COMPLIANCE OF INDIAN PHARMACOPOEIA BY DRUGS REGULATORY BODIES,DRUGS TESTING LABORATORIES & PHARMACEUTICAL INDUSTRY

Published by The Indian Pharmacopoeia Commission in collaboration with The Central Drugs Standards Control Organization and WHO-Country Office (India)

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FORE WORD/SCOPE This Manual is for the use of regulatory bodies, manufacturers, independent drugs testing laboratories and all those who are involved in activities relating to testing of drugs and are to use the Indian Pharmacopoeia in accordance with the provisions of the Drugs & Cosmetics Act 1940 and Rules 1945 there under. This manual is not an addendum or supplement to the Indian Pharmacopoeia or a part of it. It is intended to enable the users of IP to perform the activities related to performance of the tests or associated activities prescribed in the IP and also to understand or interpret the requirements of IP for proper compliance of the requirements thereof.

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CONTENT
S.No 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.1. Page No. Acknowledgments 4 Contributors 5 Expert core committee members 6 Glossary 7 Introduction 12 IP 2010 Legal status in Drugs and Cosmetics Act 1940 and Rules 15 1945 IP 2010 and Addendum 2012 Salient features 21 Good Laboratory Practices (GLP): Schedule L1 and its Interpretation 26 Reporting of errors and anomalies in the IP 42 Guidelines to Users of IP 43 Process of IP Monographs Development 49 Guidelines for stability testing of pharmaceutical products 54 Analytical method validation for pharmacopoeial analysis of drugs 69 Calibration of Equipments and apparatus Part I : Calibration of 73 Sophisticated instruments and glassware in Drugs Testing Laboratories Calibration of Equipments and apparatus Part II : Calibration of 94 Volumetric Glassware General requirements for the competence of testing and calibration 101 laboratories NABL/ISO/IEC 17025 Practical Risk-Based Systems Approach-Quality assurance in QC 112 labs Challenges in compliance of pharmacopoeial standards 116 Standards of Herbal drugs in IP 122 IP Guidelines for the quality of herbal drugs and its products 135 Guidelines for Indian Pharmacopoeia Reference Substances 138 Guidance Document for Biotechnology Derived Therapeutic 145 Products Guidance note on quality of water system for pharmaceutical 148 purposes Annexure I: IP 2010 General Notices 165 Annexure IIA: SOPs for laboratories 176 Annexure IIB: Model SOP 178 Annexure III: Accredited calibration laboratories/agencies in India 187 Annexure IV: List of equipments required for drugs testing 193 laboratories Annexure V: List of experts and participants of IPC workshops 195 Annexure VI List of drugs added and omitted in IP 2010 202 Feed back format 207 Title

14.2. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

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1. ACKNOWLEDGMENTS
The IPC wishes to acknowledge and place on record the contributions from officials, experts, representatives and scientists of the pharmaceutical industry, academics and drugs testing laboratories. The Drugs Controller General of India, Dr. Surinder Singh needs special mention for his whole hearted support and encouragement to the IPC in general and for the conduct of the workshops in particular. IPC puts on record the appreciation to Dr. R. A. Singh, Director, RDTL, Chandigarh and his staffs, Dr. Girish Sahni, Director, IMTech, Chandigarh, Dr. Gopa Ghosh, Director CDTL, Mumbai and Dr. Ramakrishna, DDC(I), CDSCO (WZ) for providing the logistical supports in conducting the workshop at IMTech, Chandigarh and CTDL, Mumbai respectively. The other officials of the Central Drugs Standard Control Organization, especially Dr. D. Roy, DDC (I), CDSCO (NZ), Dr. P. K. Guha, Director, CDL, Kolkata, also need special mention for their contributions. Special thanks are also due to the WHO-Country Office (India), New Delhi in general and Dr. Madhur Gupta in particular as they made the conduct of the workshops cum symposia and publication of this manual possible by extending the financial and technical supports needed. The Scientific staffs of the IPC has played key roles in organizing the workshops, delivering lectures on the various aspects of the IP and in contributing articles to this Manual. In particularly Dr. Jai Praksh, Dr. Raman Mohan Singh, Dr. Manish Kumar Dare, Dr. Kalai Selvan, Dr. Anil Kumar Teotia, Dr. Robin Kumar, Dr. Nishant Dafale, Mr. Anuj Kumar, Mr. Alok Sharma, Mrs. M. Kalaivani and several others have contributed in one way or other in the workshops and in compiling this manual with Dr. Jai Prakash shouldering many responsibilities. The valuable guidances and supports given by the Secretary cum Scientific Director of the IPC, Dr. G. N. Singh and the initiative taken by him to make the workshops and related events possible need special mention. Several scientists and experts in the fields of drugs regulation, pharmacy education and research and industries participated in the workshops and made contributions by making scientific presentations and by taking part in the discussions and deliberations to decide many issues. The list of the contributors, resource persons for this manual and the lists of experts and participants for the workshops are furnished and the IPC wishes to express sincere thanks to every one of the participants for their contributions. The scientists and the secretarial staff who had rendered whole hearted services in publishing the I P and in the conduct of the workshops and publication of this manual take pride in accomplishing the tasks entrusted to them successfully and the IPC thanks one and all of the staff of the IPC for their devotion to their duties and rendering relentless efforts to the causes of the IPC. The services of Mr. S.S. Venkatakrishnan, Drugs Controller (Retd.), Kerala who provided all possible technical support for organising the workshops-cum-symposia and compilation of this manual is gratefully acknowledged. IPC thanks the printer for bringing this Manual to the present shape.

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2. CONTRIBUTORS
1. Mr. Alok Sharma, Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002. Dr. Anil Kumar Teotia Senior Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002. Dr. Anurag Rathore, Associate Professor, Department of Chemical Engineering, Indian Institute of Technology, New Delhi. Dr. Gopa Ghosh, Director, Central Drugs Testing Laboratory, Mumbai. Dr. Jai Prakash, Principal Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002. Dr. V. Kalaiselvan, Senior Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad - 201 002. Dr. Manish Kumar Dare, Principal Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002. Dr. D. B. A. Narayana, 15 (Old No. 1101/927), 1, F Main Road, 2nd Stage, Giri Nagar, Bangalore - 560085. 9. Dr. Nishant A Dafale Senior Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002.

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10. Dr. P. M. Dixit Watson Pharma Pvt. Ltd., Plot No. K-7, MIDC, Additional Ambernath, Anand Nagar, Ambernath (E) - 421 506. 11. Dr. Raman Mohan Singh, Principal Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad- 201 002. 12. Dr. R. A. Singh, Director, Regional Drugs Testing Laboratory, Chandigarh. 13. Dr. Robin Kumar Senior Scientific Officer, Indian Pharmacopoeia Commission, Sector-23, Raj Nagar, Ghaziabad - 201 002. 14. Mr. Sipahimalani 10-C, Ananta, Dr. R. Patel Lane, Opp. Breach Candy Hospital, Mumbai - 110 025. 15. Mr. S. K. Gaind, Techno-Management Consultant. 16. Mr. S. S.Venkatakrishnan, Drugs Controller (Retd.), Kerala.

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3. Expert Core Committee Members

1. Dr. V. G. Somani (Chairman), DCG (I), Central Drugs Standars Control Organisation (CDSCO), FDA Bhawan, Kotla Road, New Delhi - 110002. Dr. G. N. Singh, Secretary-cum-Scientific Director, Indian Pharmacopoeia Commission, Ghaziabad. Dr. Surinder Singh, Ex-DCG (I), Director, National Institute of Biologicals, Noida. Prof. B. Suresh, Chairman Scientific Body of IPC, Vice Chancellor, JSS University, Mysore 570015 (Karnataka). Prof. Y.K. Gupta, Head, Department of Pharmacology, All India Institute of Medical Sciences (AIIMS), Ansari Nagari, New Delhi. 6. Dr. D. Roy, DDC (I), CDSCO North Zone, C.G.O. Building-I, Kamla Nehru Nagar, Hapur Chungi, Ghaziabad 201002. Dr. Madhur Gupta, Representative to WHO Country Office (India), 3rd Floor, Shri Ram Bhartiya Kala Kendra, 1, Copernicus Mar, New Delhi 110001. Mr. P.K. Guha, Director, Central Laboratory, 3, Kyd Street, Kolkata 700016.

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Drugs

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Dr. R.N. Gupta, Vice President, Indian Pharmaceutical Association & Associate Professor, Birla Institute of Technology, MESRA, Ranchi (Bihar).

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4.GLOSSARY
1. IPC: IPC is the Indian Pharmacopoeia Commission. It is an autonomous body under the Ministry of Health and Family Welfare, Government of India. The IPC was constituted in the year 2005 with mandate to function as the standards setting institution for drugs under the modern system of Medicine and to bring out IP, the compendia of the standards set out for drugs as above periodically. The IPC has its headquarter at Raj Nagar, Ghaziabad. It has a General Body and Governing Body and Scientific body. The head of this commission is the Secretary-cum-Scientific Director. Besides publishing IP periodically, the IPC is vested with the duty of publishing the NFI (National Formulary of India) periodically and providing IP reference substances. 2. IPL: IPL is Indian Pharmacopoeia Laboratory. This is the laboratory division of the IPC. The Central Indian Pharmacopoeia Laboratory (CIPL), Raj Nagar Ghaziabad, a laboratory functioning under the DGHS was amalgamated with the IPC in the year 2009 to provide the laboratory facilities that the Commission needed for activities of test and analysis of materials that the Commission has to perform to carry out its functions. IPL is the NABL accredited laboratory. 3. IP: IP is Indian Pharmacopoeia. It is a compendium of official standards for drugs and materials used for formulating of drugs. It comprises of monographs for APIs in the forms of bases and salts, dosage forms, drugs, combinations of drugs etc. It is the official book of standards under the Drugs and Cosmetics Act 1940 and Rules 1945. Drugs sold in the country, whether manufactured within or imported, shall comply with the standards set out in IP, if the drug is specified in it. The standards such as BP, USP etc can be appliedly if a drug does not find place in the current or its immediate previous edition of IP. IP covers almost 95% of the drug used in the country. IP is to be published once in two years with an addendum in between to prescribe or update standards for drugs or to delete obsolete ones. 4. IPRS: IPRS is Indian Pharmacopoeia Reference Substance(s). The tests for identity, purity and assay of drugs involve use of authentic substances, against which quality of the drug under test can be compared. IPRS are primary reference substances. 5. API: API is Active Pharmaceutical Ingredient. A substance that is used as an active constituent of a drug formulation and is responsible for pharmacological action. Active Pharmaceutical Ingredients are of chemical or biological origin. 6. CDSCO: CDSCO is Central Drugs Standard Control Organization. This is a division of the Directorate General of Health Services, Government of India, Ministry of Health & Family Welfare. It is headed by the Drugs Controller General of India (DCGI). It has its headquarters

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at FDA Bhawan, Kotla Road, New Delhi and has zonal offices at Ghaziabad (North Zone), Kolkota (East Zone), Mumbai (West Zone) and Chennai (South Zone). The Central Drugs laboratory (CDL), Kolkota, the appellate laboratory for drugs under the Drugs and Cosmetics Act, the Regional Drugs Testing Laboratories (RDTL) at Guwahathi and Chandigarh, the Central Drugs Testing Laboratories (CDTL) at Mumbai, Hyderabad and Chennai, the Central Research Institute (CRI) at Kasauli are under the control of the CDSCO. The key functions of the organization are to lay down standards of cosmetics, diagnostics and devices; to lay down regulatory measures, amendments to the Drugs & Cosmetics Act 1940 an dthe Rules thereof; to regulate market authorization of New drugs; to regulate clinical research in India; to approve licences to manufacture certain categories of drugs as Central Licence Approving Authority for Blood Banks, Large Volume Parenterals, vaccines and sera; to regulate the import and standards of imported drugs; works relating to the Drugs Technical Advisory Board(DTAB) and the Drugs consultative Committee(DCC), testing of drugs by the Central Drugs Laboratories. It also coordinates the functions of the State Drugs control administrations, screening of drugs formulations available in the country etc. Details of subzonal offices of the CDSCO and other functions of the organization etc can be obtained from the site www.cdsco.nic.in 7. DCGI: DCGI is Drugs Controller General of India. The person is the head of the CDSCO. He is the statutory licensing authority for manufacture, sale and distribution of drugs mentioned above and for import of drugs. He is also the statutory controlling authority of all Inspectors under the Drugs and Cosmetics Act in the CDSCO. 8. GLP: GLP is the short name for Good Laboratory Practices. It implies the statutory norms prescribed in Schedule L1 of the Drugs and Cosmetics Rules 1945. It is applicable to the laboratories of manufacturing units under rules 74 and 78 of the Drugs & cosmetics Rules 1945 and approved drugs testing laboratories under rule 150E and is intended to secure effective regulation of the functioning of laboratories for testing of drugs. It prescribes the requirements of infrastructure in terms of building, equipments, personnel and other services and facilities; standard operating procedures to be developed and adopted for equipments, environment, activities of tests and analysis of drugs and associated matters, documentation etc. 9. IP Monograph: A Monograph is the documentation of the quality parameters for drugs. It comprises of the name and synonym of the drug; where appropriate, the chemical, empirical and structural formulae of the molecule the base or its salt involved, its molecular weight, production, definition, category, dose, usual strength, description, solubility, tests for identity, tests for impurities, tests for assay or potency in general and in the case of injectables, tests for pyrogen, sterility and in the cases of certain biological products abnormal toxicity and storage. All the parameters of quality set out in a monograph are designed to determine the quality of a drug.

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10. IP General Chapters: It provides the information about the common analytical procedures applicable to IP monographs and information pertaining to the quality requirements of pharmaceutical products. The interpretation of a monograph must be in accordance with all the general requirements, testing methods, texts and notices pertaining to it, in the IP. A product is not of standard quality unless it complies with all the requirements of the monograph. 11. WHO: Unless the situation so describes, the abbreviation refers to the World Health Organization, India Country office. The WHO India Country Office is located in New Delhi. 12. APLAC: APLAC is Asia Pacific Laboratory Accreditation Cooperation. It is a cooperation of accreditation bodies in the Asian Pacific region that accredits laboratories, inspection bodies and reference material producers. It is recognized by the Asia Pacific Economic Cooperation (APEC) as one of five specialist Regional Bodies (SRBs). 13. ILAC: ILAC is the International Laboratory Accreditation Cooperation, an international cooperation of laboratory and inspection accreditation bodies formed more than 30 years ago to help remove technical barriers to trade. 14. NABL: NABL is the National Accreditation Board for Testing and Calibration Laboratories. It is an autonomous body under the aegis of Department of Science and Technology, Govt. of India. It has been established with the objective to provide a scheme for third party assessment of the quality and technical competence of testing and calibration labs. Further details can be obtained from http://www.nabl-india.org.in 15. SOPs: SOPs are Standard Operating Procedures. SOPs are written documents to carry out the specified activities. The action steps are usually listed in a chronological order. They facilitate to ensure that everyone performs each procedure the same way every time thus, provide a stable pattern of function by the laboratory staff to ensure consistency of quality in lab results. They are essential for the laboratory quality management system. 16. PPM: Parts Per Million. 17. EU: It is Endotoxin Unit. 1 EU= 1 IU. The quantities of endotoxins are expressed in defined Endotoxin Units. With the adoption of the second International Standard for endotoxin by the Expert Committee on Biological Standards of the WHO. 18. Accelerated stability testing: Studies designed to increase the rate of chemical degradation and physical change of a drug by using exaggerated storage conditions as part of the formal stability testing programme. The data thus obtained, in addition to those derived from realtime stability studies, may be used to assess longer-term chemical effects under nonaccelerated conditions and to evaluate the impact of short-term excursions outside the label

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storage conditions, as might occur during shipping. The results of accelerated testing studies are not always predictive of physical changes. 19. Batch: A defined quantity of product processed in a single process or series of processes and therefore required to be homogeneous. In continuous manufacture, the batch must correspond to a defined fraction of production, characterized by its intended homogeneity. The foot notes to clause (v) of Sub-rule (1) of Rule 96 of the Drugs and Cosmetics Rules explain the scope of the word Batch and also batch number for various categories of drugs. 20. Climatic zones: The four zones into which the world is divided based on the prevailing annual climatic conditions. 21. Expiry date: The date given on the individual container (usually on the label) of a drug product up to and including which the product is expected to remain within specifications, when stored under specified conditions. It is established by adding the shelf-life period to the date of manufacture. The Note of Explanantion to Rule 96 of the Drugs and Cosmetics Rules, 1945 require the date of expiry to be in terms of month and year and shall shall mean that the drug is recommended till the last day of the month. 22. Mean kinetic temperature: The single test temperature for a drug product corresponding to the effects on chemical reaction kinetics of a given temperature-time distribution. A mean kinetic temperature is calculated for each of the four world climatic zones according to the formula developed by Haynes (2). It is normally higher than the arithmetic mean temperature. 23. Real-time (long-term) stability studies: Experiments on the physical, chemical, biological, biopharmaceutical and microbiological characteristics of a drug, during and beyond the expected shelf-life and storage periods of samples under the storage conditions expected in the intended market. The results are used to establish the shelf-life, to confirm the projected shelflife, and to recommend storage conditions. 24. Shelf-life: The period of time during which a drug product, when stored under the specified conditions, is expected to comply with the specification 1 as determined by stability studies on a number of batches of the product. The shelf-life is used to establish the expiry date of each batch.

"Shelf-life specification" means the requirements to be met throughout the shelf-life of the drug product (should not be confused with "release specification").

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25. Stability: The ability of a pharmaceutical product is to retain its chemical, physical, microbiological and biopharmaceutical properties within specified limits throughout its shelflife. 26. Stability tests: A series of tests designed to obtain information on the stability of a pharmaceutical product in order to define its shelf-life and utilization period under specified packaging and storage conditions. 27. Supporting stability data: Supplementary data, such as stability data on small-scale batches, related formulations, and products presented in containers other than those proposed for marketing, and scientific rationales that support the analytical procedures, the proposed retest period or the shelf-life and storage conditions. 28. Utilization period: The period of time during which a reconstituted preparation or the finished dosage form in an opened multidose container can be used.

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5. INTRODUCTION
The Indian Pharmacopoeia (IP) 2010 was released by the Honourable Union Minister for Health & Family Welfare on 04.08.2010 and it came into effect from 01.12.2010. It is the official book of standards for drugs in India. It supersedes the IP 2007. As per the provisions of the Drugs & Cosmetics Act 1940 & the Rules 1945, the laws governing the activities of Import, Manufacture, Sale and Distribution of drugs in India, the standards of identity, purity and strength prescribed in the IP 2010 apply to all drugs involved in the above said activities in India. For drugs not included in the IP 2010, but included in the IP 2007, the standards prescribed in that book apply. In short the drugs made available to the consumers in the country by whatever process as the case may be, are to conform to the standards prescribed in the IP 2010 or in IP 2007 as described above. Only in the case of drugs not covered by these two books of standards other standards apply, which includes other official pharmacopoeias or in the case of new drugs, the norms applicable to them. Failure to comply with the standards set out in the IP could result in supply of drugs that are legally not of standard quality. Apart from the exercises of including monographs for more drugs that did not figure in the earlier version and deleting obsolete ones, the IP 2010 and its Addendum include revisions or upgrading of tests for identity, purity, impurity etc of drugs by adopting more accurate instrument methods. This exercise also enables harmonization of testing procedures with internationally accepted procedures and adds value to the drugs produced in the country for its acceptance globally. Unless the norms prescribed in IP 2010 are understood and adopted by the stakeholders, the purposes of the publication of the new version may to not be achieved. The stakeholders are the regulatory officials, pharmaceutical industry and private drugs testing laboratories and to sensitize the stakeholders of all matters related to IP 2010, the Indian Pharmacopoeia Commission (IPC), in association with the WHO Country Office for India, organized two workshops cum symposia, one at IPC campus at Raj Nagar, Ghaziabad, Uttar Pradesh on 8th and 9th of December 2010 and the second at Microbial Institute of Technology, Chandigarh on 7th and 8th of April 2011. Regulatory officials, representatives of industry and private drugs testing laboratories, academicians and officials of the Ministry of Health and Family Welfare, Govt. of India participated in the Workshops-cum-symposia. Another workshop was organized by IPC on 26th and 27th of May 2011 at Central Standard Control Organization, Zonal Office (West Zone) exclusively for the Government Analysts of the Central and State Governments on the matters relating to the IP so that the standards of IP can be effectively implemented in the Drugs Testing Laboratories of the Country. The Scientists of the IPC as well a few members of the Scientific Body also attended the programmes not only to give clarifications in any matter associated to the issues discussed, but also to get views of experts and participants in the issues so that further editions of IP or the Addendum/ supplement of IP could be compiled in better manner. Lectures

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on different topics related to the issues at hand were delivered by identified experts in the field who responded to the queries from the participants. The WHO Country Office India provided the financial and technical supports for workshops. Representative from Essential Drugs & Medicines), Health Systems Development Cluster, WHO Country Office for India attended the programmes to give guidance in the matter. Workshops-cum-Symposia has enabled preparation of these guidelines, which are expected to go a long way in the proper adoption of the IP 2010 and its Addendum to be issued and the future issues of the IP. This in turn is expected to improve the qualities of the medicines supplied to the consumers. For the guidance of the users, the legal status of the IP, its important features, mode of addressing anomalies, if any noted, and appropriate recommendations to the users are incorporated in this manual. The General Notices of the IP 2010 are also reproduced for the immediate reference and special attention of the users of IP. Requests are received from stakeholders on modifications/ amendments needed in the IP monographs to accommodate newer technologies and better methods for tests of identity, strength and purity of drugs. Requests are received for incorporation of newer monograph also. The IPC needs certain basic data for considering these needs and to make suitable changes to the IP and the standard format for making such requests is included in this manual. Besides, guidance for Validation of Analytical Procedures, procurement/ availability and use of IP Reference Substances, calibration of equipments & glass wares, matters relating to phyto-pharmaceutical substances, SOPs relevant to the matter including model SOP and infrastructure requirement for a drugs testing laboratory for performance of the tests as per the IP 2010 are also incorporated in this guidance manual. Needless to mention, the requirements of SOP, infrastructure requirements are only the basic ones and are not the exhaustive ones. Individual laboratories are to provide need based requirements bearing in mind the basic needs outlined. IPC requests all stakeholders to send their feedbacks on this guidance manual. A format for the feedback is presented at the end of this manual. Views can be communicated through e-mails also. Stakeholders are also requested to visit the IPC website regularly for updated informations relating to the IP and for their comments and contributions to the causes of the same. E-mail id of the IPC is: ipclab@vsnl.net. Web-site: www.ipc.gov.in Contact telephone and fax numbers: +120 2783401,2783392

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Disclaimer: The provisions of laws and their interpretations presented in this manual are as they are available from the authors. They have been verified and reviewed by experts before incorporation in this manual. Users are advised to verify amendments to the legal provisions. Users are also advised to verify the authentic books for changes in the laws quoted and also the methods and procedures. Clarifications on any matter presented in the manual will be issued with due verification with the author(s) concerned only. Copy right: The contents of this Manual are not to be copied in full or part or reproduced in any manner without the authority of the IPC and the author of the part concerned.

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6. IP 2010 LEGAL STATUS IN THE DRUGS & COSMETICS ACT 1940 AND RULES 1945

IP is the Official book of standard for drugs in India under the Drugs & Cosmetics Act 1940 and its rules. Section 8 relating to import of drugs (into India) and Section 16 of the Act) lay down as under: 8. Standards of quality. (1) For the purposes of this Chapter, the expression standard quality means (a) in relation to a drug, that the drug complies with the standard set out in the Second Schedule, 16.Standards of quality. (1) For the purposes of this Chapter, the expression standard quality means (a) in relation to a drug, that the drug complies with the standard set out in the Second Schedule, ... Clause 5 of the Second Schedule to the Act states as under: 5. Other drugs: - Drugs included in the Indian Standards of identity, purity and Pharmacopoeia strength specified in the edition of the Indian Pharmacopoeia for the time being in force and such other standards as may be prescribed In case the standards of identity, purity and strength for drugs are not specified in the edition of the Indian Pharmacopoeia for the time being in force but are specified in the edition of the Indian Pharmacopoeia immediately preceding, the standards of identity, purity and strength shall be those occurring in such immediately preceding edition of the Indian Pharmacopoeia and such other standards as may be prescribed.

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Drugs not included in the Indian Pharmacopoeia but included in the official Pharmacopoeia of any other country.

Standards of identity, purity and strength specified for drugs in the edition of such official Pharmacopoeia of any other country for the time being in force and such other standards as may be prescribed.

This status is laid down in the D& C Rules also. Rule 124 states as under: 124Standards of drugs:-- (1) Drugs included in the Indian Pharmacopoeia-(a) The standards for identity, purity and strength shall be those as may be specified in the edition of the Indian Pharmacopoeia for the time being in force. (b) In case the standards for identity, purity and strength for drugs are not specified in the edition of the Indian Pharmacopoeia for the time being in force but are specified in the edition of the Indian Pharmacopoeia immediately preceding, the standards for identity, purity and strength shall be those occurring in such immediately preceding edition of the Indian Pharmacopoeia. (2) For other drugs-(a) The standards for identity, purity and strength shall be those as may be specified in the edition of the official pharmacopoeia, for the time being in force, of any country to which the drug claims to comply with. (b) In case the standards for identity, purity and strength for drugs are not specified in the edition of such official pharmacopoeia for the time being in force, but are specified in the edition immediately preceding, the standards for identity, purity and strength shall be those occurring in such immediately preceding edition of such official pharmacopoeia to which the drug claims to comply with. Thus all drugs imported into the country except those intended for personal use or in small quantities for tests and analysis, are to comply with the standards set out in the IP 2010 or IP 2007 as the case may be and other standards apply only in cases not covered by the IP2010 and IP 2007. A drug that does not conform to the above standards is one Not of standard quality and activities of import, manufacture, sale and distribution of a drug not of standard quality, is an offence punishable under the Drugs and Cosmetics Act 2010.

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The letters IP in relation to a drug is to be used only for the purpose of informing the user or others as the case may be that the drug is of IP standards. Rule 104 of the Drugs and Cosmetics Rules lays down as: 104 Use of letters I.P. etc.- The letters I.P and recognised abbreviations of pharmacopoeias and official compendia of drug standards prescribed under these rules shall be entered on the label of the drug only for the purpose of indicating that the drug is in accordance with standards set out in the Indian Pharmacopoeia or in any such pharmacopoeia or official compendium of drug standards recognised under the Rules. Labels of drugs are to conform to Rule 96 of the Drugs and Cosmetics Rules and clause (b) of sub-rule (1) of this rule stipulates as under: 96. Manner of Labelling: --- (1). (1) Subject to the other provisions of these rules, the following particulars shall be either printed or written in indelible ink and shall appear in a conspicuous manner on the label of the innermost container of any drug and on every other covering in which the container is packed, namely:(i) The name of the drug: For this purpose, the proper name of the drug shall be printed or written in a more conspicuous manner than the trade name, if any, which shall be shown immediately after or under the proper name and shall be (a) for drugs included in Schedule F or Schedule F(1), the name given therein; (b) for drugs included in the Indian Pharmacopoeia or the official pharmacopoeias and official compendia of drug standards prescribed in Rule 124, the name or synonym specified in the respective official pharmacopoeias and official compendia of drug standards followed by the letters I.P. or, as the case may be, by the recognised abbreviations of the respective official pharmacopoeia and official compendia of drug standards; (c) for drugs included in the National Formulary of India, the name or synonym specified therein followed by the letters N.F.I.; (d) for other drugs, the international non-proprietary name, if any, published by the World Health Organization or where an international non-proprietary name is not published, the name descriptive of the true nature or origin of the substance. Any drug not conforming to the above labelling requirements is a misbranded drug as defined and punishable under the law.

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Rule 96 as stated above applies to imported drugs also as laid down in Rule 32. Rule 32: 32.Packing and labelling of imported drugs. __No drug shall be imported unless it is packed and labelled in conformity with the rules in Parts IX and X and further conforms to the standards laid down in Part XII provided that in the case of drugs intended for veterinary use, the packing and labelling shall conform to the rules in Parts IX and X and Schedule F(1). These are some of the excerpts from the Drugs & Cosmetics Act and Rules and the users are cautioned not to deviate from the legal provisions in public interest apart from own interests to avoid violations of the law inadvertently or otherwise. Schedule N of the Drugs & Cosmetics Rules require a pharmacy to keep IP as a book of reference. The requirement is as under: A Pharmacy shall be provided with the following minimum books necessary for making of official preparations and prescriptions:Books: The Indian Pharmacopoeia (Current Edition). National Formulary of India (Current Edition). The Drugs and Cosmetics Act, 1940. The Drugs and Cosmetics Rules, 1945. The Pharmacy Act, 1948. The Dangerous Drugs Act, 1930 ----------------------------------------------------------------------------------------------------Schedule of the Drugs and cosmetics Rules, 1945 requires application of IP parameters to Patent and Proprietary medicines as under: SCHEDULE V (See rule 124B) STANDARDS FOR PATENT OR PROPRIETARY MEDICINES
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2. Standards for patent or proprietary medicines, containing vitamins:

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4. General Standards for Different Categories of Patent or Proprietary Medicines. - In the case of pharmaceutical products containing several active ingredients, the selection shall be such that the

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Patent or proprietary medicines containing vitamins for prophylactic, therapeutic or paediatric use shall contain the vitamins in quantities not less than and not more than those specified below in single or in two divided daily doses, namely: -

ingredients do not interact with one another and do not affect the safety and therapeutic efficacy of the product. The combination shall not also lead to analytical difficulties for the purpose of assaying the content of such ingredient separately. The substances added as additives shall be innocuous, shall not affect the safety or therapeutic efficacy of the active ingredients, and shall not affect the assays and identity tests in the amount present.

Subject to the provisions of these rules, patent or proprietary medicines shall comply with the following standards, namely: 1. Patent or proprietary medicines shall comply with the general requirements of the dosage form under which it falls as given in the Indian Pharmacopoeia. If the dosage form is not included in the Indian Pharmacopoeia, but is included in any other pharmacopoeia, prescribed for the purpose of the Second Schedule to the Act, it shall comply with the general requirements of the dosage of such pharmacopoeia. Without prejudice to the generality of the foregoing requirements, general requirements shall include compliance with colour consistency, clarity, stability, freedom from contamination with foreign matter or fungal growth, defects like chipping and capping of tablets, cracking of the coating, mottled appearance and other characteristic defects that can be perceived by visual inspection.

2. Without prejudice to the generality of the following paras, dosage forms of patent or proprietary medicines shall comply with the following requirements, namely:(a) Tablets: Medicines shall comply with requirements for tablets as laid down in the Indian Pharmacopoeia. The nature of coating shall be indicated on the label. Permitted colours may, however, be added and declared on the label. Nature of tablets, such as uncoated, sugar coated or film coated, shall be declared on the label.
(b) Capsules : Medicines shall comply with the requirements for capsules laid down in the Indian Pharmacopoeia. However, the capsules shall be free from distortion or shape, dis-colouration and other physical defects like leakage of powder from joints, pinholes or cracks I the capsules;

(c) Liquid oral dosage forms: Emulsions and suspensions shall disperse uniformly on shaking. Homogeneous solutions shall contain no sediments. The volume of the product (net content) in the container shall be not less than the labelled volume. The limit for ethanol content of pharmaceutical products shall be not less than 90 per cent and not more than 110 per cent of the labelled contents. (d) Injections: Medicines shall comply with the requirements for injections as laid down in the Indian Pharmacopoeia.

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(e) Ointments: Medicines shall comply with the requirements for injections as laid down in the Indian Pharmacopoeia.

3. The content of active ingredients, other than vitamins, enzymes and antibiotics, in patent or proprietary medicines shall be not less than 90 per cent and not more than 110 per cent of the labelled content; however, for enzymes and vitamins, only for lower limit of 90 per cent shall apply. In all dry formulations containing antibiotics, the limit shall be 90 to 130 per cent of the labelled contents and in case of liquid antibiotic formulations, the limit shall be 90 to 140 per cent of labelled contents. Fiducial limits for error for microbiological assay of antibiotics may be estimated depending upon the design of assay procedure. Methods, used for assaying active ingredients shall employ the same basic principles and shall use same organisms as given in the latest edition of the Indian Pharmacopoeia or shall follow any other methods as approved by the authority competent to grant licence to manufacture. 4. All patent or proprietary medicines containing aspirin shall be subjected to Free Salicylic Acid Test and the limit of such acid shall be 0.75 per cent. Except in case of soluble type aspirin in which case the limit of such acid shall be 3 per cent. 5. Patent or proprietary medicine to be tested under the provisions of rule 121-A for pyrogen shall be tested by injecting into rabbits not less than the human dose of the medicine based on body weight of a 60 kg. human being. Methodology and limits shall be based on the method recorded in the Indian Pharmacopoeia. Dose selected shall be indicated in the protocol but the dose shall be not greater than 5 times the human dose based on body weight of 60 kg for man. 6. In injectable patent or proprietary medicines, the test for freedom from toxicity, shall be performed as described in the Indian Pharmacopoeia. Dose selected shall be indicated in the protocol but the dose shall not be less than five times the human dose based on body weight of 60 kg. human being.

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7. INDIAN PHARMACOPOEIA 2010 AND ADDENDUM 2012SALIENT FEATURES

I P 2010: Published by: Indian Pharmacopoeia Commission, Ghaziabad. Printed by: National Institute of Science Communication And Information Resources (NISCAIR), CSIR, near Pusa Gate, New Delhi. Released by: Hon Union Health Minister Sh. Gulam Nabi Azad on 4th August, 2010 at Nirman Bhawan, New Delhi Further extended:- 01st Dec., 2010 Effective Date: Previously :- 01st Sept., 2010 , General Features IP 2010 is presented in three volumes. Above 1850 monographs. Above 2800 pages. Volume 1 704 pages Volume 2 1018 pages Volume 3 1107 pages Total pages 2829 pages Specific Features Addition: (Annexure VI) (i) New monographs (287) 95 APIs, 175 Formulations, 17 Others monographs (ii) Category, Dose and Usual Strengths. (iii) General Chapter on Liposomal Preparations. Adopted for latest drug delivery system (Liposomal Amphotericin B Injection). The scope of the Pharmacopoeia has been extended to include products of biotechnology, indigenous herbs and herbal products, Veterinary vaccines and additional antiretroviral drugs and formulations, inclusive of commonly used fixed-dose combinations. Standards for new drugs and drugs used under National Health Programmes are added in this edition and drugs as well as their formulations not in use now a days are omitted from this edition. The number of monographs of Excipients, Anticancer drugs, Herbal products and Anti HIV drugs have been increased in this edition. Monographs of Vaccines and Immunosera are also upgraded in view of latest technology in the field.

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Salient features Updating and upgrading tests - The thrust given to the IP 2010 is to upgrade and update the norms for performing tests for identity and impurities with a view to establish the identity of a drug very accurately and to eliminate impurities to the extent possible. General chemical tests for identification are almost eliminated and replaced with IR or LC tests. Inclusion of 287 new monographs including those of herbals and veterinary. The list of monographs added is appended. 51 Monographs that figured in IP 2007 have been deleted. This list is also appended (Annexure VI). Harmonization of Pharmacopoeial standards to those used internationally. Information on usual Strengths of drugs reinstated. Use of Chromatographic methods has been extended with the need for specificity in assays and in assessing extent and nature of impurities in ingredients / products. Test for Pyrogens involving animals has been virtually eliminated and is replaced by BET, which is now applicable to more items. Specific importance has been given to the biological products monographs. General chapters on Biologicals have been updated and General chapter on Biotechnology has been revised. General chapters on Microbial contamination in non-sterile products and Microbial quality of Pharmaceutical preparations have been harmonized (Appendices 2.2.9 and 5.9 respectively). Microbial incubation temperature, wherever applicable, has also been harmonized. Preparations for Addendum-2012 of IP -2010 and for IP-2013 IP publication schedule as decided by SB of IPC: - Every two years a new edition - An Addendum between these - Comprising of: Amendments list proposed till date New Monographs prepared New Chapters Format of IP Monograph A one-column format shall be used for all pages of the monographs. The font shall be Arial and the size for the text matter shall be 10 pt as given in the program Microsoft Word. Capital letters, bold and italic types shall not be used indiscriminately since they have a special significance in the Pharmacopoeia.

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Reagents, buffer solution, chemicals other substances that are described or defined in the Pharmacopoeia shall be in italics. However, where a specific reagent is prepare for a specific test in a monograph and reference to it made subsequently in the monograph it need not be in italics. Italic types shall also be used for the systematic names of plants and micro-organisms and for sub-headings of tests and texts (such as precautions to be observed while performing the tests, or which identification tests may be omitted etc) and for some parts of the chemicals names. The title of any monograph i.e. the name of the Pharmacopoeia substance shall be printed with initial letters in capitals and other letters in small case. Titles of monographs and headings of tests shall be in bold letters. The title shall be aligned on the left with the text. Synonyms, if any, shall be printed two spaces below the main title and shall not be in bold letters. Single-line spacing shall be followed and the alignment of the text of the monographs shall be justified. Each test parameter and the accompanying text shall be separated from the other by a space of 1.5 lines. All other details are available on our website www.ipc.gov.in.

Upgradation of Existing Monographs of IP-2010 Based on: Related Substances test: TLC method to LC method From normalization method to using identified impurities Added new RS method Assay Method: From UV method to LC method From GC method to LC method Addendum 2012 to the IP 2010: The addendum is to take effect from the Note notified for the purpose. The features of the Addendum 2012 are Features of Addendum 2012 to IP 2010 1) This Addendum has to be used in conjunction with the three main volumes of Indian Pharmacopoeia 2010. It contains information on new monographs and changes to, or additional information on the items covered in volumes I, II and III of IP 2010. 2) Total No. of New Monographs No. of API Monographs No. of Dosage Forms Monographs : : : 52 10 30

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Blood and Blood-related Product Monographs : No. of Herbs and Herbal Products Monographs : No. of Monographs Upgraded : 3)

08 04 MT 250

Added API monographs whose formulation monographs was already in IP-2010 and formulation monographs whose API monographs was given in IP 2010. Added 6 New Appendices related to Blood Products. Added New General Chapter on Analytical Method Validation.

4) Added 11 new HPLC Chromatogram of Herbal Products. Added 4 new IR Spectra in IR Spectra bank. Extensively worked on the harmonization of existing IP Monographs in IP-2010 as per other International Pharmacopoeias. 5) Additions A list of New Appendices/ Monographs added to the Indian Pharmacopoeia 2010 through this Addendum is given below. Appendices 2.3.50. Fatty Acid Composition by Gas Chromatography 2.8.13. Assay of Human Anti- thrombin III 2.8.14. Anti-A and Anti-B Haemagglutinins (Indirect Method) 2.8.15. Assay of Human Coagulation Factor XI 2.8.16. Assay of Human Protein C 2.8.17. Assay of Human Protein S 2.8.18. Assay of Human Plasmin Inhibitor (a2 -Antiplasmin) Monographs Calcium Carbonate Tablets Cetrimide Emulsifying Ointment Cholecalciferol Injection Cholecalciferol Tablets Divalproex Sodium Docusate Tablets Efavirenz, Emtricitabine and Tenofovir Tablets Ergocalciferol Ergocalciferol Tablets Fenofibrate Capsules Fusidic Acid Cream Indapamide Ipratropium Inhalation Ipratropium Powder for Inhalation Levonorgestrel Tablets Magnesium Sulphate Injection Medroxyprogesterone Injection Medroxyprogesterone Tablets Mefloquine Tablets Methyl Salicylate Ointment Ondansetron Paracetamol Oral Suspension Pilocarpine Eye Drops Promazine Hydrochloride Rizatriptan Benzoate Rizatriptan Tablets Salicylic Acid Ointment Sodium Citrate Eye Drops Sodium Citrate Irrigation Solution

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Sumatriptan Succinate Vasopressin Vitamin A Capsules Vitamin A Paediatric Oral Solution Zinc Chloride Injection Zinc Oxide and Salicylic Acid Paste Zinc Sulphate Monohydrate Zinc Sulphate Oral Solution Zinc Sulphate Tablets Zolmitriptan Zolmitriptan Tablets Herbs and Herbal Products Bhumiamla Dry Extract Omissions Artemisinin Calciferol Calciferol Capsules Calciferol Injection Calciferol Oral Solution Calciferol Tablets

Gudmar Dry Extract Kunduru Dry Extract Mandukaparni Dry Extract Blood and Blood-related Products Antithrombin III Concentrate Hepatitis B Immunoglobulin Tetanus Immunoglobulin Rabies Immunoglobulin Plasma (Pooled and Treated for Virus Inactivation) Anticoagulant Heparin Solution Factor IX Complex Blood Grouping Serums

Gatifloxacin Gatifloxacin Infusion Gatifloxacin Tablets Phenylpropanolamine Hydrochloride Rosiglitazone Maleate Rosiglitazone Tablets

Author: Dr. Raman Mohan Singh, Principal Scientific Officer, Indian Pharmacopeia Commission, Ghaziabad Email: ipclab@vsnl.net.

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8. GOOD LABORATORY PRACTICES (GLP): SCHEDULE L1AND ITS INTERPRETATION

Good Laboratory Practices norms are part of the IP but are very much relevant in the proper application of IP as very often the main cause of inadequate or improper application of the IP norms in the analysis of drugs is failure to comply with GLP requirements. The GLP that has been notified as statutory requirements under the Drugs and Cosmetics Rules is intended to ensure availability of proper infrastructure facilities, personnel, procedures and proper documentation of activities and maintenance of records, which in turn would ensure proper compliance of the IP parameters of quality. The GLP as notified by the Government of India is appended below for the immediate and ready reference of the users. Users shall refer to statutory updates/ amendments, if any, also in the matter. The broad interpretations of the GLP norms are also provided for guidance.

SCHEDULE L-I
Published in the Gazette of India (extraordinary) Part-II, section 3, sub-section (i) vide G.S.R.780(E) , dated 10th November, 2008. (See rules 74, 78 and 150 E) Good Laboratory Practices and Requirements of Premises and Equipments 1. General Requirements:(a) The laboratory or the organisation of which it is a part must be an entity that is legally authorised to function and can be held legally responsible. (b) It is the responsibility of the management to ensure that the laboratory carry out its testing, calibration, validation, and all other technical activities in such a way as to meet Good Laboratory Practices (GLP) requirements. (c) Laboratory management shall have a qualified individual to be known as quality manager or technical manager for carrying out all technical activities and for the implementation of documented quality system and shall report to the top management directly. (d) The quality manager shall prepare a schedule for technical audit of the laboratory for GLP compliance by an expert or experts appointed by the top-management other than the 26

in-charge of the laboratory and shall ensures the maintenance of documented quality system as per quality, manual 2. Premises:(a) (i) the laboratories shall be designed, constructed and maintained so as to prevent entry of insects and rodents besides cross contamination; (ii) interior surface (walls, floor, and ceilings) shall be smooth and free from cracks, and permit easy cleaning and disinfection; (iii) adequate provision is made not only for space and equipment for carrying out necessary test but also for utilities like water, power and gas; (iv) air ventilation system shall ensure dust free environment. (b) The laboratories shall be provided with adequate lighting and ventilation and if necessary, air-conditioning to maintain satisfactory temperature and relative humidity that will not adversely affect the testing and storage of drugs or the accuracy of the functioning of the laboratory equipments or instruments. (c) The drainage system facilities shall be such as to facilitate proper maintenance and prevent water logging in the laboratory. (d) Tabletops shall be constructed with acid, alkali and solvent resistant material and shall be smooth and free from crevices as far as possible.(e) All bio-medical laboratory waste shall be destroyed as per the provisions of the BioMedical waste (Management and Handling) Rules, 1996. (f) Adequate space with proper storage conditions in the laboratory shall be provided for keeping reference and working standards and be maintained by the quality control department. Standard Operating Procedure (SOP) for the maintenance of reference standards and evaluation of Working and Secondary standards shall be prepared by the laboratory. (g) The air circulation is maintained in the area where sterility test is carried out as per Schedule M. (h) Bio-burden shall be routinely maintained in the controlled and uncontrolled area, (e.g.. air locks) (i) Animals House:(i) Animal House shall have the approval of the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA). (ii) Designed in such a way that there is an arrangement to quarantine the new animals procured or purchased and have a provision for clean corridor and dirty corridor. (iii) In case of a diseased animal proper diagnosis shall be done and proper record of treatment shall be maintained. 27

(iv) Different types of animals shall be housed separately with proper identification. (v) A Standard Operating Procedure shall be prepared for breeding and care of animals, maintenance, cleaning or sanitation with suitable schedule for cleaning of animal cages, racks, floor and other equipments. (vi) The animal house shall have proper air-conditioning (temperature and humidity) with proper lighting and be monitored regularly and documented periodically. 3. Personnel:(a) Staff in the laboratory shall possess necessary qualification, proper training and shall have adequate, experience for the assigned duties. (b) A training record of all the personnel shall be maintained. (c) Head of the laboratory must be of high professional standing with experience in drug analysis and laboratory management who is responsible for. (i) ensuring the control and maintenance of documents including the quality system as per the requirements of regulatory authorities which involves all raw data, SOPs, documentation exhibits, protocols, training charts, etc; (ii) planning and organising the audit of the quality system and initiation as well as follow up action of the corrective actions, if any; (iii) investigation of technical complaints; (iv) taking final responsibilities for recommending any regulatory action in the event of noncompliance of tested samples. 4. Equipments:(a) The laboratory shall be furnished with all types of equipments as may be necessary for carrying out the different activities within the laboratory. (b) The analytical instruments shall be housed in dust-free environment and whenever required, conditions of temperature and humidity shall be maintained and periodic checks on temperature and humidity be made and recorded. (c) The instruments, instrument bench and surrounding areas shall be kept clean and tidy at all times. (d) Instruments requiring calibration shall be calibrated at regular intervals and records of such calibration or maintenance be maintained and there shall be written instructions in the form of Standard Operating Procedures for the operation, maintenance and calibration of instruments. (e) Equipment records shall be maintained and such records shall contain the following:(i) name of equipment or machine or apparatus; (ii) manufacturers name, model number and type of identification; (iii)serial number; (iv) date on which equipment was received in laboratory; 28

(v) current location; (vi) condition when received (e.g. new, used, re-conditioned); (vii) copy of the manufacturers operating instructions; (viii) frequency of calibration; (ix) frequency of maintenance; (x) log Book (day to day entry including status of the equipment); (xi) staff responsible for monitoring the calibration and maintenance status of the equipment; (xii) calibrating records; (xiii) list of authorised users or operators, if any; (xiv) history of any damage, malfunction, modification or upgradation, repair and calibration; (xv) list of spares and accessories, if any. (f) A progress register for non-functional equipments and action for procurement of spares and accessories, monitoring thereof, shall be maintained. (g) A Standard Operating Procedure for preventive maintenance of machine or equipment or apparatus shall be prepared by the laboratory. (h) Other equipments such as burettes, pipettes, volumetric flasks, weight boxes, thermometers, etc., shall be thoroughly checked for accuracy of calibration before acceptance for use. (i) Maintenance procedure in the form of Standard Operating Procedures must be prepared and regular servicing must be performed by the maintenance engineer or specialist (j) Equipments, instruments giving anomalous results or defective must be labeled as outof order till they are repaired and after instrument is repaired it should be calibrated before use. (k) The maintenance of equipments for services like electricity, gas, water, steam, and compressed gas shall be handled by competent person. (l) Autoclaves must meet the requirements described for operations, safety and validation procedures, and the validation carried out by the laboratory shall be recorded. (m) Fume Cupboards.Work involving the evolution of harmful and obnoxious vapours shall be carried out in a fume cupboard. The exhaust system of the fume cupboard shall be checked frequently to ensure that it is in order. There should be a water drainage system inside the fume cupboard and shall be checked frequently to ensure that there is no water logging and it is in order. 5. Chemicals and Reagents:

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(a) The storage and handling of chemicals and reagents shall be done in a manner considering the physicochemical properties of these substances and the hazards involved in their use. (b) All reagents and solutions in the laboratory shall be properly identified with a label. (c) A standardisation register shall be maintained by the laboratory along with its raw data and Standard Operating Procedure for preparation and standardisation on stock solutions, standard solutions, volumetric solutions must be prepared for the guidance of staff. (d) Containers of stock solutions and of standard solutions shall bear the following details:(i) name of analytical chemist who prepared the solution; (ii) date of preparation; (iii) Each volumetric solution shall have use before date depending upon the stability of the solution; and (iv) standardization records. (e) The transfer of hazardous chemicals and reagents from one container to another container shall be carried out with suitable equipment by taking the care of safety and no make-shift or hazardous methods must be resorted to. 6. Good house keeping and safety.(a) General and specific written down instructions for safety shall be circulated to each staff member and the instructions be revised periodically as appropriate (e.g., poster displays, audio-visual material and by seminars/conferences) (b) Standard Operating Procedure for safety, house-keeping and loss prevention shall be prepared in accordance with the various rules, and regulations of the Government of India and include the following requirements, namely:(i) safety data sheets must be made available to staff before testing is carried out; (ii) drinking, eating and smoking shall not be permitted in the laboratories; food for human consumption shall not be kept in working or storage areas; food meant for test animals shall be handled by the workers under the guidance of a veterinary doctor or qualified person. In the animal house, the facilities for collection and disposal of animal waste or safe sanitary storage of waste before removal from testing be provided; (iii) staff must wear laboratory coats or other protective clothing including gloves and face masks and eye protection wherever required; (iv) the laboratories shall have adequate first aid kit and fire fighting equipments located at the right places and the staff must be familiar and trained with the

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(v) (vi) (vii)

use of fire fighting equipment including fire extinguishers, fire blankets and gas masks, operators carrying out sterility tests shall wear sterilised garments including headgear, face masks and shoes; the staff must be educated in the first aid techniques, emergency care and use of antidotes; and safety rules in handling cylinders of compressed gases must be observed and staff must be familiar with relevant colour identification codes;

(c) Protective Precautions to be taken in Laboratories: (i) water showers shall be installed at appropriate places in the laboratory; (ii) rubber suction bulbs must be used on manual pipettes and siphons; (iii) warnings, precautions, and written instructions must be given for work with violent, uncontrollable or dangerous reactions (e.g. mixing water and acids, biological such as infectious agents, etc.); (iv) appropriate facilities for the collection, storage, and disposal of wastes shall be made available. (v) staff must be aware of methods for safe disposal of corrosive or dangerous products by neutralisation or deactivation and of the need for complete disposal of mercury and its salts. (vi) Staff must also be aware about the safety precautions to be adopted while handling potassium cyanide and cyanogen bromide. (vii) Standard Operating Procedure for handling, collection, disposal of chemical and biological wastes be prepared. 7. Maintenance, calibration, and validation of equipments:(a) All equipments, instruments and other devices used in the laboratory shall use appropriate methods and procedures for all tests or calibrations and they shall be regularly calibrated and validated. The frequency of calibration may differ from instrument to instrument. (b) The original equipment manufacturers recommendations along with the experience of the laboratory staff and the use of equipment per day may also be considered while fixing the frequency of calibration. (c) For most of the equipments and instruments, Standard Operating Procedures for calibration and calibration schedule be prepared by the laboratory and a logbook shall also be prepared by each laboratory for proper documentation of calibration results. 8. Reference materials:(a) Reference materials are necessary for the testing and, or calibration, validation or verification of a sample or of equipment, instruments or other devices and all such

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materials shall be traceable to agency authorised by Government of India or any other International body. (b) The laboratory shall prepare working standard by comparing with the reference standards and shall be routinely checked for their purity by selecting parameters such as identity, loss on drying or on water, impurity and assay, etc. (c) Whenever, any new reference material is received by the laboratory, a code number shall be assigned and this code number shall be quoted on the laboratory note book and analytical work sheet. The working standard shall also be provided with identification code. (d) A register pertaining to reference and working materials must be maintained by the laboratory. The following details may be mentioned in the register: (i) source of supply; (ii) code number of the reference material; (iii) date of receipt; (iv) batch number or identification number of the supplying agency; (v) details like assay value, water content or any other information provided; (vi) storage condition of the material; and (vii) date of expiry, if any and date of manufacturing if possible (e) All working standards shall be checked at appropriate intervals or before use to ensure that it has not deteriorated or decomposed during storage. These observations be recorded in a register. All the reference and working standards shall be stored at appropriate storage condition; those requiring storage between 2-8C shall be stored in a refrigerator. Wherever recommended the material may not be allowed to be frozen. 9. Microbiological Cultures:(a) Standard Operating Procedure for maintenance of microbial culture and sub-culture must be prepared by the laboratories (b) If the cultures have become non-viable or mutant, proper procedure shall be followed to destroy these cultures by autoclaving under authorised personnel for biological testing. Preferably not more than five passages may be prepared. (c) All activities be carried out in a aseptic area by authorised person. (d) The laboratories shall perform standard biochemical tests on the sub-culture as given in literature to ensure their viability. 10. Quality system.The quality system shall be designed to ensure the following objectives:(a) the measurements and calibrations shall fully conform to the compendia requirements and the methods demonstrably based on validation protocols are followed. (b) It shall be effective in providing necessary assurance that the activities or processes or techniques or practices comply with planned arrangements. (c) It helps in early detection and correction of non conformities.

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(d) Remedial action on the observations by internal and external audits are taken appropriately and (e) It shall have a documented quality policy for the organisation. 11. Internal quality system audits.(a) Internal audits are done to assure the integrity of the analysis and such audits shall be conducted periodically with a predetermined schedule and procedure with appropriate checklist, to verify that the operations continue to comply with the requirements of quality system and requirements of regulatory authorities. Internal quality audits shall be carried out by trained and qualified personnel who are independent of the activity to be audited. (b) The periodicity of quality audit shall be fixed by the Head of the laboratory so that each activity is audited at least once in a year. (c) Head of the laboratory will be responsible for initiation of the corrective action arising from audits and verification of corrective action. (d) Whenever any non-compliance or any diversion is noticed by the team in implementing quality policy or quality system, protocols, the same will be attended by the Quality Manager. The problem will be analysed and necessary actions will be taken with proper documentation. (e) The Quality Manager shall maintain all the records of the analysis being conducted which includes test system, the type of analysis, date on which analysis is done, etc and quality Manager shall also maintain copies of all protocols pertaining to different activities being checked by the audit team. 12. Management review Quality system reviews shall be conducted by the top management atleast once in every twelve months and the agenda of review shall generally cover the following:(i) report or input of internal audits; (ii) matter arising from previous reviews; (iii) report of external audits, if any; (iv) surveillance report, if any; (v) result of proficiency testing; (vi) complaints or feedback received from users of laboratory services; (vii) details of in-house quality control checks; (viii) need of amendment of the quality system and documentation;. (ix) induction training of new staff; and (x) any other requirements of the laboratory. 13. Standard Operating Procedures:(a) Standard Operating Procedures are written procedures for different activities being conducted in a laboratory and shall include the following characteristics:

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(i) they shall be written in a chronological order listing different steps leading to an analysis of drugs or calibration of an instrument; (ii) testing laboratories shall have Standard Operative Procedure manuals and have its periodic review; (iii) it shall be user friendly documents and shall include designation of the person responsible for intended activity. (b) Standard Operating Procedures in addition to those recommended under various ctivities shall also be prepared to the minimum in respect of the following: (i) sample handling and accountability; (ii) receipt identification, storage, mixing and method sampling of the test and control articles; (iii) record keeping, reporting, storage and retrieval of data; (iv) coding of different studies, handling of data including use of computerized data system; (v) operation of technical audit personnel in performing and reporting audits, inspections and final report reviews; (vi) routine inspection of cleaning, maintenance, testing, calibration and standardisation of instruments; (vii) action to be taken in respect of equipment failure; (viii) analytical data methods; (ix) the raw data; (x) data handling and storage retrieval; (xi) health and safety protection; (xii) animal room preparations; (xiii) animal care; (xiv) storage and maintenance of microbial cultures; (xv) maintenance of sterility room (i.e. constant maintenance and monitoring of aseptic condition of sterility room); (xvi) use and storage of reference standards (xvii) procurement of stores and equipment; (xviii) monitoring of testing of samples; (xix) method of retention of unexpended samples, their location, maintenance and disposal; (xx) document control; (xxi) redressal of technical complaints; (xxii) housing-keeping; (xxiii) corrective and preventing action; (xxiv) working procedure (test methods); (xxv) calibration Manual; and (xxvi) training manual. 34

14. Protocols and specifications archive.(a) Every laboratory shall have a specification archive and current versions of all necessary specifications shall be kept as per the requirements of the Act and the rules made thereunder and the National Pharmacopoeia (Indian Pharmacopoeia). (b) All updates and corrections must be noted in the master volumes of Pharmacopoeias to prevent the use of obsolete sections; supplement and addendum shall also be made available in the laboratory. (c) The specification archive shall contain the following:(i) list of all the pharmacopoeias; (ii) a file on patent and proprietary medicines (non-pharmacopoeial) test methods to specifications prepared and validated by the manufacturer or by the laboratory itself. The test methods shall be submitted to the concerned Drug Control Authority. The validated test methods developed by the manufacturer or the laboratory shall stand to the requirements of compendial parameters in regard to its precision, accuracy, reproducibility, specificity, linearity, and ruggedness etc. 15. Raw data:(a) Raw data refers to the laboratory work sheet, note books or analysis sheet, records, memorandum, notes or extract copies thereof that may be the results of general observations and other activities and such raw data shall include hand written notes, photographs, software, drawings, computer printouts, spectral charts, dictated observations or recorded data from automated equipments. The raw data also includes record on receipt of animals, result of environmental monitoring, calibration, records of equipments, integrator output from analytical equipment, including work-sheet used to read a note, information from Light Emitting Diode (LED) display of any equipment. (b) A single line shall strike through the data being changed; the correct information shall be recorded along with the old data and the reason of change. The analyst making the change shall be identified by his signature with date. In case of automated data collection system, the person responsible shall be identified at the time of data output. The original entry must be saved and the system shall have audit trial for all the data. (c) Data integrity and security shall be maintained and the data shall not be accessible to any unauthorised person. 16. Storage and archival.(a) The residual sample shall be retained in proper storage condition for a period of one year after the final report. (b) The laboratory must establish and maintain procedures for the identification collection, indexing, retrieval, storage, maintenance, and disposal of all quality documents. (c) All the raw data, documentation, Standard Operative Procedures, protocols, and final reports are to be retained and there shall be archives for orderly storage and expeditious retrieval of all raw data, documentation, protocols, interim and final report. The archive 35

shall provide a suitable environment that will prevent modification, damage, or deterioration and/or loss. (d) The condition under which the original documents are stored must ensure their security and confidentiality. (e) Paper documents shall not be kept for long periods under high humidity and raw data in the form of tape and discs are to be preserved with care. (f) In case of storage of only optical disc, the life of disc shall be longer than the storage time. (g) Raw data on thermal paper might fade away with time; therefore, a photocopy of the thermal paper shall also be retained in the archive. (h) Time for which records are retained shall be prescribed in the documents. [F.No.X-11014/3/2006-DFQC] DEBASISH PANDA, Jt. Secy. Foot Note. The Principal Rules were published in the Gazette of India vide notification No. F.28-10/45H(I), dated 21st December, 1945 and was last amended vide notification G.S.R. 592(E), dated 13-8-2008.

INTERPRETATION OF GLP (SCH L 1) NORMS

There have been only a few published reviews about this provision of the Drugs & Cosmetics Rules 1945. While there is a claim that the provisions are at par with the WHO norms, there is also the view that the rules have been framed taking into consideration the prevailing situations in the Indian Pharmaceutical Industry and the drugs testing laboratories functioning as part of the drugs regulatory bodies. It is believed that the main objective of Schedule L1 is to improve the quality, integrity and reliability of data and reports generated without much adding to the cost to the infrastructure requirements and testing processes at the small and medium scale pharmaceutical units and in the State Drugs Testing laboratories in India. The thrust is more on establishing correct procedures and adherence to technical and statutory requirements. The WHO norms on the other hand cover all aspects of and related to the laboratory procedure with a view to ensure scientific proof that will stand any technical scrutiny. The data generated and the reports furnished do not stand legal scrutiny very often and the reports of government analysts are liable to be set aside on grounds of reliability. Schedule L1 is expected to remove this situation. The WHO (world body) adopted GLP in its 36th report in 1999 as Good practices for national pharmaceutical control laboratories. With a view to extend the guidelines to national control laboratories, manufacturers in-house laboratories and other 36

commercial testing houses, WHO issued guidance in WHO Technical Report Series, No. 957, 2010, forty- fourth report as Annex 1: WHO good practices for pharmaceutical quality control laboratories. The Drugs and Cosmetics Act and Rules are intended to regulate import, manufacture, sale and distribution of drugs in the country. A basic question is raised as to whether the Schedule applies to all drugs testing laboratories or the in-house facilities of licensed manufacturers alone or to licensed manufacturers and approved laboratories etc. Schedule L1 refers to Rule 74, which relates to conditions of licence in forms 25, Rule 78 which relates to conditions of licences in forms 28, 28B and 28D and to Rule 150 E which relates to approved laboratories. It would therefore be prudent to conclude that the provision applies to the in-house testing facilities of licensed manufacturers and approved laboratories. However, the drugs testing laboratories of drugs control administrations cannot be viewed differently. Though it is not regulated by this rule, the principles shall be observed in letter and spirit by these laboratories also. Good Laboratory Practices and Requirements of Premises and Equipments commonly known as GLP were notified by the Government of India as part of the Drugs and Cosmetics Rules 1945 as per the Drugs and Cosmetics (Third Amendment) Rules, 2008 MINISTRY OF HEALTH AND FAMILY WELFARE (Department of Health) NOTIFICATION, G.S.R.780(E) dated 10th November, 2008. The notification specifies the 1st day of November 2010 as the date from which it was to take effect. The Schedule refers to rules 74, 78 and 150 E of the Drugs and Cosmetics Rules together which it is to be read and applied. The Schedule has different clauses to specify different requirements. For proper application of the requirements, it is essential to examine the individual clause and also the collective effect of these clauses. 1. General Requirements:(a) The laboratory or the organisation of which it is a part must be an entity that is legally authorised to function and can be held legally responsible. (b) It is the responsibility of the management to ensure that the laboratory carry out its testing, calibration, validation, and all other technical activities in such a way as to meet Good Laboratory Practices (GLP) requirements. 37

(c) Laboratory management shall have a qualified individual to be known as quality manager or technical manager for carrying out all technical activities and for the implementation of documented quality system and shall report to the top management directly. (d) The quality manager shall prepare a schedule for technical audit of the laboratory for GLP compliance by an expert or experts appointed by the top-management other than the in-charge of the laboratory and shall ensures the maintenance of documented quality system as per quality manual The first requirement is that the laboratory as such or the organization of which it is a part should have legal authority for the activities carried out. There are establishments that function as Drugs Testing Laboratory exclusively or as part of a drugs manufacturing unit or other establishment. The requirement is that the unit shall have legal approval. Private drugs testing laboratories take approval from the licensing authorities concerned. For Government Drugs Testing Laboratories, there is no separate system of approval. Laboratories functioning as part of manufacturing units get their authority as part of the licence granted to the whole unit. The second requirement is that the management concerned is responsible for the functioning of the laboratory in accordance with GLP norms The third requirement is that there shall be a qualified person designated as the Quality or Technical Manager and reporting directly to the management for carrying out the technical activities of the laboratory and for implementation of the quality management system documented for the laboratory. The final requirement under this clause is that the quality/ technical manager shall prepare schedule of technical audit of the laboratory for GLP compliance by an expert or experts appointed by the top-management other than the in-charge of the laboratory and shall ensure the maintenance of documented quality system as per quality manual. By this requirement the quality manager prepares a schedule of technical audit for the laboratory and such audit shall be by outside experts appointed by the management. The mention of quality manual implies that a quality manual should be in place. All quality management systems require preparation and adoption of quality manual. 2. Premises: This clause details the requirements in terms of premises for the laboratory. There is no specification of the individual sections or the minimum areas 38

for these sections. There are requirements common for all laboratories and exclusive for specific laboratories. For example, animal house, stability chamber etc are not required for all laboratories. All laboratories need dedicated arrangements for handling samples received, their storage and distribution to individual sections, arrangements for storing chemicals, reagents, spare glassware and other accessories/ spares, chemical/ physicochemical divisions, instruments section and microbiology division, dedicated arrangements for storage of reference substances dedicated arrangement for keeping reference samples, facilities for uninterrupted power supply, adequate water and gas supplies. While the sections performing different testing activities require separate dedicated areas appropriate to their nature and workload, storage of chemicals, reagents, spares and accessories, reference substances reference samples etc can be done in common areas with proper dedicated arrangement for their preservation. In laboratories performing testing of several samples, segregation of areas may be necessary and there may be need to provide library, records and archives divisions also. Schedule L 1 emphasizes hygiene and sanitation also especially in sterile areas and animal houses. Comprehensive SOPs for house-keeping are essential in all cases. There is no specific norm that insists separate facilities for lactum antibiotics, sex hormones etc as in the case of Schedule M. However, to avoid cross-contaminations and minimising risk, the right approach would be to have dedicated facilities. There is a requirement that the air ventilation system shall ensure dust-free environment. This would be possible only by having AHUs (Air Handling Units), which would take care of control of humidity and temperature also. There are also stipulations that air circulation is maintained in the area where sterility test is carried out as per Schedule M and that Bio-burden shall be routinely maintained in the controlled and uncontrolled area, (e.g.. air-locks).This would be possible by providing separate AHUs. 3. Personnel: Here the requirement is that there should be personnel who are qualified for the activity, experienced, capable of taking preventive and corrective actions to check non-conformities and where there is non-compliance (of the quality parameters) of the tested samples, the personnel are accountable for regulatory actions. This schedule does not spell out the qualification and experience that the personnel are to possess. Requirements, if any, specified in the rules relating to approval of the laboratory in the case of approved laboratories and as part of the conditions laid down for grant and renewal of Drugs licences also apply the matter. However, there is a stipulation that the head of the laboratory must be of high professional standing with 39

experience in drug analysis and laboratory management. The management will have to frame their own minimum requirements to meet this stipulation. 4. Equipments: The schedule does not list the equipments needed. The implication is that these are need based and the simple message is that all equipments needed for carrying out the intended activities shall be available. The schedule gives thrust for their design, location, operation and maintenance. Maintenance of not only the equipment, but also the surroundings and control of environment are stressed in the schedule. There is thrust on certain SOPs and safety precautionary measures also to ensure proper working, operation and maintenance of the equipments. 5. Chemicals & Reagents: The requirements of chemicals and reagents are need based and are not listed. However, the norms for storage, standardization of solutions and their labeling including the details to be stated in such labels, certain safety measures to be adopted for handling hazardous materials are specified in this schedule. 6. Good house-keeping and safety: Without proper house-keeping and safety arrangements and procedures, the other facilities in the form of premises, personnel, equipments and supplies provided will not serve the intended purposes. The schedule specifies some of the essential requirements in this regard. 7. Maintenance, calibration and validation of equipments: Preventive and corrective maintenance arrangements are essential for proper functioning of the equipments. Methods for performing the tests, calibration and validation wherever indicated are essential. 8. Reference materials: Here the thrust is on procurement of reference materials from authentic sources with traceable origins, their proper preservation, documentation and development of working standards. 9. Microbial cultures: Preparation of microbial culture and sub-culture shall be in accordance with validated procedures and where the cultures have become non-viable or mutant, the same shall be destroyed by proper means. 10. Quality system: The need is to have an authentic quality policy and quality manual that would ensure prevention of non-conformities and correction of nonconformity, if any arises. 11. Internal quality audit system: This is a system to verify and assure the integrity of the analysis works performed by auditing all the systems and facilities. Here again 40

non-conformities arising out of deviations or non-observance of procedures shall be identified and remedial and preventive measures shall be taken. 12. Management review: The management is required to conduct reviews of the status of the quality system. The review shall be performed at least once in twelve months. It is to be noted that the specification is not once in a year, but once in twelve months, the implication being that within a period of twelve months, there shall be at least one review taken. There is no bar to hold more than one meeting. The matters to be considered necessarily during the reviews are also specified. 13. Standard Operating Procedures: Standard Operating Procedures (SOPs) are intended to ensure that every activity that influences the quality of the product or service or result directly or indirectly is controlled by validated procedures. The SOPs specified in this clause are in addition to those stated in the various other clauses. SOPs are to be tailor made for the laboratory concerned by the expert staff there and are not to be copied from those of others. SOPs shall be readily available for reference in the location of the activity or equipment or other facility. 14. Protocols and specifications archive: Archives of protocols and specifications are essential for proper performance of tests. The Second Schedule of the Act specifies the standards applicable to drugs and specification relied upon for the tests to be performed shall be available in the laboratory. The current version of the I P together with its addendum if any, its immediate preceding edition and the Addendum thereof, if any, own methods developed and adopted together with their processes of validation, other pharmacopoeial specifications if any, relied upon etc shall be available. List of such specifications (Pharmacopoeias) and others shall be available for their reference. In the case of patent and proprietary medicines, the dossier/ file on the method developed and validated in accordance with the norms applicable by the manufacturer or the laboratory itself, as the case may be, shall be available. 15. Raw data: Raw data records are very important records as the reports are generated based on these records. The records shall be authenticated. There is specification for changes made also and for preserving the original version. It is to be borne in mind that data pertaining to observations need no change as these are recordings of what had been observed. Any change or correction thereof, even if authenticated, could suggest manipulation of results. 16. Storage and archival: Residual samples shall be preserved properly for reference for a period of one year after generation of the final report. There shall be dedicated facility for the purpose and the residual samples shall be stored in orderly manner for 41

easy retrieval when needed. There shall be well-laid procedures for their maintenance, preservation, retrieval, disposal etc. The precautions to be taken for the storage and archival are specified in this clause.

Compiled by: Mr. S.S. Venkata Krishnan, Retd. Drugs Controller, Kerala State Email: ssvkrishna1947@gmail.com

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9. REPORTING OF ERRORS AND ANOMALIES IN THE IP

IPC has received comments from several quarters on IP 2010 and most of these relate to composing errors or a few technical anomalies and matters relating to availability of IPRS (IP Reference substances for identity, purity or impurities). The guidelines in these matters are as under: Anomalies:

42

(i)

All errors in composing that have been pointed out have been set right. These will be incorporated in the Addendum to IP 2010. Some of the points addressed to have been put up in the official website of IPC www.ipc.gov.in. One may log on to the site for clarifications sought. If any fresh anomaly is to be pointed out, the same may be sent by e-mail to ipclab@vsnl.net. IP 2010 has restored the former system of stating the strengths of drugs in the monographs. Strengths had not been included in the IP2007. However, in the light of the requirements of the Second Schedule to the Drugs and Cosmetics Act and the decision of the DCC, strengths are included. It has already been clarified through the website that strengths already licensed by the licensing authorities before publication of IP 2007 could continue. Technical anomalies have also been addressed and put up in the official website. These will be incorporated in the Addendum to be published. In the matter of IPRS, one may log on to the official website for informations and guidance. Details of Primary Reference Substances not available will be put up in the official website. A general notice that tests for which RSs are not available need not be performed will be incorporated in the Addendum and issues of IP to come. The method of preparing working standards will be added. Allowing preparation of own RS if IPRS is not available will also be incorporated in the lines of USP.

(ii)

(iii)

(iv)

10. GUIDELINES TO USERS OF IP

9.1. IP and IP monographs: 1. Users are advised to read the General notices and general requirements given in the IP. This is essential for proper application of the tests and for arriving at the correct conclusion on the quality of the drugs tested. 43

2. All the tests specified in a monograph are to be performed before deciding whether the substance tested, complies with the IP parameters or not. 9.2. Infrastructure facilities needed: A. Pre-requisites for Drugs Testing Laboratories: Schedule L1 of the Drugs and Cosmetics Rules 1945, pertaining to the requirements for a drug testing laboratory, Infrastructure requirements, procedures to be adopted, records to be maintained etc are detailed in this document. The presentation here under is just to bring to the attention of the stakeholders some of the matters for their guidance and not the whole of the requirements. Adequate space with proper layout, sufficient areas for accommodation of each activity, proper layout of different sections of the laboratory for ensuring smooth and efficient functioning, regulation and control of entry of persons not associated with the works of the laboratory, proper installation of the equipments enabling their operation in the precise manner, their easy servicing and maintenance, supply of electrical power through points and fittings suitable to the need, supply of water, heating gas, providing safety needs and observing safety measures, hygiene and sanitation, facilities needed for disposal of wastes that include organic, inorganic, biological, chemical and other wastes, especially inactivation of the hazardous chemical, biological and other wastes before disposal, are all part of the requirements. Compliance with GLP norms and securing NABL and other accreditations for the facilities will go a long way to ensure proper testing and analysis, which is the right way for compliance of IP parameters. There is also need for proper space for keeping samples received and reference samples, adequately furnished Store Section and environment controlled with fire-proof arrangement as may be needed. Spare glassware, accessories of equipments and separate area for keeping obsolete ware before disposal, are all essential needs. A well equipped area for stability studies is also an essential requirement. Animal House is required, where the sample testing requires the use of animals. Ensure that the layout enables orderly location of the sections and the ancillary areas associated to ensure efficient functioning. 9.2.1. Equipments & glassware:

44

1. Proper infrastructure is required for the laboratory to perform tests specified in the various monographs of the IP. The basic requirements of infrastructure facilities for a laboratory to perform the tests as per IP are given in the annexure to this manual. Users are cautioned that the requirements specified are not exhaustive ones and the needs of the individual laboratory are to be decided on the nature and extent of activities. 2. The infrastructure facilities required include proper environmental controls also for performance of microbiological tests, instrumentation tests etc. Certain tests are required to be performed at controlled temperatures and in diminished light or darkness. Improper environmental conditions could affect the results of the tests performed. 3. Proper installation Uninterrupted/ steady power supply are required for the proper performance of most equipments. The user manual of the equipments shall be checked for proper installation, operation, service and maintenance. 4. Necessary accessories such as HPLC columns are very essential for performing the tests specified. 5. Arrangements in the form of maintenance contracts are essential for the proper maintenance of equipments. In the absence of proper arrangements for maintenance of the equipments, accuracy of the results cannot be ensured. 6. It is to be ensured that only competent persons handle instruments. Handling of equipments by inexperienced persons could not only lead to producing inaccurate results, but also could cause damage to the equipment. Operation of equipments, cleaning and maintenance etc., are all to be done by competent persons. Equipments are to be cleaned immediately after every use in accordance with the in-house procedure prescribed for the purpose and kept properly preserved. 7. Calibration of equipments as per the calibration schedules and in accordance with the SOPs are important for the accuracy of the results. Validation of equipments, systems and procedures where ever applicable are also important to generate accurate results.

8. Different glasswares are required for everyday use. Adequate supply of glassware shall be available. The glassware shall be of appropriate quality. Damaged glassware shall not be used. 45

9. Establish appropriate cleaning procedures for cleaning the glassware; removal of stain etc. Glassware shall not remain unclean after use. Drying of calibrated glassware in ovens shall be in low temperature to preserve their properties. Calibrate the glassware in accordance with the procedure established wherever applicable. Maintain calibration schedule and record of calibration for glassware and equipments. 10. Store glassware in use and spares in their appropriate places. (Refer Annexure I for List of requirements of equipments & apparatus) Consumables:

9.2.2

1. These include reference substances, chemicals, reagents, media for sterility tests etc. Several consumables are required in a laboratory for day-to-day use for performing tests and analysis. It is important and essential that all consumables that are regularly or frequently used and required are stored in sufficient quantities to perform tests without interruption. It is also important that consumables of the right quality and quantity are procured from identified sources. In the case or consumable that are rarely used and not readily stocked, sources or repute and reliability shall be identified and arrangements made for supplies as and when needed. 2. There should be proper arrangements to store the consumables. Inflammable ones shall be preserved in cool places well protected and with proper safety measures. Corrosive items shall also be preserved in proper containers. Due care shall be exercised in the handling of inflammable and corrosive consumables. Care should be taken to avoid damages to the labels of the containers of materials, damages to workstations and equipments etc. 3. Reference substances shall be procured from authentic sources and preserved in accordance with the instructions. Users are advised to log on to the official website of the IPC in the matter of IPRS availability. Working standards may be developed in accordance with authentic procedures. 4. Reference substances, chemicals and reagents shall be handled by authorized persons only. 5. Standard solutions prepared shall be properly labelled and preserved. 9.2.3 Reference books and journals and other materials: Many of the drugs available in the country are included in the IP. IP is regularly updated with the publication of addendum or new editions. Procure authentic 46

copy of the IP and its addendum in sufficient numbers for use in different divisions of the laboratory. IP is now available in a DVD also. Keep authentic copies of other reference materials also. Copied versions are not legal and could also have omissions or other alterations. 9.2.4 Personnel:

1. Technical and supportive staff constitute the personnel of the laboratory. Entry to the laboratory shall be restricted to the personnel working there only. Visitors and others shall not be allowed to handle equipments or materials. 2. The personnel shall be given periodical training to update their knowledge and skill. 3. Ensure proper supervision of trainees and new recruits. 9.2.5 Supportive facilities such as power, water, gas supply etc:

1. Standby electrical power source shall be available to provide uninterrupted power supplies to the laboratory in general and to work-stations and equipments that are to function continuously without interruption in particular. 2. Where gas cylinder is used as the source of gas supply for the burner/ stove, the cylinder shall be located outside the work area, safely secured. The supply pipeline shall be easily available and insulated, if needed. 3. Water supply shall be available for washing areas and to the water shower provided for use in emergencies. 4. Water purifier/ distillatory required for preparation of standard solutions and other preparations shall also be available to provide adequate supply of the water of desired quality. 9.2.6 Records:

1. Records are to be maintained by persons responsible for the activity concerned. 2. Records shall be authentic with the entries/ details there in properly authenticated by the competent person responsible for the activity. Raw data records are the basis for deciding the quality of the material tested. Corrections/ over-writing/ 47

erasing of entries etc in records in general and in raw data records in particular are irrelevant and shall be avoided. Inadvertent actions of such nature shall be properly explained and authenticated. Un-authenticated records have no merits. 9.2.7 Procedures: B.Guidelines for users of IP 1. General: Well laid down procedures are essential to ensure performance of an activity properly, efficiently and in a precise manner every time. SOPs are to be prepared and adopted for every activity that could influence its result directly or indirectly. This manual lists some of the SOPs but these are not the whole of the procedures. As stated elsewhere also in this manual, SOPs are to be prepared and adopted by the laboratories to have proper systems in place to control all activities. 2. Calibration of glass-wares/ Validation of methods: Procedures of calibration of glass wares and equipments that have not been presently stated in the IP are detailed in this manual for the guidance of the users. Method validation procedure is also given for guidance. 3. Interpretation of General Notices and requirements specified in IP: There could be errors on the part of bench chemists or the decision making scientist in interpreting the IP norms or in declaring the quality of the drug tested. General notices and requirements specified in the IP are to be studied thoroughly and applied correctly as otherwise the result reported could be erroneous. IPC gives clarifications as and when required for the guidance of the users of IP. Where such clarifications are needed to be limited to individual cases reported alone, the matter is conveyed to the specified laboratory or individual only directly and where it is felt necessary to notify all in general, the clarification issued is notified through the official website also. Clarification on migration of shell-constituents (including colours) of soft gelatin capsules: A note issued on the migration of shell-constituents of soft gelatin capsules into the shell contents is furnished below for guidance: It has been brought to the notice of the IPC that a drug in soft gelatin capsule has been declared as not of standard quality for the reason that the content of the capsule showed presence of a colouring matter. It is represented to the IPC that the situation was the result of migration of colour from the capsule shell into the contents. The IP prohibits added colours to the contents of capsules other than modified release capsules vide IP2010, vol II, page 721, column 1, paragraph 3 of the clause relating 48

to Capsules. In the same page, in column 2, in paragraph 4, it is stated that As soft gelatin shells contain appreciable amounts of water, migration of capsule contents, particularly of water soluble ingredients, may occur. While individual cases as to whether the presence of colouring substance in the content of gelatin capsules was the result of addition of colours or due to migration can be decided by regulatory bodies after due verifications. IPC advises the analysts to consider the situation of possible migration of colouring or other matters into the contents from the capsule shells before giving their verdict on the quality of the drug to avoid possible errors in their declaration of the quality of the drug. IPC is to inform that where manufacturers have the evidence that the declaration of a drug as not of standard quality by a Government Analyst was due to erroneous decision on part of the Government Analyst, the right solution is to seek legal remedy as provided in the law by preferring appropriate appeals. IPC desires to clarify that anomalies and lacunae, if any, in the IP will be rectified expeditiously. Updating or harmonization of I P norms with international norms will be carried out while publishing new editions of I P and IPC is not the forum to set right errors or suspected errors on the part of regulatory bodies in their decisions. General strengths: The Second Schedule of the Drugs and Cosmetics Act lays down that the standards of Identity, Strength and Purity apply to the drugs imported/ manufactured/ sold in India. I P 2007 had not specified the strengths of drugs in the monographs. As prescribing the strength is a statutory mandate, and the Drugs Consultative Committee (DCC) had advised the IPC to remove the lacuna, I P 2010 has included strengths of drugs and the specifications have been made in accordance with the inputs available to the IPC. In pursuance of decisions of the DCC, a clarification has been issued in the matter. The clarification issued is stated below for general guidance. Use of excipients: Use of excipients in formulations is permitted to the extent they are needed to make the dosage form. The excipients are required to be of such nature that they do not alter the properties or interfere with the analysis of the active ingredient. It is therefore essentially a regulatory requirement to be observed at the time of formulating a drug and during its statutory approval. The analyst is in no position to know the excipients other than those stated in the labels, the quantities of which used are also not known. Finding of any extraneous matter other than the impurities known could be due to presence of other impurities or due to excipients. Analysts are to judge the merits of the individual cases while deciding the purity of the drug. -------------------

49

11. PROCESS OF IP MONOGRAPHS DEVELOPMENT

Indian Pharmacopoeia (IP) is published by the Indian Pharmacopoeia Commission (IPC) in fulfilment of requirement of Drugs and Cosmetics Act 1940 and Rules thereunder. It prescribes the standards of identity, purity and strengths for the drugs produced and/or marketed in India and thus contributes in the control and assurance of quality of medicines. The standards prescribed in this Pharmacopoeia are authoritative and legally enforceable. The principle of Openness, Justice and Fairness is followed during compiling, verifying/validating and editing the content of the monographs in IP. To keep pace with the growth of pharma sector in India, efforts are on to publish IP every two years with an Addendum in between. If need be the Secretary-cum-Scientific Director is authorized to issue the amendments to IP. IP provides an account of the general chapters and specific monographs of active pharmaceutical ingredients (APIs), their formulations, excipients etc. The specific monographs of IP detail about synonym, molecular structure, molecular formula, molecular weight, definition of article, potency of the article, category, dose, description, identification, tests, assay, impurity profile, storage specifications and labelling requirements etc. Monographs are included in IP based on suggestion/feedback from the stakeholders. Stakeholders of IP Pharma Industry Regulatory Bodies

Analytical Laboratories

IP
Research Institutions Academia

Others

The process of IP monograph development includes following steps: Step 1: Preparation of initial list of monographs for IP 50

The Scientific staff of IPC prepares initial list of APIs and formulations based on current knowledge, for which monographs are to be included in IP. This list is then thoroughly deliberated in the Clinical Medicine and Pharmacology Committee of the Commission. The Clinical Medicine Committee set out the following inclusion/exclusion criteria for IP monographs: Inclusion Criteria Drugs used in National Health Programs of India Drugs listed in Essential Medicines List Drugs approved by CDSCO (Generics not less than 3) Fixed Dose Combinations approved by CDSCO and recommended by the IPC Experts Drugs considered appropriate by the Indian Pharmacopoeia Commission Exclusion Criteria Drugs banned in India Obsolete Drugs Drugs considered inappropriate by Indian Pharmacopoeia Commission The inclusion/exclusion criteria are displayed on the IPC website www.ipc.gov.in. The monographs inclusion request form is also displayed on IPC website and is re-presented below.

51

MONOGRAPH INCLUSION REQUEST FORM 1. 2. 3. 4. Therapeutic Category Name of the Molecule Monograph (Please tick) Is it approved in India? API Dosage Form Both Any Other

5.

6. 7.

In case of Dosage Form, provide details wrt for how long product is being marketed in India? Details of the Product/ Companies marketing product. Benchmark International Product/Company Category (Please tick) National Health Programs of India Essential Medicines List Fixed Dose Combination Any Other

8.

9.

Justification of Inclusion of Monograph:

Reviewers Remarks:

52

1. _____________________ Authorized by:

2. _____________________

1. ___________________ Details/samples attached Specs STP WS Impurity Standards Validation The list of monographs cleared by this Committee is then put up to the Scientific Body of the Commission for its review. The members examine the list and suggest for further action, if any. Step 2: Acquisition of Monographs from the Stakeholders The quality specifications of the APIs/Dosage forms/General Chapters along with validation data are obtained from the industry. Efforts are made to obtain reference substance and sample also from the industry. When we are not easily getting the above material, follow up is done to expedite the matter. Stakeholders can also send monographs directly to IPC. Step 3: Drafting of Monographs in IP Format IPC scientific staff drafts the monographs in IP format. Simultaneous verification/validation of data is performed at the IP Laboratory. The different subject expert committees examine the relevant monographs data for their suitability in terms of the technical contents, feasibility, typographical/technical errors. Step 4: Obtaining Public Comments The drafted monographs are displayed on the website of the Commission for specified period as well as given wide publicity by circulating the list of proposed monographs in IDMA Bulletin/Pharmabiz etc. for obtaining public comments. Monographs are circulated electronically as well as by post also. Step 5: Review of Comments The comments obtained by any mode are examined by the scientific staff of IPC/experts. Further revision, if required is carried out and comments/responses displayed on IPC website, mailed to the stakeholders. If no revision required then it is accepted and processed for publication. The gally proof of the entire manuscript is reviewed by the IPC 53

scientific staff/experts. Other necessities such as obtaining ISBN and Copyright related provision are complied with before final printing of the IP.

The public review and comments process for IP is summarized below:

Public Review and Comment Process Step 6: Release of IP 54

The final print of IP bearing the official seal of IPC and a unique book number is then released by the competent authority for use by the stakeholders. The IP becomes effective from such date as specified/approved by the Secretary-cum-Scientific Director, Indian Pharmacopoeia Commission.
Author: Dr. Jai Prakash Principal Scientific Officer, Indian Pharmacopeia Commission, Ghaziabad Email: ipclab@vsnl.net

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12. GUIDELINES FOR STABILITY TESTING OF PHARMACEUTICAL PRODUCTS CONTAINING WELL ESTABLISHED DRUG SUBSTANCES IN CONVENTIONAL DOSAGE FORMS
General The stability of finished pharmaceutical products depends, on the one hand, on environmental factors such as ambient temperature, humidity and light and, on the other, on product-related factors, e.g. the chemical and physical properties of the active substance and of pharmaceutical excipients, the dosage form and its composition, the manufacturing process, the nature of the container-closure system and the properties of the packaging materials. For established drug substances in conventional dosage forms, literature data on the decomposition process and degradability of the active substance (1) are generally available together with adequate analytical methods. Thus, the stability studies may be restricted to the dosage forms. Since the actual stability of a dosage form will depend to a large extent on the formulation and packaging-closure system selected by the manufacturer, stability considerations, e.g. selection of excipients, determination of their level and process development should be given high priority in the developmental stage of the product. The possible interaction of the drug product with the packaging material in which it will be delivered, transported and stored throughout its shelf-life must also be investigated.

55

The shelf-life should be established with due regard to the climatic zone(s) (see section 2) in which the product is to be marketed. For certain preparations, the shelf-life can be guaranteed only if specific storage instructions are complied with. The storage conditions recommended by manufacturers on the basis of stability studies should guarantee the maintenance of quality, safety, and efficacy throughout the shelflife of a product. The effect on products of the extremely adverse climatic conditions existing in certain countries to which they may be exported calls for special consideration (see section 6). To ensure both patient safety and the rational management of drug supplies, it is important that the expiry date and, when necessary, the storage conditions are indicated on the label. 1. Stability testing The main objectives and uses of stability testing are shown in Table 1. 1.1 In the development phase Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf-life and storage conditions determined. Real-time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in multidose containers, especially for topical use. 1.2 For the registration dossier The drug regulatory authority will require the manufacturer to submit information on the stability of the product derived from tests on the final dosage form in its final container and packaging. The data submitted are obtained from both accelerated and real-time studies. Published and/or recently obtained experimental supporting stability data may also be submitted, e.g. on the stability of active ingredients and related formulations. Table 1. Main objectives of stability testing Objective Type of study To select adequate (from the Accelerated Use Development of the 56

viewpoint of stability) formulations and containerclosure systems To determine shelf-life and Accelerated and storage conditions real-time To substantiate the claimed shelflife To verify that no changes have been introduced in the formulation or manufacturing process that can adversely affect the stability of the product Real-time Accelerated and real-time

product

Development of the product and of the registration dossier Registration dossier Quality assurance in general, including quality control

Where the product is to be diluted or reconstituted before being administered to the patient (e.g. a powder for injection or a concentrate for oral suspension), in use stability data must be submitted to support the recommended storage time and conditions for those dosage forms. With the approval of the drug regulatory authority, a tentative (provisional) shelf-life is often established, provided that the manufacturer has undertaken, by virtue of a signed statement, to continue and complete the required studies and to submit the results to the registration authority. 1.3 In the post-registration period

The manufacturer must carry out on-going real-time stability studies to substantiate the expiry date and the storage conditions previously projected. The data needed to confirm a tentative shelf-life must be submitted to the registration body. Other results of ongoing stability studies are verified in the course of GMP inspections. To ensure the quality and safety of products with particular reference to degradation, national health authorities should monitor the stability and quality of preparations on the market by means of a follow-up inspection and testing programme. Once the product has been registered, additional stability studies are required whenever major modifications are made to the formulation, manufacturing process, packaging or method of preparation. The results of these studies must be communicated to the competent drug regulatory authorities. 2. Intended market The design of the stability testing programme should take into account the intended market and the climatic conditions in the area in which the drug products will be used. 57

Four climatic zones can be distinguished for the purpose of worldwide stability testing, as follows: Zone I: temperate. Zone II: subtropical, with possible high humidity. Zone III: hot/dry. Zone IV: hot/humid. (See Schumacher P. Aktuelle Fragen zur Haltbarkeit von Arzneimitteln. [Current questions on drug stability.] Pharmazeutische Zeitung, 1974, 119:321-324.) The mean climatic conditions calculated data and derived storage conditions in these zones are summarized in Tables 2 and 3. Since there are only a few countries in zone I, the manufacturer would be well advised to base stability testing on the conditions in climatic zone II when it is intended to market products in temperate climates. For countries where certain regions are situated in zones III or IV, and also with a view to the global market, it is recommended that stability testing programmes should be based on the conditions corresponding to climatic zone IV. In a stability study, the effect on the product in question of variations in temperature, time, humidity, light intensity and partial vapour pressure are investigated. The effective or mean kinetic temperature therefore reflects the actual situation better than the measured mean temperature; a product kept for 1 month at 20C and 1 month at 40C will differ from one kept for 2 months at 30C. Moreover, the storage conditions are often such that the temperature is higher than the average meteorological data for a country would indicate.

Table 2. Meanclimaticconditions:measureddataintheopenairandinthe Climatic zone I II III IV storageroom1 Measured data in the open air C % RH 10.9 75 17.0 70 24.4 39 26.5 77 Measured data in storage room C % RH 18.7 45 21.1 52 26.0 54 28.4 70

58

RH = relative humidity. Table 3. Mean climatic conditions: calculated data and derived storage conditions1 Climatic zone C2 I II III IV 20.0 21.6 26.4 26.7 Calculated data C MKT3 20.0 22.0 27.9 27.4 % RH4 42 52 35 76 Derived storage conditions (for real-time studies) C 21 25 30 30 % RH 45 60 35 70

Based on: Grimm W. Storage conditions for stability testing in the EC, Japan and USA; the most important market for drug products. Drug development and industrial pharmacy, 1993, 19:2795-2830. 2 Calculated temperatures are derived from measured temperatures, but all measured temperatures of less than 19C were set equal to 19C. 3 MKT = mean kinetic temperature (see p. 67). 4 RH = relative humidity.

Amendment from Draft of the 37th Report of The WHO Expert Committee on Specifications for Pharmaceutical Preparations. Geneva, 22-26 October 2001 WHO guidelines for stability testing of pharmaceutical products containing wellestablished drug substances in conventional dosage forms The Committee discussed and adopted the recommended modification of storage conditions published in the WHO guidelines for stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms to read 30C ( 2C) and 65% ( 5%) RH for real-time stability studies destined for climatic zone IV. It was also agreed that where special transportation and storage conditions were identified as being outside these criteria, additional study data supporting these conditions may need to be made available. For some dosage forms, especially liquid and semi-solid ones, the study design may also need to include subzero temperatures, e.g. -10 to -20 C (freezer), freeze-thaw cycles or temperatures in the range 2-8 C (refrigerator). For certain preparations it may be important to observe the effects caused by exposure to light. 3. Design of stability studies

Stability studies on a finished pharmaceutical product should be designed in the light of the properties and stability characteristics of the drug substance as well as the climatic 59

conditions of the intended market zone. Before stability studies of dosage forms are initiated, information on the stability of the drug substance should be sought, collected and analysed. Published information on stability is available on many well established drug substances. 3.1 Test samples For registration purposes, test samples of products containing fairly stable active ingredients are taken from two different production batches, in contrast, samples should be taken from three batches of products containing easily degradable active ingredients or substances on which limited stability data are available. The batches to be sampled should be representative of the manufacturing process, whether pilot plant or full production scale. Where possible, the batches to be tested should be manufactured from different batches of active ingredients. In on-going studies, current production batches should be sampled in accordance with a predetermined schedule. The following sampling schedule is suggested: one batch every other year for formulations considered to be stable, otherwise one batch per year; one batch every 3-5 years for formulations for which the stability profile has been established, unless a major change has been made, e.g. in the formulation or the method of manufacture.

Detailed information on the batches should be included in the test records, namely the packaging of the drug product, the batch number, the date of manufacture, the batch size, etc. 3.2 Test conditions 3.2.1 Accelerated studies An example of conditions for the accelerated stability testing of products containing relatively stable active ingredients is shown in Table 4. For products containing less stable drug substances, and those for which limited stability data are available, it is recommended that the duration of the accelerated studies for zone II should be increased to 6 months. Table 4. Example of conditions for accelerated stability testing of products containing relatively stable active ingredients Storage temperature (C) Relative humidity (%) Duration of studies (months) 60

Zone IV- For hot climatic zones or global market: 402 755 6

Zone II - For temperate and subtropical climatic zones: 402 755 3

Alternative storage conditions may be observed, in particular, storage for 6 months at a temperature of at least 15 C above the expected actual storage temperature (together with the appropriate relative humidity conditions). Storage at higher temperatures may also be recommended, e.g. 3 months at 45-50 C and 75% relative humidity (RH) for zone IV. Where significant changes (see below) occur in the course of accelerated studies, additional tests at intermediate conditions should be conducted, e.g. 30 2 C and 60 5% RH. The initial registration application should then include a minimum of 6 months data from a 1-year study. A significant change is considered to have occurred if: the assay value shows a 5% decrease as compared with the initial assay value of a batch; any specified degradation product is present in amounts greater than its specification limit; the pH limits for the product are no longer met; the specification limits for the dissolution of 12 capsules or tablets are no longer met; the specifications for appearance and physical properties, e.g. colour, phase separation, caking, hardness, are no longer met.

Storage under test conditions of high relative humidity is particularly important for solid dosage forms in semi-permeable packaging. For products in primary containers designed to provide a barrier to water vapour, storage conditions of high relative humidity are not necessary. As a rule, accelerated studies are less suitable for semi-solid and heterogeneous formulations, e.g. emulsions. 3.2.2. Real-time studies The experimental storage conditions should be as close to the projected actual storage conditions in the distribution system as practicable (see Table 3). For registration purposes, the results of studies of at least 6 months' duration should be available at the time of registration. However, it should be possible to submit the registration dossier before the end of this 6-month period. Real-time studies should be continued until the end of the shelf-life. 61

3.3

Frequency of testing and evaluation of test results

In the development phase and for studies in support of an application for registration, a reasonable frequency of testing of products containing relatively stable active ingredients is considered to be: for accelerated studies, at 0, 1, 2, 3 and, when appropriate, 6 months; for real-time studies, at 0, 6 and 12 months, and then once a year. For on-going studies, samples may be tested at 6-month intervals for the confirmation of the provisional shelf-life, or every 12 months for well established products. Highly stable formulations may be tested after the first 12 months and then at the end of the shelf-life. Products containing less stable drug substances and those for which stability data are available should be tested every 3 months in the first year, every 6 months in the second year, and then annually. Test results are considered to be positive when neither significant degradation nor changes in the physical, chemical and, if relevant, biological and microbiological properties of the product have been observed, and the product remains within its specification. 4. Analytical methods

A systematic approach should be adopted to the presentation and evaluation of stability information, which should include, as necessary, physical, chemical, biological and microbiological test characteristics. All product characteristics likely to be affected by storage, e.g. assay value or potency, content of products of decomposition, physicochemical properties (hardness, disintegration, particulate matter, etc.), should be determined; for solid or semi-solid oral dosage forms, dissolution tests should be carried out. Test methods to demonstrate the efficacy of additives, such as antimicrobial agents, should be used to determine whether such additives remain effective and unchanged throughout the projected shelf-life. Analytical methods should be validated or verified, and the accuracy as well as the precision (standard deviations) should be recorded. The assay methods chosen should be those indicative of stability. The tests for related compounds or products of decomposition should be validated to demonstrate that they are specific to the product being examined and are of adequate sensitivity.A checklist similar to that used in the WHO survey on the stability of pharmaceutical preparations included in the WHO Model 62

List of Essential Drugs (Appendix 1) can be used to determine the other stability characteristics of the product. 5. Stability report A stability report must be established for internal use, registration purposes, etc., giving details of the design of the study, as well as the results and conclusions. The results should be presented as both a table and a graph. For each batch, the results of testing both at the time of manufacture and at different times during storage should be given. A standard form should be prepared in which the results for each pharmaceutical preparation can be summarized (see Appendix 2).The stability of a given product, and therefore the proposed shelf-life and storage conditions, must be determined on the basis of these results. 6. Shelf-life and recommended storage conditions Shelf-life is always determined in relation to storage conditions. If batches of a product have different stability profiles, the shelf-life proposed should be based on the stability of the least stable, unless there are justifiable reasons for doing otherwise. The results of stability studies, covering the physical, chemical, biological, microbiological and biopharmaceutical quality characteristics of the dosage form, as necessary, are evaluated with the objective of establishing a tentative shelf-life. Statistical methods are often used for the interpretation of these results. Some extrapolation of realtime data beyond the observed range, when accelerated studies support this, is acceptable. A tentative shelf-life of 24 months may be established provided the following conditions are satisfied: the active ingredient is known to be stable (not easily degradable); stability studies as outlined in section 3.2 have been performed and no significant changes have been observed; supporting data indicate that similar formulations have been assigned a shelflife of 24 months or more; the manufacturer will continue to conduct real-time studies until the proposed shelf-life has been covered, and the results obtained will be submitted to the registration authority.

Products containing less stable active ingredients and formulations not suitable for experimental studies on storage at elevated temperature (e.g. suppositories) will need more extensive real-time stability studies. The proposed shelf-life should then not exceed twice the period covered by the real-time studies. After the stability of the product has been evaluated, one of the following recommendations as to storage conditions can be prominently indicated on the label: 63

- store under normal storage conditions; 1 - store between 2 and 8 C (under refrigeration, no freezing); - store below 8 C (under refrigeration); - store between -5 and -20 C (in a freezer); - store below -18 C (in a deep freezer). Normal storage conditions have been defined by WHO (3) as: storage in dry, wellventilated premises at temperatures of 15-25 C or, depending on climatic conditions, up to 30 C. Extraneous odours, contamination, and intense light have to be excluded. These conditions may not always be met, bearing in mind the actual situation in certain countries. Normal conditions may then be defined at the national level. Recommended storage conditions must be deter-mined in the light of the conditions prevailing within the country of designated use. General precautionary statements, such as protect from light and/or store in a dry place, may be included, but should not be used to conceal stability problems. If applicable, recommendations should also be made as to the utilization period and storage conditions after opening and dilution or reconstitution of a solution, e.g. an antibiotic injection supplied as a powder for reconstitution.

This statement may not always be required for products intended for areas with a temperate climate.

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Appendix 1 Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet A checklist similar to that shown here can be used to determine the stability characteristics of a product. Name of reporting person Address Country Climatic zone NAME OF ESSENTIAL DRUG: Description of product Dosage form 1. tablet coated uncoated 2. capsule hard soft 3. injection liquid powder 4. oral liquid solution suspension 5. topical semi-solid cream ointment 6. eye preparations liquid semi-solid 7. other (please state) Packaging (material and type) 1. glass 2. plastic 3. paper 4. metal 5. blister pack 6. other (please state) State of packaging Storage conditions According to the manufacturers indications? Shelf-life (if available) claimed by the manufacturer percentage elapsed when tested

bottle bottle box

vial vial

ampoule ampoule bag

intact damaged

yes

no

years %

months

Source of product tested 1. manufactured in country of use 2. imported from neighbouring country/countries 3. imported from distant country/countries _______________________________________________________________________ 65

Problems encountered Occurrence 1. very frequent 2. occasional, but important 3. rare

Pharmacopoeial non-compliance 1. Identification 2. assay 3. purity tests 4. other pharmacopoeial test(s) Microbial 1. microorganisms visible 2. tests for bacteria positive Microbial (continued) 3. tests for fungi positive 4. tests for pyrogens positive 5. other (please state)

Organoleptic 1. change of colour 2. visible changes, i.e. capping, cracking, foam Organoleptic (continued) 3. inhomogeneous appearance 4. crystallization 5. particles, turbidity, precipitation 6. sedimentation, caking, agglomeration 7. smell, i.e. gas formation 8. rancidity 9. phase separation of emulsion 10. interaction with packaging material 11. other (please stat

Additional information

Date: ___________________________________________________________________ 1. A separate answer sheet should be completed for each of the above preparations in a specific finished dosage form, e.g. one for tetracycline capsules and another for tetracycline ointment. Also applicable for other categories such as packaging material, source of drug product, etc. 2. Climatic zones (Schumacher P. Aktuelle Fragen zur Haltbarkeit von Arzneimitteln. [Current questions on drug stability.] Pharmazeutische Zeitung, 1974, 119:321-324): zone I zone II zone III zone IV - temperate - subtropical with possible high humidity - hot and dry - hot and moist.

66

67

Appendix 2 Stability testing: summary sheet An example of a form in which the results of stability testing can be presented is shown below. A separate form should be completed for each pharmaceutical preparation tested. Accelerated/real-time studies Name of drug product Manufacturer . Address ..

Active ingredient (INN) . Dosage form ... Packaging Batch number 1 .............. 2 .................. 3 .................. Shelf-life Batch size 1 .................. 2 .................. 3 .................. Date of manufacture ../../20.. ../../20.. ../../20.. year(s) Expiry date ../../20.. ../../20.. ../../20.. ... month(s)

Type of batch (experimental, pilot plant, production) . . .

Samples tested (per batch) .. Storage/test conditions: Temperature ... C Humidity % Light cd Results 1. Chemical findings . .. 2. Microbiological and biological findings ... 68

 3. Physical findings

4.

Conclusions . Responsible officer ......................................................... Date ../../20.. References: 1. WHO 2006 QAS/06.179. Pharmaceutical Products.

Stability

testing

of

Active

substances

and

2. Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e. V.Arbeitsgemeinschaft for Pharmazeutische Verfahrenstechnik e.V Richtlinie and Kommentar [Guidelines and commentary]. Pharmazeutische Industrie, 1985, 47(6): 627-632. 3. European Community-Stability test on active ingredients and finished products. Note for guidance concerning the application of Part 1, Section F. Annex to Directive 75/318. In: The rules governing medicinal products in the European Community. Vol, l, the rules governing medicinal products for human use in the European Community (111/3574/92). Brussels, EEC Office for Official Publications of the European Community, 1991:50. 4. European Organization for Quality Control-Cartwright AC. The design of stability trials (memorandum and conclusions). London, European Organization for Quality Control, Section for Pharmaceutical and Cosmetic Industries, 1986. 5. Food and Drug Administration, USA-Guidelines for stability studies for human drugs and biologics. Rockville, MD, Center for Drugs and Biologics, Office of Drug Standards, Food and Drug Administration, 1987. 6. Food and Drug Administration, USA-Expiration dating and stability testing for human drug products. Inspection technical guide. Rockville, MD, Food and Drug Administration, 1985, No. 41. 7. Former German Democratic Republic-Testing of medicaments. International digest of health legislation, 1987, 38(2): 309-316. (For original reference, see: First regulations of 1 December 1986 for the implementation of the Medicaments Law. Testing, authorization, and labelling of medicaments intended for use in

69

human medicine. Gesetzblatt der Deutschen Demokratischen Republik, Part I, 10 December 1986, 37:479-483.) 8. Pharmacopoeia of the German Democratic Republic, English version. Berlin, 1988:99 (AB DDR 85). 9. International Conference on Harmonisation (Q1-A, B, C, D, E)Stability testing of new drug substances and products. Harmonised tripartite guideline. 1993 (available from ICH Secretariat, c/o IFPMA, 30 rue de St-Jean, 1211 Geneva, Switzerland). 10. Japan-Draft policy to deal with stability data required in applying for approval to manufacture (import) drugs and draft guidelines for stability studies. Tokyo, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, 1990. 11. Pharmaceutical Inspection Convention-Stability of pharmaceutical products: collected papers given at a seminar, Salzburg, 9-11 June 1976 (available from the Secretariat to the Convention for the Mutual Recognition of Inspections in Respect of the Manufacture of Pharmaceutical Products, c/o EFTA Secretariat, 911 rue de Varembe, 1202 Geneva, Switzerland). 12. Accelerated stability studies of widely used pharmaceutical substances under simulated tropical conditions. Geneva, World Health Organization, 1986 (unpublished document WHO/PHARM/86.529; available on request from Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland). 13. Haynes JD. World wide virtual temperatures for product stability testing. Journal of pharmaceutical sciences, 1971, 60:927-929. 14. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-first report. Geneva, World Health Organization, 1990 (WHO Technical Report Series, No. 790).
Author: Dr. Manish dare, Principal Scientific Officer, Indian Pharmacopeia Commission, Ghaziabad Email: ipclab@vsnl.net

Note: The above guidelines on stability testing have no direct application to any of the quality parameter specified in the IP. Formulations of drugs specified in the IP are manufactured by different manufacturers by different processes but are claimed to 70

conform to IP adopting a shelf-life and expiry date as available in the Schedule P of the Drugs and Cosmetics Rules.The compliance of the product with IP requirements through out its shelf-life could depend upon proper stability studies and these guidelines are intended for the guidance of the manufacturers in the matter.

13. ANALYTICAL METHOD VALIDATIONS FOR PHARMACOPOEIAL ANALYSIS OF DRUGS

Scope: Validations of Chemical Methods of Analysis described in Pharmacopoeia. Validation of Pharmacopoeial Methods: Pharmacopoeial Requirements USP, EP, BP & IP USP 1225 VALIDATION OF COMPENDIAL PROCEDURES The Current Good Manufacturing Practice regulations [21 CFR 211.194(a)] require that test methods, which are used for assessing compliance of pharmaceutical articles with established specifications, must meet proper standards of accuracy and reliability. Also, according to these regulations [21 CFR 211.194(a)(2)], users of analytical methods described in USPNF are not required to validate the accuracy and reliability of these methods, but merely verify their suitability under actual conditions of use. Recognizing the legal status of USP and NF standards, it is essential, therefore, that proposals for adoption of new or revised compendial analytical procedures be supported by sufficient laboratory data to document their validity. BP/EP The test methods given in the monographs and general chapters have been validated in accordance with accepted scientific practice and current recommendations on analytical validation. Unless otherwise stated in the monograph or general chapter, validation of the test methods by the analyst is not required. Basic Question: Pharmacopoeial methods: Do they need to be validated? If Yes, to what extent? Types of Tests: Major Types of Pharmacopoeial Tests: 1. Identification 2. Testing for Impurities 3. Assay 71

Dissolution Drug Content/ Potency

API: Pharmacopoeial Test Method used as is for: Identification -By Infrared Spectral technique -By Ultraviolet Spectral technique -By Chromatographic technique -By chemical tests The validity of these methods can be checked by comparing the results obtained with an authentic standard except for chromatographic technique where specificity needs to be proved additionally. Pharmacopoeial Test Method used as is for: Assay: Titrimetric Method No validation required Chromatographic method: - Specificity - Precision Related Substances Test: - LOD - LOQ - Specificity - Linearity - Range Robustness (only for critical separations) Pharmacopoeial Test Method used as is Residual Solvents by GC -LOD -LOQ -Specificity -Linearity -Range -Accuracy (To ensure release from drug matrix) If pharmacopoeial method is modified beyond acceptable variance: Requires complete validation of the method as per ICH Guidelines Drug Product: 72

 Pharmacopoeial Test Method used as is -Identification -By Infrared Spectral technique -By Ultraviolet Spectral technique -By Chromatographic technique Specificity of all these techniques need to be proved Pharmacopeial Test Method used as is Assay -Specificity with reference to known impurities -Specificity by forced degradation study - Linearity - Range - Accuracy Pharmacopoeial Test Method used as is Related Substances Test LOD LOQ Specificity wrt known impurities Specificity by forced degradation study Linearity Range Accuracy Robustness Pharmacopoeial Test Method used as is Test for Dissolution - Linearity - Range - Accuracy

If pharmacopoeial method is modified beyond acceptable variance: Requires complete validation of the method as per ICH Guidelines. Challenges: API - Availability of process impurities and degradation product 73

- Stability of API and impurities - Chiral complexity - Drug Product Multi component product Complexity of formulation Solubility of API General Errors: Flaws in deciding the system suitability criteria Flaws in Forced Degradation studies Selection of Range for assay and Impurities Flaws in Linearity Studies Flaws in Precision Studies Flaws in determining LOD and LOQ Flaws in Robustness Studies

Author: Dr. P M Dixit,

-------------------------

74

14.1. CALIBRATION OF SOPHISTICATED INSTRUMENTS AND GLASSWARE IN DRUGS TESTING LABORATORY

1. Calibration: Calibration is the process of establishing how the response of measuring device varies with respect to the Parameter being measured. The usual way to perform a calibration is to subject known amount of the Parameter i.e. using a Reference material [traceable to national & international standard] to the measurement and monitor the measurement response. Calibration involves applying standards value to the Equipment / Instrument and observing how it responds. After verifying the response if possible minimize the error by any of the action which is applicable reset, adjust / correct the equipment or Corrective factor/ calibration constant are developed and incorporated in the measurement. 1.1. Calibration and Performance Verification: Calibration is the process of comparison of two instruments, one of which is a standard of known accuracy, to detect or adjust any difference in accuracy of the instruments measuring device being compared to the standard. Verification is the processes to check or confirm the performance of the instruments or method to see that it is within predetermined set of instruments or limit set. Basically calibration is a part of performance verification. 1.2 Objective of Calibration To ensure the accuracy/reliability of the reading obtained from instruments/equipments, laboratory glass ware with authentic reference standard having a Traceability of NABL Accredited agency. To check and establish the accuracy of an instrument or a measuring device to give reliable data. To track the measurement results back to national & international standard.

75

 To maintain the quality control & quality assurance in the production to comply with requirements of global trade. To promote international recognition like NABL, GLP, ISO 9000, HACCP,ISO/IEC 17025 etc. 1.3. Frequency of calibration Varies from instrument to instrument Depends on the ruggedness of the instrument Criticality of the test performed Extent of use Recommendation from manufacturer Laboratory experience NABL Documents-103 NATA-National Association of Testing Authorities

Normally calibration must be done at the time of : Installation Serviced/Repaired Disturbed / Re-located pH meter every time before use Glass ware one time (not to be exposed to high temp.) Chromatography 6 to 12 months* Spectrophotometer 3 to 6 months* *- (as per SOP) 1.4. Basic requirements for calibration Standard reference material / calibrator Controlled environmental condition Competence of calibration lab. Personnel. SOP for calibration. Traceability of standard Documentation / records of calibration 1.5. Suggested Environmental conditions Temperature 25(+)(-) 20 C Relative humidity 45-60 % Light 400-500 lux Acoustic level (sound) 60 dBA(max.) Power supply Regulated(+)(-) 1 76

 Vibration

Almost nil

1.6. Do all the Instruments need to be calibrated ----? In common all measuring devices and instruments need periodic calibration to monitor the changes in performance - pH meter, Volumetric flask However, conventionally instruments that are used only for indicators, where the indicated Values are not important, probably do not need Calibration. Eg. Conical flask Most of the instruments do need to be calibrated whether they are simple devices, state of the art system or fundamental in nature. 1.7. List of Instruments: 1. Karl Fischer Apparatus Graduated Pipette/liquid delivery system. 2. Calibration of Weight Box Set of Weights 3. Analytical Balance 4. UV-Visible Spectrophotometer 5. Infra-Red Spectrophotometer 6. pH Meter 7. Refractometer 8. Polarimeter 9. B.O.D. Incubator 10. Laboratory Oven 11. Disintegration Test Apparatus 12. Dissolution Test Apparatus 13. Thermometer 14. Gas Chromatograph (G.L.C.) 15. H.P.L.C./LC-MS 16. HPTLC 17. AAS/ICP-MS 18. Glass Apparatus (used for measurement) etc 2. Calibration Procedures: 2.1. Calibration of PIPETTE SINGLE MARK - IS-1117:1975/ IP-2007,Vol-I (2.1.6) Requirments : 77

Calibrated balance Calibrated thermometer Dried beakers which have been previously rinsed with acetone Calibrated stop watch

Calibration frequency: Initial calibration Verification frequency: Quarterly checking for delivered volume. Determination of volume Clean the pipette thoroughly. Fill up the pipette with distilled water to the mark. Care shall be taken to ensure that there are no air bubbles inside the pipette. Weigh the dried empty beaker (W1). Deliver the water from the pipette to its maximum in the beaker (W2). The pipette should be held in vertical direction and its tip should touch the beaker. Weigh the beaker with water (W2). Note the temperature of the distilled water using a calibrated thermometer Repeat the whole procedure till difference in two subsequent readings (W2 & W1) differ not more than 0.01g. Volume of the pipette is determined by using the following formula Volume, V=W/D Where V=Volume of the pipette in cm3 W=Weight of the water contained in the beaker obtained by the difference of the weights W2 & W1 in gms. D=Density of water at 27oC i.e. 0.9965/gm/cc Determination of Delivery time Fill the pipette with distilled water to the maximum mark Ensure that there are no air bubbles in the pipette Remove the finger from the jet and deliver the water from the pipette in the beaker. Start the stopwatch simultaneously at the start of the delivery of water from the mark on the pipette. Stop the stopwatch as the pipette has emptied at the maximum delivery. Repeat the procedure 3 to 4 times to determine reproducibility Note the time of delivery in seconds and compare with limits as per nominal capacity and type as per IS-1117-1975. Maximum permitted tolerances as per IS :1117 - 1975

78

S.no.

Nominal capacity(ml.)

Maximum permitted tolerance(ml.) Class A Class B 0.01 0.015 0.02 0.03 0.04 0.06 0.06 0.10 0.16 0.20

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

0.5 1 2 5 10 20 25 50 100 200

0.005 0.007 0.010 0.015 0.02 0.03 0.03 0.05 0.08 0.10

Precautions The filled pipette should not contain any air bubbles. The temperature of water should be measured after every reading using a calibrated thermometer with traceability of NABL accredited agency. Whole procedure of Calibration should be undertaken at 27oC Reporting Report the actual volume of water contained in the pipette. Report the delivery time in seconds.

79

Calibration Certificate 1 2 3 4 5 6 7 8 Sample description Normal Capacity Identification No Calibrating Parameter Least Count Temperature Protocol Used Major Equipments/ Materials Used Date of Calibration Next Due Date Calibration Results Normal Capacity (ml) 5.0 12 Reference Traceability Particulars Set of weight Digital Thermometer = Certificate No 3179/03/058/2002/NPL Valid up to 22.05.2011 04.06.2011 = = = = = Pipette One Mark 5 ml APL/C/03001 Capacity volume -270C IS: 1117 1975 Distilled Water, Balance, Set of weight, Digital Thermometer 22.03.2010 -- --

9 10 11

= =

Actual Capacity (ml) 5.0186

80

Calibration Sticker Company/ Institution Name S. No./ code no. :Equipment :Calibrated on :Identification :Next Calibration Due on :Authorized Signatory : -

:-------------------------------------------

2.2. THERMOMETER - IS:6274-1971 Basic type of Calibration (i) Fixed point Calibration- Freezing, Melting or Triple point of pure material are used to define the fixed reference temperature. (ii) Comparison Calibration- Widely used method of Calibration it involves immersing thermometer under Calibration in a stable temperature source along with a standard reference calibrated thermometer. Requirements: 1. Reference thermometer of suitable range(traceable to NPL/NABL accredited laboratory ) 2. Source of constant temperature (i) Water bath with stirrer and adjustable temperature. (ii) Oil bath with stirrer and adjustable temperature (iii) Dry block Calibrator Calibration frequency: For PRT(ref.) 10yrs.* Liquid- in- glass thermometer (ref.) 10yrs.* Liquid- in- glass thermometer (working) 5yrs.* (* reference: NABL doc 103, Pg. 43 / 88./National association of testing Authorities(NATA) Calibration procedure: Set the oil bath at the desirable temperature. Fix reference thermometer and test thermometer in oil bath at the same point. Note the temperature of both reference & test thermometer. Calculate the difference between the test thermometer and the reference thermometer.

81

 Draw a graph between the test thermometer reading and the difference observed against reference thermometer. Apply the correction factor from graph to the test thermometer reading to get true value Precaution: The least count of reference thermometer should less than the LC of test thermometer. (Min.10 times) The thermometer should be marked properly for its identification.

Test thermometer reading v/s error (0)C

24

1 0.8 0.6 ERROR (0)C 0.4 0.2 0 -0.2 -0.4 -0.6 -0.8 TEST THERMOMETER READING (0)C 0 50 100 150 200

82

Calibration Certificate Certificate No: NR- 03031602 Received on: 1 2 3 4 5 6 7 8 9 10 Sample Description Issue Date: Make Identification No Calibrating Parameter Least Count Range Temperature Protocol Used Major Equipments/ Materials Used Date of Calibration Principle Laboratory Thermometer Zeal England APL/C/03006 Temperature 10C 50 to 150 IS: 1117/1975 Digital Thermometer, Serial No 2030602 MDI (PRT) 08.04.2009 Calibration of Laboratory Thermometer by comparing the observations at set points with a reference thermometer.

11

12

Calibration Results: S.No Reference thermometer reading 1 50 2 100 3 150 Reference Traceability Particulars Digital Thermometer

Test thermometer Comparison to the test reading thermometer (0C) 49.6 100.9 150.4 Certificate No 3178/06/66/200 +0.4 -0.9 -0.4 Valid up to 04.06.2011

2.3. WEIGHTS AND BALANCES Visual observations : Check the weights for their cleanliness quality of surfaces and edges freedom from extraneous matter and closeness of fit of the screw knob. Weight should not be magnetic. 83

 Fractional weights should be quickly identifiable and should not be punctured Calibration Procedure : Clean and dry the sample weights to make them free from moisture (if any) Weigh one by one the standard (calibrated) weights and sample weights using a precision balance of suitable capacity and accuracy. Record the observations. Repeat the process for each weight at least four times. Precautions Before undertaking the calibration ensure that the balance is levelled and supported on rigid vibration free table. All observations should be undertaken at a room temperature i.e 27oC. Reporting Report for the actual mass value for each weight including the rider against the standard weight, which have traceability to a national or international accredited agency/NABL/NPL. 2.4. Infrared Spectrophotometer (IR/FTIR):

Io line flatness: The Io line (100% transmittance line) should not deviate from horizontal line at any point by more than the amount stated in the manufacturers specification. Verification of the Wave number scale : Run a spectrum of polystyrene film (0.05mm thickness.) the position of the absorption peaks shown below should not differ from the values specified. 3027.1(+ 0.3) 2924 (+ 2) 2850.7 (+ 0.3) 1944 (+ 1) 1871.0 (+ 0.3) 1801.6 (+ 0.3) 1601.4 (+ 0.3) 1583.1 (+ 0.3) 1181.4 (+ 0.3) 1154.3 (+ 0.3) 1069.1 (+ 0.3) 1028.0 (+ 0.3) 906.7 (+ 0.3) 698.9 (+ 0.5)

Spectral Resolution performance: In the spectrum of polystyrene film (0.05mm thickness) check the following

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(a) The depth of the trough from the maximum at about 2851 cm-1 to the minimum at about 2870 cm-1 should be greater than 18% transmittance for grating instrument and 6%for prism instrument. (b) The depth of the trough from the maximum at about 1583 cm-1 to the minimum at about 1589 cm-1 should be greater than 12% transmittance for grating instrument and 6% for prism instrument. 2.5. UV / VIS spectrophotometer: (i) Io- line flatness: The Io line (100% transmittance line) should be checked at wavelengths between 220 nm and 700 nm in accordance with the instruction of the manufacturer. Confirm that the instrument meets the specified requirements. (ii) Stray light This should be checked by measuring the transmissions of solution of KCI (12 gm/Lt in water) and potassium dichromate (0.25gm/Lt in aq. 0.05 M KOH) at 200 and 370 nm respectively. The values should be less than 1.0% transmittance or greater than 2.0 absorbance units, when compared with water as a reference liquid (iii) Resolution power: The ratio of the absorbance of a 0.02 % v/v solution of toluene in hexane at the maxima and minima at about 269 and 266 nm respectively should not be less than 1.5. (iv) Control of Wavelength: (i)Verify the wavelength scale in the range 200-600nm, using the absorption maxima of Holmium oxide (4.0%w/v in HCLO4), Scan in the range of 200-600nm.it gives the characteristic peaks. The permitted limits are*: +- 1 nm range 200-400nm. +- 3 nm range 400-600nm. *NABL/J C Travis et al.,analytical chemistry,3408-3415,2002. (ii)Wavelength calibration can be performed using holmium oxide or Didynium glass filter traceable to international standards. (v) Photometric accuracy: Prepare a solution 14.2% w/v of potassium nitrate in water. Dilute this solution to obtain solution with concentrations of 1.065%, 0.710% and 0.355% w/v. Measure the absorptions of these solutions at about 302nm. Assuming the A (1%, 1cm) value of 0.751, 0.500, and 0.250. The actual absorbance should not differ from the calculated values by more than 0.010 (vi) Control of Absorbance: Check the absorbance of potassium dichromate solution UV-(60mg / Lt. in 0.005M Sulphuric acid for 235 to 350 nm and 60mg/100ml for 430 nm )(Appendix-2.4.7, I.P.2007) and compare the result as per Table. 85

Wavelength (nm) 235(minima) 257(maxima) 313(minima) 350(maxima) 430(maxima)

A(1%, 1cm) 124.5 144.0 48.6 106.6 15.9

Maximum Tolerance 122.9 to 126.2 142.4 to 145.7 47.0 to 50.3 104.9 to 108.2 15.7 to 16.1

Typical spectrum of Potassium Chromate solution in 0.1n H2SO4 for checking absorbance accuracy of UV visible spectrophotometer

2.6. Polarimeter /Digital Polarimeter Using calibrated quartz plate: 86

 Obtain the optical rotation of the quartz plate and then a further four readings while rotation the plate through 45{o} between each reading. The range of result should not exceed 0.06{o} Calculate the value of the optical rotation of the quartz plate. It should not vary from the stated value by more than 0.05{o}. Using sucrose solution: Prepare sucrose solution of various concentrations like 10.0,20.0,30.0,40.0,50.0 gm / 100ml using sucrose NIST traceable and previously dried at 105{o} for 3 hours. Measure the optical rotation of the solutions in 2 dm tube at 25{o}C. Calculate the specific optical rotation (SOR).

CALIBRATION DATA

Ref:- * I.P. 2007, Volume I, Appendix 2.4.22

Disintegration Test Apparatus: Procedure: Ensure that the equipment is clean. Ensure that the equipment is free from any operational defects. 87

Calibration: Switch on the equipment and start the motor. Switch on the temperature controller knob and set the temperature at 37oC. Verify the temp. of immersion fluid with calibrated thermometer 37oC. (+)(-)2. Count the paddle movement raising and lowering cycles of the seemly (RPM) manually using a stopwatch. Verify the counts with the set point specified count of 28-32 Cycle per minute through a distance 50-60mm. Take at least three to four readings for better accuracy and reproducibility. The time required for upward stroke should be equal to the time required for downward stroke. Requirements for Physical Verification : Calibrated vernier calipers Calibrated thermometer Calibrated stop watch Calibrated Tachometer Requirements for Performance Verification : USP prednisone tablets RS (disintegrating). USP salicylic acid tablets RS (non-disintegrating). Verification of standard accessories : (at the time of installation) 1. Basket Stirring Element 2. Paddle stirring element. 3. Dissolution test vessel. Validation of Physical Parameter 1. Basket wobble. 2. Paddle wobble. 3. Paddle centering. 4. D-1 (dist. b/w the bottom of the basket to the inner surface of vessel) 5. D-2 (dist. b/w the bottom of the paddle to the inner surface of vessel)

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VALIDATION OF STANDARD ACCESSORIES (USP) Apparatus 1: Basket Stirring Equipment Dimension Dim Dim Dim Dim Dim Dim Dim Dim Dim J Remarks A B C D E F G H USP 6.3 25.0 20.2 37.0 27.0 2.0 5.1 20.2 22.2 Limits 6.5 1.0 0.5 0.5 OR 3.0 1.0 3.0 mm mm mm 0.1 1.0 9.4 mm mm mm open Vent mm mm 10.1 screen Hole mm Dia. Basket No Measured Value 1 9.92 24.94 20.00 36.34 26.28 1.94 5.00 20.30 22.00 OK 2 9.92 25.06 20.00 36.44 26.42 1.96 4.98 20.12 21.92 OK 3 9.92 25.00 19.96 36.84 27.06 2.00 5.06 20.22 20.22 OK 4 9.92 25.12 19.92 37.14 27.42 1.96 5.08 20.16 21.94 OK 5 9.98 24.96 20.02 36.46 26.66 1.96 5.00 20.14 22.46 OK 6 9.92 25.96 20.12 36.80 27.28 1.96 5.04 20.08 21.94 OK 7 9.98 25.04 19.98 36.78 26.58 2.00 4.94 20.16 22.06 OK 8 9.94 25.10 20.12 36.18 26.64 1.96 5.02 20.22 22.02 OK NOTE: The Mesh dimension is ensured during manufacturing & are within the USP specified limit.

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VALIDATION OF STANDARD ACCESSORIES (USP) Apparatus 2: Paddle Stirring Element Dimension Dim A Dim Dim Dim Dim Remarks B C D G USP 9.40 42.0 74.00 19.0 4.00 Limits 10.10 mm 0.50 1.00 mm 75.00 mm mm before mm coating Basket No Measured Value 1 9.94 42.12 74.34 18.98 3.98 OK 2 9.92 42.04 74.42 18.94 4.02 OK 3 9.98 42.28 74.38 18.92 4.04 OK 4 9.94 42.12 74.28 18.92 3.98 OK 5 9.92 42.22 74.42 18.94 4.00 OK 6 10.00 42.56 74.38 18.92 4.04 OK 7 10.00 42.42 74.40 18.94 4.00 OK 8 9.94 42.42 74.28 18.94 3.98 OK NOTE: The Mesh dimensions E,F and H are ensured during manufacturing and are within the USP specified limits. Tolerances are 1.00 mm unless otherwise stated. X & Y dimensions are not to vary more than 0.5 mm when part is rotated on centre line axix. Shaft and Blade material: 303 (or equivalent) stainless steel.

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Performance Calibration: RPM checking:Check the range setting from 30 to 200 RPM attaching all the paddles/ baskets in all vessels with the help of traceable tachometer. Check the range setting from 30-40 (o) C . Fill the jars with water and place them in bath. Check the temperature inside the bath with traceable thermometer with 0.1(o) C resolution (room temp.). Set the temp. to 37.0 (O)C . Verify the temp. in all vessels. Calibrate the instrument with the help of USP reference dissolution calibrator (USP prednisone tablets RS (disintegrating) & USP salicylic acid tablets RS (nondisintegrating). Verify the results with claim value of calibrator. Temperature checking:

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2.7. Laboratory Oven Procedure: Switch on the instrument. Ensure that the temperature indicator/controller is in working condition i.e. the set temperature should be maintained/retained properly. Ensure that the door of laboratory oven is properly closed and does not loosen during operation. Calibration: Ascertain and set the points at which calibration is required. Switch on the laboratory oven and allow it to reach the set point temperature. Insert the sensor of the reference/calibrator sensor (PRT) in the laboratory oven as near as possible to the sensing tip or sensor of the temperature controller/indicator of the laboratory oven. When the temperature is stable note down the temperature reading as indicated by on the laboratory oven and the reference indicator simultaneously. Take at least three to four readings for better accuracy and reproducibility. Set the next point and record the temperature readings accordingly. Correlate the readings observed with the reference standards and apply corrections, if necessary. Calibration Frequency- 12 months* (* reference: NABL doc 103, Pg. 43 / 88./NATA. Insert the sensor of the reference/calibrator sensor (PRT) in the laboratory oven as near as possible to the sensing tip or sensor of the temperature controller/indicator of the laboratory oven. When the temperature is stable note down the temperature reading as indicated by on the laboratory oven and the reference indicator simultaneously. Take at least three to four readings for better accuracy and reproducibility. Set the next point and record the temperature readings accordingly. Correlate the readings observed with the reference standards and apply corrections, if necessary. Calibration Frequency- 12 months* (* reference: NABL doc 103, Pg. 43 / 88./NATA. 2.8. pH meter Requirements: Reference buffer solutions of pH 4.0,7.0 and 10.0 Calibrated Voltmeter (multimeter) Procedure. 93

 As per SOP set the instrument at pH 4.0,7.0&10.0 using Reference buffer solutions. Check the electrode for its milli-volts output and compare with the initial one Calibration frequency Every time for pH performance Six month for electrode performance 2.9. Karl Fischer Apparatus/ Auto Titrator: Requirements: Calibrated cylinder of 10 ml capacity. Calibrated Voltmeter(multimeter) Procedure: As per SOP set the instrument and check for liquid delivery system. Check the electrode for its millivolts output and compare with initial one/manufacturers specification. Calibration frequency: Depends on type of instrument and extent of use. Six month for electrode performance. 2.10. Gas Chromatography (GLC) Requirements : Auto sampler Mechanical & functional testing. Gas flow verification Calibrated gas flow meter. Temperature Verification- Heated zone -Oven, Injector and detector using calibrated PRT. Detector response. - Run the instrument using chromatographic condition supplied with CRM and checked the sensitivity of detector (in use) & calculate RSD of min 10 injections. (< 2.0) %) 2.11. HPLC STSTEMS: CALIBRATION OF PUMP Pressure pulsation Compositional Accuracy Mobile Phase A Mobile phase B Detector set at set 1000psi +-20 - (for binary system - water - Acetone -265nm.

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1. 2. 3. 4. 5.

A-100 % A-00% A-10 % A-50% A-90 %

B-0% B-100 % B- 90% B-50 % B- 10%

no AU 496.0 AU 446.0AU 248 AU 49.6AU

Run the instruments using the following ratio of mobile phase and records the absorbance Flow accuracy. Fill the reservoir with filtered and degassed methanol. Set the pump to various flow rates and check the actual flow rates with which the mobile phase is delivered (table 1) S.No 1 2 3 4 Set flow rate 1ml/min 1ml/min 2ml/min 2ml/min Run time 5 min 10 min 5 min 10 min Actual volume 5ml 10 ml 10 ml 20 ml Tolerance 0.5% 0.5% 0.5% 0.5%

Detector evaluation: Wavelength verification: Set the system with following parameters Column C18 25cmX4.6mm, 5 micron Detector UV Flow rate- 1ml/min Mobile phase- 10ppm dilution of caffeine CRM in water. Connect outlet of pump directly into inlet of detector. set at 205 run the inst.after 5 min. absorbance 0.9-1.3 AU. Wavelength accuracy .cont. the instrument in the range 200 to 300nm. Maxima must occur at 205 and 273nm ISO/IEC 17025:2005

Author: Dr. R A Singh, Director, Regional Drugs Testing Laboratory (RDTL), Chandigarh. Email: directorrdtlchd@yahoo.com

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