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  1. 1. International Council for Harmonization (ICH) Roshan Gomaji Bodhe SVPM’S College of pharmacy Baramati
  2. 2. Organisational Changes: The International Council for Harmonisation (ICH), formerly the International Conference on Harmonisation (ICH) ICH announces organisation changes as it marks 25 year of successful harmonisation.  
  3. 3. • The ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry.
  4. 4. • • Mission ICH’s mission is to make recommendations towards achieving greater harmonisation in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during the research and development of new human medicines.
  5. 5. Contd.. ICH's mission is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.
  6. 6. • ICH is a joint initiative involving both regulators and research-based industry representatives of the EU, Japan and the US in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.
  7. 7. History • • • Harmonization of regulatory authority requirement was pioneered by the European community in the 1980. The EC moved towards the development of a single marketed for pharmaceuticals the success achieved in Europe demonstrated the harmonization was feasible. At the same time there were Internal discussion between Europe, Japan and US on possibilities for the harmonization.
  8. 8. Cont.. • • • The birth of ICH took place at a meeting in April 1990. The ICH steering committee was established at the meeting has since met at least twice a year with the location rotatory between the three region. The ICH process was first drawn up at the steering committee meeting in Washington march 1992 and amended in Tokyo sep. 1992.
  9. 9. Objectives • • • • • • To achieve greater harmonization in the interpretation and application of technical guideline. Requirement for the product registration. To reduce or obviate the need to duplicate the testing carried out during the research and development of new medicine. To maintain a forum for a constructive dialogue b/w regulatory authorities and the pharmaceutical industries on the real and perceived difference in the technical requirement for product registration in Europe, USA and Japan. To contribute to the protection of public health from international perspective. To maintain and update harmonized technical requirement leading to a grater mutual acceptance of research and development data.
  10. 10. Cont… • • • To avoid divergent future requirement through harmonization of selected topic needed as result of therapeutic advances and the development of new technologies for the production of medicinal products. To facilitate the adoption of new of improved technical research and development approaches which updates or replace current practices. To facilitate the dissemination and communication of information on harmonized guidelines and their use such as to encourage the implementation and integration of common standards.
  11. 11. MEMBERSHIP • • • Current Members and Observers As of June 2016, the ICH Association comprises the following Members and Observers Founding Regulatory Members The European Commission (EC) The US Food and Drug Administration (FDA) The Ministry of Health, Labour and Welfare of Japan (MHLW) also represented by the Pharmaceuticals and Medical Devices Agency (PMDA)
  12. 12. • • • Founding Industry Members The European Federation of Pharmaceutical Industries and Associations (EFPIA) The Japan Pharmaceutical Manufacturers Association (JPMA) The Pharmaceutical Research and Manufacturers of America (PhRMA)
  13. 13. • • • • • • Standing Regulatory Members The Health Canada The Swiss medic Industry Members The International Generic and Biosimilar Medicines Association (IGBA) The World Self-Medication Industry (WSMI) Standing Observers The International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) The World Health Organisation (WHO)  
  14. 14. • • • • • • • • • • Observers Legislative or Administrative Authorities The Agência Nacional de Vigilância Sanitária (ANVISA, Brazil) The Central Drugs Standard Control Organization (CDSCO, India) The Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS, Mexico) The Health Sciences Authority (HSA, Singapore) The Ministry of Food and Drug Safety (MFDS, South Korea) The Roszdravnadzor (Russia) The Food and Drug Administration (TFDA, Chinese Taipei) The Therapeutic Goods Administration (TGA, Australia)  
  15. 15. • • • • • • Regional Harmonisation Initiatives (RHIs) The Asia-Pacific Economic Cooperation (APEC) The Association of Southeast Asian Nations (ASEAN) The East African Community (EAC) The Gulf Cooperation Council (GCC) The Pan American Network for Drug Regulatory Harmonization (PANDRH) The Southern African Development Community (SADC)
  16. 16. • • • • • International Pharmaceutical Industry Organisations The Biotechnology Innovation Organisation (BIO) International Organisations with an Interest in Pharmaceuticals The Council for International Organizations of Medical Sciences (CIOMS) The European Directorate for the Quality of Medicines & HealthCare (EDQM) The International Pharmaceutical Excipient Council (IPEC) The United States Pharmacopeia (USP)
  17. 17. Steps in the ICH Process • • • • • 1. Consensus building 2. Start of regulatory action 3. Regulatory consolation 4. Adoption of a triplicate harmonized text 5.Implementation
  18. 18. 1. Consensus building • • The rapporteur prepare an initial draft of a guidelines based on the objective in the concept paper, and in consultation with expert designated to the EWG. The initial draft and successive revision are circulated for comment interim reports are made to each meeting to the ICH steering committee if consensus is reached within the agreed time table with consensus text with EWG signature is submitted to the steering committee for adaptation as step to of ICH.
  19. 19. 2. Start of regulatory action • Step is to reach when steering committee agrees, on the basis report from expert working groups that there is sufficient scientific consensus on the technical issues, for the draft guidelines to proceed to next stages regularity consolation. This agreement is conformed by steering committee members.
  20. 20. 3. Regulatory consolation • • • • At this stage embodying the scientist consensus leaves the ICH process, become the subject of normal wide ranging regulatory consolation in the three region. In the EU it is published as a draft CPMP guidelines . In the USA it is published as a draft guidance. Japan it is translated and issued by MHLW for internal and external consulation.
  21. 21. 4. Adoption of a triplicate harmonized text • • At step four the topic returns to ICH forum where the steering committee receive a report from the regulatory rapporteur. If both regulatory and industry parties are satisfied that the consensus achieved at step two is not substantially altered as a result of consultation. The text is adapted by steering committee.
  22. 22. 5.Implementation • • Having reached step four the tripartite harmonized text moves immediately to final step of the process which is regulatory implementation. This is carried according to same national/ regional procedure that applied to other regulatory guidelines and requirement in the EU, Japan and USA.
  23. 23. ICH GUIDELINES • The ICH topics are divided into four categories and ICH topic codes are assigned according to these categories. Quality guidelines Safety guidelines Efficacy guidelines Multi disciplinary guidelines
  24. 24. Quality Guidelines • Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management.
  25. 25. Safety Guidelines • ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years.
  26. 26. Efficacy guidelines • The work carried out by ICH under the Efficacy heading is concerned with the design, conduct, safety and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better targeted medicines.
  27. 27. Multidisciplinary Guidelines • Those are the cross-cutting topics which do not fit uniquely into one of the Quality, Safety and Efficacy categories. It includes the ICH medical terminology (MedDRA), the Common Technical Document (CTD) and the development of Electronic Standards for the Transfer of Regulatory Information (ESTRI).
  28. 28. Related to mfg. QA Non clinical pharmacology & toxicology studies Clinical safety, dose response studies, good clinical practices , clinical evaluation Medical terminology, electronic standards for transmission of regulatory information etc. Summary:
  30. 30. Safety Guidelines S A F E T Y
  31. 31. Efficacy Guidelines E f F I c a c y
  32. 32. Multidisciplinary Guidelines
  33. 33. uality guidelines
  34. 34. • • Guideline Q1A is the parent guideline that provides considerable details on how to conduct stability studies for drug substances and drug products. This guideline is designed to provide detailed requirements for registration stability programs but since it is frequently used as a basis for designing many other types of stability study, it is proposed in this module to conduct a detailed review with interpretations of many of its provisions. In addition, comparisons with some other non ICH guidelines will be provided. History
  35. 35. • This Guideline provides recommendations on stability testing protocols including temperature, humidity and trial duration for climatic Zone I and II. Furthermore, the revised document takes into account the requirements for stability testing in Climatic Zones III and IV in order to minimise the different storage conditions for submission of a global dossier.
  36. 36.   The ICH Q1 topic on stability testing is covered by 5 separate guidelines The ICH Q1 series of guidelines are designed for stability programs 41
  37. 37. Climatic Zone Definition Storage Conditions I Temperate climate 21°C / 45% RH II Subtropical and Mediterranean climate 25°C / 60% RH III Hot, dry climate 30°C / 35% RH IV Hot, humid climate 30°C / 70% RH Classification of Climatic Zones    Criteria used to classify a site according to climatic zone Mean annual temperature measured in the open air Calculated mean annual Temperature (< 19°C) Mean annual Water vapour partial pressure
  38. 38. I II III IV Europe: EU, Belarus, Bulgaria, Estonia, Hungary, Latvia, Lithuania, Norway, Rumania, Russia, Switzerland, Ukraine America: USA, Argentina, Bolivia, Chile, Canada, Mexico, Peru, Uruguay Africa: Egypt, Algeria, Canary Islands, Libya, Morocco, Namibia, Rwanda, South Africa, Tunisia, Zambia, Zimbabwe Asia: Japan, Afghanistan, Armenia, Azerbaijan, China, Georgia, Iran, Israel, Kazakhstan, Kirghizia, Korea, Lebanon, Nepal, Syria, Tadzhikistan, Turkey, Turkmen, Uzbekistan, Australia, New Zealand. America: Barbados,Brazil, Costarica, Dominican Republic, Equador, Salvador, Guatmela, Haiti, Handures, Jamaica, Columbia, Cuba, Dutch, Antiles, Panama, Paragua. Africa: Angola, Ethiopia, Benin, Cameron, Kenya, Liberia, Congo, Madagascar, Mahwi, Mali, Mayrtiania, Mozambique, Niger, Somalia, Sudan, Tanzania, Uganda, Zaire, Central African Republic. Asia: Behrain, Bangladesh, Hongkong, India, Indonesia, Iraq, Jordan, Kambechev, Quatar, Kuwait, Malaysia, Maldives, Myanmar, UAE, Oman, Yemen. Australian oceanic: Fisi, Society Island, Marshal Island, Piping New Guinea. Countries which come under different climate zones
  39. 39. The following definitions are provided to facilitate interpretation of the guideline: Accelerated testing Studies: Designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Climatic zones The four zones in the world that are distinguished by their characteristic prevalent annual climatic conditions. This is based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202, 1985 and 29:39-47, 1986). Drug substance The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form.
  40. 40. Drug product The dosage form in the final immediate packaging intended for marketing Excipient Anything other than the drug substance in the dosage form. Expiration date The date placed on the container label of a drug product designating the time prior to which a batch of the product is expected to remain within the approved shelf life specification if stored under defined conditions, and after which it must not be used.
  41. 41. Re-test date The date after which samples of an API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given FPP. Shelf life (expiration dating period, conformance period) The time period during which an API or a FPP is expected to remain within the approved shelf-life specification, provided that it is stored under the conditions defined on the container label.
  42. 42.    Formal stability studies Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP. Stress testing – forced degradation (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress testing – forced degradation (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.
  43. 43. STABILITY PROTOCOL AND REPORT           Batches tested General information Container/closure system Literature and supporting data Stability-indicating analytical methods Testing plan Test parameters Test results Other requirements (post-approval commitments) Conclusions Result sheets must bear date and responsible person signature / QA approval
  44. 44. GUIDELINES FOR “DRUG SUBSTANCES” • • • • • • • • • • General Stress Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labeling
  45. 45. GUIDELINES FOR “DRUG PRODUCT” • • • • • • • • • • General Photo stability Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labeling
  46. 46. ILLUSTRATIVE DATA OF API STABILITY BATCHES Batch number Date of manufacture Site of manufacture Batch size (kg) Primary packing materials Date of initial analysis The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.
  47. 47. ILLUSTRATIVE DATA OF CAPSULE/TABLET STABILITY BATCHES Batch number Date of manufacture Site of manufacture Batch size (kg) Batch size (number of units) Primary packing materials Date of initial analysis Batch number of the API The batches should be representative of the manufacturing process and should be manufactured from different batches of APIs.
  48. 48. Bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. BRACKETING Design Factors Design factors are variables (e.g., strength, container size and/or fill) to be evaluated in a study design for their effect on product stability
  49. 49. Design Example Example is based on a product available in three strengths and three container sizes. In this example, it should be demonstrated that the 15 ml and 500 ml high- density polyethylene container sizes truly represent the extremes. The batches for each selected combination should be tested at each time point as in a full design
  50. 50. MATRIXING Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point.    Each storage condition should be treated separately under its own matrixing design At a given time point (other than the initial or final ones) not every batch on stability needs to be tested Full testing must be performed at the maximum storage period at the time of submission
  53. 53. STRESS TESTING IN API Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathways. Stress testing may be carried out on a single batch of the API. It should include the effect of temperature, humidity.
  54. 54. FORMAL STABILITY STUDIES In general an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its 91 sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage and shipment. Type of study Storage condition Minimum time period covered by data at submission Long term 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 Months Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 Months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 Months
  55. 55. STABILITY RESULTS    A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API. A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label. An API is considered as stable if it is within the defined/ regulatory specifications when stored at 30±2oC and 65±5% RH for 2 years and at 40±2oC and 75±5%RH for 6 months.
  56. 56. POTENTIAL INSTABILITY ISSUES OF FPPS         Loss/increase in concentration of API Formation of (toxic) degradation products Modification of any attribute of functional relevance Alteration of dissolution time/profile or bioavailability Decline of microbiological status Loss of package integrity Reduction of label quality Loss of pharmaceutical elegance and patient acceptability
  57. 57. STABILITY-INDICATING QUALITY PARAMETERS Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets: appearance hardness friability moisture content dissolution time degradants assay microbial purity
  58. 58. STRESS TESTING OF FPPS Storage conditions Testing 40°C, 75 % RH; open storage** 3 months 50-60 °C, ambient RH; open storage 3 months Photostability according to ICH * 3 months or 5-15% degradation, whatever comes first ** For API1-API2, or API-excipient, or FPP without packing material, typically a thin layer of material is spread in a Petri dish. Open storage is recommended, if possible.
  59. 59. SELECTION OF BATCHES    At the time of submission data from stability studies should be provided for batches of the same formulation and dosage form in the container closure system proposed for marketing. Stability data on three primary batches are to be provided. The composition, batch size, batch number and manufacturing date of each of the stability batches should be documented and the certificate of analysis at batch release should be attached. Where possible, batches of the FPP should be manufactured by using different batches of the API.
  60. 60. TESTS AT ELEVATED TEMPERATURE AND/OR EXTREMES OF HUMIDITY (ICH-Q1F)   Special transportation and climatic conditions outside the storage conditions recommended in this guideline should be supported by additional data. For example, these data can be obtained from studies on one batch of drug product conducted for up to 3 months at 50°C/ambient humidity to cover extremely hot and dry conditions and at 25°C/80% RH to cover extremely high humidity conditions. Stability testing at a high humidity condition, e.g., 25°C/80% RH, is recommended for solid dosage forms in water-vapour permeable packaging, e.g., tablets in PVC/aluminum blisters, intended to be marketed in territories with extremely high humidity conditions in Zone IV. However, for solid dosage forms in primary containers designed to provide a barrier to water vapour, e.g. aluminum/ aluminum blisters, stability testing at a storage condition of extremely high humidity is not considered necessary.
  61. 61. 2018/1/9 66 EVALUATION    A systematic approach should be adopted in the presentation and evaluation of the stability information. Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient. An approach for analysing data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the (lower) acceptance criterion (95% assay).
  62. 62. 1. 2. 3. 4. 5. No significant change at accelerated conditions within six (6) months. Long-term data show little or no variability and little or no change over time. Accelerated data show little or no variability and little or no change over time. Statistical analysis is normally unnecessary. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data EVALUATION – BEST CASE
  63. 63. VARIATIONS Once the FPP has been registered, additional stability studies are required whenever variations that may affect the stability of the API or FPP are made, such as major variations The following are examples of such changes: — change in the manufacturing process; — change in the composition of the FPP; — change of the immediate packaging; — change in the manufacturing process of an API.
  64. 64.    ONGOING STABILITY STUDIES The purpose of the ongoing stability programme is to monitor the API and to determine that the API /FPP remains, and can be expected to remain, within specifications under the storage conditions indicated on the label, within the re-test period in all future batches. This mainly applies to the FPP in the container closure system in which it is supplied, but consideration should also be given to inclusion in the programme of bulk products. The number of batches and frequency of testing should provide suffi cient data to allow for trend analysis. Unless otherwise justifi ed, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year).
  65. 65.     Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. The shelf life (expiry date) of FPPs is derived from formal stability studies. Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date. CONCLUSION
  67. 67. This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state.
  68. 68. The following types of drug substances are not covered in this guideline: Biological / biotechnological, peptide, oligonucleotide, radiopharmaceutical, fermentation product and semi-synthetic products derived there from, herbal products, and crude products of animal or plant origin.
  69. 69. • • • • Impurities in new drug substances are addressed from two perspectives: Chemistry Aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures; and Safety Aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies.
  70. 70. • • • CLASSIFICATION OF IMPURITIES Impurities can be classified into the following categories: Organic impurities (process- and drug-related) Inorganic impurities Residual solvents
  71. 71. • • • • • Organic impurities can arise during the manufacturing process and/or storage of the new drug substance. They can be identified or unidentified, volatile or non-volatile, and include: Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts
  72. 72. • • • • Inorganic impurities can result from the manufacturing process. They are normally known and identified and include: Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal)
  73. 73. Solvents are inorganic or organic liquids used as vehicles for the preparation of solutions or suspensions in the synthesis of a new drug substance. Since these are Impurities in New Drug Substances generally of known toxicity, the selection of appropriate controls is easily accomplished (see ICH Guideline Q3C on Residual Solvents).
  74. 74. RATIONALE FOR THE REPORTING AND CONTROL OF IMPURITIES Organic Impurities: The applicant should summarize the actual and potential impurities most likely to rise during the synthesis, purification, and storage of the new drug substance. The applicant should summaries the laboratory studies conducted to detect impurities in the new drug substance. The studies conducted to characterize the structure of actual impurities present in the new drug substance at a level greater than (>) the identification threshold.
  75. 75. • Where attempts have been made to identify impurities present at levels of not more than (≤) the identification thresholds, it is useful also to report the results of these studies. Inorganic Impurities Inorganic impurities are normally detected and quantified using pharmacopoeial or other appropriate procedures.
  76. 76. • Solvents: As per ICH Q3C Guideline for Residual Solvents
  77. 77. ANALYTICAL PROCEDURES • Analytical procedures are validated and suitable for the detection and quantification of impurities (see ICH Q2A and Q2B Guidelines for Analytical Validation). The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold. Reference standards used in the analytical procedures for control of impurities should be evaluated and characterized according to their intended uses.
  78. 78. REPORTING IMPURITY CONTENT OF BATCHES • • • • • • • For each batch of the new drug substance, the report should include: Batch identity and size Date of manufacture Site of manufacture Manufacturing process Impurity content, individual and total Use of batches Reference to analytical procedure used
  79. 79. • Any impurity at a level greater than (>) the reporting threshold and total impurities observed in these batches of the new drug substance should be reported with the analytical procedures indicated. Below 1.0%, the results should be reported to two decimal places (e.g., 0.06%, 0.13%); at and above 1.0%, the results should be reported to one decimal place (e.g., 1.3%).
  80. 80. LISTING OF IMPURITIES IN SPECIFICATIONS • The specification for a new drug substance should include a list of impurities. Those individual impurities with specific acceptance criteria included in the specification for the new drug substance are referred to as " specified impurities" in this guideline. Specified impurities can be identified or unidentified.
  81. 81. • • • • • • • In summary, the new drug substance specification should include, where applicable, the following list of impurities: Organic Impurities Each specified identified impurity Each specified unidentified impurity Any unspecified impurity with an acceptance criterion of not more than (≤) the identification threshold Total impurities Residual Solvents Inorganic Impurities
  82. 82. QUALIFICATION OF IMPURITIES • • Qualification is the process of acquiring and evaluating data that establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified. The applicant should provide a rationale for establishing impurity. The "Decision Tree” for Identification and Qualification" describes considerations for the qualification of impurities when thresholds are exceeded.
  83. 83. • Threshold
  84. 84. Decision Tree
  86. 86. Introduction Objective of the guideline: This document provides guidance for registration applications on the content and qualification of impurities in new drug products This guideline is complementary to the ICH Q3A(R) guideline “Impurities in New Drug Substances”, which should be consulted for basic principles.
  87. 87. Introduction • Scope of the guideline: This guideline addresses only those impurities in new drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system (collectively referred to as “degradation products” in this guideline).
  88. 88. 2. RATIONALE FOR THE REPORTING AND CONTROL OF DEGRADATION PRODUCTS • • The applicant should summaries the degradation products observed during manufacture and/or stability studies of the new drug product. Any degradation product observed in stability studies conducted at the recommended storage condition should be identified when present at a level greater than (>) the identification thresholds.
  89. 89. • • Degradation products present at a level of not more than (≤) the identification threshold generally would not need to be identified. However, analytical procedures Degradation products present at a level of not more than (≤) the identification
  90. 90. ANALYTICAL PROCEDURES • • The registration application should include documented evidence that the analytical procedures have been validated and are suitable for the detection and quantitation of degradation products (ICH Q2A and Q2B guidelines on analytical validation). The quantitation limit for the analytical procedure should be not more than (≤) the reporting threshold.
  91. 91. • Reference standards used in the analytical procedures for control of degradation products should be evaluated and characterised according to their intended uses. The drug substance can be used to estimate the levels of degradation products.
  92. 92. REPORTING DEGRADATION PRODUCTS CONTENT OF BATCHES           For each batch of the new drug product described in the registration application, the documentation should include: Batch identity, strength, and size Date of manufacture Site of manufacture Manufacturing process Immediate container closure Degradation product content, individual and total Use of batch (e.g., clinical studies, stability studies) Reference to analytical procedure used Batch number of the drug substance used in the new drug product Storage conditions for stability studies
  93. 93. LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS • • The specification for a new drug product should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions. In this guideline, the use of two decimal places for thresholds does not necessarily indicate the precision of the accept degradation products and total degradation products.
  94. 94. • • • • In summary, the new drug product specification should include, where applicable, the following list of degradation products: Each specified identified degradation product Each specified unidentified degradation product Any unspecified degradation product with an acceptance criterion of not more than (=) the identification threshold. Total degradation products.
  95. 95. QUALIFICATION OF DEGRADATION PRODUCTS The level of any degradation product present in a new drug product that has been adequately tested in safety and/or clinical studies would be considered qualified.
  96. 96. • The "Decision Tree for Identification and Qualification of a Degradation Product“ describes considerations for the qualification of degradation products when thresholds are exceeded.
  97. 97. • Threshold
  100. 100. PART I • • • • • • • • • 1.INTRODUCTION 2.SCOPE OF THE GUIDELINE 3.GENERAL PRINCIPLES Classification of Residual Solvents by Risk Assessment Methods for Establishing Exposure Limits Options for Describing Limits of Class 2 Solvents Analytical Procedures Reporting levels of residual solvents 4. LIMITS of RESIDUAL SOLVENTS Solvents to Be Avoided Solvents to Be Limited Solvents with Low Toxic Potential Solvents for which No Adequate Toxicological Data was Found
  101. 101. • • • • 4.1 Solvents to Be Avoided 4.2 Solvents to Be Limited 4.3 Solvents with Low Toxic Potential 4.4 Solvents for which No Adequate Toxicological Data was Found
  102. 102. • • • • • • GLOSSARY APPENDIX 1. LIST OF SOLVENTS INCLUDED IN THE GUIDELINE APPENDIX 2. ADDITIONAL BACKGROUND 2.1 Environmental Regulation of Organic Volatile Solvents. 2.2 Residual Solvents in Pharmaceuticals APPENDIX 3. METHODS FOR ESTABLISHING EXPOSURE LIMITS
  104. 104. • • Objective: The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents.
  105. 105. SCOPE OF THE GUIDELINE • • • Residual solvents in drug substances, excipients, and in drug products are within the scope of this guideline. Therefore, testing should be performed for residual solvents when production or purification processes are known to result in the presence of such solvents. If the calculation results in a level Impurities is equal to or below that recommended in this guideline, no testing of the drug product for residual solvents need be considered. If, however, the calculated level is above the recommended level, the drug product should be tested to ascertain whether the formulation process has reduced the relevant solvent level to within the acceptable amount.
  106. 106. • This guideline does not apply to potential new drug substances, excipients, or drug products used during the clinical research stages of development, nor does it apply to existing marketed drug products.
  107. 107. • The guideline applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in certain cases such as short term (30 days or less) or topical application. Justification for these levels should be made on a case by case basis. * Appendix 2 for additional background information related to residual solvents
  108. 108. General Principle Classification of Residual Solvents by Risk Assessment: The term "tolerable daily intake" (TDI) is used by the International Program on Chemical Safety (IPCS) to describe exposure limits of toxic chemicals and "acceptable daily intake" (ADI) is used by the World Health Organization (WHO) and other national and international health authorities and institutes. The new term "permitted daily exposure" (PDE) is defined in the present guideline as a pharmaceutically acceptable intake of residual solvents to avoid confusion of differing values for ADI's of the same substance.
  109. 109. • • Residual solvents assessed in this guideline are listed in Appendix 1 by common names and structures. Three classes as follows: Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards. Class 2 solvents: Solvents to be limited Non-genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity. Solvents suspected of other significant but reversible toxicities.
  110. 110. • Class 3 solvents: Solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 sol.vents have PDEs of 50 mg or more per day
  111. 111. Methods for Establishing Exposure Limits In Appendix 3. Summaries of the toxicity data that were used to establish limits are published in Pharmeuropa, Vol. 9, No. 1, Supplement, April 1997.
  112. 112. • • • • Options for Describing Limits of Class 2 Solvents Two options are available when setting limits for Class 2 solvents. Option 1: The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1) below by assuming a product mass of 10 g administered daily. Concentration (ppm)= 1000 x PDE dose / Dose Here, PDE is given in terms of mg/day and dose is given in g/day.
  113. 113. • • Option 2: It is not considered necessary for each component of the drug product to comply with the limits given in Option 1. May be applied by adding the amounts of a residual solvent present in each of the components of the drug product. The sum of the amounts of solvent per day should be less than that given by the PDE.
  114. 114. Analytical Procedures • • Residual solvents are typically determined using chromatographic techniques such as gas chromatography. Any harmonised procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible. Otherwise, manufacturers would be free to select the most appropriate validated analytical procedure for a particular application. If only Class 3 solvents are present, a nonspecific method such as loss on drying may be used.
  115. 115. • Validation of methods for residual solvents should conform to ICH guidelines Text on Validation of Analytical Procedures and Extension of the ICH Text on Validation of Analytical Procedures.
  116. 116. Reporting levels of residual solvents Manufacturers of pharmaceutical products need certain information about the content of residual solvents in excipients or drug substances in order to meet the criteria of this guideline. The supplier might choose one of the following as appropriate: Only Class 3 solvents are likely to be present. Loss on drying is less than 0.5%. Only Class 2 solvents X, Y, ... are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, ...) Only Class 2 solvents X, Y, ... and Class 3 solvents are likely to be present. Residual Class 2 solvents are below the Option 1 limit and residual Class 3 solvents are below 0.5%.
  117. 117. • • • If Class 1 solvents are likely to be present, they should be identified and quantified. "Likely to be present" refers to the solvent used in the final manufacturing step and to solvents that are used in earlier manufacturing steps and not removed consistently by a validated process. If solvents of Class 2 or Class 3 are present at greater than their Option 1 limits or 0.5%, respectively, they should be identified and quantified.
  118. 118. LIMITS OF RESIDUAL SOLVENTS • • • • Solvents to Be Avoided (Table 1) Solvents to Be Limited (Table 2) Solvents with Low Toxic Potential (Table 3) Solvents for which No Adequate Toxicological Data was Found (Table 4)