regulatory requirement in pharmaceutical analysis as per ICH

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REGULATORY REQUIREMENT IN PHARMACEUTICAL ANALYSIS (AS PER ICH) Prepared By: Bindiya Jadeja M.Pharm Sem. II Q.A department S.J Thakkar College Of Pharmacy Opp. NRI Bungalows , Rajkot “Education is the Chief Defense of the Nation” 1 Guided by : Dr. Rina H Gokani Associate professor

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Content: : 

Content: Introduction Objectives ICH guideline ICH documentation Quality guideline Safety guideline Efficacy guideline Multidisciplinary guideline 3

Introduction : 

Introduction Regulatory requirements are part of the process of drug discovery and drug development. Regulatory requirements describe what is necessary for a new drug to be approved for marketing in any particular country. International Conference on Harmonization (ICH) was created in 1990. The first Conference was held in Brussels in 1991, followed by ICH 4

Objectives : 

Objectives Identification and elimination of the need to duplicate studies to meet different regulatory requirements Better consumer information. Post marketing safety. Aim to produce a single set of technical requirements for the registration of new drug products to streamline development 5

ICH Guideline : 

ICH Guideline 6

ICH Quality -Documents : 

ICH Quality -Documents Q1 Stability Q2 Analytical Validation Q3 Impurities Q4 Pharmacopoeias Q5 Quality of Biotechnological Products Q6 Specifications Q7 Good Manufacturing Practice Q8 Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality Systems 7

Q-1 Stability testing of new drug substances and products : 

Q-1 Stability testing of new drug substances and products First published in Sept-1994 and revised in August 2001. To provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors. 8

ICH Stability Zone : 

ICH Stability Zone Zone Type of climate Zone I Temperate zone Zone II Mediterranean/subtropical zone Zone III Hot dry zone Zone IV Hot humid/tropical zone Zone IV(b) Hot/higher humidity 9

Storage condition in stability : 

Storage condition in stability 10 Drug substances intended for storage in a Refrigerator.

Stability Guidance : 

Stability Guidance General: Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. Stress Testing: Identify the likely degradation products. It include. the effect of temperatures (50°C, 60°C) humidity Selection of Batches: Data from formal stability studies should be provided on at least three primary batches of the drug substance. 11

Stability Guidance : 

Container Closure System: The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. Specification: Specification, which is a list of tests, references to analytical procedures, and proposed acceptance criteria. 12 Stability Guidance

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Stability Commitment: When available long term stability data on primary batches do not cover the proposed re-test period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re-test period. Evaluation: The purpose of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (including, results of the physical, chemical, biological, and microbiological tests) . 13

Q-2 Analytical validation : 

Q-2 Analytical validation Specificity Linearity Range Accuracy Precision Limit of Detection Limit of Quantization 14

Q-3 Impurities : 

Q-3 Impurities Qualification: The process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the level(s) specified. Qualification Threshold: A limit above (>) which a degradation product should be qualified. Identification Threshold: A limit above (>) which an impurity should be identified. Specified Impurity: Individually listed and limited with a specific acceptance criterion in the new drug substance specification. Unspecified Impurity: general acceptance criterion, but not individually listed with its own specific acceptance criterion, in the new drug substance specification. 15

Classification : 

Classification 16 Impurity Inorganic Solvent Organic Arise during the manufacturing process and/or storage of the new drug substance. include: Starting materials By-products Intermediates Degradation products Reagents, ligands and catalysts Result from the manufacturing process. include: Reagents, ligands and catalysts Heavy metals or other residual metals Inorganic salts Other materials (e.g., filter aids, charcoal Class 1 solvents: Solvents to be avoided Known human carcinogens and environmental hazards. Class 2 solvents: Solvents to be limited Non- Genotoxicity animal carcinogens. Class 3 solvents: Solvents with low toxic potential.

Impurity : 

Impurity Impurities are found in API’s unless, a proper care is taken in every step involved throughout the multi-step synthesis. In synthetic organic chemistry, getting a single end product with 100% yield is very rare; there is always a chance of having by-products. 17

Decision tree for Identification and Qualification. : 

Decision tree for Identification and Qualification. 18

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Q – 4 Pharmacopoeias : 

Q – 4 Pharmacopoeias These are the three relevant topics that appear on the ICH website Q4 Pharmacopoeias Q4A Pharmacopoeial Harmonisation Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC) PDG – The three-party Pharmacopoeial Discussion Group, comprised of representatives from the European Directorate for the Quality of Medicines in the Council of Europe; the Ministry of Health, Labour and Welfare, and the United States Pharmacopoeial Convention, Inc. Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC) – Acceptance by the ICH member regulatory authorities of APAC that have been evaluated by Q4B. 20

Q-5 Quality of Biotechnological Products : 

Q-5 Quality of Biotechnological Products This document presents guidance regarding the characterisation of the expression construct for the production of recombinant DNA protein products in eukaryotic and prokaryotic cells. monoclonal Ab. : Antiasthmatic – Omalizumab White biotechnology: It is also known as industrial biotechnology. 21

Q-6 Specifications : 

Q-6 Specifications A specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria. It establishes the set of criteria under which a new drug substance or new drug product should acceptable for its use. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures for new drug substances. 22

Q-7 Good Manufacturing Practice : 

Q-7 Good Manufacturing Practice This document (Guide) is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity that they purpose. 23

Q-8 Pharmaceutical Development : 

Q-8 Pharmaceutical Development The Pharmaceutical Development section provides an opportunity to present the knowledge gained through the quality risk management to the development of a product and its manufacturing process. The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. 24

Q-9 Quality Risk Management : 

Q-9 Quality Risk Management 25 Quality Risk Degree to which a set of inherent properties of a product, system or process fulfills requirements combination of the probability of occurrence of harm and the severity of that harm Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle Management QRM

Q-10 Pharmaceutical Quality Systems : 

Q-10 Pharmaceutical Quality Systems This document establishes a new ICH guideline describing a model for an effective quality management system for the pharmaceutical industry, referred to as the Pharmaceutical Quality System. ICH Q10 demonstrates industry and regulatory authorities’ support of an effective pharmaceutical quality system to enhance the quality and availability of medicines around the world in the interest of public health. 26

ICH Safety - Documents : 

ICH Safety - Documents S1 -Carcinogenicity Studies S2 -Genotoxicity Studies S3 -Toxic kinetics & Pharmacokinetics S4 -Toxicity Testing S5 -Reproductive Toxicology S6 -Biotechnological Products S7 -Pharmacological studies S8 &S9 -Immunotoxicological studies 27

S - 1 Carcinogenicity Studies: : 

S - 1 Carcinogenicity Studies: Identify a tumorigenic potential in animals and to assess the relevant risk in humans. Define the conditions under which carcinogenicity studies, should be conducted. Factors to consider for carcinogenicity testing: Duration and Exposure Cause for Concern Indication and Patient Population Route of Exposure. 28

S-2 Genotoxicity Studies: : 

S-2 Genotoxicity Studies: Genotoxicity tests can be defined as in vitro and in vivo tests designed to detect compounds which induce genetic damage directly or indirectly by various mechanisms. Guidelines for the testing of pharmaceuticals for genetic toxicity have been established in the European Community (1987) and Japan (1989). E.g. Japan laboratory identify insoluble compound. 29

S-3 Toxic kinetics & Pharmacokinetics: : 

S-3 Toxic kinetics & Pharmacokinetics: The primary objective of toxic kinetics is to describe the systemic exposure achieved in animals and its relationship to dose level and the time course of the toxicity study. Secondary objectives are to relate the exposure achieved in toxicity studies to toxicological findings and contribute to the assessment of the relevance of these findings to clinical safety. 30

S-4 Toxicity Testing: : 

S-4 Toxicity Testing: The objective of this guidance is to set out the considerations that apply to chronic toxicity testing in rodents and non rodents as part of the safety evaluation of a medicinal product. For chronic toxicity testing in non-rodents, there were different approaches to the duration of testing. 31

S-5 Reproductive Toxicology: : 

S-5 Reproductive Toxicology: Aim of study is effect of one or more active substance(s) on mammalian reproduction. Investigations and the interpretation of the results should be related to all other pharmacological and toxicological data available to determine whether potential reproductive risks to humans are greater, lesser or equal to those which by other toxicological manifestations. Further, repeated dose toxicity studies can provide important information regarding potential effects on reproduction, particularly male fertility. 32

S-6 Biotechnological Products : 

S-6 Biotechnological Products The primary goals of preclinical safety evaluation are: To identify an initial safe dose and subsequent dose escalation schemes in humans. To identify potential target organs for toxicity and for the study of whether such toxicity is reversible. To identify safety parameters for clinical monitoring. 33

S-7 Pharmacological studies : 

S-7 Pharmacological studies This guideline provides a definition, general principles and recommendations for safety pharmacology studies. Applies to new chemical entities and biotechnology-derived products for human use. The objectives of safety pharmacology studies are: To identify undesirable Pharmacodynamic properties of a substance that may have relevance to its human safety. To evaluate adverse Pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies. 34

S8 & S9 Immunotoxicological : : 

S8 & S9 Immunotoxicological : The general principles that apply to this guideline are: All new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity. Methods include standard toxicity studies (STS) and additional immunotoxicity studies conducted as appropriate. The objectives of this guideline are to provide Recommendations on nonclinical testing approaches to identify compounds which have the potential to be immunotoxic. 35

ICH Efficacy - Document : 

ICH Efficacy - Document E1 & E2 -Clinical Safety E3 - Clinical study reports E4 - Dose response studies E5 - Ethnic factors E6 - Good clinical practice E7 - E11 - Clinical trials E12 - Guidelines for Clinical Evaluation by Therapeutic Category E14 - Clinical Evaluation 36

E1 & E2 -Clinical Safety : 

37 E1 & E2 -Clinical Safety The objective of this guideline is to present an accepted set of principles for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening diseases. The safety evaluation during clinical drug development is expected to characterise and quantify the safety profile of a drug over a reasonable duration of time consistent with the intended long-term use of the drug.

E-3 Clinical Study Report : 

E-3 Clinical Study Report The objective of this guideline is to allow the compilation of a single core clinical study report acceptable to all regulatory authorities of the ICH regions. Title Page In Clinical Study Reports should contain following information: Study title Name of test drug/ investigational product Indication studied Protocol identification (code or number) Development phase of study 38

E – 4 Dose response studies : 

E – 4 Dose response studies It is graphing the pattern of physiological response to varied dosage in which there is typically little or no effect at very low dosages and a toxic or unchanging effect at high dosages. Dose-Response Information Knowledge of the relationships among dose, drug-concentration in blood, and clinical response is important for the safe and effective use of drugs in individual patients. 39

E5 - Ethnic factors : 

E5 - Ethnic factors To describe the characteristics of foreign clinical data that will facilitate their extrapolation to different populations and support their acceptance as a basis for registration of a medicine in a new region. To describe regulatory strategies that minimise duplication of clinical data and facilitate acceptance of foreign clinical data in the new region. It is not necessary to repeat the entire clinical drug development program in the new region. All data in the clinical data package, including foreign data, should meet the standards of the new region with respect to study design and conduct and the available data should satisfy the regulatory requirements in the new region. 40

E6 - Good clinical practice : 

E6 - Good clinical practice Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. To provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities. This guideline should be followed when generating clinical trial data that are submitted to regulatory authorities. Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). 41

E7 - E11 Clinical trials : 

E7 - E11 Clinical trials The ICH document "General Considerations for Clinical Trials" is intended to: Describe internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products. Facilitate the evaluation and acceptance of foreign clinical trial data by promoting common understanding of general principles, general approaches and the definition of relevant terms. Present an overview of the ICH clinical safety and efficacy documents. 42

clinical trial : 

For each clinical trial contributing to a marketing application, all important details of its design and conduct and the principal features of its proposed statistical analysis should be clearly specified in a protocol written before the trial begins. The procedures in the protocol are followed and the primary analysis is planned The protocol should be approved by the responsible personnel, including the trial statistician. The trial statistician should ensure that the protocol cover all relevant statistical issues clearly and accurately, using technical terminology as appropriate. 43 clinical trial

E12 – Guideline FOR CLINICAL EVALUATION OF NEW ANTIHYPERTENSIVE DRUGS. : 

E12 – Guideline FOR CLINICAL EVALUATION OF NEW ANTIHYPERTENSIVE DRUGS. This document provides general principles for the clinical evaluation of anti-hypertensive drugs. It describes core principles for the evaluation of antihypertensive that are accepted in the three ICH regions, but some region-specific differences remain. These differences may be harmonized in future, but it is important at present to refer to existing regional guidelines and to discuss the specific requirements with regional regulatory authorities, if required. 44

E14 - Clinical Evaluation : 

E14 - Clinical Evaluation 45 This document provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac Repolarisation. This assessment should include testing the effects of new agents on the QT interval as well as the collection of cardiovascular adverse events. The focus is on agents being developed for uses other than the control of arrhythmias, as antiarrhythmic drugs can prolong the QT interval as a part of their mechanism of clinical efficacy.

ICH Multidisciplinary - Documents : 

ICH Multidisciplinary - Documents Multidisciplinary: combining the disciplines of many different branches of learning or research. M1 - Medical Terminology M2 - Electronic standards for the transfer of regulatory information. M3 - Non clinical safety studies for the conduct of human trials & marketing authorization for pharmaceuticals. M4 - The Common Technical Document M5- Data elements & standards for drug dictionaries. 46

M-1 Medical Terminology : 

M-1 Medical Terminology "Medical terminology" (including Medical Dictionary for Regulatory Activities Terminology,) was developed as a medical terminology covering all aspects of drug regulation ranging from authorization to post-marketing surveillance. It provides an international medical dictionary applicable to all phases of product development & to maintain and develop the terminology to meet Users' needs. In case of M-1 Guideline. (1) periodic safety update information (2) case reporting. 47

M-2 Electronic standards for the transfer of regulatory information. : 

M-2 Electronic standards for the transfer of regulatory information. The objective was to represent the document in a way that would make possible transfer of its contents from one database to another. 48

M-3 Non clinical safety studies for the conduct of human trials & marketing authorization for pharmaceuticals : 

M-3 Non clinical safety studies for the conduct of human trials & marketing authorization for pharmaceuticals The recommendations for the extent of non-clinical safety studies to support the various stages of clinical development differ among the regions of Europe, USA and Japan. Other non-clinical studies include (safety pharmacology) and pharmacokinetic (ADME) studies. These types of studies and their relation to the conduct of human clinical trials are presented in this guideline. The goals of the non-clinical safety evaluation includes a characterisation of toxic effects with respect to target organs, dose dependence 49

m-4 The Common Technical Document : 

m-4 The Common Technical Document This guideline presents the agreed upon common format for the preparation of a well-structured Common Technical Document for applications that will be submitted to regulatory authorities. A common format for the technical documentation will significantly reduce the time and resources needed to compile applications for registration of human pharmaceuticals and will ease the preparation of electronic submissions. 50

m-5 Data elements & standards for drug dictionaries : 

m-5 Data elements & standards for drug dictionaries It is desirable for regulators and pharmaceutical industry to engage in an intensive information exchange during the drug development phase, the drug evaluation and approval phase and the post-authorization phase. Due to the lack of a common and harmonized approach the following issues: No possibility to exchange medicinal product information between regulators and industry. Difficulties in ensuring data consistency and in evaluating and comparing medicinal product-related information across the ICH regions due to the lack of harmonized definitions of terminologies and data sets. 51

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Discuss the storage conditions for stability testing as per the ICH guidelines. Write a short note on decision tree for the identification and qualification of impurities as per ICH guidelines. Write a short note on genotoxicity impurity, Define impurity, Identified impurity, specified impurity. And describe briefly different classes of solvents. Discuss organic impurity. What is impurity & impurity profile? Give suitable classification. Write a note on validation of analytical method. 53

Reference : 

Reference www.ich.org http://apps.who.int/medicinedocs/en/d/Jh2993e/7.html 54

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For your attention 55