World Health Organization

World Health Organization
January 2006 Requirements on documentation of API and FPP quality and evaluation process Presented by Rutendo Kuwana Prequalification of Medicines Programme QSM / EMP / HSS Welcome Good morning and welcome to all delegates to this training course offered by the World Health Organization to develop the practical implementation of the WHO GMP text of Good Manufacturing Practice for Pharmaceutical Products. Thanks Our thanks to ______________________ for the arrangements that have been made to accommodate us all for the duration of the programme. Housekeeping (cover fire or emergency procedures, and domestic arrangements including location of toilet facilities, tea or coffee breaks, meal breaks)

WHO Reference text for Multisource (Generic) products / Definitions
World Health Organization January 2006 Active Pharmaceutical Ingredient (API) A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a therapeutically active compound (ingredient) Pharmaceutical Product Any preparation for human or veterinary use that is intended to modify or explore physiological systems or pathological states for the benefit of the recipient. Finished Pharmaceutical Product (FPP) A product that has undergone all stages of production, including packaging in its final container and labelling. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Reference texts Prequalification quality guidelines for dossier submission World Health Organization January 2006 Guideline on submission of documentation for prequalification of multi-source (Generic) Finished Pharmaceutical Products (FPPs) used in treatment of HIV/AIDS, Malaria and Tuberculosis (Main Generic guide with 8 annexes) [under revision] Supplement 1 : Dissolution testing Supplement 2 : Extension of the WHO list of stable APIs (not easily degradable) Guidelines for registration of fixed-dose combination medicinal products Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure Guidance on variations to a prequalified dossier ICH notes for guidance (When WHO or PQ guidelines silent) Prequalification of Generic products approved by Stringent Regulatory Authorities (SRAs) NEW Requalification Draft not finalised and not yet adopted Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Guidelines for Product dossier /Quality Main Generic guide
World Health Organization January 2006 Guideline on Submission of Documentation for Prequalification of Multisource (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis [under revision] Annex 1 - Model Certificate of a Pharmaceutical Product Annex 2 - Model Batch Certificate of Pharmaceutical Product Annex 3 - Model Stability Report of Active Pharmaceutical Ingredient (API) Annex 4 - Model Stability Report of Capsules/Tablets Annex 5 - Suggested Structure of the Summary of Product Characteristics (SmPC) Annex 6 - Suggested Structure of the Package Information Leaflet (PIL) Annex 7 - Presentation of Bioequivalence Trial Information (BTIF) Annex 8 - Presentation of Pharmaceutical Quality Information (PQIF) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Assessment Process - Quality
Submission of application PQIF, Dossier, BTIF Screening (Internal) Acceptance Pre – Assessment Screening Assessment Report Additional data Prequalification LoPQ Requalification

Quality dossier / Section 1
World Health Organization January 2006 Information on the FPP 1.1. Details of the Product - Name, dosage form and strength of the product - Approved generic name (INN) - Visual description of the FPP - Visual description of the packaging 1.2. Samples to be provided (for visual examination of assessors and comparison with the SPC and PIL) 1.3. Regulatory situation in Member States / list countries - Countries where a MA has been issued - Countries where a MA has been withdrawn - Countries where a Marketing Application has been rejected, deferred Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 Active Pharmaceutical Ingredient (API) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)
World Health Organization January 2006 Scientific data on the API can be submitted using following ways and order of preference A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 and presented in CTD format (see APIMF guideline) Complete submission of data requested in Section 2 Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Quality dossier / Section 2 of PQIF - Active Pharmaceutical Ingredient (API) World Health Organization January 2006 2.1. Nomenclature 2.2. Properties of the API 2.3. Site(s) of manufacture 2.4. Route(s) of synthesis 2.5. Specifications 2.6. Container- closure system 2.7. Stability testing Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

CTD Structure of API Sections
2.3.S DRUG SUBSTANCE 2.3.S.1 General Information 2.3.S.2 Manufacture 2.3.S.3 Characterisation 2.3.S.4 Control of Drug Substance 2.3.S.5 Reference Standards or Materials 2.3.S.6 Container Closure System 2.3.S.7 Stability

2.3.S DRUG SUBSTANCE 2.3.S.1 General Information
2.3.S.1.1 Nomenclature Include INN, compendial name, chemical name(s), company/laboratory code, other non-proprietary names eg USAN, JAN, BAN and Chemical Abstracts Service (CAS) registry number. 2.3.S.1.2 Structure Include structural formula with relative and absolute stereochemistry, molecular formula, and the relative molecular mass. 2.3.S.1.3 General Properties Physicochemical and other relevant properties of the API.

2.3.S.2 Manufacture Information on the manufacturer;
A brief description of the manufacturing process (including, for example, starting materials, reagents, solvents, critical steps, and reprocessing) and the controls intended to result in the routine and consistent production of API. A flow diagram; A description of the Source and Starting Material and raw materials used in the manufacture of the API;

2.3.S.2 Manufacture Cont’d A discussion of the selection and justification of critical manufacturing steps, process controls, and acceptance criteria. Discuss critical process intermediates; A description of process validation and/or evaluation. A brief summary of major manufacturing changes made throughout development and conclusions from the assessment used to evaluate product consistency. The QOS should cross-refer to the non-clinical and clinical studies that used batches affected by these manufacturing changes.

2.3.S.3 Characterisation A summary of the interpretation of evidence of structure and isomerism. When an API is chiral, it should be specified whether specific stereoisomers or a mixture of stereoisomers have been used in the nonclinical and clinical studies, and information should be given as to the stereoisomer of the API that is to be used in the final product intended for marketing.

2.3.S.3 Characterisation Cont’d: Impurities
Summary of the data on potential and actual impurities arising from the synthesis, manufacture and/or degradation, and should summarise the basis for setting the acceptance criteria for individual and total impurities. Summary of the impurity levels in batches of the API used in the non-clinical studies, in the clinical trials, and in typical batches manufactured by the proposed commercial process. The QOS should state how the proposed impurity limits are qualified. A tabulated summary, with graphical representation, where appropriate should be included.

2.3.S.4 Control of Drug Substance
A summary of the specification(s), the analytical procedures, and validation should be included. A tabulated summary of the batch analyses.

2.3.S.5 Reference Standards or Materials
Information on primary and working standards of the API and specified impurities.

2.3.S.6 Container Closure System
A brief description and discussion of the primary and secondary packaging components.

2.3.S.7 Stability This section should include a summary of the studies undertaken (conditions, batches, analytical procedures) and a brief discussion of the results and conclusions, the proposed storage conditions, retest date or shelf-life. The post-approval stability protocol should be included.

Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)
World Health Organization January 2006 PQ dossier section 2 CTD 2.1 Nomenclature 2.2 Properties of API (s) S.1 General Information - Nomenclature - Structure - General Properties 2.3 Site(s) of Manufacture 2.4 Route(s) of synthesis - API not described in pharmacopoeia - Specifications of raw materials and intermediates used in synthesis - API described in a pharmacopoeia S.2 Manufacture - Manufacturer - Description of manufacturing process - Control of materials - Control of critical steps and intermediates - Process validation - Manufacturing process development S.3 Characterisation - Elucidation of structure - Impurities 2.5 Specifications S.4 Control of Drug Substance S.5 Reference Standards or Materials 2.6 Container Closure System 2.7 Stability testing S.6 Container Closure System S.7 Stability testing Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 Finished Pharmaceutical Product (FPP) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)
World Health Organization January 2006 3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients Control of the FPP Container/closure system (s) and other packaging Stability testing Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.12. Container labelling 3.13. Product information for health professionals 3.14. Patient information and package leaflet 3.15. Justification for any differences to the product in the country OR countries issuing the submitted WHO-type certificate(s) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.1. Manufacturing and Marketing Authorization Valid manufacturing authorization for pharmaceutical production including the pharmaceutical form applied for Marketing authorization to demonstrate the product is registered / licensed in accordance with national requirements 3.2. Pharmaceutical development The aim is to build a quality product by design. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development The section should contain information on the development studies conducted to establish that the dosage form, the formulation, the manufacturing process, the container closure system, microbiological attributes and storage and usage instructions are appropriate for the purpose specified in the dossier. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (pre-formulation) Physico-chemical characteristics of the APIs solubility (composition) water content (stability) hygroscopicity (stability) particle size (solubility, bioavailability, suspension properties, stability …) polymorphism (solubility, bioavailability, stability) Data obtained from literature : Books, Journals, International Pharmaceutical Abstracts, Chemical Abstracts, Analytical Abstracts, Internet …… Experimental data (if necessary) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (choice of excipients) Intended function of each excipient Criteria compatibility of excipients with API(s), characteristics of the excipients (water content, particle size, flowability, density, rheological behavior…) Particularly : other non active constituents (lowest acceptable concentration to be chosen e.g. concentration of parabens as preservatives) Experimental data needed. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (choice of the manufacturing process) Parameters : characteristics of the APIs, dosage form, composition…. . Rational behind the choice (e.g. why a non over kill process as a sterilisation process instead of terminal sterilisation in final container) Justification of the overage (if any) Identification of the critical steps In Process Control (IPC) Selection and optimisation of manufacturing process Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (dissolution testing) To study dissolution operating conditions (media, pH, rotation, …) To develop a discriminatory dissolution method Comparative dissolution testing is a tool, mandatory in development pharmaceutics section of the dossier in PQ, See Supplement 1 Help in selection of the formulation - compare formulation(s) with innovator product, - a basic strategy in development to maximize the chances of bioequivalence Comparison of pivotal batches to commercial batches/ post-approval changes Setting of dissolution specifications Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (comparative dissolution testing) Three media ml or less - all at 37°C Buffer pH 1.2 or 0.1M HCl Buffer pH 4.5 Buffer pH 6.8 Water may be used additionally (not instead of) Paddle at 50 or basket at 100 rpm Twelve units of each product in all 3 media Dissolution samples collected at short intervals, e.g. 10, 15, 20, 30, 45 and 60 minutes Analyse samples for all APIs, when applicable Calculate similarity factor f2 Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (details of batches studied) Provide a summary of development of the FPP from pre- formulation to production scale. Provide a comparison of formulas (tabulated form) of: bio-batche(s) (clinical / bioequivalence), development batches, stability batches, batches for validation/production Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.2. Pharmaceutical development (choice of formulation and compatibility) Compatibility of APIs with the excipients Compatibility of APIs between each other in case of fixed dose combinations Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.3. Formulation Formula in tabulated form for : Administration unit (e.g. one tablet), Typical batch - Precise any overage, - Precise quantity adjustment of the API, - Precise q.s. for excipient. Excipients : State function (e.g. lubricant, disintegrant), Precise technical grade (e.g. micronised, purified water), describe also those removed during process (e.g. water), Describe also those not always added (e.g. acid & alkali for pH adjustment, Capsule shells, inked imprints on dosage form, Also gas (inert atmosphere). Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.4. Manufacturing sites Name and street address of each facility where any aspect of manufacture occurs including production, sterilisation, packaging and quality control – include Units and/or Blocks Include any alternative manufacturers Certificate issued by the Competent DRA according to WHO Certification scheme for each site where a major step of manufacturing is performed Submit a valid GMP certificate Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.5. Manufacturing process (cont.) Flow chart with indication of each step showing where materials enter the process. Indication of critical steps and in-process controls Description of manufacturing/packaging including Scale Equipment by type (e.g. tumble blender) & working capacity Process parameters for steps, (e.g. time, temperature, pH) Environmental conditions, e.g. relative humidity for hygroscopic FPPs., area class for sterile FPPs Steps of the process Alternative methods Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.5. Manufacturing process (cont.) Proposal for reprocessing – justified with data. Copy of master formula. Batch manufacturing record – real batch. Sterile products – sterilisation steps and/or aseptic procedures. Description of in-process tests including plan of sampling and acceptance limits. Data for 3 full scale batches to support achievement of predetermined specifications. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.6. Manufacturing Process Controls of Critical steps and Intermediates Identification of critical steps with test methods and justified acceptance criteria Information on quality of isolated intermediates, test methods and justified acceptance criteria to control them Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.7. Process Validation and Evaluation Validation mandatory for processes including a critical step The aim is to show that critical steps are under control and lead continuously to the desirable quality Examples of critical steps (list non exhaustive) mixing, coating, granulation, emulsification, non-standard sterilisation Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.7. Process Validation and Evaluation (details on 3 first production batches) Batches . batch number . batch size . place and date of manufacture . batch number of API(s) . yield . batch purpose (validation, stability, clinical trial …) Process . equipment . process parameters . validation protocol. Results . critical steps . in process control . finished product Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.7. Process Validation and Evaluation Concurrent validation carried out during normal production on the first 3 production batches OR For well-established processes process data, in-process controls and quality controls on a total of batches to present a statistically significant picture Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.7. Process Validation and Evaluation If validation data (on production scale batches) are not available submit validation protocol, commitment that validation report will be submitted later for evaluation, commitment that data will be available in case of inspection, commitment that WHO will be informed of any significant deviation. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.7. Process Validation and Evaluation Validation protocol should include brief description of the process with summary of critical steps and parameters to be followed during validation, specifications of the FPP at release, details of analytical procedures and limits, sampling plan, unifromity of dosage units essential for FDCs, proposed timeframe Validation report when submitted should include results for each batch, certificates of analysis, batch production records, report on unusual findings, modifications, observations and conclusions Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.8. Specifications for excipients - Non pharmacopoeial substances - Details for manufacturing process, - Specifications (description of procedures and acceptance criteria) - Stability data - Cross-reference to non-clinical (toxicological)- clinical data for safety aspects - Certificates of analyses - Pharmacopoeial excipients Copy of the pharmacopoeial monograph used for control + certificates of analysis - For excipients of animal, human, microbial origin - TSE (Transmissible Spongiform Encephalopathy) risks and viral safety should be addressed - TSE CEP preferred Permitted colorants are those allowed in UE, USA and Japan Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.9. Control of the FPP 2 sets of specifications are possible: at release and at the end of shelf-life (list of attributes non exhaustive) Description of the FPP /appearance Identification of API Assay of API: ± 5% of the label claim at release and ±10% at the end of shelf-life Degradation products Pharmaceutical tests e.g. dissolution, disintegration (where applicable) Uniformity of dosage units (mass or content) Identification of colorants, identification and assay of anti-oxidants, chemical preservatives Microbial contamination, Sterility, bacterial endotoxins Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.9. Control of the FPP (cont.) Monographs of Ph. Int., USP, BP are acceptable for the FPP + complementary tests If non-pharmacopoeial FPP, note for guidance Q6A applicable Description of all analytical procedures in details if not described in a pharmacopoeial monograph Validation of analytical methods and/or demonstration of applicability for pharmacopoeial methods Batch analyses for 3 lots with details of each lot (batch no, size, date of manufacture, use of batch) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.10. Container-closure system Discussion on the choice of container Choice of the material Protection against light and humidity compatibility/interaction of materials in contact with dosage form Safety of materials used Detailed description of the container Specifications of the container with dimensions and drawings Specifications of materials in contact with FPP Composition of these materials, compliance with pharmacopoeia Identification of components e.g. IR for plastic materials Description of the secondary packaging Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.11. Stability testing The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light and to establish a shelf-life for the FPP, to determine the storage conditions and the in-use stability. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.11. Stability testing Lots included in the study: 1 production batch and 2 of pilot scale manufactured according to the process described in the dossier 3 Pilot scale batches are acceptable (exception for 2nd line TB products: 2 pilot batches) Pilot scale batch for solid dosage forms is 10% of production scale or whichever is greater Parameters susceptible to change over storage should be followed: . Organoleptic properties . Assay of each API: ±10% of the label claim possible at the end of shelf-life . Assay of degradation products . Assay of antioxidants and chemical preservatives, check also for their efficacy . Dissolution testing (limits should remain unchanged to release) . Microbial contamination, sterility, bacterial endotoxins In-use stability data (if applicable) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.11. Stability testing Study should be performed in the claimed commercial packaging (container-closure) Storage conditions and frequency of testing according to WHO stability guideline in TRS 953 Minimum stability data to be submitted at time of submission: Long term 12 months or 6 months or 3 months (as appropriate according to Supplement 2 to the Main Generic guide and exception for TB 2nd line products) 6 months intermediate 30°C/65% RH 6 months accelerated 40°C/75% RH Unless otherwise justified, 30°C / 75% RH is the recommended storage condition for Prequalification Definition of "significant change" in WHO stability guide is the same as ICH Q1A (R2) Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.11. Stability testing Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water loss in low relative humidity condition). The storage condition will be long term ICH 25°C / 40% RH OR 30°C/35% RH and accelerated 40°C/25% RH Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments Supplement 2: tentative 2 year re-test period and /or shelf-life may be accorded to APIs and corresponding solid forms (tablets and capsules) listed in Supplement 2 based only on 6 months accelerated data and 6 months long term data Long term stability should anyhow be followed to cover the whole shelf-life accorded Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.12. Container labelling Outer packaging : Where no outer packaging, on immediate packaging, e.g. HDPE bottle. Labelling should include at least the following : The name of the FPP. Method of administration. A list of API(s) (using INNs if applicable) showing the amount of each present in a dosage unit, and a statement of the container, e.g. number of dosage units, weight or volume. List of excipients known to be a safety concern for some patients, e.g. lactose, gluten, metabisulfites, parabens, ethanol, or tartrazine. Instruction on use. The batch number assigned by the manufacturer. The expiry date in an uncoded form. Storage conditions or handling precautions that may be necessary. Directions for use, and any warnings or precautions that may be necessary. The name and address of the manufacturer, company or person responsible for placing the product on the market. Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.12. Container labelling Blisters and strips should include, as a minimum, the following information Name, strength and pharmaceutical form of the FPP Name of the manufacturer, company or person responsible for placing the product on the market The batch number assigned by the manufacturer The expiry date in an un-coded form Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.13. Product information for Health Professionals Summary of product characteristics (SmPC) Aimed at medical practitioners and health professionals Changes to SmPC to be approved by WHO See Annex 5 of the main generic guide Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization January 2006 3.14. Patient information and package leaflet Copy of the patient information leaflet (PIL) In conformance with SmPC See Annex 6 of the main Generic guide Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

January 2006 Thank you for your attention Next we will have a short session on Self-inspection. We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject. This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module. We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions. This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

World Health Organization

Similar presentations

Presentation on theme: "World Health Organization"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

World Health Organization

Similar presentations

Presentation on theme: "World Health Organization"— Presentation transcript:

Similar presentations

About project

Feedback