The implementation of uniform standards at the international level is a rather long process, especially if these standards relate to complex processes. However, global harmonization of regulatory requirements in the pharmaceutical sector is gaining momentum. At the root of this trend lies the ever-increasing degree of globalization of the pharmaceutical industry itself. In addition to increasing efficiency, harmonization of regulatory requirements should ultimately ensure wide access to quality medicines for all those who need them, regardless of where they are located.
Today the harmonization process is still far from an acceptable level. This leads to significant losses of time and money in the pharmaceutical industry. For example, according to data from a review by the European Federation of Pharmaceutical Industries and Associations (EFPIA), in some cases, the cost of preparing a dossier for a new drug can be 15-20% of the cost of clinical trials in which invest hundreds of millions of dollars. The study showed that there are a large number of inspection organizations, partly unnecessary, which require hundreds of thousands of dollars a day to exist. Indeed, it takes from 1000 to 2500 man-hours to inspect one production facility. Harmonization of approaches to the preparation of dossiers, the introduction of uniform standards for inspection of production facilities would help to avoid unnecessary costs in the pharmaceutical sector as a whole and to direct the saved resources to solving the necessary tasks. (Europe Today)
Significant results have been achieved over the past five years in the area of \u200b\u200bstandardization of R&D and clinical trials requirements, as well as harmonization of regulatory requirements for finished dosage forms, active pharmaceutical ingredients (APIs) and excipients.
The main driving force behind the regulatory harmonization process in the pharmaceutical sector is the International Conference on Harmonization (ICH). For 21 years, ICH has focused on eliminating redundant documentation and simplifying the development, manufacturing and registration of pharmaceuticals. ICH is composed of representatives from regulatory authorities, Pharmacopoeias and manufacturers drugs from the USA, Japan and European countries. Through the efforts of this organization, a common approach to the problem of harmonization was developed and priorities were set for the implementation of this complex and multilateral project.
In addition to the ICH, a number of other organizations are involved in the harmonization of regulatory requirements in the pharmaceutical sector, for example, the US Pharmacopeias Discussion Group. The World Health Organization is also involved in the harmonization process, as is the Society for the Harmonization of Medicines of America. Other groups working to harmonize regulatory requirements in different countries have focused their efforts on specific issues in the area of \u200b\u200bactive pharmaceutical ingredients and excipients.
Some advances in harmonization
An example is the progress made by the United States and European countries to harmonize regulatory requirements in the pharmaceutical sectors of these countries. Applying ICH quality standards guidelines and using a common format for technical documentation, the US and Europe have come up with a single dossier for a range of drugs.
Japan, which five years ago moved along the path of national standards, now shows significant interest in cooperation in the direction of harmonization of regulatory requirements in pharmaceuticals.
Perhaps the most significant symbol of the 21st century progress in harmonization is the single electronic form of technical documentation that companies use to prepare registration dossiers. As a joke, they now recall the time when it was necessary to take a truck to deliver the entire volume of registration dossier documents to the regulatory authorities.
In the area of \u200b\u200bharmonization of pharmaceutical manufacturing standards, the ongoing process is a direct reflection of the realities of the supply of most APIs to the United States and Europe from India and China. Two years ago, the Food and Drug Administration (FDA) and the United States (USP) opened offices in China, India and Latin America. The presence of representations and USPs directly in the producing countries allowed them to improve their interaction with local regulatory authorities, manufacturers and pharmacopoeias.
Progress in Harmonization of Pharmacopoeias, APIs and Excipients
Harmonization of the Pharmacopoeias began about 10 years ago. Over time, good cooperation has been established between the Pharmacopoeias of the United States, Japan and Europe. However, harmonization in this area is a long and extremely laborious process. For example, the US Patent Documentation Group (USP's PDG) has so far only worked out 27 of 34 general provisions and 40 of 63 excipient monographs.
Attempts are being made to harmonize monographs up to finished medicinal products.
At the global level, one of the key points is the harmonization of the quality parameters of APIs and excipients. The US is slated to contain monographs on all pharmaceutical excipients as listed. This will create an international working group to disseminate best practices. The European Directorate for the Quality of Medicines & HealthCare (EDQM) has established two-way relations with the US FDA and similar agency in Australia
(Australia's Therapeutic Goods Administration - TGA) for the exchange of confidential information on APIs and excipients. Within the framework of these agreements, as a pilot project, mutual inspections began last year.
Several possibilities are being considered for the global harmonization of the quality parameters of excipients. One of them is the application of requirements for the production of excipients; the other is the participation of manufacturers in a voluntary production inspection program by independent auditors. The International Pharmaceutical Excipients Auditing is being registered with the American National Standards Institute to act as an independent quality auditor.
Remaining differences
Harmonization does not mean literally repeating all pharmaceutical registration procedures. There will always be differences in the approach taken by different regulatory agencies. Even within the framework of one European Union, a new one can be registered "centrally", i.e. through EU authorities, or go through registration with national agencies. The US FDA's strategy is to harmonize the safety requirements for pharmaceuticals in the US and the EU, although some differences in approaches and procedures will still remain.
The national specificity is seen in the example of the inspection of pharmaceutical production. The US FDA, for example, focuses on abnormal investigations, validation rules, and the maintenance and cleanliness of equipment and production facilities. In the EU countries, the main efforts are focused on the compliance with cleanliness of premises and their classification, equipment maintenance and laboratory control. In Japan, inspectors place high demands on the quality of raw materials, cleanliness of production equipment and appearance finished pharmaceutical products.
"Pharmaceutical industry", April # 2 (19) 2010
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The Eurasian Economic Commission has developed a draft Rules for conducting research on biological medicines on the territory of the Eurasian Economic Union (EAEU). The purpose of the document is to facilitate the collection and provision of data annexed to applications for registration of biological medicinal products.
The rules are necessary for the formation of a common drug market in the EAEU, which will start operating on January 1, 2016. From this date, safe, effective and high-quality drugs will be able to move freely throughout the Union.
The draft Regulation was developed on the basis of the provisions set out in the relevant documents of the International Conference on Harmonization of Technical Requirements for Registration of Medicines (ICH) and the European Medical Agency (EMA).
The document regulates the development, safety, efficacy and quality research of both new molecules of biological drugs and biosimilar drugs. At the same time, the Rules contain chapters dealing with general research issues: from banks producing cells to finished pharmaceuticals. There is a separate chapter that contains drug-specific requirements for the development, production and research of biosimilar drugs.
Strict adherence to the Rules will help pharmaceutical manufacturers complete the full cycle of studying biological products, confirm their safety, quality and efficacy, ensuring that the reproduced biomolecules correspond to their prototypes. This will make it possible to substitute drugs with comparable safety and efficacy.
It should be noted that the Rules are mandatory for authorized bodies and expert organizations when performing the procedure for examining the safety, quality and effectiveness of this group of drugs in the process of evaluating their registration dossiers.
A high degree of harmonization of the Rules with the requirements of the relevant international documents will facilitate the process of entry of the named drugs into foreign markets, will facilitate the recognition of data on pharmaceutical development and the results of confirmation of safety, quality and effectiveness when they are registered outside the Union.
The draft decision of the EEC Council on the approval of the Rules for conducting research on biological medicinal products in the territory of the Eurasian Economic Union was published on the websites of the Eurasian Economic Union in the section "Public Discussions and ODS" and the Eurasian Economic Commission on the page of the Department of Technical Regulation and Accreditation of the EEC in the section "Public discussion of draft regulatory legal acts ".
All interested parties can, within 30 days from the date of publication of the draft document, submit comments to the EEC Department of Technical Regulation and Accreditation.
reference
TO biological medicinal products include immunobiological and biotechnological drugs, drugs obtained from human blood plasma, probiotic (eubiotic) drugs, bacteriophage drugs, high-tech drugs.
International Conference on the Harmonization of Technical Requirements for Drug Registration (ICH) - an organization that brings together regulatory authorities and the pharmaceutical industry in Europe, Japan and the United States to discuss the scientific and technical aspects of drug registration.
European Medical Agency (EMA) - an agency of the European Union, which is responsible for the scientific evaluation of drugs developed by pharmaceutical companies for use in the EU.
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The rapid development of the international pharmaceutical industry in the 70-80s. The 20th century and the globalization of the pharmaceutical market began to be hampered by fragmented national drug registration systems, primarily by differences in technical requirements. Along with this, the increase in the cost of spending on health care, on research work on the creation of new drugs, the need for quick access of the population to modern more effective drugs demanded harmonization of regulatory requirements. In 1989, at the Paris Conference of Medicines Regulatory Authorities, held annually by WHO, the issue began to be addressed by regulators in the US, EU and Japan. In April 1990, representatives of these countries 'agencies and manufacturers' associations established the International Conference on Harmonization, the secretariat of which is located in Geneva at the headquarters of the International Federation of Pharmaceutical Manufacturers Associations. (IFPMA). The initial task of the ICH was to harmonize the technical requirements for registration dossiers submitted to the EU, USA and Japan. As the conference was successful, its tasks were expanded. The main objectives of the ICH for the current decade were defined at its 5th conference in San Diego in 2000:- creating a forum for constructive dialogue between regulatory authorities and the pharmaceutical industry regarding current and objective differences in registration requirements in the US, EU and Japan in order to ensure faster introduction of new medical products into practice and patient access to them; participation in the protection of public health with international prospects; monitoring and updating harmonized technical requirements leading to greater mutual acceptance of data on research and development of medicines; elimination of various requirements in the future by harmonizing selected areas necessary for the further development of therapy and new technologies for the production of medical products; ensuring the dissemination and understanding of harmonized guidelines and approaches that update or replace current regulations and allow more economical use of human and material resources without compromising safety; ensuring the dissemination and understanding of harmonization these guidelines, their use to implement and combine common standards.
- On behalf of the European Union, the ICH is represented by the European Medicines Agency (EMEA) and the European Federation of Pharmaceutical Manufacturers and Associations (EFPIA) .From the US, the ICH includes the US Food and Drug Administration (FDA) and the US Pharmaceutical Developers and Manufacturers Association. (PhRMA) From Japan, the Medicines and Medical Devices Agency of the Ministry of Health, Labor and Social Affairs of Japan and the National Institute of Health Sciences and the Japanese Pharmaceutical Manufacturers Association (JPMA) are participating in the harmonization work.
- safety
Document code | Manual title |
Mutagenicity studies |
|
| S1A | The need for drug mutagenicity research |
| S1B | Testing for mutagenicity of drugs |
| S1C (R1) | Dose selection for drug mutagenicity studies and dose limit |
| S2A | Guidance on Specific Aspects of Regulatory Genotoxicity Testing for Drugs |
| S2B | Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals |
| S3A | Guidance Note Toxicokinetics: Assessment of Total Exposure in Toxicity Studies |
| S3B | Pharmacokinetics: Guidelines for Tissue Repeated Dose Distribution Studies |
Toxicity test |
|
| S4 | Single dose toxicity tests |
| S4A | Duration of Permanent Toxicity Test in Animals (Rodent and Non-Rodent Toxicity Test) |
Generative toxicology |
|
| S5 (R2) | Detection of reproductive toxicity of medical products and reproductive toxicity in males |
| S5A | ICH Support Toxicity Guidelines for Male Fertility |
Biotech products |
|
| S6 | Assessment of preclinical safety of biotechnologically derived drugs |
Pharmacology research |
|
| S7A | Safety pharmacology studies for human drugs |
| S7B | Non-clinical assessment of the potential for delayed ventricular repolarization (QT intermediate prolongation) of drugs in humans |
Immunotoxicological studies |
|
| S8 | Immunotoxicological studies on medicines for humans |
- efficiency (efficacy)
Clinical research safety |
|
| E1 | Number of patients undergoing clinical safety studies of drugs intended for long-term treatment non-life threatening conditions |
| E2A | Clinical safety data management: definitions and standards for urgent reporting |
| E2B (R3) | Clinical Safety Data Management: Data Item for Transporting Special Case Safety Messages |
| E2C (R1) | Clinical safety data management: Periodic update of safety reporting for marketed drugs E2C Supplement: Periodic update of safety reporting for marketed drugs at E2C (R1)) |
| E2D | Post-Market Safety Data Management: Definitions and Standards for Reports |
| E2E | Pharmacovigilance planning |
Clinical trial reports |
|
| E3 | Structure and Content of Clinical Trials Reports |
Dose-dependent studies |
|
| E4 | Dose-effect information for entering data in the registration dossier |
Ethnic factors |
|
| E5 (R1) | Ethnic factors in the acceptability of foreign clinical data |
Gcp(Good Clinical Practice) |
|
| E6 (R1) | GCP (Good Clinical Practice) |
Clinical trials |
|
| E7 | Confirmation Studies in Specific Populations: Geriatrics |
| E8 | Basic consideration of clinical trials |
| E9 | Statistical Principles for Clinical Trials |
| E10 | Selection of control group and associated data in clinical trials |
| E11 | Clinical study of medical products in children |
Clinical Assessment Guidelines for Therapeutic Category |
|
| E12 | Principles for the clinical evaluation of new antihypertensive drugs |
Clinical evaluation |
|
| E14 | Clinical assessment of QT / QTc prolongation interval and proarrhythmic potential for non-antiarrhythmic drugs |
Pharmacogenomics |
|
| E15 | Terminology in pharmacogenomics |
- quality
| Document code | Manual title |
Stability |
|
| Q1A (R2) | Stability Testing of New Drug Substances and Products "Testing the stability of new pharmaceutical substances and drugs" |
| Q1B | Stability Testing: Photostability Testing of New Drug Substances and Products "Testing the photostability of new pharmaceutical substances and preparations" |
| Q1C | Stability Testing for New Dosage Forms "Testing the stability of new dosage forms" |
| Q1D | Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products "Grouping methods for testing the stability of new pharmaceutical substances and drugs" |
| Q1E | Evaluation of Stability Data "Evaluation of stability data" |
| Q1F | Stability Data Package for Registration Applications in Climatic Zones III and IV "The volume of stability data for registration dossiers for drugs used in climatic zones III and IV" |
Validation |
|
| Q2 (R1) | New title: Validation of Analytical Procedures: Text and MethodologyPreviously: Text on Validation of Analytical ProceduresNew title: "Validation of Analytical Procedures: Content and Methodology" to replace the manuals "Content of Validation of Analytical Procedures" and "Validation of Analytical Procedures: Methodology" |
| Impurities | |
| Q3A (R2) | Impurities in New Drug Substances "Impurities in new pharmaceutical substances" |
| Q3B (R2) | Impurities in New Drug Products "Impurities in new drugs" |
| Q3C (R2) | Impurities: Guideline for Residual Solvents Impurities: Guideline for Residual Solvents |
| Pharmacopoeia | |
| Q4 | Pharmacopoeias "Pharmacopoeias" |
| Q4A | Pharmacopoeial Harmonization "Harmonization of pharmacopoeias" |
| Q4B | Regulatory Acceptance of Analytical Procedures and / or Acceptance Criteria (RAAPAC) "Regulatory Acceptance of Analytical Procedures and / or Acceptance Criteria" |
| The quality of biotechnological products | |
| Q5A (R1) | Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin "Evaluation of the viral safety of biotechnology products derived from human and animal cell strains" |
| Q5B | Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products "Quality of Biotechnological Products: Analysis of Expression Gene Constructs in Cells Used to Produce Protein Products Using Recombinant DNA" |
| Q5C | Quality of Biotechnological Products: Stability Testing of Biotechnological / Biological Products “The quality of biotechnological products; assessment of the stability of biotechnological / biological products " |
| Q5D | Derivation and Characterization of Cell Substrates Used for Production of Biotechnological / Biological Products "Derivation and characterization of cell substrates used in the production of biotechnological / biological products" |
| Q5E | Comparability of Biotechnological / Biological Products Subject to Changes in their Manufacturing Process "Comparability (identity) of biotechnological / biological products in case of changes in the technological process of their production" |
| Specifications | |
| Q6A | Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including Decision Trees) "Specifications: Quality parameters and acceptance criteria for new pharmaceutical substances and drugs: chemical substances (including algorithms)" |
| Q6B | Specifications: Test Procedures and Acceptance Criteria for Biotechnological / Biological Products "Specifications: Quality Parameters and Acceptance Criteria for Biotechnological / Biological Products" |
| Good Manufacturing Practice | |
| Q7 | Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients "Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients" |
| Development of pharmaceutical products | |
| Q8 | Pharmaceutical Development "Development of pharmaceutical products" |
| Quality Risk Management | |
| Q9 | Quality Risk Management "Quality Risk Management" |
| Q10 | Pharmaceutical Quality system "Quality system at a pharmaceutical enterprise" Stage 3. |