The EU system for marketing authorization
- 1. College of Pharmacy Chapter 2 European Union & Australia
- 2. The EU system for marketing authorization (MA) 2 www.DuloMix.com
- 3. Introduction • The European regulatory system aims to ensure providing safe, efficient and good quality medicines to its citizens. Providing patients with the necessary medicinal products involves registering them in the different member states of the European Union. • The National Competent Authorities (NCAs) are dealing with the authorisation of medicinal products through national, decentralised and mutual recognition procedures, with conduct of post-marketing activities, clinical trials, providing national scientific advice and conducting inspections for companies in their area of responsibility. 3 www.DuloMix.com
- 4. Introduction • Even if the NCAs are trying to avoid duplication of assessment and focus on sharing workload and scientific expertise, there are still many national requirements that the applicants are to fulfil in order to obtain the national registration of the product in all concerned Member States. The aim of a harmonised single market, that is one of the principles of EU foundation, is still not yet realised, due to the additional local requirements for registering a product in the EU Member States, different timelines for granting the approval, legal status of medicines, other assessment disagreements. • In case the Concerned Member States are not agreeing with the assessment of the Reference Member States due to potential serious risks to public health, the scientific coordination work is done based on an Article 29(1) procedure by the coordination group for mutual recognition and decentralised procedures, human (CMDh) or veterinary (CMDv), respectively. As in this master thesis only the requirements for the medicinal products for human use will be considered, the reference will be made in the following to the CMDh. 4 www.DuloMix.com
- 5. Introduction • The scope of the pharmaceutical companies is to timely bring their medicinal products on the market, by obtaining the marketing authorizations. Therefore, the preparation of the dossier (clinical, non-clinical and chemical manufacturing and control modules) for submission must be planned well in advance. The requirements for modules 2 to 5 are so far harmonised across EU Member States. The differences appear usually in module 1, in the specific Additional Data that are requested and in the provision modality of these documents (only copies, originally signed, notarized). • Submission of the application is not limited to the dossier. Samples and mock-ups of the medicinal product, payment of fees and the different modalities of dossier submission, electronic or paper submission, both and/or in parallel, should be clarified and taken into consideration in order to assure a smooth dossier submission. 5 www.DuloMix.com
- 6. Introduction 6 Clinical Trials Herbal Medicinal Products Generics Biosimilars Pharmacovigilance Orphan Drugs Regulation (EC) No 726/2004 EMA - Centralised Procedure Directive 2001/83/EC Community Code MRP - DCP Paediatrics Advanced Therapies Falsified Medicinal Products Good Manufacturing Practices Notice to Applicants ❑ EU Pharma Legislation www.DuloMix.com
- 7. 7 First EU legislation on medicinal products. ➢ To prevent a recurrence of the thalidomide disaster ➢ To safeguard public health by not allowing medicinal products ever again to be marketed without prior authorisation ➢Authorization only granted after demonstration of the: safety, efficacy and quality of the product Establishment of: ➢The EU centralized authorization system for medicinal products ➢The European Medicines Agency (EMA) 1995 1965 ❑ Key Milestones The EU system for Marketing Authorization www.DuloMix.com
- 8. 8 The EU system for Marketing Authorization ❑ Key Actors LEGISLATION Proposal: European Commission Adoption: + European Council European Parliament Interpretation: European Court of Justice Implementing Acts: European Commission Committee of EU MSs + www.DuloMix.com
- 9. 9 The EU system for Marketing Authorization AUTHORIZATIONS Appeal: European Court of Justice Application to: European Medicines Agency EMA Decision : European Commission Committee of EU MSs + Centralised Procedure ❑ Key Actors www.DuloMix.com
- 10. 10 The EU system for Marketing Authorization A medicinal product may only be placed on the market in the European Union when a marketing authorisation has been issued: • by the competent authority of a Member State (National authorisations) or • by the Commission for the whole EU (Union authorisation). Authorisations are granted on the basis of the criteria of QUALITY, SAFETY and EFFICACY ❑ Marketing Authorizations www.DuloMix.com
- 11. 11 The EU system for Marketing Authorization Quality overall summary Clinical study Non- Clinical Overview Quality Module 3 Module 4 Non Clinical Study Reports Module 5 Clinical Study Reports Module2 ▪ Authorisation of medicines in the EU reflects the internationally agreed standards ▪ EU–CTD (Common Technical Document) presentation is applicable irrespective of the type of procedure (centralised, mutual recognition or national). ▪ Companies need to submit data of tests and trials, demonstrating the Efficacy, Safety and Quality of the medicinal product. Admin & Prescribing Information Non- Clinical Overview Clinical Overview Module1 ❑ Application requirements www.DuloMix.com
- 12. Organization and structure of EU • European Union was founded between 1952 (the European Coal and Steel Community) and 1956 (European Economic Community) and includes currently 28 countries • The European Economic Area, established 1 January 1998, comprises besides the countries of the European Union also Iceland, Lichtenstein and Norway. All these EEA Member States are implementing the regulatory requirements valid in the European Union. • The basis for registration of the medicinal products in the European countries was first laid down by the Directive 65/65/EEC, according to which medicinal products can be nationally registered in one Member State. Starting with the Regulation 75/319/EEC, the registration of medicinal products in several EU countries is possible. The Mutual Recognition procedure was first mentioned within the Directive 93/39/EEC 12 www.DuloMix.com
- 13. EMA • The European Medicines Agency (EMA) is a decentralised agency o the European Union (EU). • The Management Board is the European Medicines Agency's integral governance body. • The Agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharmaceutical ompanies for use in the EU. • EMA protects public and animal health in 28 EU Member States, as well as the countries of the European Economic Area, by ensuring that all medicines available on the EU market are safe, effective and of high quality. • EMA serves a market of over 500 million people living in the EU. 13 www.DuloMix.com
- 14. Mission of EMA •The mission of the European Medicines Agency (EMA) is to foster scientific excellence in the evaluation and supervision of medicines, for the benefit of public and animal health in the European Union (EU). 14 www.DuloMix.com
- 17. What EMA Don’t Regulate? 17 www.DuloMix.com
- 18. What EMA Don’t Regulate? 18 www.DuloMix.com
- 20. EDQM • The EDQM (EUROPEAN DIRECTORATE FOR QUALITY MEDICINES) is an organisation that protects public health by enabling the development, supporting the implementation and monitoring the application of quality standards for medicines and their safe use. • The EDQM traces its origins and statutes to a European treaty promoting the elaboration of a common pharmacopoeia in Europe. MISSION: to contribute to a basic human right; access to good quality medicines and healthcare . 20 www.DuloMix.com
- 21. EDQM – Milestones • A Council of Europe Directorate • 1964: Activities based on an International • Convention of the Council of Europe to promote free movement of medicines in Europe (Partial Agreement) • Mandatory status reinforced in 1975 in the EU pharmaceutical legislation • 994: EU signed the EP Convention • 1994: creation of the European Network for • Official Medicines Control Laboratories (OMCL) 21 www.DuloMix.com
- 22. EDQM – Milestones • 1994: creation of the procedure of certification of suitability to the monographs of the European Pharmacopoeia • 2007: transfer of activities on blood transfusion and organ transplantation • 2008: transfer of activities on counterfeits, pharmaceuticals and pharmaceutical care • 2009: transfer of activities on cosmetics and primary packaging for foodstuff 22 www.DuloMix.com
- 23. 1. Establishment and provision of reference standards and materials (chemical and biological) 2. Pharmaceutical terminology – Standard terms for -Dosage forms -Routes of administration -Containers – ISO 23 EDQM Activities www.DuloMix.com
- 24. EDQM Activities 3. Certification of Suitability • European pharmaceutical legislation requires the applicant to demonstrate the suitability of the pharmacopoeial monograph to control the quality of active substances used • EDQM’s certification scheme as the “preferred way” for existing substances • Recognised throughout Europe and in many other countries (e.g. Canada) • Includes GMP inspections for API (in line with the EMEA “trigger document”) 24 www.DuloMix.com
- 25. EDQM Activities 4. The OMCL Network • General coordination of activities - Fostering of mutual confidence & recognition - Implementation of quality assurance system - Audits of OMCLs by peers (EDQM and Network members) - Proficiency testing studies (PTS) - Training courses (Procedures, QA and techniques in OMCLs) 25 www.DuloMix.com
- 26. EDQM Activities 5. Blood Transfusion •Program based on three general principles: - Non-commercialisation of substances of human origin - Volontary and non-remunerated donation - Protection of health of donors and receivers of blood transfusions 26 www.DuloMix.com
- 27. EDQM Activities 6. Organ Transplantation • General principles of the work program: - To garantuee the dignity of the human being, - To ensure adherence to human rights and fundamental freedom, - To ensure the non-commercialisation of substances of human origin - To protect donors and receivers. 27 www.DuloMix.com
- 28. EDQM Activities 7. Medicinal Products and Counterfeits • Multisectoral program on the protection of public health, risk management and risk prevention and improvement of international cooperationbased : - - Elaboration of model procedures for risk management in the public and private sector, - Establishment of an internationl network of Single Points of Contact (SPOC) - Training programs and conferences - Databases – “Track-and-trace” pilot 28 www.DuloMix.com
- 29. EDQM Activities 8. Legal Classification of Medicines • The work program forsees harmonisation of the legal classification of medicines with regards to their prescription status, which has an important impact on the safety of patients, access to medicines and the responsible management of health expenditures. • A specific data base for this activity, MELCLASS, is publicly available and is linked to a network of other international data bases on this subject. 29 www.DuloMix.com
- 30. Marketing Authorization procedures in EU • The three described procedures are published by the European Commission in consultation with the competent authorities of the Member States, the European Medicines Agency (EMEA), and interested parties. 30 ❑ Procedures for granting a marketing Authorization Mutual Recognition Procedure (MRP) Decentralised Procedure (DCP) Centralis ed Procedur e (CP) www.DuloMix.com
- 31. Marketing Authorization procedures in EU 31 ➢Mutual Recognition Procedure (MRP) ➢Decentralised Procedure (DCP) ➢Centralised Procedure (CP) ➢ National Authorisation Approval in one Member State ROUTE? CHOICE? Depends on: • Type of product • Authorisation history in EU • Regulatory & marketing strategy • Company preferences etc … ❑ The procedural set-up www.DuloMix.com
- 32. 32 MS: Member State Marketing Authorization procedures in EU www.DuloMix.com
- 33. National procedures • The majority of medicines available in the EU are authorised at national level: - Authorised before EMA creation - Not in the scope of the centralize procedure • Each EU Member State has its own national authorization procedures 33 Marketing Authorization procedures in EU www.DuloMix.com
- 34. 1. The Centralised Procedure • The Centralised Procedure (CP), having the legal basis in the Regulation (EEC) No 2309/93 and subsequently Regulation EC No 726/2004 is mandatory for biologicals, orphans, medicinal products containing a new substance not registered in the Community before 20 May 2004 and other products as listed in the Article 3 and the Annexes of this Regulation. The registration of a medicinal product through the CP results in a single marketing authorization that is valid in all EU MS. • In the Centralized Procedure, the applicant applies to the EMEA for marketing authorization and finally receives one European approval, which is valid in all 28 countries in the community, as well as Norway, Iceland and Liechtenstein. At least seven months before submission, the applicant should notify the EMEA of their intention to submit an application. 34 Marketing Authorization procedures in EU www.DuloMix.com
- 35. 35 Marketing Authorization procedures in EU www.DuloMix.com
- 36. 36 Marketing Authorization procedures in EU www.DuloMix.com
- 37. 1. The Centralised Procedure • Applicants have the opportunity to meet the EMEA in a pre- submission meeting, to discuss any procedural or regulatory issues. The applicant’s request for eligibility for evaluation via the Centralized Procedure, together with a justification and other documents is presented to all CHMP members. Following discussion at CHMP, the EMEA informs the applicant of the CHMP position, whether the medicinal product is eligible for evaluation via the Centralized Procedure. • For any scientific evaluation, a Rapporteur, and if relevant, a Co- Rapporteur, is appointed from amongst the members of the CHMP. The role of the Rapporteur is to perform the scientific evaluation and to prepare an Assessment Report for the CHMP according to the timetable approved for the evaluation procedure. Where appropriate, the Rapporteur can be supported by a Co-Rapporteur who prepares a separate full Assessment Report or a critique of the Rapporteur’s report at the discretion of the CHMP. 37 Marketing Authorization procedures in EU www.DuloMix.com
- 38. 38 Marketing Authorization procedures in EU www.DuloMix.com
- 39. 1. The Centralised Procedure Steps • Once the application is validated as complete and the Rapporteur and Co-Rapporteur have confirmed that they have received the dossier, the EMEA starts the procedure at the monthly starting date published on the EMEA website. The Rapporteur/Co-Rapporteur’s initial Assessment Reports are provided to the CHMP members and EMEA on Day 80. • The CHMP members are assigned to conduct a peer review of the Rapporteur/Co-Rapporteur’s scientific evaluation, as well as the validity of the scientific/regulatory conclusions reached. The adoption of the CHMP List of Questions, as well as the overall conclusions and review of the scientific data, is sent on Day 120 to the applicant. The EMEA stops the clock in order to allow the applicant time to prepare a response document. After receipt of the responses from the applicant, the CHMP adopts a timetable for the evaluation of the responses. The EMEA ensures that the opinion of the CHMP is given in 90 additional days 39 Marketing Authorization procedures in EU www.DuloMix.com
- 40. 1. The Centralised Procedure Steps • After the adoption of a CHMP positive opinion, the applicant provides the EMEA with final translations of the necessary documents in all EU languages including Norwegian. Finally, within 30 days the EMEA transmits the CHMP opinion and other required documents to the European Commission, and the Members of the Standing Committee, and to Norway and Iceland. The marketing authorization is granted by the European Commission and is valid throughout the Community and confers the same rights and obligations in each of the Member States as a marketing authorization granted nationally. The European Public Assessment Report (EPAR) will be published on the EMEA website, once the Commission decision has been issued. 40 Marketing Authorization procedures in EU www.DuloMix.com
- 41. 41 The Centralised Procedure Marketing Authorization procedures in EU www.DuloMix.com
- 42. 42 Biotech, AIDS, Diabetes, Cancer, Orphan, Neurodegenerative Significant therapeutic, scientific or technical innovation Responses submitted by applicant (Day 121) CHMP Opinion (Day 210) Mandatory Optional Application dossier sent to EMA EMA validation (14 days) CHMP starts evaluation (Day 0) List of questions sent to applicant (Day 120) Checks application meets criteria Clock starts - Reviews by rapporteur and corapporteur Review clock stops (up to 3 months) Review clock restarts Potential for further questions and clock stops for responses or oral explanation Review ends ❑ Centralised Procedure (CP) Marketing Authorization procedures in EU www.DuloMix.com
- 43. 43 ❑ Centralised Procedure (CP) Draft Commission Decision Standing Committee (Member States) Commission Decision Publication in the Official Journal of the EU European Public Assessment Report (EPAR) Approval Refusal Within 30 days, EMA transmit: ▪Opinion ▪ Assessmentreport ▪ Summary of Product Characteristics ▪Labelling and Package to: ▪ European Commission ▪ Member States ▪ Applicant 3-4 months CompanyAppeal Second Opinion CHMP Opinion (Day 210) Marketing Authorization procedures in EU www.DuloMix.com
- 44. 2. Mutual Recognition Procedure (MRP) • The MRP has been in place in the EU since 1995. The objective of this procedure is to obtain marketing authorizations in one or several Member States, when the medicinal product has already been granted authorization by at least one country in the European Community. In this case, the applicant requests one or more CMS(s) to mutually recognize the authorization granted by the RMS. If the marketing authorization in the RMS is based on an old dossier format, it is an obligation to reformat the dossiers before starting the MRP. • RMS= Reference Member State 44 Marketing Authorization procedures in EU www.DuloMix.com
- 45. 45 Marketing Authorization procedures in EU www.DuloMix.com
- 46. ❑ Mutual Recognition Procedure ➢Starts from an already existing national marketing authorisation granted by one Member State – the Reference Member State (RMS) CMS RMS CMS CMS ➢One or more Member States – the Concerned Member States (CMS) – are asked to recognize the authorization granted by the Reference Member State. ➢In case of disagreement the matter is referred to: ➢- the CMDh (60 days), and, if needed, to ➢- the CMPH (60 days). Marketing Authorization procedures in EU www.DuloMix.com 46
- 47. 2. Mutual Recognition Procedure (MRP) • An application for this procedure can be sent to one or more Member States. The applications sent should be similar and all Member States must be informed of them. When a Member State decides to assess the application (at this point it becomes the "Reference Member State" RMS), it announces the decision to other Member States (which then become the "Concerned Member States" CMS), to whom applications have also been submitted by the applicant. At this juncture the CMS will suspend their evaluations on the particular application and waits for the RMS’s decision on the application. 47 Marketing Authorization procedures in EU www.DuloMix.com
- 48. 48 Authorisation in one Member State, the Reference Member State (RMS) (210 days) Submission to chosen Concerned Member States (CMS) for recognition of Authorisation (90 days) In case of disagreement referral to CMD(h)/CHMP (60 + 60 days) Authorisation in CMS (within 30 days) ❑ Mutual Recognition Procedure (MRP) Serious risk to public health Referralto CMD(h) ! CMD(h) : Coordination Group for Mutual Recognition and Decentralised Procedures – Human CHMP: Committee for Medicinal Products for Human Use (EMA) Marketing Authorization procedures in EU www.DuloMix.com
- 49. 49 CHART FORTHE MUTUAL RECOGNITION PROCEDURE Marketing Authorization procedures in EU www.DuloMix.com
- 50. 2. DECENTRALISED PROCEDURE: • The new Decentralised procedure came into effect in the European Union in 2005 and is regulated by Directive 2004/27/EC. The main purpose of this procedure is to acquire marketing authorizations in several Member States, even though there are no marketing authorization has been granted in the European area. • The objective of this procedure is to obtain marketing authorizations in several Member States, when no marketing authorization has been granted in the European Community. • The applicant should send an application to the competent authorities of each of the Member States, where there is intent to obtain a marketing authorization. The applicant may designate a country to act as the Reference Member State (RMS). Selection of the RMS depends on many considerations including workload, previous experience, interests, and acceptance of the dossier by the RMS. 50 Marketing Authorization procedures in EU www.DuloMix.com
- 51. 51 Marketing Authorization procedures in EU www.DuloMix.com
- 52. 52 ➢No pre-existing marketing authorisation granted by one Member State. CMS RMS CMS CMS ➢Simultaneous application to a RMS and several CMS. ➢Assessment by RMS and reactions by the CMS. ➢In case of disagreement the matter is referred to: ➢- the CMDh (60 days), and, if needed, to ➢- the CMPH (60 days). ❑ Decentralised Procedure Marketing Authorization procedures in EU www.DuloMix.com
- 53. Steps involved in Decentralized procedure (DCP): The applicant has to send an application to the respective authorities of each and every member States, where there is plan to attain a marketing authorization. Unlike MRP, here the applicant may assign a country to act as the Reference Member State. This selection can be based on many criteria like workload, previous experience, interests of the applicant and acceptance of the applied dossier by the RMS. The RMS will commence the assessment after the application is decided to be complete by both the RMS and all the CMS(s). The RMS then forwards a preliminary Assessment Report on the submitted dossier to the CMS(s) and the applicant in a period of 70 days. The CMS(s) is requested to give comments on the proposed national prescription status and to inform the RMS. 53 Marketing Authorization procedures in EU www.DuloMix.com
- 54. Steps involved in Decentralized procedure (DCP): On day 105, the RMS will forward all observation and remarks from the CMS(s) to the applicant and stops the clock if necessary, until the applicant prepares a response document for the comments sent. The RMS prepares a Draft Assessment Report on day 120 and may close the procedure if a consensus has been reached between the CMS(s) and the RMS. Otherwise the CMS(s) has 90 more days to approve the Draft Assessment Report, and other documents. Authorities of the RMS and the CMS(s) agree to a decision within 30 days after acknowledgement of their agreement to the Assessment Report and other documents. Upon the positive agreement, a national marketing authorization will be issued in the RMS and each of the CMS(s). 54 Marketing Authorization procedures in EU www.DuloMix.com
- 55. 55 • No MA existing in EEA • Application to RMS & CMS • Initial assessment by RMS and comments by CMS (120 days) Second phase of assessment and position by Member States (90 days) In case of disagreement referral to CMD(h)/CHMP (60+ 60 days) Authorisation in CMS (within 30 days) ❑ Decentralised Procedure (DCP) Serious risk to public health Referral to CMD(h) ! CMD(h) : Coordination Group for Mutual Recognition and Decentralised Procedures – Human CHMP : Committee for Medicinal Products for Human Use (EMA) Marketing Authorization procedures in EU www.DuloMix.com
- 56. 56 CHART FORTHE Decentralized procedure Marketing Authorization procedures in EU www.DuloMix.com
- 57. 1. Introduction (background) The main objective of the Active Substance Master File (ASMF) procedure, formerly known as the European Drug Master File (EDMF) procedure, is to allow valuable confidential intellectual property or 'know- how' of the manufacturer of the active substance (ASM) to be protected, while at the same time allowing the Applicant or Marketing Authorisation (MA) holder to take full responsibility for the medicinal product and the quality and quality control of the active substance. National Competent Authorities/EMA thus have access to the complete information that is necessary for an evaluation of the suitability of the use of the active substance in the medicinal product. 57 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 58. 2. Scope • This Guideline is intended to assist Applicants/MA holders in the compilation of the active substance section of their dossiers for a Marketing Authorisation Application (MAA) or a Marketing Authorisation Variation (MAV) of a medicinal product. It is also intended to help ASMF holders in the compilation of their ASMFs. • 3. Legal basis Annex I to Directive 2001/83/EC as amended Part I, 3.2 Basic principles and requirements, (8) Active Substance Master File (for Human medicinal products) and Annex I to Directive 2001/82/EC as amended, Part 2.C.1 General Requirements, 1.1. Active Substances (for Veterinary medicinal products). 58 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 59. • 4. Content of the Active Substance Master File • The overall content of the ASMF should contain detailed scientific information as indicated under the various headings of the relevant Notice to Applicants for Marketing Authorisations for Medicinal Products in the Member States of the European Union (NtA). • ASMFs linked to human medicinal products should be presented in the format of the Common Technical Document (CTD. 59 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 60. • 4. Content of the Active Substance Master File 60 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 61. • 5. Use of the Active Substance Master File Procedure • An ASMF can only be submitted in support of an MAA or MAV. The relationship between the quality of the active substance and its use in the medicinal product needs to be justified in this MAA. • Although the ASMF procedure is developed to keep intellectual property of the ASM confidential, it is also permissible to use the procedure when there is no confidentiality issue between the Applicant/MA holder and the ASM (e.g. when the Applicant/MA holder synthesises the active substance himself). It is expected that the ASM is also the holder of the ASMF. 61 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 62. • 5. Use of the Active Substance Master File Procedure • The ASMF procedure can be used for the following active substances, including herbal active substances/preparations. i.e.: • A. New active substances; • B. Existing active substances not included in the European Pharmacopoeia (Ph. Eur.) or the pharmacopoeia of an EU Member State; • C. Pharmacopeial active substances included in the Ph. Eur. or in the pharmacopoeia of an EU Member State. • The ASMF procedure cannot be used for biological active substance. 62 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 63. • 5. Use of the Active Substance Master File Procedure • The ASMF holder may have an ASMF as well as a Certificate of Suitability (CEP) issued by EDQM for a single active substance. Generally, it is however not acceptable that the Applicant/MA holder refers to an ASMF as well as to a CEP for a single active substance of a particular MAA/MAV. In cases where the CEP contains too little information (e.g. stability) the National Competent Authorities/EMA may decide that additional information should be provided in the dossier. In such case it may be acceptable to refer both to an ASMF and a CEP. 63 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 64. 6. Changes and updates to the Active Substance Master File • As for medicinal products, ASMF holders should keep the content of their ASMFs updated with respect to the actual synthesis/manufacturing process. The quality control methods should be kept in line with the current regulatory and scientific requirements. • ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each National Competent Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. • ASMF holders should provide the updated ASMF to all interested parties with reference to the revised version number. 64 Active Substance Master Files (ASMF) system in EU www.DuloMix.com
- 65. What is IMPD? • The Investigational Medicinal Product Dossier (IMPD) is one of several pieces of Investigational Medicinal Product (IMP) related data required whenever the performance of a clinical trial is intended in one or more European Union Member States. The IMPD includes summaries of information related to the quality, manufacture and control of any IMP, and data from non- clinical and clinical studies. 65 Content and approval process of IMPD www.DuloMix.com
- 66. Guidance and Legal Basis • Guidance concerning IMP Dossiers can be found in the communication from the European Commission titled. • The guidance is based on Regulation (EU) No 536/2014 on Clinical Trials on Medicinal Products for Human Use (Repealing Directive 2001/20/EC) on the approximation of laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. • The Regulation comes into force in 2016, harmonising the laws, regulations and administrative provisions of the Member States relating to the implementation of Good Clinical Practice (GCP) in the conduct of clinical trials on medicinal products for human use 66 Content and approval process of IMPD www.DuloMix.com
- 67. Full and Simplified IMPDs • When applying for a clinical trial authorisation, a full IMPD is required when little or no information about an IMP has been previously submitted to competent authorities, when it is not possible to cross-refer to data submitted by another sponsor and/or when there is no MA in the Community. • A simplified IMPD may be submitted if information has been assessed previously as part of a Marketing Authorisation in any MS or a clinical trial to that competent authority. • There are also situations where the Summary of product characteristics (SmPC) of a Marketed Product will suffice as the IMPD. A SmPC may be submitted if the IMP has a Marketing Authorisation in any EU Member State and is being used in the same form, for the same indication and with a dosing regimen covered by the SmPC. 67 Content and approval process of IMPD www.DuloMix.com
- 73. Regulatory considerations for manufacturing, packaging and labeling of pharmaceuticals in EU 73 www.DuloMix.com
- 74. • All medicinal products for human use manufactured or imported into the EU, including medicinal products intended for export, are to be manufactured in accordance with the principles and guidelines of Good Manufacturing Practice (GMP). • GMP is that part of quality assurance which ensures that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation (MA).GMP is concerned with both production and quality control. 74 Regulatory considerations for manufacturing: EU www.DuloMix.com
- 75. • Good Manufacturing Practice Inspections • GMP inspections are conducted to assess compliance with EU GMP Guidelines as specified in the provisions of the Medicines Act, 2003 and relevant EU Directives. These inspections also ensure that the conditions of the manufacturing licence are being met. By ensuring that EU GMP standards are met during the production of medicinal products one is ensuring that medicines that reach the patient are safe, of good quality and efficacious. The inspection process is a vital safeguard to public health. 75 Regulatory considerations for manufacturing: EU www.DuloMix.com
- 76. There are various types of GMP inspections: • New applications - These types of inspections are conducted following an application for a manufacturing licence. A manufacturing license can be recommended or rejected depending on the outcome of the inspection. • Renewals of manufacturing licenses - Manufacturing license sites are periodically inspected to assess compliance with GMP. • Follow up inspections - These inspections are conducted to follow up a previous inspection. • For cause inspections - These types of inspections may be warranted in specific circumstances or following a complaint. • Variation inspections - Variation inspections are conducted when an application to vary the manufacturing license is received from the license holder. 76 Regulatory considerations for manufacturing: EU www.DuloMix.com
- 77. • Good Manufacturing Practice Guidelines • EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines • S.L. 458.42 - Good Manufacturing Practice in Respect of Medicinal and Investigational Medicinal Products for Human Use Regulations. • S.L. 458.36 - Manufacture and Importation of Medicinal Products for Human Use (Amendment) Regulations. • S.L. 458.47 - Good Clinical Practice and Requirements for Manufacturing or Import Authorisation of Investigational Medicinal Products (Human Use) Regulations. 77 Regulatory considerations for manufacturing: EU www.DuloMix.com
- 78. • The Packaging (Essential Requirements) Regulations 2015 (SI 2015/1640) (“the Regulations”) consolidates and revokes all earlier Regulations. 2. The Regulations implement those provisions of the European Parliament and Council Directive on Packaging and Packaging Waste (94/62/EC) ("the Directive") that relate to the essential requirements for packaging. • The Regulations also implement relevant provisions of EU instruments amending the Directive: Directives 2004/12/EC, 2013/2/EU and (EU) 2015/720 and Commission Decisions 1999/177/EC, 2001/171/EC, 2006/340/EC and 2009/292/EC. 78 Regulatory considerations for Packaging: EU www.DuloMix.com
- 79. • Display of information about a product on its container , packaging, or the product itself. • In Europe , Labeling of drug for human controlled by CHMP under EMA. • All the requirements and items are listed in Title V of Directive 2001/83/EC. 79 Regulatory considerations for labeling : EU www.DuloMix.com
- 80. • RECOMMENDATIONS FORTHE LABELLING • Labelling covers both outer packaging and inner packaging. • Labelling ensures that the critical information is legible, easily • accessible. • The recommendations given in the package leaflet (section A) may be applicable • to labelling . • The particulars appearing on the label of all medicinal products should be • printed in characters of at least 7 points, leaving a space between lines of at least 3 mm. 80 Regulatory considerations for labeling : EU www.DuloMix.com
- 81. • Legal Framework • According to Article 54, Article 55 and Article 59 of Directive 2001/83/EC of the European Parliament, medicinal products for human use medicinal products must be accompanied by outer and/or immediate packaging information (labeling) and a package leaflet. • Article 58 of Directive 2001/83/EC allows for the omission of a package leaflet where all the required information can be directly conveyed on the packaging. • Article 56 of Directive 2001/83/EC requires that the particulars to be included in the labeling shall be easily legible, clearly comprehensible and indelible. • According to Article 57 of Directive 2001/83/EC, additional labelling requirements may apply in particular Member States in respect of price, legal status for supply and identification and authenticity. • Labelling must contain all elements required by Article 54 of Directive 2001/83/EC or a lesser set of elements where the provisions of Article 55 of the same Directive apply. • Nevertheless, of the information items listed in Article 54 of Directive 2001/83/EC, certain items are deemed critical for the safe use of the medicine. 81 Regulatory considerations for labeling : EU www.DuloMix.com
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- 83. 83 Regulatory considerations for labeling : EU www.DuloMix.com
- 84. 84 Regulatory considerations for labeling : EU www.DuloMix.com
- 85. 85 Regulatory considerations for labeling : EU www.DuloMix.com
- 86. 86 Regulatory considerations for labeling : EU www.DuloMix.com
- 87. 87 Regulatory considerations for labeling : EU www.DuloMix.com
- 88. 88 Regulatory considerations for labeling : EU www.DuloMix.com
- 89. 89 Regulatory considerations for labeling : EU www.DuloMix.com
- 90. 90 Regulatory considerations for labeling : EU www.DuloMix.com
- 91. 91 Regulatory considerations for labeling : EU www.DuloMix.com
- 92. 92 Regulatory considerations for labeling : EU www.DuloMix.com
- 93. 93 Regulatory considerations for labeling : EU www.DuloMix.com
- 94. 94 Regulatory considerations for labeling : EU www.DuloMix.com
- 95. 95 Regulatory considerations for labeling : EU www.DuloMix.com
- 96. 96 Regulatory considerations for labeling : EU www.DuloMix.com
- 97. 97 Regulatory considerations for labeling : EU www.DuloMix.com
- 98. 98 Regulatory considerations for labeling : EU www.DuloMix.com
- 99. 99 Regulatory considerations for labeling : EU www.DuloMix.com
- 100. 100 Regulatory considerations for labeling : EU www.DuloMix.com
- 101. 101 Regulatory considerations for labeling : EU www.DuloMix.com
- 102. 102 EudraLex (The Rules Governing Medicinal Products in the European Union) • EudraLex is the collection of rules and regulations governing medicinal products in the European Union. www.DuloMix.com
- 103. • EudraLex consists of 10 volumes: Concerning Medicinal Products for Human use: • Volume 1 - Pharmaceutical Legislation • .Volume 2 - Notice toApplicants. -Volume 2A deals with procedures for marketing authorisation. -Volume 2B deals with the presentation and content of the application dossier. -Volume 2C deals with Guidelines. • Volume 3 – Guidelines Concerning Medicinal Products for human use in clinical trials (investigational medicinal products) • Volume 10 - Clinical trials. Concerning Veterinary Medicinal Products: • Volume 5 - Pharmaceutical Legislation. • Volume 6 - Notice toApplicants. • Volume 7 - Guidelines. • Volume 8 - Maximum residue limits. • Concerning Medicinal Products for Human and Veterinary use: • Volume 4 - Good Manufacturing Practices. • Volume 9 - Pharmacovigilance. • Miscellaneous: Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03) • Directives 103 EudraLex www.DuloMix.com
- 104. 104 Eudralex (directives for human medicines) www.DuloMix.com
- 106. 106 Eudralex (directives for human medicines) www.DuloMix.com
- 108. 108 Eudralex (directives for human medicines) www.DuloMix.com
- 110. 110 Eudralex (directives for human medicines) www.DuloMix.com
- 111. 111 Variations & extensions EU www.DuloMix.com
- 112. • What is a Variation….? A variation to the terms of a marketing authorization is an amendment to the contents of the documents of the approved dossier • Variations in European Union (EU) are regulated by following regulations and Guidelines: • Commission Regulation (EC) No. 712/2012 of 3 August 2012 amending Regulation (EC) No. 1234/ 2008 concerning examination of variations to the terms of marketing authorisations • for medicinal products for human use and veterinary medicinal products. • Annex I – Extensions of marketing authorisations. • Annex II – Classification of variations. • Annex III – Cases for grouping variations. • Annex IV – Elements to be submitted. • Annex V –Variations concerning a change to or addition of therapeutic indication, addition of • non-food producing target species, replacement or addition of a stereotype, strain, antigen etc. 112 Variation www.DuloMix.com
- 113. • Guidelines of 16.05.2013 on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures. 113 Variation www.DuloMix.com
- 115. • In general changes are categorized into three types: 115 Variation Administrative changes CMC (Quality changes) Safety, PV, Efficacy etc.. www.DuloMix.com
- 116. • Variations are classified into following types – 116 TYPES OFVARIATIONS Variations Type IB (Minor Variation) Type II (Major Variation) Extension (new application) Type IA (Minor Variation) www.DuloMix.com
- 117. 117 Type IA variations ➢ Type lA variations: Type lA variations are the minor variations which have only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product, and do not require prior approval before implementation ("Do and Tell" procedure). Such a minor variations are “classified” two subcategories, which impact on their submission: • Type lA variations requiring immediate notification (‘IA IN‘) • Type lA variations NOT requiring immediate notification (‘lA’) (Variations which do not require immediate notification may be submitted by the marketing authorisation holder (MAH) within 12 months after implementation). www.DuloMix.com
- 118. 11 ➢ Why certain minor variations of Type IA require immediate notification ? Certain minor variations of Type IA require immediate notification after implementation, in order to ensure the continuous supervision of the medicinal product. ➢ When should I submit my Type IAINvariation? This should be submitted immediately and generally within 2 weeks of implementation of the change. ➢ What is meant by 'implementation' for Type IA variations? For quality changes, implementation is when the company makes the change in its own quality system. Type IA variations www.DuloMix.com
- 119. EXAMPLESOFTYPE IAVARIATIONS 11 Type IA Changes - Only a minimal impact or no impact at all, on the quality, safety or efficacy of the medicinal product ("Do and Tell" procedure ): ➢ Examples of Type IAIN variation: ▪ Change in the name and/or address of the marketing authorisation holder ▪ Change in the name and/or address of a manufacturer/importer of the finished product (including batch release or quality control testing sites) ▪ Changes in imprints, bossing or other markings ▪ Change in the shape or dimensions of the pharmaceutical form perticularly Immediate release tablets, capsules, suppositories and pessaries. ➢ Examples of Type IA variation: ▪ Addition of physico-chemical test in specification. ▪ Deletion of non-significant test (ex: Identification test in Stability study). ▪ Tightening of specification limits (ex: Tightening of test limit for water content, Residual solvents and Related substances..etc. ▪ CEP updates/renewal. ▪ API and FP Batch size increase/decrease within 10 fold. www.DuloMix.com
- 120. Type IB variations 12 • Commission Regulation (EC) No 1234/2008 ('theVariations Regulation') defines a minor variation orType 1B as a variation which is neither aType lA variation nor Type II variation nor an Extension. • Such minor variations must be notified to the NationalCompetent Authority/European MedicinesAgency by the Marketing Authorisation Holder (MAH) beforeimplementation. • However, the MAH must wait a period of 30 days to ensure that the notification is acceptable by theAgency before implementing the change (Tell,Wait and Doprocedure). www.DuloMix.com
- 121. EXAMPLESOFTYPE IBVARIATIONS 12 Type IB Changes - Min to moderate impact on product quality (Tell, Wait and Do procedure): ➢ Major change the approved Analytical method ➢ FP Mfg. site changes ➢ Shelf-life extension ➢ Change in storage condition ➢ Minor changes to approved manufacturing process ➢ Change in batch size beyond 10 fold category ➢ SmPC /PIL changes in-line with innovator product www.DuloMix.com
- 122. Type II variations 12 • Commission Regulation (EC) No 1234/2008 ('the Variations Regulation') defines a major variation of Type II as a variation which is not an extension and which may have a significant impact on the Quality, Safety or Efficacy of a medicinal product. EXAMPLES OF TYPE II VARIATIONS Type II Changes (Significant impact on product quality, safety & efficacy): ➢ Addition of alternate/new API DMF supplier ➢ Relaxation of approved specification ➢ Major change in approved manufacturing process ➢ Major change in approved composition www.DuloMix.com
- 123. ExtensionApplications 12 • Definition for Extension of marketing authorisation: Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC) No1234/2008 are regarded as "extensions" of the marketing authorisation. Examples of extension changes: 1. Changes to the active substance(s) - replacement of a chemical active substance by a different salt/ester complex/derivative. with the same therapeutic moiety, where the efficacy/safety characteristics are not significantly different; 2. Change to strength, pharmaceutical form, route of administration • Change of bioavailability; • Change of pharmacokinetics e.g. change in rate of release; • Change or addition of a new strength/potency; • Change or addition of a new pharmaceuticalform; • Change or addition of a new route of administration. • Such applications will be evaluated in accordance with the same procedure as for the granting of the initial marketing authorisation to which it relates. • The extension can either be granted as a new marketing authorisation or will be included in theinitial marketing authorisation to which itrelates. www.DuloMix.com
- 125. Grouping of variations 12 • It is possible to group variations of different categories the same marketing authorisation (MA) and submit them in one submission, under a single application form, to the same relevant authority. This is permissible where variations are covered under the cases listed in Annex Ill to the variations regulation. • Examples are any group of lA changes, a group comprising a Type IB or Type II change plus one or more of the same or lower category which are consequential to the first, and a group of administrative changes to labelling. • If a projected group is not listed in Annex Ill, the regulation and supporting guidances permit the MAH to request agreement of the relevant authority(ies) to grouping of related changes where a single data package and evaluation are meaningful. • 14 cases of Groupings listed in Annex Ill • CMDh Guidance for Examples for Acceptable and Not- Acceptable Groupings for MRP/DCP Products -Doc. Ref: CMDh/173/2010/Rev.10 July 2013 www.DuloMix.com
- 126. Documentation required for variation filling 12 ➢ The following documents should be submitted for filing of Variations applications: • Cover letter. • The completed EU variation application form • Reference of variation guidelines, indicating that all conditions and documentation requirements are met. • Relevant documentation in support of the proposed variation including any documentation specified in the Annex to these guidelines. • In case that the variations affect the summary of product characteristics, labelling or package leaflet: the revised product information presented in the appropriate format. • Update or Addendum to the detailed critical summaries (quality, safety, efficacy as appropriate) www.DuloMix.com
- 127. VARIATION APPROVALTIMELINE ➢ How shall my Type IA/ IAin notification be processed (timetable) by Health Authority? A ‘notification of receipt’ letter would be issued by the Agency within five days of receipt of a Type IA application. Within 30 days of receipt, the notification would be reviewed. The Health authority will check the correctness of the application form, ensure the required documentation is present and compliance with the required conditions. The outcome of the process, an approval and/or refusal, would be communicated to the MAH via the post or the portal. There will be no interaction with the marketing authorisation holder (MAH) during the procedure, and no request to provide missing information Type IA notification is a ‘Do and tell’ procedure, therefore changes must be implemented prior to submission of notification. 12 www.DuloMix.com
- 128. 12 How shall my Type IB notification be processed (timetable) by Health Authority? For Type IB notifications, the target pre-assessment processing time is 14 days. Substantive assessment is done within 30 days, and leads either to approval or a request for further information (RFI) letter within that 30 days. The company’s response to the RFI letter needs to be received within 30 days. Assessment of that response is within a further 30 days. VARIATION APPROVALTIMELINE www.DuloMix.com
- 129. ➢ How shall my Type II notification be processed (timetable) by Health Authority? Type II variations follow a 30-day, 60-day or 90-day procedure (Depending upon complexity of the variation application) 12 VARIATION APPROVALTIMELINE www.DuloMix.com
- 130. 130 Compliance of European Pharmacopoeia (CEP)/ Certificate of Suitability (CoS) www.DuloMix.com
- 131. European Directorate for the Quality of Medicines & HealthCare (EDQM) A Council of Europe Directorate, based on the Convention on the Elaboration of a European Pharmacopoeia (PA, 1964) Mission: to contribute to a basic human right: access to good quality medicines and healthcare www.DuloMix.com 131
- 132. European Pharmacopoeia (Ph. Eur.) • Protecting public health - one common compulsory standard. •The Ph. Eur. is the official pharmacopoeia in Europe – complemented by national pharmacopoeias for texts of interest to only one Member State. •Mandatory at the same date in 37 Member States (CoE) and the EU. •Legally binding quality standards for ALL medicinal products in its member states, i.e. raw material, preparations, dosage forms, containers must comply with the Ph. Eur. requirements when they exist. www.DuloMix.com 132
- 133. European Pharmacopoeia MonographsToday • Active substances (organic, inorganic) • Excipients • Substances of biological origin and biotechnology (insulin, somatropin...) • Herbal drugs, essential oils and fats, preparations • Radiopharmaceuticals • Vaccines, sera (human, veterinary), blood derivatives • Homeopathic preparations • General monographs on dosage forms • General texts on quality issues and standard analytical methods www.DuloMix.com 133
- 134. General Notices Put at the very beginning of the Ph. Eur., they address general issues and are aimed at providing basic information to the user. ► Apply to all texts ► Rules to understand texts, conventional expressions Essential reading before starting to use Monographs www.DuloMix.com 134
- 135. Flexibility in the Ph.Eur. -Alternative methods • Ph. Eur. tests are reference methods, essential in cases of dispute. • Compliance is required, but alternative methods may be used as long as they lead to the same pass/fail result. It is the responsibility of the user to demonstrate their suitability. Approval of the competent authority is necessary in many cases. www.DuloMix.com 135
- 136. Flexibility in the Ph.Eur. – General Notices “An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product….. An enhanced approach to quality control could utilise process analytical technology (PAT) and/or real-time release testing (including parametric release) strategies as alternatives to end-product testing alone.” (Suppl. 8.2.) www.DuloMix.com 136
- 137. What does compliance mean? • Compliance with a monograph • All mandatory parts of a monograph. • Compliance until time of use for raw materials, ingredients. • Compliance throughout period of validity for preparations. • In-use compliance decided by licensing authority for each preparation. www.DuloMix.com 137
- 138. What must comply? • Mandatory for all substances for pharmaceutical use • Ingredients (incl. excipients) of final formulation • Components of solvents, buffers etc. in or used to make up final formulation • Reagents? Not usually needed for upstream use www.DuloMix.com 138
- 139. Validation of Pharmacopoeial methods 9 www.DuloMix.com The test methods …. have been validated ….. Unless otherwise stated in the monograph or general chapter, validation of the test methods by the analyst is not required.” “When implementing a pharmacopoeial method, the user must assess if and to what extent the suitability of the method under the actual conditions of use needs to be demonstrated « 8th edition 139
- 140. Why general chapters? Analytical methods: • Editorial convenience: avoid repeating standard methods in each monograph • Provide standard methods that can be used where there is no monograph • Give general requirements for equipment, equipment verification • Not mandatory “per se” but when referred to in a monograph, they become part of the standard Also other types of general chapters… www.DuloMix.com 140
- 141. Examples • Chapter 5.10 Control of impurities in substances for pharmaceutical use ➔ cross referenced in General monograph 2034 Substances for pharmaceutical use ➔ chapter 5.10 is to be applied to all API (whether or not an individual monograph exists in the Ph. Eur.) • Chapter 5.2.8 Minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products ➔ creation of General monograph 1483Products with risk of transmitting agents of animal spongiform encephalopathies which cross-references the chapter 5.2.8 ➔ chapter 5.2.8 is legally binding www.DuloMix.com 141
- 142. Why general monographs? Two types: • General monographs on classes of substances • General monographs on dosage forms • Apply to all products (“General monographs apply to all substances and preparations within the scope of the Definition section of the general monograph, except where a preamble limits the application, for example to substances and preparations that are the subject of a monograph of the pharmacopoeia.” General notices) • No cross-reference in individual monographs www.DuloMix.com 142
- 143. General monographs (cont.) 14 www.DuloMix.com • “Classes” defined by different criteria: production method, origin, risk factors • Aspects that cannot be treated in each individual monograph ➢ Residual solvents ➢ TSE/BSE ➢ Pesticides in herbals ➢ etc. …
- 144. Which has priority, a general monograph or an individual monograph? • Basic principle is that general and individual monographs are complementary and one does not overrule the other. • Exceptions are clearly indicated either in the general monograph or in the individual one. www.DuloMix.com 144
- 145. Substances for pharmaceutical use (2034) • Requirements laid down in this general monograph apply to all substances for pharmaceutical use whether or not the substance is covered by an invidual monograph. • “Where a substance for pharmaceutical use not described in an individual monograph of the Pharmacopoeia is used in a medicinal product prepared for the special needs of individual patients, the need for compliance with the present general monograph is decided in the light of a risk assessment that takes account of the available quality of the substance and its intended use”. www.DuloMix.com 145
- 146. Pharmaceutical Preparations (2619) • reference source of standards in the European Pharmacopoeia on active substances, excipients and dosage forms, which are to be applied in the manufacture/preparation of pharmaceuticals, but not a guide on how to manufacture as there is specific guidance available covering methods of manufacture and associated controls. • does not cover investigational medicinal products, but competent authorities may refer to pharmacopoeial standards when authorising clinical trials using investigational medicinal products. www.DuloMix.com 146
- 147. General monographs on dosage forms • Contain requirements common to all dosage forms of the type defined (tablets, capsules, parenteral preparations, etc.) • Classified by pharmaceutical form/route of administration • Applied during licensing • Framework specification: acceptance criteria and extra tests are proposed by manufacturer and approved by competent authority www.DuloMix.com 147
- 148. The Certification Procedure • To demonstrate that the quality of a substance is controlled by the Ph. Eur. monograph and additional tests if needed (“Chemical CEP” or “Herbal CEP”) • To guarantee compliance with the Products with TSE risk (“TSE CEP”) www.DuloMix.com 148
- 149. The Certification Procedure (cont.) •CEPs are accepted in 37 Member States + EU, and beyond (e.g. Canada, Australia, Singapore, South Africa, etc.) •Directive 2003/63/EC: Where the active substance and/or raw and starting material or excipient(s) are the subject of a monograph of the EP, the applicant can apply for a certificate of suitability that, where granted by the EDQM, shall be presented in the relevant section of the Module. Those certificates of suitability …are deemed to replace the relevant data of the corresponding sections described in the Module… www.DuloMix.com 149
- 150. The CEP procedure (cont.) Provides: • Centralised assessment - saves time and resources • Information on the need to update Ph. Eur. monographs • Facilitates management of MAAs and variations • Application submitted directly to EDQM by the manufacturer of the pharmaceutical substance • Confidentiality of data •Governing document for the Certification procedure : •Resolution AP-CSP (07) 1 www.DuloMix.com 150
- 151. Scope of the CEP Procedure • Substances described in monographs in the Ph. Eur. (Active substances, excipients, herbal drugs / herbal preparations) •→ “Chemical” or “Herbal” CEP • Products with risk of TSE (SM, intermediates, reagents,..) •→ “TSE” CEP • Open to any manufacturer regardless of geographical origin www.DuloMix.com 151
- 152. Out of Scope of the CEP Procedure • Substances not included in Ph. Eur. • Biologicals (PA/PH/CEP (09) 152 rev 01) • Human tissues derivatives, blood derivatives, vaccines • Mixtures of API with excipients (unless justified) • Substances which do not comply with the Definition section of the monograph • Finished products www.DuloMix.com 152
- 153. How to apply for a CEP • Application form (for new application) available on the website. It contains tables to be filled in, statements and declarations to be signed • Quality Overall Summary (see template on the EDQM website) • Fees: • Electronic submissions encouraged (eCTD, NeeS, pdf) • Dossier in English (preferably) or French (see documents on the EDQM website) www.DuloMix.com 153
- 155. What does it mean? • A chemical CEP certifies that the quality of the substance is suitably controlled by the Ph. Eur. monograph with addition of tests if necessary (mentioned on the CEP) • A TSE CEP certifies that the substance complies with the EMA NfG on minimising the TSE risk. It DOES NOT certify that the quality of the substance is suitably controlled by a specific Ph. Eur. monograph • It DOES NOT replace a certificate of analysis • It IS NOT a GMP certificate www.DuloMix.com 155
- 156. Certification - Inspection • Integral part of the Certification Procedure • Article 111 of Directive 2001/83/EC and Article 80 of Directive 2001/82/EC, Compilation of Community Procedures) • Performed before or after the CEP is granted • Aim: to verify the compliance with ✓ Submitted dossier ✓ EU GMP Part II ✓ EU GMP Annexes (e.g. Annex 1 / sterile substances) Actions are taken immediately after the inspection in case of major or critical deficiencies (public health issue) www.DuloMix.com 156
- 158. Marketing Authorization (MA) transfers www.DuloMix.com 158
- 159. Article 1 This Regulation lays down the procedure for the examination of applications for the transfer of a marketing authorization granted in accordance with Council Regulation (EC) No 2309/93, except for the situations covered by point 3 of Annex I to Commission Regulation (EC) No 542/95. Definition Article 2 For the purposes of this Regulation, “transfer of a marketing authorization” means the procedure of changing the addressee (hereinafter referred to as “the holder”) of the marketing authorization decision adopted pursuant to Article 10 (1) and (2) or Article 32 (1) and (2) of Council Regulation (EEC) No 2309/93, the new holder not being the previous holder. Marketing Authorization (MA) transfers www.DuloMix.com 159
- 160. Administrative Procedure Article 3 1. To obtain a transfer of a marketing authorization, the holder of this authorization shall submit an application to the European Agency for the Evaluation of Medicinal Products (hereinafter referred to as “the Agency”), accompanied by the documents mentioned in the Annex to this Regulation. 2. Such an application shall only concern the transfer of one marketing authorization and shall be accompanied by the relevant fee provided for by Council Regulation (EC) No 297/95 on fees payable to the European Agency for the Evaluation of Medicinal Products (1). Article 4 1. The Agency shall submit, within 30 days following receipt of an application within the meaning of Article 3 (2), an opinion concerning this application to the holder of the marketing authorization, to the person to whom the transfer shall be granted and to the Commission. Marketing Authorization (MA) transfers www.DuloMix.com 160
- 161. Administrative Procedure Article 5 1. The Agency's opinion referred to in Article 4 can only be unfavourable if the documents submitted in support of the application are incomplete or if it appears that the person to whom the transfer shall be granted is not established within the Community. Article 6 1. In the case of a favourable opinion and without prejudice to the application of other provisions of Community law, the Commission shall immediately amend the decision taken in accordance with Articles 10 or 32 of Council Regulation (EEC) No 2309/93. Marketing Authorization (MA) transfers www.DuloMix.com 161
- 162. Administrative Procedure Article 7 1. The transfer of the marketing authorization shall be authorized from the date of notification of the amendment of the Commission decision referred to in Article 6 (2). 2. The date on which the transfer actually takes place shall be set by the Agency by mutual agreement with the holder of the marketing authorization and the person to whom the transfer is to be granted. The Agency shall immediately inform the Commission of this date. 3. The transfer of a marketing authorization shall not affect any of the time limits provided for in Articles 13 and 35 of Council Regulation (EC) No 2309/93. Article 8 1. This Regulation shall enter into force on the third day following its publication in the Official Journal of the European Communities. Marketing Authorization (MA) transfers www.DuloMix.com 162
- 163. Marketing Authorization (MA) transfers www.DuloMix.com 163
- 164. 164 Qualified Person (QP) in EU www.DuloMix.com
- 165. 165 www.DuloMix.com
- 166. Certification by a Qualified Person and Batch Release www.DuloMix.com 166
- 167. Certification by a Qualified Person and Batch Release www.DuloMix.com 167
- 168. Certification by a Qualified Person and Batch Release www.DuloMix.com 168
- 169. Certification by a Qualified Person and Batch Release www.DuloMix.com 169
- 170. Certification by a Qualified Person and Batch Release www.DuloMix.com 170
- 171. Certification by a Qualified Person and Batch Release www.DuloMix.com 171
- 172. Certification by a Qualified Person and Batch Release www.DuloMix.com 172
- 173. Certification by a Qualified Person and Batch Release www.DuloMix.com 173
- 174. Certification by a Qualified Person and Batch Release www.DuloMix.com 174
- 175. Certification by a Qualified Person and Batch Release www.DuloMix.com 175
- 176. Certification by a Qualified Person and Batch Release www.DuloMix.com 176
- 177. Certification by a Qualified Person and Batch Release www.DuloMix.com 177
- 178. Certification by a Qualified Person and Batch Release www.DuloMix.com 178
- 179. Certification by a Qualified Person and Batch Release www.DuloMix.com 179
- 180. 180 Legislation and regulations for import, manufacture, distribution and sale of cosmetics in European Union & Australia www.DuloMix.com
- 181. National authorities in each EU country are in charge of reviewing the safety assessments and checking products already on the market. Cosmetics Legislation requires that every cosmetic product placed on the market in Europe is safe to use. The EU Cosmetic Regulation 1223/2009 came into force in 2013 and concerns 31 European countries (28 countries of the EU + Norway + Iceland + Lichtenstein). The regulation is based on three principles: • Safety of Raw Materials and Ingredients • Good manufacturing practices • Invigilating of cosmetic market Europe Cosmetic Requirements www.DuloMix.com 181
- 182. These principles translate into requirements for the cosmetic brand (non-exhaustive list): • Designate a Responsible Person (RP) • Prepare a Product Information file (PIF) including a Safety Assessment • Respect the Good manufacturing practices (GMP) for cosmetics • Comply with Labeling and Packaging requirements • Ensure notification via the Cosmetic Products Notification Portal (CPNP) With this regulation, the European Union sets a higher level of transparency for finished cosmetic products, prevents the placing on the market of hazardous substances, and strengthens safety for consumers Europe Cosmetic Requirements www.DuloMix.com 182
- 183. The Product Information File: PIF is the mandatory compilation of technical documentation required for each cosmetic product to be placed on the EU market. According to the EU Cosmetics Regulation 1223/2009/EC, the elements of the PIF include but are not limited to: • Product Description • Safety Report: • Part A: Cosmetic Product Safety Information • Part B: Cosmetic Product Safety Assessment Report • Method of Manufacturing, Evidence of compliance with Good Manufacturing Practices (GMP), Proof of the effect claimed (where justified), Data on Animal Testing, Labeling (taking into account the container and outer packaging), Data on Serious Undesirable Effects Europe Cosmetic Requirements www.DuloMix.com 183
- 184. I. Labelling: In EU regulations they have as well systematic mandatory information that must be printed in “indelible, easily legible and visible lettering”: •Name and address of the Responsible Person: If applicant is outside the EU, it is mandatory to designate Responsible Person (RP), in order to market the product. If cosmetic brand based in the EU, applicant will be acting as the RP by default. List of ingredients: In decreasing order of weight, except for ingredients below 1%. Country of origin: Add the mention: “Made in country” unless the product is made in Europe in which case such mention is not mandatory. Note: the “Made in” expression does not need any translation. Europe Cosmetic Requirements www.DuloMix.com 184
- 185. Nominal content: The nominal content must appear in grams (g) or milliliter (ml) and in first position. Date of minimum durability (DOMD) & Period after opening (PAO): If the durability is inferior or equal to 30 months, manufacturer need to indicate the “hour glass” symbol and print date (MMYY / DDMMYY). If the durability is superior to 30 months then you must indicate the PAO. Manufacturer will need to print the “open jar” symbol with the number of months (M) or year (Y) inside or next to the open jar. Particular precautions of use and warnings: Depending on the type of cosmetic product, some particular precautions of use and warnings might be useful to consumers or even mandatory in certain cases. Batch number: is mandatory, although no particular format is required. Product function: The function of the product must be clearly indicated, e.g.: hand moisturizer as to prevent any misuse. Product claims: In the labelling, making available on the market and advertising of cosmetic products, text, names, trademarks, pictures and figurative or other signs shall not be used to imply that these products have characteristics or functions which they do not have Europe Cosmetic Requirements www.DuloMix.com 185
- 186. II. Observation of EU cosmetic regulations: Cosmetics in EU to avoid the complex have clarified by establishing the “Illustrative list by category of Cosmetic Products”. EU has stringent laws where companies are required to submit the proof of the claims made by the product as borderline cosmetic products are already classified. EU cosmetic regulations expressly prohibit the use of any substances determined to be carcinogenic, mutagenic, or toxic to reproductive systems. The EU’s Cosmetic Regulation also specifies those colorants, preservatives and UV-filters that are approved for use in cosmetic products. Toward this end, manufacturers are responsible for identifying a “responsible person” who can address issues of non-compliance identified by authorities. Europe Cosmetic Requirements www.DuloMix.com 186