Control of veterinary products and vaccines Inspection system, monitoring plan, monitoring of vaccines distribution

Transcription

1 Workshop for OIE national Focal Points for Veterinary Products (2 nd cycle) Vienna (Austria), November 2012 Control of veterinary products and vaccines Inspection system, monitoring plan, monitoring of vaccines distribution Dr. Catherine LAMBERT Anses/ANMV OIE Collaborating Centre on Veterinary medicinal products BP FOUGERES CEDEX, FRANCE

2 Inspection system monitoring plan monitoring of distribution of vaccines 1st part : activities and inspection systems 2 nd part : monitoring plan 3rd part : monitoring of distribution of vaccines Conclusion 2

3 Système d inspection Plan de surveillance Contrôle de la distribution des vaccins - Contrefaçons 1st part : activities and inspection systems Inspection Activities : how to deal with an inspection system covering production, importation and distribution of veterinary vaccines? Inspection system Atelier pour les Points Focaux nationaux de l OIE 3

4 1st part : activities and inspection systems 1- General principle Definition Inspection: Careful examination in order to control, to supervise and to check Observation Investigation Compliance Assessment Monitoring Confrontation with facts Study Inquiry 4

5 1st part : activities and inspection systems 1. General principle Manufacturing and distribution of veterinary medicinal products and vaccines Authorised and regularly inspected manufacturers and distributors in A documentary one or on site An Inspection can be: programmed d or unexpected 5

6 1st part : activities and inspection systems 2. Inspection standards for manufacture: Why do we need them? For inspection and certification of vaccines manufacturers: Good manufacturing practices (GMP) standard is a tool used to make sure that vaccines are manufactured in the framework of a quality system in conformity with the requirements of the marketing authorisation GMP impose an obligation of MEANS 6

7 1st part : activities and inspection systems 2. Inspection standards for manufacture: 2.1. List Different guides for Good Manufacturing Practices exist (EU / FR, PIC/S) "The rules governing medicinal products in the European Union : Annex 5 : Manufacture of immunological VMPs Annex 1 : Manufacture of Sterile medicinal products «Manual of Diagnostic Tests and vaccines For Terrestrial Animals»: Chapter : Principles of veterinary vaccines production Marketing authorisation dossier with manufacture and control methods 7

8 1st part : activities and inspection systems 3- Inspection standard for distribution A good distribution practice guide regarding VMPs exists in France (arrêté du 21 avril 2005) Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03) However, no difference between distribution of human medicines and veterinary medicines 8

9 1st part : activities and inspection systems 4. Inspection standards for imports Activity between manufacture and distribution: Requirements generally defined by the national regulation No specific standard for «good importation practices» Inspectors refer to GMP and GPD guides Risks are related to: Storage conditions Transportation Reception, in particular duration and temperature 9

10 1st part : activities and inspection systems 4. Inspection standards for imports Inspection : Legislative aspects: conformity with the authorisation of importation, presence of the required certificates, Physical aspects: state of the goods, respect of the conditions of conservation of the products, If necessary: complete analytical control for the release (example: asked for importation in EU in case of VMP manufactured in a third country without Mutual recognition agreement MRA) 10

11 1st part : activities and inspection systems 5. Realisation of inspections In routine or punctually : For manufacturer: buildings, personnel, Quality assurance system, production methods and analytical controls (every 2 years in general) Regulatory documentation, products state and transportation conditions for the imports (systematic inspection) For distributor: buildings, personnel and quality assurance system (inspection every 2 to 3 years) Carried out by experienced inspectors with good knowledge of the industrial practices, GMP, GPD and methods of inspection 11

12 1st part : activities and inspection systems 5. Realisation of inspections Qualification and experience 12 Purpose: accreditation for all types of inspection (GMP, GDP ) Requirements: Knowledge in Quality assurance management Pharmaceutical manufacture Dosage forms Quality control Distribution Inspection management

13 1st part : activities and inspection systems 5. Realisation of inspections Maintenance of the accreditation based on: Regular inspections Meetings with other inspectors Annual supervision by a senior inspector Ongoing training Regular meeting with other pharmaceutical organisations 13

14 1st part : activities and inspection systems 6. Sanctions For manufacturer: or a GMP certificate (3 years validity maximum) a non conformity certificate with consequences on activity: total or partial closing or suspension of manufacture activities For distributor : the authorisation/license is maintained or withdrawn in case of non conformity 14

15 Système d inspection Plan de surveillance Contrôle de la distribution des vaccins - Contrefaçons 1st part : activities and inspection systems Inspection Activities : how to deal with an inspection system covering production, improtation and distribution of veterinary vaccines? Inspection system 15

16 1st part : inspection systems 1. Organisation An inspection system is composed of : An authority involved in supervision and control in accordance with laws and regulations A team of trained inspectors (approximately 1 to 2 years of formation for GMP and 6 months for GDP) and qualified for this kind of inspection An administrative system in charge of: the facilities management the planning of the inspections the certification 16

17 1st part : inspection systems 2. Quality Assurance Pharmaceutical inspectorates must fulfill the quality assurance rules in order to guarantee the harmonization of decisions Described in «Quality System Requirements for Pharmaceutical Inspectorates»: PIC/S recommendation for inspectorates in charge of GMP and GPD inspections Included in the compilation of the EU procedures This document and the included questionnaires for audits are used to evaluate the equivalence of the inspection systems of national authorities (for example: for MRA, for adhesion to PIC/S) 17

18 1st part : inspection systems 4. Particular Case : vaccines inspection 4.1. first of all Vaccines must fulfil the criteria of Quality, safety, efficacy until the date of expiry Every vaccine should be : Authorised (marketing authorisation) in the distribution zone or at least in the country of origin Manufactured in a GMP compliant manufacture or at least fulfil the requirements (manufacturing and controls) described in the Chapter of OIE manual of diagnostic tests and vaccines for terrestrial animals 18

19 1st part : inspection systems 4. Vaccines Inspection 4.2. Inspection procedure should be different depending on the country of origin Local manufacture inspections can be made by the national authority Manufacture in a third country depending on the confidence in the inspection system 19

20 1st part : inspection systems Manufacture in a third country (1) 1 st case : Importing country authority recognises the inspections made by the exporting country in this case a copy of the GMP certificate (inspection made within the 3 past years) will be required for any importation However, it is always possible to ask for a targeted inspection on the concerned product 20

21 1st part : inspection systems Manufacture in a third country (2) 2 nd case : Certificates from the country where the vaccine is manufactured are not recognised it is better to carry out or ask for an initial inspection and to regularly renew it (every 2 years ) 21

22 1st part : inspection systems 4. Vaccines Inspection: 4.3. constraints Difficulty to put in place and maintain an inspection team: Initial training: long and fastidious Need for maintaining competences by continuous training and a sufficient number of inspections each year In practice: Maintenance of GMP inspection team at national level is not possible for a country having less than 10 manufacturers Easier at a regional level However, administrative activities can be maintained at national level and GMP inspections sub-contracted to another authority In that case the authority in charge decides to import (or not) the VMP taking into account the information and proposals indicated in the inspection report 22

23 1st part : inspection systems 5. Control of imported vaccines Control procedure will be different depending on: The country of origin Confidence in its inspection system (example: PIC/S member or not) Transit countries and duration of the transit Cold chain, duration and conditions of storage and transportation Kind of product Live vaccine or inactivated vaccines, virulence of the active substance Pharmacovigilance data, non-conformities and quality default previously recorded 23

24 1st part : inspection systems 5. Control of imported vaccines According to the risk analysis the competent authority may require : A complete analytical control on the release tests indicated in the marketing authorisation dossier A partial analytical control Or accept a documentary release Example: for imports in EU coming from third country without a MRA with EU, a complete control is required when arriving 24

25 Inspection system monitoring plan monitoring of distribution of vaccines 1st part : activities and inspection systems 2nd part : monitoring plan 3rd part : monitoring of distribution of vaccines Conclusion 25

26 2 nd part: monitoring plan Definition A monitoring plan is composed of the controls to be carried out on products and on manufacturing and distribution process taking into account risks and potential defaults preliminary identified in a risk analysis 26

27 2 nd part: monitoring plan 1. Risk analysis 1.1. Theory (cf. GMP annex 20 et ICH Q9) Risk analysis consists of the identification of hasards and evaluation of risks associated with exposure to those hazards This is a qualitative and quantitative process based on current knowledge about assessing the probablility, severity and sometimes detectability of the risk Quality risk management is a systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle 27

28 2 nd part: monitoring plan 1. L analyse de risque : théorie (suite) 28

29 2 nd part: monitoring plan 2. Existing tools in EU Pharmacovigilance Official batch release Monitoring Plan of vaccines quality Monitoring plan of manufacturers and distributors Obligation for the manufacturer to declare a quality default 29

30 2 nd part: monitoring plan 2. Existing tools in EU 2.1. Veterinary pharmacovigilance Definition: Detection and investigation of the effects due to the use of VMPs, mainly aimed at safety in animals and safety in people exposed to the products Pharmacovigilance may also cover : Lack of expected efficacy Potential environmental problems Pharmacovigilance relies on a network of the different parties involved in vaccines (users, veterinarians, distributors, marketing authorisation holders, authorities) Pharmacovigilance is generally part of the authority activities and relies as a minimum on: A national or regional database An assessment made by pharmacovigilance experts (scientific committee) A scientific secretariat 30

31 2 nd part: monitoring plan 2. Existing tools in EU 2.2. Official release of vaccines OCABR : «Official Control Authority Batch Release» Quality control in an official laboratory + documentary control OBPR : «Official Batch Protocol Review» Documentary control only by the competent authority 31

32 2 nd part: monitoring plan 3. Products to control in priority: Impact on public health : biologicals involved in the control of zoonosis Economical impact : biologicals involved in the control of regulated diseases Impact on animal health and environment : live vaccines Environnemental impact : recombinant vaccines Testing history :previous quality default on vaccines Based on risk analysis 32

33 Inspection system monitoring plan monitoring of distribution of vaccines 1st part : activities and inspection systems 2nd part : monitoring plan 3rd part : monitoring of distribution of vaccines Conclusion 33

34 3rd part : monitoring of distribution of vaccines States Some VMPs need a particular follow-up for public health reasons (antimicrobials/résidues/resistance / vaccines/epizooties). Some distributed VMPs may be counterfeited or without a marketing authorisation. Industry provides that more than 50% of the newly approved drugs be thermosensitive products (vaccines). 34

35 3rd part : monitoring of distribution of vaccines It is necessary to: To ensure a control of the whole chain of distribution, from the manufacture to the sale to public (contamination, protection, traceability) to guarantee the optimum conditions of conservation, transportation and handling of the drugs during this phase. To find any defective VMP and to establish an effective recall procedure. GPD And GPD inspection 35

36 3rd part : monitoring of distribution of vaccines Return of experience from authorities involved in GDP 25% of vaccines reach their final destination in a degraded state (WHO) 1,2% of the variations over period are related tostorage and distribution (EMA) 27% of the major or critical variations are connected to the controls and the followup of the temperature storage and non satisfactory conditions of transport (MHRA) 36

37 3rd part : monitoring of distribution of vaccines Controls carried throughout the vaccines distribution chain at : The entrance of the country Wholesalers Retailers Important also to detect counterfeits and illegal markets 37

38 3rd part : monitoring of distribution of vaccines HARBOURS AIRPORTS BORDERS MANUFACTURE Veterinary vaccines distribution THIRD COUNTRY NATIONAL MANUFACTURE HARBOURS AIRPORTS BORDERS NON AUTHORISED IMPORT AUTHORISED IMPORTERS Merchants/ Parallel market WHOLESALING PHARMACISTS VETERINARIANS OTHER VETERINARY SERVICES Retail on markets PUBLIC 38

39 Inspection system monitoring plan monitoring of distribution of vaccines 1st part : activities and inspection systems 2nd part : monitoring plan 3rd part : monitoring of distribution of vaccines conclusion 39

40 Inspection system monitoring plan monitoring of distribution of vaccines All control procedures may differ widely from a country to another Depends on the legal basis International standards are available : PIC/S : EU Documents : GMP: Inspection procedures OIE terrestrial manual : Risk based approach control should be establisshed in each country/region 40

41 Merci de votre attention Organisation mondiale de la santé animale World Organisation for Animal Health Organización Mundial de Sanidad Animal 12 rue de Prony, Paris, France - oie@oie.int