Organisation of sampling programmes EU experience Jean-Marc Spieser / Marta Miquel Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, September

Sampling and testing for Quality Control Laboratories, Nairobi, September |2 | Sampling & Testing programmes within the OMCL Network  The EDQM coordinates a series of (voluntary) collaborative programmes within the OMCL Network, with the aim of controlling the quality of medicinal products available on the European market: 1.MSS (Market Surveillance Studies) 2.MRP/DCP Post Marketing Surveillance Scheme (Mutual Recognition Procedure/Decentralised Procedure) 3.CAP Sampling and Testing Programme (Centrally Authorised Products)  Advantages of having coordinated surveillance programmes:  Sharing of work => avoid duplication of tests => save resources  Exchange of information/results

Sampling and testing for Quality Control Laboratories, Nairobi, September |3 |  In order to allow confidence, harmonisation and mutual recognition of results => a common approach is needed (when planning, performing and reporting the testing activities) => harmonised Quality Management Systems (QMS)  Advantages of having a well established QMS  processes/activities are under control => reduce the risk of errors.  increases traceability of activities (possible to go back and find cause of error).  increases confidence in test results => mutual recognition of results between labs/countries.  facilitates cooperation/exchanges/harmonisation between labs.  better use of resources => reduction of costs => labs can be more efficient.  better protection of public health. Sampling & Testing programmes within the OMCL Network

Sampling and testing for Quality Control Laboratories, Nairobi, September |4 |  With the purpose of establishing/maintaining harmonised QMS within the OMCL Network => EDQM coordinates 2 External Quality Assessment Programmes (voluntary, but participation is strongly recommended): –Audit/Visit/Training programme aimed to coach and help OMCLs establishing and improving their QMS (based on ISO/IEC and complementary OMCL guidelines, e.g. validation of analytical methods, uncertainty of measurement, qualification of equipment, etc). –PTS (Proficiency Testing Studies) aimed to provide the laboratories (within and outside the OMCL Network) with an objective and independent tool to demonstrate that the results they produce are accurate and reliable ( regular comparison of a laboratory’s results at intervals with those of other laboratories). Sampling & Testing programmes within the OMCL Network

Sampling and testing for Quality Control Laboratories, Nairobi, September |5 | Drug Quality Surveillance Programmes within the OMCL Network 1.MSS 2.MRP/DCP 3.CAP

Sampling and testing for Quality Control Laboratories, Nairobi, September |6 | 1 - Market Surveillance Studies (MSS)  Objective: control of the quality of the medicines (“screening”) on the European market, which are, as a rule, commercialised with a national marketing authorisation (MA).  Products tested: different types of preparations of active ingredients, herbals...  29 MSS have been finalised since the beginning of the programme, with an average participation of 12 OMCLs per MSS.  Since 1995 a yearly MSS programme is elaborated by EDQM, based on proposals from:  Advisory Group of the OMCL Network  OMCLs (e.g. after detection of quality problems during routine analytical work)  Inspectorates

Sampling and testing for Quality Control Laboratories, Nairobi, September |7 | Steps: 1.EDQM collects MSS proposals => programme => adopted by OMCL Network (annual meeting). 2.Head of MSS project appointed (normally from the proposing OMCL) => proposes the testing method (common protocol for all participants) + provides the Common Testing Sample. 3.Protocol is verified by a second laboratory (EDQM Dlab or another OMCL). 4.SAMPLING: participant OMCLs take samples along the distribution chain (wholesalers, retail pharmacies) from their national markets, in connection with the national competent services. 5.Participant OMCLs test the samples according to the common protocol. 6.In case of OOS, the product is retested using the method of the MA file. 7.OMCLs send results to EDQM => statistical evaluation of results => MSS report. 8.Subsequent actions and follow-up are the responsibility of the National Competent Authorities. 9.If a Pharmacopeia issue is identified, the report is forwarded to the concerned EDQM Dpt. Market Surveillance Studies (cont.)

Sampling and testing for Quality Control Laboratories, Nairobi, September |8 | Examples of Market Surveillance Study : Tablets and/or capsules containing lithium, tamoxifen, acyclovir, ibuprofen, lisinopril dihydrate, etc. Erythromycin Liquid Preparations. Omeprazole gastro-resistant tablets. Procaine in aqueous solutions for injection. Suspensions of dihydrostreptomycin or amoxicillin. Cadmium in herbal drugs. Studies on pharmaceutical technology (preparations for inhalation, uniformity of unidose preparations, tablets for which subdivision is authorised…). Market Surveillance Studies (cont.)

Sampling and testing for Quality Control Laboratories, Nairobi, September |9 | 2 - Post Marketing Surveillance Scheme of MRP/DCP  Objective: control of the quality of medicinal products on the EU/EEA market (European Union/European Economic Area = 27 EU countries + Norway, Iceland, Liechtenstein) having received a MA through the Mutual Recognition Procedure (MRP) or the Decentralised Procedure (DCP) => identical MA dossier in all concerned member states (identical specifications and test methods).  Yearly programme, regularly run since 2005 (Trial Phase ). About 300 medicinal products tested per year, including generics.  More than 2300 MRP projects have been registered in a database (information shared) since  2 basic principles of the Scheme:  Work-sharing => to reduce duplication of testing => 1 single “testing lab”  Exchange of test results => Database

Sampling and testing for Quality Control Laboratories, Nairobi, September | Post Marketing Surveillance Scheme of MRP/DCP (cont.) Steps 1.Programme: OMCLs register in the database the product they plan to test. Tested material: approx. 2% APIs; 98% finished dosage forms. A risk based model for targeting medicinal products for market surveillance testing has been developed within the OMCL Network. 2.SAMPLING: the “testing OMCL” (or the Competent Authority of the Member State) takes samples from the national market. Other participating OMCLs might voluntarily send samples taken from their country to the testing OMCL. 3.Testing: tests are performed as a rule in one lab, according to MA dossier, or a method developed and validated by the OMCL (in-house method), or compendial methods. 4.Reporting: testing OMCL publishes the test results on the database. 5.Follow-up: follow-up measures are reported in the database. In general follow-up activities are the responsibility of the National Competent Authorities.

Sampling and testing for Quality Control Laboratories, Nairobi, September | 3 - CAP Sampling and Testing Programme  Objective: control of the quality of medicinal products on the EU/EEA market, having received a MA valid throughout EU/EEA => Centrally Authorised Products “CAP” (according to regulation EC/726/2004) (about 550 CAPs are currently available).  Unless a major issue is identified, CAPs are not tested by national authorities in their routine testing programmes.  Since 1999 the EMEA (European Medicines Agency) has implemented a post- authorisation sampling and testing programme: CAP programme.  As EMEA has no lab facilities => CAP programme is run by EDQM on behalf of EMEA, in collaboration with the EEA OMCL Network and the EEA National Inspection Services.  354 CAP projects have been run since the beginning of the CAP programme.

Sampling and testing for Quality Control Laboratories, Nairobi, September | Steps: 1)EMEA proposes the CAP programme => from 2010, products will be exclusively selected on the basis of a risk analysis, including a 5% of randomly selected additional products per year. 2)The MAH sends MA file and technical SOPs to EDQM. 3)EDQM prepares the testing protocol accord. to recommendations from the assessors (NCAs). 4)EDQM proposes the list of participating OMCLs => approved by the OMCL Network. 5)EDQM proposes a sampling plan based on the information received from the MAHs about the marketing situation 6)Sampling plan is sent to Inspectorates (sampling contact points). 7)SAMPLING is done along the distribution chain (preferably as closely as possible to patients) by the competent national services in 3 countries (1 batch per country => 3 batches). CAP Sampling and Testing Programme (cont.)

Sampling and testing for Quality Control Laboratories, Nairobi, September | Steps (cont.): 8)Inspectors send samples to EDQM under the required transport conditions. 9)EDQM requests the MAH to send 1 sample (control test sample) + reference materials. 10)Samples are labelled at EDQM + dispatched to testing OMCLs (1 OMCL if chemical/physico- chemical tests are requested, 2 OMCLs if biological tests are requested) + protocol + Results Data Sheet + ref. materials + Safety Data Sheet + other info if required. 11)OMCLs send back results to EDQM. 12)EDQM prepares individual product report => sent to EMEA and the OMCL Network via a secured system. 13)EMEA is responsible for the actions and follow up measures as an outcome of the results (feedback received from the assessors of the NCAs). CAP Sampling and Testing Programme (cont.)

Sampling and testing for Quality Control Laboratories, Nairobi, September | EMEA EDQM OMCLs (testing) National Inspectors (sampling) MAHs protocol report ref. mat. samples ref.mat. documentation CAP

Sampling and testing for Quality Control Laboratories, Nairobi, September | 1- MSS2- MRP/DCP3- CAP National MAMA via MRP/DCP procedureMA via Centrally Authorised Procedure Whole OMCL NetworkEU/EEA OMCL Network Variable no. participants (many testing OMCLs) Variable no. participants (1 testing OMCL as a rule) Defined no. participants (1 OMCL for chemical, 2 for biologicals) Variable no. samples Defined no. samples Protocol established by the Head of the MSS project Protocol based on the MA dossier + SOPs of manufacturer, or internal method or compendial Protocol based on MA dossier + SOPs from manufacturer Table of differences: Objective of the 3 programmes: survey of the quality of medicinal products

Sampling and testing for Quality Control Laboratories, Nairobi, September | Potential impact in case of confirmed OOS results:  Major or minor variations in the marketing authorisation file (change of specifications of an active substance or finished product and/or change of method).  Recall of a batch (in case of a confirmed quality defect).  If European Pharmacopoeia methods are concerned:  Revision of a monograph/general chapters and methods  Establishment of a new method

Sampling and testing for Quality Control Laboratories, Nairobi, September | MSS: MRP/DCP: CAP: QA: PTS: PTS programme 2009: QA OMCL Guidelines: For more information on EDMQ/OMCL Network programmes:

Sampling and testing for Quality Control Laboratories, Nairobi, September | Thank you for your attention