Organisation of Sampling Programmes Background Information

1. 2-3 Organisation of Sampling ProgrammesBackground Information Richard Wanko Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009

2. Outline • Some definitions… • Why sampling? • For which purpose should be sampled? • Where can / should be sampled? • Who can sample test material? • What should be sampled? • How should be sampled?

3. What is a Sample? A portion, piece, or segment that is representative of a whole. In the context of medicines “a portion/piece/segment” means: x g/ml active pharmaceutical ingredient / excipient / bulk material… or x units of the finished dosage form (tablet, bottle,…) representative of a batch Reference: http://www.thefreedictionary.com/

4. What is a Batch (Lot)? In the context of medicines: A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. Reference: Eudralex Vol 4 – Medicinal Products for Human and Veterinary Use: GMP, Part II

5. What Does Sampling Mean? The act, process, or technique of selecting an appropriate sample. In the context of quality control of medicines “an appropriate sample” means: representative sample to evaluate the quality of the whole batch Reference: http://www.thefreedictionary.com/

6. Reference Sample / Retention Sample • Reference sample provides a sample for analytical testing A sample of a batch of starting material, packaging material or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned. Where stability permits, reference samples from critical intermediate stages (e.g. those requiring analytical testing and release) or intermediates, that are transported outside of the manufacturer’s control, should be kept. Reference: EU Guidelines to GMP, Annex 19

7. Reference Sample / Retention Sample Retention sample provides a specimen of the fully finished product A sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes. For example, presentation, packaging, labelling, patient information leaflet, batch number, expiry date should the need arise during the shelf life of the batch concerned. There may be exceptional circumstances where this requirement can be met without retention of duplicate samples e.g. where small amounts of a batch are packaged for different markets or in the production of very expensive medicinal products. Reference: EU Guidelines to GMP, Annex 19

8. Reference Sample / Retention Sample Reference sample e.g. in cases where Out-of-Specification (OOS) results need to be verified Retention sample e.g. in cases where the authenticity of a product needs to be confirmed (e.g. counterfeit identification)

9. Common/Control Test Sample • Common Test Sample Used in the context of the General European OMCL Network (GEON) in Market Surveillance Studies (MSS). Sample acts as “unifier” and is tested by all participants of a post-marketing surveillance testing campaign (= study covering – as a rule - a group of products on the different national markets) to get an idea about the comparability of performance of the different laboratories.

10. Common/Control Test Sample • Control Test Sample This term is used in the sampling and testing programme for Centrally Authorised Products (CAPs) of the CAP Network, which is organised jointly by the European Medicines Agency (EMEA) and EDQM. The purpose of the sample is to compare a new, recently released batch with test samples drawn along the distribution chain.

11. Why is Sampling Possible/Necessary? • Homogeneity of test material; production under GMP conditions should guarantee standardised / controlled processes and should lead to homogeneous products within defined specification limits • Capacity restrictions; representative spot testing instead of checking the whole of a batch • Many quality control tests are destructive methods; thus as a rule it is not possible to test the whole of a batch, but only a representative portion in order not to consume the complete material before use

12. Example for 100% Sample Check • Ph.Eur. 2.9.20 Particulate contamination: visible particlesOn-line analysis in parenteralia

13. For Which Purpose? • Routine batch release by QC laboratory at manufacturing site • Routine Official Control Authority Batch Release (OCABR) of immunological medicinal products and medicinal products derived from human blood or plasma • Routine market surveillance testing (post-marketing surveillance) • During routine GMP inspection / Quality assessment to complement “paper work” 1/3

14. For Which Purpose? • Pre-qualification • Inspection for customs clearance • Suspicion of inferior quality / safety or efficacy issue • Suspicion of deterioration; product suspected to be responsible for adverse clinical reactions or ineffective • Suspicion of counterfeited (falsified) / illegal material • Suspicious of (deliberate) contamination, falsification or adulteration 2/3

15. For Which Purpose? • Confirmation of quality defect • Confirmation of OOS result • Stability testing • Development and research within the regulatory frame work of medicinal products 3/3

16. At Which Time Point of Production? • Before start of manufacture (starting materials) • In-process control / Control of intermediates • Before batch release • After batch release, but before market launch • After launch along the distribution chain QC OMCL

17. Where is Sampled? • Manufacturing site • MAH warehouse • Wholesaler • Retail pharmacy (pharmacy shop) • Hospital => Control of legal environment 1/2

18. Where is Sampled? • Airport / Harbour • Internet • Fitness (Body building) centres • Bars • Illegal laboratories / manufacturing sites => Investigation in illegal environment 2/2

19. Who is Sampling? • Suitably trained and qualified persons within companies • e.g. QA department => written training records required • (GMP) inspectors • Normally without power of enforcement • Other trained persons of National Competent Authorities • e.g. OMCL staff members • Enforcement officers • Customs officers • Police force

20. What Kind of Test Material? • Active pharmaceutical ingredients (APIs) • e.g. comparison of impurity profiles (finger prints) from different API sources • Excipients • e.g. quality control against compendial (pharmacopoeial) standard • Intermediates (in manufacturing process) • e.g. in-process control 1/2

21. What Kind of Test Material? Bulk material (before packaging) e.g. assessment of stability during transit / shipment Drug products (DP) e.g. follow-up of complain Packaging material including Patient Information Leaflet (PIL), label etc. e.g. market surveillance campaign Processing agents, cleaning agents, compressed gases e.g. cleaning validation 2/2

22. What Kind of Supportive Material? • Reference material/standards • e.g. Pharmacopoeia RS, working standards • Reagents • e.g. product-specific not purchasable material (biological testing) • Control/Common Test Sample (CTS) • e.g. used in EDQM OMCL Network market surveillance programmes

23. What Kind of Accompanying Documents? • Certificate of Analysis (CoA) • For Control Test Sample (CTS) to have a comparison of the performance of the batch releasing QC lab and the independently testing OMCL • Safety Data Sheets (SDS), where applicable • To allow lab staff taking necessary safety measures – e.g. handling of cytostatic material • Valid Test Method (MA dossier, SOP) • To perform test for compliance against the Marketing Authorisation 1/2

24. What Kind of Accompanying Documents? Valid Shelf-life Specification To perform test for compliance in post-marketing situation Composition of DP To allow the interpretation of observed impurity profile (Analytical) method validation data To support method transfer Storage conditions for sampled material To guarantee correct transport and sample storage 2/2

25. What to be Considered During Planning? For annual post-marketing working programme • Need to cover different climatic zone conditions? • Risk-based selection of material with a minimum of randomised sampling (about 5%) e.g. use of risk-based models considering following aspects • occurrence-related (=risk of quality defect) • exposure-related (=extent of quality defect) • harm-related (=severity in case of quality defect) 1/3

26. RB Approach for OMCLs Example of a risk-based model used by the General European OMCL Network (GEON) Reference: RB Model for Targeting Medicinal Products for MS Testing, PA/PH/OMCL (07) 87 6R

27. What to be Considered During Planning? For annual post-marketing working programme Sufficient amount of material; if possible from different batches On basis of selected test parameters On basis of used test method To allow ideally more than one full test run and repetitions for a sound statistical evaluation of the results To enable repeated testing in case of OOS results To cover a big quality range of the product 2/3

28. What to be Considered During Planning? For annual post-marketing working programme Availability of competence within the OMCL Sub-contracting to private laboratories should be avoided, if possible Collaboration with other OMCL should be given priority Replacement policy for sampled material Voucher system for replacement of taken samples Special treatment of orphan drugs (low market volumes) Nevertheless: sampling plans should be made on scientific grounds and not be driven by budgetary considerations 3/3

29. Voucher System Example used in the CAP programme

30. What to be Considered During Sampling? Storage requirements for samples during shipment and on-site storage Cold chain – controlled transport with temperature recording (data logger) for unstable products Light and/or moisture protection, where applicable Special sampling plan for samples intended for sterility testing Sufficient number of samples to make a sound statistic evaluation (according to pharmacopoeial requirements) Time points and location of sampling 1/3

31. What to be Considered During Sampling? • Suitable sampling equipment • Raw / Bulk material vs. finished product in marketed packaging • Storage location of retained samples • Storage under same condition as test samples, preferably at testing site or in case of low market volume products (orphan products) at sampling location • Acknowledgement of Receipt procedure • In case of shipment of samples feedback to the sampler about the receipt of sample and condition at receipt 2/3

32. Acknowledgement of Receipt Form Example used in the CAP programme

33. What to be Considered During Sampling? • Immediate check of visual appearance • The visual appearance of the samples at time of sampling should be recorded because it can provide valuable information about possible quality defects • Sample yourself and don’t let the company do it for you • To avoid manipulation • To select a representative sample • To guarantee independency 3/3

34. Specific Precautions Sampling in warehouses (starting material, intermediates or bulk products): • Prevent contamination of the opened container, the materials and the operator • Prevent cross-contamination by other materials and the environment • Protect the operator (sampler) during sampling • Where possible, sampling should be performed in an area or booth designed for and dedicated to this purpose • The area of sampling should be recorded in the sampling record 1/2

35. Specific Precautions Sampling in pharmacies/hospitals/at wholesalers (original sales package): • As a rule keep the sample in the original outer package at the time of sampling and during transport • Samples with different batch numbers and/or from different locations should be treated separately Sampling via internet: • Purchase the material “incognito” in case of investigation for illegal products 2/2

36. Conduct of Samplers • To be conscientious, meticulous and careful • To be alert to any signs of contamination, deterioration or manipulation, and record any suspicious sign • To be aware of relevant health/safety information (e.g. Safety Data Sheet) • To be trained in specific safety precautions, if required (e.g. respiratory equipment) • To wear appropriate protective clothing • Samplers should have safe access to get in and out from the sampling place

37. Consequence of Sampling for Testing? Testing complements paperwork and helps to find an answer regarding • the quality of a product against its Marketing Authorisation (MA) or other standards (e.g. Ph.Eur.) • GMP findings • safety/efficacy issues (pharmacovigilance cases) but in a strict sense test results alone only allow to draw conclusion for the tested batch(es) and not for the product in total

38. New Approach • Real Time Release Testing (RTR testing) The ability to evaluate and ensure the quality of in-process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls. • Parametric Release One type of RTR testing. Parametric release is based on process data (e.g. temperature, pressure, time for terminal sterilisation) rather than the testing of a sample for a specific attribute. 1/2

39. New Approach Shift from • Bench top analysis (batch analysis) – e.g. HPLC test to • In-line analysis (in-process control) – e.g. pH, NIR monitoring Is this the end of classic punctual sampling? or New challenge for post-marketing sampling and testing? =>RTR testing is not the end of market surveillance and “classic” sampling will still be necessary 2/2

40. Conclusion • Sampling should be done – wherever possible - by trained staff • A careful planning is essential • A comprehensive sample documentation is important to guarantee smooth testing afterwards • The independency of sampling needs to be guaranteed • Quality control starts at the sampling stage

41. http://www.edqm.eu Thank you for your attention Dr Richard Wanko Scientific Officer Council of Europe European Directorate for the Quality of Medicines and HealthCare (EDQM) Biological Standardisation, OMCL Network & HealthCare Department (DBO) 7 alleeKastner, CS 30026 F- 67081 Strasbourg, France Tel.: + 33 (0) 3 90 21 40 13 Fax: + 33 (0) 3 88 41 27 71 E-mail: richard.wanko@edqm.eu