Swiss Medic Training Sampling

Transcription

1 Swiss Medic Training Sampling Paul Sexton

2 Sampling Preparation for Sampling Representative Sample Re-sampling

3 Sampling Part I What to sample? Why sample? Where to sample? Who performs sampling? How to sample? Part II Reduced Sampling Reduced Testing by Manufacturer Periodic / Skip Lot Testing

4 What to Sample? Starting Materials Packaging Materials Intermediates Finished Products Equipment Environment

5 Why Sample? To obtain a portion of the material for analysis against a specification which is representative of the whole batch. Quality Control Testing against relevant specification Preparation of Reference & Retention Samples for future testing / examination Annex 19 Reference sample for testing purposes Retention sample sample of finished product pack

6 Why Sample? Strategic sampling confirming characteristics of a specific portion of material - identity of individual containers (Annex 8) - defect investigations o o assist establishing root cause for a defect isolating potentially defective materials / product - sampling after interventions during aseptic processing Process Validation o o Multiple strategic samples, including stressed locations verifying compliance with test specifications / assessing uniformity

7 Sampling - Why? Strategic sampling confirming characteristics of a specific area Environmental monitoring - Sampling including particular focus on critical zones Cleaning Validation Strategic samples including hardest to clean locations

8 Sampling - Why? Regulatory Requirements Annex 8 Sampling of starting and packaging materials Annex 19 Reference and retention samples Annex 16 - Batch Release and Certification by the QP (EU) (Sampling of imported products)

9 Materials Staged for Receipt & Sampling

10 Where to Sample

11 Booth within sampling room

12 Sampling high potency materials Glove box (barrier) technology Extra containment & protection provided to the operator Cleaning requirements

13 Sampling Where? Specific area for purpose of sampling Product exposure GMP requirements Filtered air Containment Appropriate finishes Cleaning procedures & records Gowning requirements for personnel

14 Sampling Where? Sampling of Imported Product Sample after importation straightforward samples taken should be representative of the imported batch. Sampling in the third country acceptable? - sending samples separately to the batch - acceptable? - What controls are required? Ref. Annex 16 (EU GMP Guide)

15 Sampling Where? Sampling of Imported Products (Annex 16 EU GMP Guide) Sampling in third country permitted if technically justified. - QRM study to evaluate risks - Equivalent transportation of sample and batch - Comprehensive study of both sampling approaches - Comparative testing between EU and 3 rd country samples - Periodic ongoing testing of samples taken in EU - Notification of unexpected or confirmed OOS results to SA

16 Sampling Who? GMP Guide -Chapter Quality Control is that part of Good Manufacturing Practice which is concerned with sampling -Chapter The Head of Quality Control.approve specifications, sampling instructions, test methods and other Quality Control procedures - Chapter 6 Principle Quality Control is concerned with sampling Warehouse personnel? Production personnel? Training of sampling personnel & Quality Culture

17 Qualification of Sample Location

18 Sampling Liquids

19 Sampling sample containers

20 Sampling - How Sample containers considerations - Sealing of the container - Headspace above material within the container - Moisture transmission - Light transmission Sample Storage - Specific storage conditions required? (e.g. temperature) - Timeframe prior to testing - Transportation (e.g. outsourced testing)

21 Sampling sample containers

22 Sampling - How Sampling by the vendor - Co-shipment samples -transported with the batch - Separate shipment of samples (e.g. 3 rd country import) - Sampling method - E.g. during filling of bulk containers (IBCs) of APIs - Audit of sampling process at vendor - Trust is it well founded through supplier history / audit? - Verified by periodic sampling on site?

23 In-process sampling from bioreactor

24 In- process sampling of granulate

25 Sampling How? Procedure & sampling documentation - where sampling should be performed - who is responsible for sampling - sampling equipment to be used - sampling plan (material specific) - how to form a composite sample - sample containers - labelling of samples and sampled containers - storage of samples

26 Sampling How? Sampling Plans - Sampling of Active Substances- - Sampling of Excipient materials - Sampling of materials for parenteral products Statistical Sampling ANSI Z-1.4 / ISO Particularly used for packaging materials (e.g. glass vials, stoppers, leaflets, cartons etc) and attribute testing of finished products (e.g. 100% post visual inspection of sterile products)

27 Sampling How Special Case Glycerol contamination with diethylene glycol Separate cases of multiple patient deaths worldwide Expected that each container to be sampled and tested for identity and presence of DEG as per Ph Eur. (see GMP / GDP Q&As on EMA website)

28 Sampling How? Annex 4 (WHO Technical Report Series, No. 929, 2005) WHO guidelines for sampling of pharmaceutical products and related materials

29 Sampling How? The n plan n = 1 + N (N = number of containers / units) - Use with caution and for uniform material from a known source of supply. - N 4, then sample every unit / container - Sampling usually from top of container - Identity testing and visual appearance of each of the n units - If results are concordant then composite for other tests. - Not recommended by WHO for drug product starting materials. Not statistically based but can be used as guiding principle.

30 Sampling How? The p plan p = 0.4 N (N = number of containers / units) - Use for uniform material from a known source of supply. - Main purpose is for identity testing - Visual inspection and identity testing appearance of each of the N units - If results are concordant then pool to form p final samples for other tests.

31 Sampling How? The r plan r = 1.5 N (N = number of containers / units) - Material suspected to be non uniform - Source of supply is not well known - May be used for herbal substances used in herbal medicines - Individual samples taken from all containers (N units) for identity testing. - If results are concordant then number r of the N samples selected for individual monograph testing. - If all pass then pool the r samples to form reference sample.

32 Sampling How? Example of 40 containers received (i.e. N=40) n plan WHO Sampling Plan p plan r plan n = = 7 p = = 3 ID testing on r = = 10 Full testing on 1 (composite) 3 (composites) 10 (individual)

33 Sampling How? Statistical Sampling (e.g. ANSI Z-1.4 and ISO ) Based on probability theory Each sampled unit is individually tested and classified as conforming or non-conforming Provide consistent level of protection which is independent of batch size. Routinely used for visual inspection, inspection of components e.g. incoming vials.

34 Sampling How? Sampling Plans AQL : Acceptable Quality Limit :- defect level (%) at which there is a high probability that the batch will be accepted by the sampling plan (e.g. probability of 95%). LTPD : Limit Tolerance Percent Defective : defect level (%) which the sampling plan will reject the batch with a high probability (e.g. probability of acceptance of 10% or 90% probability of rejection).

35 Sampling How? Each sampling plan has an Operating Characteristic Curve

36 Sampling How? Sampling Levels Z-1.4 / ISO Batch Size = 1300 units AQL = 1.5% General Inspection Level I Level II Level III Sample Size Accept Reject 3 6 8

37 Sampling How? Comparison of Operational Characteristic Curves for General Inspection Levels I, II & III

38 Sampling How? Sampling Levels Z-1.4 / ISO Batch Size = 1000 units AQL = 1.5% General Inspection Level II Reduced Normal Tightened Sample Size Accept Reject 4 4 3

39 Sampling How? Comparison of Operational Characteristic Curves

40 Sampling How? Assigning AQL value Classify defects : Critical - Major - Minor AQL assigned commensurate with risk presented to the patient by given defect. Sampling Level and AQL should be justified based on QRM principles

41 Sampling How? Comparison of ANSI Z-1.4 (General Level I) and N+1 Accept 0 ; Reject 1 for both plans - Similar sample sizes..and similar AQLs. are sampling plans statistically equivalent? (NB General Level I) Pharmaceutical Technology Vol 33 Issue 10

42 Sampling - How Sampling all containers for ID test - potentially significant challenge Mobile NIR Calibration of probe Creation of reference library Current guidelines: Ph. Eur. monograph EMA guidance

43 Sampling How? Complexities of sampling powder blends - How many samples? - What size of sample? - usually 3 x unit dose - How many locations? - Errors introduced by sampling tools - Errors in subdivision of samples in the laboratory FDA Draft Guidance Powder Blends and Finished Dosage Units Stratified In-Process Dosage Unit Sampling and Assessment (Oct 2003) Withdrawn in August 2013

44 Sampling How? Sampling blends of pellets and powder (intermediate) prior to compression

45 Sampling How? Finished Product Sampling for Final QC testing - Sampling of bulk dosage form eg bulk unlabelled vials of sterile product Acceptable or not? - Sampling of bulk tablets which after testing will be packed for a number of different markets. Acceptable of not? Expected Controls? - Combining of multiple batches of bulk tablets for packaging under as a single Superbatch sampling expectations?

46 Part II Reduced Sampling Reduced Testing by Finished Product Manufacturer Periodic or Skip Testing

47 Reduced Sampling Annex 8- PICS GMP Guide Identity testing expected for all containers except where a validated procedure to ensure no mislabelling has occurred. Validation to take account of ; - Nature of material and manufacturing process - Supply chain (direct from manufacture or via broker) - History of supply Circumstances for reduced sampling for identity are defined.

48 Reduced Sampling Annex 8- PICS GMP Guide Reduced sampling not likely to be accepted where Material is supplied by a broker and the source of manufacture is unknown to the manufacturer of the medicinal product Starting materials are used in manufacture of parenteral products.

49 Reduced Testing by FP Manufacturer - Applied to testing of starting materials - All specified material tests are still carried out but not necessarily by the manufacturer of the medicinal product. - Outsourcing of testing - Conditions of outsourcing - (see earlier presentation)

50 Periodic or Skip Testing ICH Q6a Section Rather than testing every lot certain tests may be conducted on predetermined lots or at a defined interval. - Justification must be provided and the skip lot testing approach approved via the Marketing Authorisation. - All intervening lots would be expected to pass - Any failure to be notified to relevant authorities - e.g. solvent testing on conduct microbiological testing every n th batch

51 Thanks for your attention! QUESTIONS???