THERAPEUTIC GOODS SAMPLING Application to Tablet Manufacture and Ingredients. David Edmonds CMC Regulatory

Transcription

1 THERAPEUTIC GOODS SAMPLING Application to Tablet Manufacture and Ingredients 1 David Edmonds CMC Regulatory

2 Sampling requirements Code of GMP PE Part 1/March 2014 The basic requirements of Quality Control are that: i. adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; 2

3 Sampling requirements Code of GMP PE Part 1/March 2014 ii. samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control; 3

4 Sampling requirements Code of GMP PE Part 1/March 2014 iv. records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated; viii. sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced. 4

5 Sampling requirements Code of GMP PE Part 1/March The sample taking should be done in accordance with approved written procedures that describe: the method of sampling; the equipment to be used; the amount of the sample to be taken; instructions for any required sub-division of the sample; the type and condition of the sample container to be used; 5

6 Sampling requirements Code of GMP PE Part 1/March 2014 the identification of containers sampled; any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials; the storage conditions; instructions for the cleaning and storage of sampling equipment. 6

7 Sampling requirements Code of GMP PE Part 1/March There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material. Bulk containers from which samples have been drawn should be identified Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn. 7

8 Sampling requirements Code of GMP PE Annexes/March Personnel who take samples should receive initial and on-going regular training in the disciplines relevant to correct sampling. This training should include: sampling plans, written sampling procedures, the techniques and equipment for sampling, the risks of cross-contamination, the precautions to be taken with regard to unstable and/or sterile substances, the importance of considering the visual, appearance of materials, containers and labels, 8 the importance of recording any unexpected or unusual circumstances.

9 Sampling requirements Code of GMP PE Annexes/March The identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material will be incorrectly identified on its label. 9

10 Summary Sampling requirements Code of GMP Samples must have or be: appropriate documented procedures, labelling and recording of sample source and container. representative of material. absence of any contamination; ie sample with clean, inert equipment to clean, inert containers. Samples must remain free of contamination at both time of material sampling and during laboratory processes. 10

11 Tablets Tablets are made from a blend of active material(s) and binders, disintegrants and lubricants which is compressed into the tablet. The blending process usually comprises preparation of a wet mix, which is then dried for optimum particle size distribution for tablet compression and flow into the tabletting machine. 11

12 12 Tablets Schematic of manufacture

13 Tablets Raw Materials Raw materials for tablets include: Active ingredient Starch Lactose Talc Magnesium stearate Polyvinyl pyrrolidone Flavour Ethanol Water Sugar (coated tablet) Methylcellulose Shellac Beeswax Pigment/Colour lakes 13

14 14 Tablets compression machine

15 Tablets - schematic of compression machine Video reference slide 46 15

16 16 Tablets detail compression machine

17 Tablets compression machine Video reference slide 47 17

18 18 Testing of Raw Materials and Tablets Raw material testing is on single entity products. Tablet testing is on products, manufactured from blended powders. Both require manufacturing procedures that have been validated to yield a consistent and reproducible product, batch to batch. In the ideal situation, testing should be regarded as confirmatory of conformance with specifications and data accumulation to evaluate manufacturing process and product trends. Testing only addresses pre-designated parameters.

19 19 Raw Material Types Raw Materials Solids may be packaged in drums with liners, multi-walled paper. Emulsions, gases, solvent in tanker deliveries Liquids in bottles or drums or tankers. Water (usually) as in-house, on-line prepared. The likelihood of physical and/or chemical and/or microbiological non-homogenity has to be addressed in choosing sampling equipment and method.

20 Raw Materials Tests are for identity and chemical and microbiological purity/impurities. Particle parameters (shape, size and size distribution) determine the performance of the tablet and must be tested where such affect the tablet performance. 20

21 Sampling Procedures Raw Materials Sampling procedures must lead to a representative sample for chemical, physical and microbiological tests. Sampling procedures must not affect the integrity of the remaining, usable product material; any sampling equipment used must be cleaned using documented and validated procedures. All procedures must be documented and personnel appropriately trained. 21 By correct documentation, samples (and their results) must be able to be traced back to the supplier.

22 Sampling Procedures Raw Materials Appropriate HSE procedures, training and equipment must be included in sampling regimen. Procedures must be administered to prevent fraud at time of sampling and sample use in the laboratory. 22

23 Sampling location Sampling Procedures Raw Materials Therapeutic goods manufacture require a designated, properly designed and functioning Sampling booth. (HEPA units, Tyvek suits, breathing apparatus) The air classification is to be at a minimum Grade D ie ISO Class 8 or Class 3500 (ISO14644) 23

24 Sampling location Sampling Procedures Raw Materials Air flow and pressure differentials are designed to minimise contamination, contain any dust and protect the operator, environment and eliminate cross contamination of other materials. 24

25 Sampling Procedures Raw Materials Equipment mobile sampling booth 25

26 Sampling Procedures Raw Materials sampling equipment Sampling Equipment Powder 26

27 Sampling Procedures Raw Materials sampling equipment Where possible use disposable single use (inert) equipment, lowering risk and saving cleaning validation. Microbiological sampling requires sterilised equipment and sample containers. Never use glass sampling equipment! 27

28 Before sampling Sampling Procedures Raw Materials Inspection of the integrity of packaging and verification of manufacturer s and in-house receipt and identification labels before sampling. (Synonyms list necessary QA to approve material if manufacturer s material name is different from in-house approved and used name.) Verify tamper evident seals are intact Verify whether C of A has been supplied or not 28

29 Sampling Procedures Raw Materials Note : secondary packed raw materials can be a particular problem regarding packaging and label integrity. 29

30 Sampling Procedures Raw Materials Sampling issues to be considered: 30 Nature of material; temperature/light sensitivity/hydroscopic/potential to oxidise. Sample size Nature of packaging to be unsealed how best done? Appropriate sampling equipment for material/packaging/container size. (Scoop/spoon, open or closed powder thief, one end open cylinder, spatula.)

31 Sampling Procedures Raw Materials Sampling issues to be considered: Use disposable sampling tools wherever possible. Resealing of primary package(s). Cleaning procedures of sampling area, material packaging sampled and associated cleaning validations. Cleaning and/or sterilisation of sampling equipment and associated validations. (Purified water/70% ethanol, autoclaving.) 31

32 Special considerations Sampling Procedures Raw Materials Narcotics (quantitative recorded reconciliations) Sterile materials 32

33 Sampling Procedures Raw Materials After sampling Transfer sample to inert lab container and seal well. Minimise headspace. Minimise headspace Clean and secure sample area of material packaging. Clean and securely store sampling equipment. Composite and prepare samples for analysis. 33

34 Tablet Raw Materials Identity tests must be performed on each Raw Material container received. (FTIR often used to perform this, at sampling site.) (Reduced sampling, in conjunction with Vendor under a validated regimen is acceptable.) 34

35 Laboratory samples Tablet Raw Materials Composites are made; pooled to a sufficient number of samples for testing where variations from sample to sample (especially impurity levels) are quantitatively detectable. (Recommend at least 5) This requires instrumental techniques rather than wet chemistry. Wet chemistry methods are being phased out. 35

36 Tablet Raw Materials (For product manufacture, in event of impurity results spread, a Raw Material of the same batch with determined high and low level impurities from different containers cannot be blended to give an overall, just within limits blend.) 36

37 Tablet characteristics Compressed hard mass requiring to be ground to fine powder for assay preparation. Active ingredient concentration varies from 2:3 to 2:2000, as mcg to gram per tablet. (Human) tablet weight varies from about 25 mg to 1.2 g. Mixing of API is required to be determined, using Uniformity of Dosage test. 37

38 Collection of samples Tabletting Depending upon batch size and time to manufacture, samples are drawn during a compression run at a pre-designated, regularly spaced, noted, periods of time. Ensure that samples at the (higher risk) start and end of a compression run are captured. Transfer each sample to inert lab container and seal well. 38

39 Tabletting Tablet samples are ultimately composited for a final sample of 20 for chemical composite testing and sufficient chemical individual tablet tests as required. Microbiological tests are performed on a weight basis. Note that during validation of the compression process, samples are taken identifying the time cut, but not composited ie each time cut is separately tested. 39

40 Tabletting Sufficient retention sample for at least 2 more test regimens are also drawn from the combined sample. 40

41 Tablet Specifications and Tests Composite sample of 20 prepared from ground and homogenised tablets Appearance (Chemical) Identity Mean weight Active Content per average tablet (concentration) Impurities Microbiological (as required) 41

42 Individual tablets Tablet Specifications and Tests Hardness Friability (usually 10) (ability to chip or fracture) Uniformity of Dosage Units * Disintegration* or Dissolution* (less frequently) 42 *The number of individual units required is staged, depending on the results determined for the initial testing, 10 for Uniformity of Dosage Units or 6 for dissolution or disintegration.

43 43 Tablet Specifications and Tests Dissolution

44 Any analytical data, interpretation and conclusions are only scientifically valid on the testing of valid and representative samples.

45 References Mobile sampling booth pg

46 References Tablet manufacture schematics _images/variousunitoperationsequences.jpg Tablet compression schematics

47 References Tablet manufacture - Natoli

48 References USP35 NF30 Page 681 Pharmacopeial Forum: Volume No. 36(3) Page a/v35300/usp35nf30s0_c1097.html Codes of GMP and Annexes

49 Appendix Ph Eur Uniformity of Dosage Unit requirements 20of%20dosage%20units.pdf

50 Acknowledgement With much thanks to input and review from Mr Denis Moore.

51 Disclaimer All views and interpretations of requirements, expressed in the preceding slides, are the author s and do not necessarily reflect the policies and requirements of any particular or number of Government Therapeutic Goods Agencies. The preceding presentation specifically exclude any guarantees that any views and advice given and/or documentation provided, while given in good faith and to the best of the Consultant s expertise, will be found satisfactory by any Agency and/or any other person or Authority to whom they are provided