Quality Assurance GMP: "Guide to Good Pharmaceutical Manufacturing Practice"

1. Quality Assurance GMP: "Guide to Good Pharmaceutical Manufacturing Practice" The Secretary of State for Social Services (Sir Keith Joseph) (Hansard 7th March 1972) DEVONPORT HOSPITAL (PATIENTS' DEATHS) Hansard 7th March 1972… http://hansard.millbanksystems.com/commons/1972/mar/07/devonport-hospital-patients-deaths#S5CV0832P0_19720307_HOC_244 I have to report with great regret to the House the deaths of five patients at the Devonport Hospital. The whole House will feel the deepest sympathy, as I do, towards those who have been so tragically bereaved. Last Saturday the doctors at the hospital confirmed their suspicion that these deaths might have a common link in that in each case an intravenous dextrose solution had been administered. These Solutions had all been from the same sub-batch from the Manufacturer, Evans Medical Ltd., of Speke. 1

2. 12th July: Clothier report The Committee concludes—in its own words in paragraph 79— that the fundamental cause of this disaster is to be found in human failings at Evans Medical, ranging from simple carelessness to poor management of men and plant. The Committee heard of no imminent technological advance in the field of production of intravenous fluids which will eliminate the need for skilful men devoted to their work. The Committee considers that too many people believe that sterilization of fluids is easily achieved with simple plant operated by men of little skill under a minimum of supervision, a view of the task which is wrong in every respect". The Government accept the report, and I have referred to the Medicines Commission a number of technical recommendations. These include consideration of the use of plastic containers, methods of identifying individual batches of dextrose, sterility testing methods, the possibility of incorporating bacterial filters and technical advice on the maintenance of autoclaves. There are also recommendations on prevention of contamination during cooling and after distribution 2

3. 4. Controls in Product Development Product Testing

4. Control in Product Development Product Testing • Characterisation; • In vitro tests • In vivo tests • Confirmation of quality; • Stability tests

5. Design in Product Development Product Testing • In vitro tests • in-process testing (tablet weight, thickness, crushing strength, friability, disintegration) • Finished product testing (description, drug content, drug-related impurities, dissolution)

6. Design in Product Development Product Testing • Dissolution testing Percentage released Time (minutes)

7. Control in Product Development Product Testing • In vivo tests: • Animal studies • Clinical trials • Bioequivalence of different formulations or same formulation made by different process or same process at a different scale (>10x)

8. Control in Product Development Product Testing • Bioequivalence testing:

9. Control in Product Development Product Testing Testing the medicine Plasma conc. Time

10. Control in Product Development Stability Testing • What are stability tests? • Determine change in chemical and physical properties of dosage form on storage (up to 5 years) - for example loss of active on increase in impurities

11. Design in Product Development Stability Testing • What does stability testing tell us? • Assurance that the efficacy, safety and quality of the active drug substance and pharmaceutical formulation are maintained throughout the shelf-life • Facilitates assignment of this shelf-life and appropriate storage conditions

12. Design in Product Development Stability Testing • Stability testing;

13. Control in Product Development Product Testing - Summary • Ideally will be able to relate in vitro performancecharacteristics with in vivo performance • Dissolution rate testing for oral dosage forms • Cascade impaction for inhaled dosage forms • Defines acceptable performance range • Stability tests define shelf-life and storage conditions which will provide assurance of quality

14. Design and Control in Product Development Ideal specification Design product Achievable specification Test product Manufacture Product Reliable test methods

15. Controls in Product Development Analytical Method Development

16. Controls in Product Development Development of Specifications • What role does the analyst play? • The analyst provides physical and chemical information on drug substances and formulations

17. Controls in Product Development Development of Specifications • Typical Tablet Specification; • Drug content • Impurity levels • Appearance • Identity • Performance measure

18. Controls in Product Development Development of Specifications • Typical Sterile Solution Specification; • Drug content • Impurity levels • Appearance • pH • Identity • Sterility • Bacterial endotoxins • Particulate matter

19. Typical Drug Substance Specification: Description Identity Related Impurities Metals Solvents Water Assay Particle size Controls in Product Development Development of Specifications

20. International Conference on Harmonisation (ICH) USAEuropeJapan FDA CPMP MHW PhRMA EFPIA JPMA

21. ICH specification of impurities • Limits not greater than those allowed from safety studies • Limits not less than process and analytical capability • Specification includes; • each specified, identified impurity • each specified, unidentifiedimpurity at or above 0.1% • any unspecified impurity with a limit of NMT 0.1%

22. ICH specification of impurities • Qualification of impurities greater than or equal to 0.1% • Identification of impurities greater than or equal to 0.1% • Identification of impurities less than 0.1% if expected to be potent

23. NMR Mass spectrometry Chromatography Infra-red spectroscopy X-ray crystallography UV spectroscopy Thermal analysis Colour tests Optical rotation Density pKa ….etc Techniques for identification of impurities

24. Potential impurities • Water Karl Fisher • Organic solvents Gas chrom • Inorganic solvents Atomic spec • drug-related impurities • polymorphs IR, Thermal methods • enantiomers chiral chromatography • synthetic/degradative chromatography

25. Analytical Development Select and develop suitable analytical methods • Assay • Impurities • Preservative(s) • Colour • pH ….etc

26. Determination of impurities Qualitative determination or limit test? • Liquid Chromatography • Assay and simultaneous impurity determination • Determination of specific impurities • Thin Layer Chromatography • overall picture

27. Separation by high pressure liquid chromatography (HPLC)

28. Annex IIQ Batch analysis of material used in toxicity tests and clinical work • The active substance used in the toxicity studies should present the same pattern of impurities as the product to be marketed, when possible. Should drug substance in the final dosage form be shown to have impurities significantly different, either in quantity or quality, from those in the test batch, then further steps should be taken to ascertain their possible toxicity.

29. Early analytical work • Collect samples of synthetic intermediates

30. Early analytical work • Collect samples of synthetic intermediates • Develop first impurity methods • HPLC (including chiral method) • TLC

31. Early analytical work • Collect samples of synthetic intermediates • Develop first impurity methods • HPLC (including chiral method) • TLC • Assess early batches of drug

32. Case study 2 Which route and batch should we use in our 6month Dog & Rat oncogenicity studies How and why did you make your selection? Comparison of Route 1 and Route 2 impurity profiles (% area) A B C D E F G Tot R1.1 3.6 1.5 0.4 0.3 0.2 0.5 0.2 7.3 R1.2 1.3 0.5 0.1 0.1 0.6 1.7 0.3 5.0 R1.3 0.9 0.4 0.1 ND 0.1 1.6 0.2 3.2 R1.4 0.6 0.5 0.1 ND 0.1 1.5 0.2 3.0 R2.1 0.2 0.2 ND ND 0.2 ND 0.1 0.8 R2.2 0.3 0.3 ND ND 0.2 ND 0.1 0.9 Impurity Synthetic route and batch

33. Early analytical work Collect samples of synthetic intermediates • Develop first impurity methods • HPLC (including chiral method) • Assess early batches of drug • Conduct preliminary forced degradation studies

34. Early analytical work A detailed knowledge of the degradative chemistry of the drug substance must be obtained

35. Accelerated degradation studies Establish the degradative effects of: • heat • light • water, oxygen, carbon dioxide (the atmosphere) • co-ingredients in the formulation • components in the packaging material

36. ICH - control of impurities in drug substance • Evidence that analytical methods are validated and are suitable for detection/ quantitation of impurities • Use of correction factors • Discussion of changes to analytical methods during development

37. Specificity Accuracy Precision Detection limit Quantitation limit Linearity Range Robustness General areas of validation

38. Areas of Validation • Specificity • the ability to measure accurately and specifically the analyte in the presence of components expected to be present • Accuracy • the closeness of the test results obtained by the method to the true result • Precision • the degree of agreement between individual test results

39. Areas of Validation • Detection limit • the lowest amount of analyte which can be detected (but not necessarily quantified) under the defined experimental conditions • Quantitation limit • the lowest amount of analyte which can be quantified with acceptable precision and accuracy under the defined experimental conditions

40. Areas of Validation • Linearity • ability of the method to give results which are directly proportional to the concentration of analyte in the samples, within a given range • Range • concentration range over which the method is demonstrated to have suitable precision, accuracy and linearity • Robustness • measure of a methods capability to remain unaffected by small variations in parameters

41. Select method parameters Select appropriate ranges Select experimental design Identify method responses Carry out experiments on appropriate sample(s) Evaluate data statistically Assess the results scientifically The method evaluation process

42. Typical results • pH range 7.0+/- 0.1 • Initial %MeCN 0-2%v/v • Final %MeCN 18-22% • Method is robust to; • buffer molarity, injection volume, column temperature • Critical resolution - peaks 3 and 4

43. Sampling considerations • Impurities are seldom distributed uniformly • Sample size

44. Stability methods - what’s special? • Samples will change

45. Stability methods - what’s special? • Samples will change • Performance of the method must be maintained over a large time interval

46. Early analytical work • Collect samples of synthetic intermediates • Develop first impurity methods • HPLC (including chiral method) • TLC • Assess early batches of drug • Conduct preliminary forced degradation studies • Draft first specifications

47. Product recalls during 2000 • Potency/content uniformity 38 • Dissolution 21 • Other product spec problems 30 • Contamination 53 • Labelling 34 • Manufacturing/Testing methods 260 • Non-compliance with NDA 28