1. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 1 Importance of ‘Good’ Measurements on Industrial Manufacturing Efficiency and Profit Importance of quality control Piper Alpha oil rig disaster in 1988 US and Soviet space missions Thalidomide

2. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 2 Quality Control of Pharmaceuticals Raw materials (including the active drug substance) Packaging materials Pharmaceutical products

3. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 3 Raw Materials Pharmaceutical excipients (e.g. lactose, magnesium stearate, microcrystalline cellulose etc) Solvents (e.g. pharmaceutical grade water, methanol etc)

4. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 4 Packaging Materials Aluminium foil High density polyethylene Glass

5. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 5 Pharmaceutical Products Tablets Injections Creams and ointments

6. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 6 Active Drug Substance Ranitidine hydrochloride (Zantac tablets) Salbutamol sulphate (Ventolin inhaler) Fluticasone propionate (Flixonase aqueous nasal spray)

7. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 7 Types of Specification In-process controls Release or manufacturing specification End-of-life specification Pharmacopoeial specification

8. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 8 Drug Substance Specification Identity Assay (or potency) Drug-related impurities Solvent content Heavy metals Particle size

9. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 9 Drug Substance Properties Solubility Chemical and physical stability Density Crystal habit Bioavailability pKa

10. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 10 Drug Substance Specification Assay  98 to 102% by weight Drug-related  not more than 2% total impurities Solvent content  not more than 1% Heavy metals  not more than 20ppm

11. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 11 Analytical Methodology Identity  Infra-red, LC Assay  LC, titrimetry Impurities  LC, thin-layer Solvent content  GC Heavy metals  Colour tests, AAS Particle size  Light scattering

12. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 12 Analytical Performance Typical precision of liquid chromatographic assay methods is around 1% RSD. Assay specification is 98 to 102% by weight.

13. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 13 Analytical Performance Key question: What happens when an assay result of 98.1% is obtained by HPLC? Does the batch pass or fail specification?

14. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 14 Analytical Performance Confidence interval is given by:

15. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 15 Analytical Performance Regulatory agencies expect drug-related impurities to be controlled from levels of 0.1% of the active drug content. HPLC detection and quantitation limits need to reflect this level of control.

16. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 16 Analytical Performance Key question: Does the analytical method (HPLC) have sufficient selectivity and sensitivity to detect and quantify drug-related impurities at or above the level of 0.1% of the active drug content?

17. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 17 Batch Assay (% by weight) A98.6 B98.0 C101.0 D100.1 E99.4 F99.7 Development of the Drug Substance Specification

18. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 18 BatchSodium content (ppm) A10 B 3 C 9 D12 E 2 F15 Development of the Drug Substance Specification

19. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 19 BatchWater (% by weight) A0.22 B0.41 C0.88 D0.69 E1.02 F0.14 Development of the Drug Substance Specification

20. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 20 BatchMethanol (% by weight) A0.79 B0.61 C3.22 D0.51 E0.27 F0.18 Development of the Drug Substance Specification

21. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 21 BatchImpurities (%by weight) PrincipalSecondaryTotal A0.90.31.6 B0.90.32.2 C0.70.51.5 D0.30.20.7 E0.30.20.7 F0.30.10.5 Development of the Drug Substance Specification

22. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 22 Review of Batch Data The assay data seem unremarkable, although these need to be reviewed in conjunction with total impurity data. –mass balance considerations A controlled upper limit for sodium may be unnecessary depending on the form in which sodium is present.

23. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 23 Review of Batch Data An upper limit for methanol should be set without attempting to encompass Batch C. The result of 3.22% indicates that this batch is atypical and this is supported by other aspects evident in the data review. An upper limit for water should be set based on the known chemical (hydrolytic) stability of the molecule.

24. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 24 Review of Batch Data The impurity data indicate an improvement in batch quality with time, so that it is likely that batches D, E and F reflect the typical quality of material now achievable during manufacture. Hence, impurity control of not more than 0.5% for the principal, 0.3% for the secondary and 1.0% for the total level is recommended.

25. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 25 Summary Assessment and assurance of the quality of pharmaceutical materials is established by the use of appropriate specifications for raw materials and products. Various types of specifications exist which reflect the need for control during various phases of drug development.

26. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 26 Summary Regulatory specifications for drug substances and products require analytical methodology capable of defined levels of performance. Final definition of quality specifications for pharmaceutical materials reflect the performance of the manufacturing process, the measurement techniques and the regulatory/safety expectations.

27. B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000 D. RuddThe Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 27 Summary Quality review of pharmaceutical materials depends heavily on an assessment against the defined specification and a recognition that the control parameters must be considered collectively rather than individually. In turn, this emphasises the importance of the analytical methodology used to generate the batch data.