b. neidhart, w. wegscheider (eds.): quality in chemical measurements © springer-verlag berlin...

D. Rudd The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit 1

B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000

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



Quality Control of Pharmaceuticals

• Raw materials

(including the active drug substance)

• Packaging materials

• Pharmaceutical products



Raw Materials

• Pharmaceutical excipients

(e.g. lactose, magnesium stearate, microcrystalline cellulose etc)

• Solvents

(e.g. pharmaceutical grade water,

methanol etc)



Packaging Materials

• Aluminium foil

• High density polyethylene

• Glass



Pharmaceutical Products

• Tablets

• Injections

• Creams and ointments



Active Drug Substance

• Ranitidine hydrochloride

(Zantac tablets)

• Salbutamol sulphate

(Ventolin inhaler)

• Fluticasone propionate

(Flixonase aqueous nasal spray)



Types of Specification

• In-process controls

• Release or manufacturing specification

• End-of-life specification

• Pharmacopoeial specification



Drug Substance Specification

• Identity• Assay (or potency)• Drug-related impurities• Solvent content• Heavy metals• Particle size



Drug Substance Properties

• Solubility• Chemical and physical stability• Density• Crystal habit• Bioavailability• pKa



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



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



Analytical Performance

• Typical precision of liquid chromatographic assay methods is around 1% RSD.

• Assay specification is 98 to 102% by weight.




Key question:

What happens when an assay result of 98.1% is obtained by HPLC?

Does the batch pass or fail specification?




Confidence interval is given by:

ts

n




• 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.




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?



Batch Assay (% by weight)

A 98.6

B 98.0

C 101.0

D 100.1

E 99.4

F 99.7

Development of the Drug Substance Specification



Batch Sodium content

(ppm)

A 10

B 3

C 9

D 12

E 2

F 15




Batch Water (% by

weight)

A 0.22

B 0.41

C 0.88

D 0.69

E 1.02

F 0.14




Batch Methanol(% by

weight)

A 0.79

B 0.61

C 3.22

D 0.51

E 0.27

F 0.18




Batch Impurities (%by weight)

Principal Secondary Total

A 0.9 0.3 1.6

B 0.9 0.3 2.2

C 0.7 0.5 1.5

D 0.3 0.2 0.7

E 0.3 0.2 0.7

F 0.3 0.1 0.5




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.




• 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.




• 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.



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.



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.



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.

b. neidhart, w. wegscheider (eds.): quality in chemical measurements © springer-verlag berlin...

Documents

types of specification

pharmaceutical grade

magnesium stearate

process controls release