Transcript Importance of `Good`

D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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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
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Quality Control of Pharmaceuticals
• Raw materials
(including the active drug substance)
• Packaging materials
• Pharmaceutical products
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Raw Materials
• Pharmaceutical excipients
(e.g. lactose, magnesium stearate,
microcrystalline cellulose etc)
• Solvents
(e.g. pharmaceutical grade water,
methanol etc)
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Packaging Materials
•
Aluminium foil
•
High density polyethylene
•
Glass
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Pharmaceutical Products
• Tablets
• Injections
• Creams and ointments
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Active Drug Substance
• Ranitidine hydrochloride
(Zantac tablets)
• Salbutamol sulphate
(Ventolin inhaler)
• Fluticasone propionate
(Flixonase aqueous nasal spray)
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Types of Specification
• In-process controls
• Release or manufacturing specification
• End-of-life specification
• Pharmacopoeial specification
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Drug Substance Specification
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•
•
•
•
•
Identity
Assay (or potency)
Drug-related impurities
Solvent content
Heavy metals
Particle size
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Drug Substance Properties
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Solubility
Chemical and physical stability
Density
Crystal habit
Bioavailability
pKa
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Drug Substance Specification
• Assay

• Drug-related

impurities
• Solvent content 
98 to 102% by weight
• Heavy metals
not more than 20ppm

not more than 2% total
not more than 1%
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Analytical Methodology
•
•
•
•
•
Identity
Assay
Impurities
Solvent content
Heavy metals
• Particle size
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Infra-red, LC
LC, titrimetry
LC, thin-layer
GC
Colour tests,
AAS
Light scattering
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Analytical Performance
• Typical precision of liquid chromatographic
assay methods is around 1% RSD.
• Assay specification is 98 to 102% by weight.
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Analytical Performance
Key question:
What happens when an assay result of 98.1% is
obtained by HPLC?
Does the batch pass or fail specification?
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Analytical Performance
Confidence interval is given by:
s
t
n
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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?
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Development of the Drug Substance
Specification
Batch
A
B
C
D
E
F
Assay
(% by weight)
98.6
98.0
101.0
100.1
99.4
99.7
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Development of the Drug Substance
Specification
Batch
A
B
C
D
E
F
Sodium content
(ppm)
10
3
9
12
2
15
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Development of the Drug Substance
Specification
Batch
A
B
C
D
E
F
Water
(% by weight)
0.22
0.41
0.88
0.69
1.02
0.14
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Development of the Drug Substance
Specification
Batch
Methanol
(% by weight)
A
B
C
D
E
F
0.79
0.61
3.22
0.51
0.27
0.18
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
Development of the Drug Substance
Specification
Batch
A
B
C
D
E
F
Impurities (%by weight)
Principal
Secondary
Total
0.9
0.9
0.7
0.3
0.3
0.3
0.3
0.3
0.5
0.2
0.2
0.1
1.6
2.2
1.5
0.7
0.7
0.5
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The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
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D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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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.
B. Neidhart, W. Wegscheider (Eds.): Quality in Chemical Measurements © Springer-Verlag Berlin Heidelberg 2000
D. Rudd
The Importance of “Good” Measurements on Industrial Manufacturing Efficiency and Profit
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.
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