461

ASSIGNMENT OF VALIDATION PARAMETERS

TABLE 9-3. Proposed Acceptance Criteria for Drug Product (DP) and Drug
Substance (DS)
Quality
Characteristics

Parameter to be Validated

Identity

Selectivity/specificity

Dissolution
(drug
product)

Accuracy (mean)
Recovery
Srel for recovery
Precision
Repeatability
Intermediate precision
Linearity
Correlation coefficient
y-intercept (absolute value)
Residual standard deviation
Stability of solutions
Sample
Reference standard
Specificity
HPLC
Range (basket/paddle)

Content
uniformity
(CU)
Drug product

Assaydrug
product

Precision
Accuracy
Stability of solutions
Specificity

Linearity
Correlation coefficient
y-intercept
Residual standard deviation
Range
Accuracy (mean)DP
Recovery
Srel for recovery

Acceptance Criteria
All known peaks are separated. Major
(API) peak is pure [Peak purity
angle peak threshold angle].
{DS and DP}
For the identity test of a 0-mg
formulation (placebo), it may be
necessary to document the absence
of drug substance, and an LOQ
determination will then be required.
{only DP}
95105%
2.5%
Srel 2.0%, n 6 {at Q time}
Project specific.
n6
r 0.990
5%
2.5%
2.0% change over specified time
2.0% change over specified time
No interference from placebo solution
at the retention time of API.
IR: 30% of specified range
MR,SR: From 50% of Q-value to 130%
of label claim.
As defined in assay

Chromatographic peaks are separated.

No indication of interference from
placebo solution at the retention
time of API.
n6
r 0.990
5.0%
2.0%
At least 70130% of declared content
98.0102.0%
2.0%, n 9 (at least three
concentrations)

462

METHOD VALIDATION

TABLE 9-3. Continued

Quality
Characteristics
Weight
percent
drug
substance

Parameter to be Validated
AccuracyDS
Comparison of methods
(i.e., titration, DSC, PSA)
Precision
Repeatability

Intermediate precision

Linearity
Correlation coefficient
y-intercept
Residual standard deviation
Stability of solutions
Sample
Reference standard
Sample
Reference standard
Specificity
HPLC

Range

Ruggedness/robustness

Drug productRelated
substances
(degradation
products)
Drug substance
(synthetic byproducts and
degradation
products)

Precision
Repeatability

Intermediate precision
[all replicates combined
from two analysts]

Specificity
HPLC

Acceptance Criteria
% difference of the mean of two
methods 2.0%
Srel 2.0%, n 6, DP
Srel 1.0%, n 6, DS
Srel 2.0%, n 4 [when combined from
two analysts]
n6
r 0.998
2.0%
2.0%
2.0% change over specified time (DP)
2.0% change over specified time (DP)
1.0% change over specified time (DS)
1.0% change over specified time (DS)
Chromatographic peaks are separated.
No indication of interference from
placebo solution at the retention time
of API.
No indication of another peak under
the API peak.
At least 80120% of declared content
(100% = concentration X of final
sample stock solution)
1.0% difference for a defined range of
intentionally altering sensitive
parameters (pH of mobile phase,
column, temperature, flow rate,
wavelength, etc.)
Level < 0.1%, Srel 30%, n 6
Level 0.1<0.2%, Srel 20%, n 6
Level 0.2<0.5%, Srel 10%, n 6
Level 0.5<5%, Srel 5%, n 6
Level 5%, Srel 2.5%, n 6
Level < 0.1%, Srel 40%, n 4
Level 0.1<0.2%, Srel 30%, n 4
Level 0.2<0.5%, Srel 15%, n 4
Level 0.5<5%, Srel 7.5%, n 4
Level 5%, Srel 4.0%, n 4
Known peaks are separated.
No indication of interference from
placebo solution at the retention time
of API.
No indication of another peak under
the API peak.

463

ASSIGNMENT OF VALIDATION PARAMETERS

TABLE 9-3. Continued

Quality
Characteristics

Parameter to be Validated
Linearity
Correlation coefficient
y-intercept

Residual standard deviation

Range
LOD
LOQ
Accuracy (mean)
Recovery

Srel for recovery

Stability of solutions [report

two decimal places]
Reference standard

Acceptance Criteria
n6
r 0.990, DP and r 0.998, DS
Level < 0.5%: 25%
Level 0.5<1%: 10%
Level 1%: 5.0%
Level < 0.2%: 20%
Level 0.2<0.5%: 10%
Level 0.5<5%: 5.0%
Level 5%: 2.5%
LOQ to 120% of specification limit of
largest impurity or related substance
Peak signal/noise ratio 3 : 1
Peak signal/noise ratio 10 : 1 and
Srel 10%, n 5
Level < 0.2%: 70130%
Level 0.2<0.5%: 80120%
Level 0.5<5%: 90110%
Level 5%: 95105%
Level < 0.5%: 10%,
Level 0.5<5%: 5%
Level 5%: 2.5%
For all, n = 9 (at least three
concentrations), a weighted average
maybe used based on the level and
the Srel.

Level < 5% of
theoretical 100%
concentration
Level 5% of
theoretical 100%
concentration

Sample

Ruggedness/robustness

Change 10%
over specified
time

Change 2.0%
over specified
time
Related substances (impurities)
Level < 0.5%
Change 20% over
specified time
Level 0.5<5%
Change 10% over
specified time
Level 5%
Change 5% over
specified time
No new peak reporting level
Defined based on an experimental
design and data (sensitive parameters
and a range for each parameter in
the final test method)