Perform an Analytical Method Comparability Study an Analytical Method Comparability Study ... 1....
Transcript of Perform an Analytical Method Comparability Study an Analytical Method Comparability Study ... 1....
Perform an Analytical Method
Comparability Study13:15 – 14:45, Day 2, Wed. 22 06 16
• Steven S. Kuwahara, Ph.D.
• GXP BioTechnology
•6336 N Oracle Rd #326-313
• Tucson, AZ 85704-5480
• e-Mail: [email protected]
Day 2, 13:15 1
Regulatory Guidance, U.S. FDA
Draft Guidance for Industry: Comparability Protocols
Protein Drug Products and Biological Products -Chemistry,
Manufacturing, and Controls Information
U.S. DHHS, FDA, CBER, CDER, CVM: September 2003.
Guidance for Industry: Comparability Protocols for Human
Drugs and Biologics: Chemistry, Manufacturing, and
Controls Information.
U.S. DHHS, FDA, CDER, CBER: April 2016 , Revision 1
• Guidance for Industry
Guidance for Industry: Analytical Procedures and Methods
Validation for Drugs and Biologics
U.S. DHHS, FDA, CDER, CBER: July 2015
Day 2, 13:15 2
Comparing Two Analytical Methods: General
• From a regulatory perspective only a procedure that has
been submitted to a regulatory agency will require a
comparability protocol (CP).
– Follow the Guidance from April, 2016 (Rev. 1) for a
format of the study.
• There are two basic types of new analytical procedures
that require a comparability study.
– A new analytical method that will be an alternative to
the existing procedure that was submitted in the
original application.
– A modification to an existing analytical method.
– A third condition is the transfer of an existing method
to a new group or site.
Day 2, 13:15 3
Comparing Two Analytical Methods: General
Criteria
• A CP to establish a new regulatory analytical procedure or
a modification of an existing analytical procedure should
include justification for the change. If the procedure will
replace an existing regulatory procedure provided in an
approved application, then the new regulatory procedure
should be scientifically sound and equivalent to or better
than the currently approved one. The CP also should
include the specific plan and acceptance criteria for
validation of the modified or new procedure. Method
validation data should be submitted with the notification of
the implemented change. For alternative analytical
procedures, comparative data to the FDA-approved
procedure should also be submitted.
Day 2, 13:15 4
Preparing for the Study that will be Reported
in the CP. I.
• Obtain copies of the original method development
study for the existing procedure and its validation
study.
– The original development study will give you the
background and basic references for the existing method.
– The original validation study and any updates or
revalidations will provide the criteria that the existing
method was able to meet.
– These will provide the criteria that the new method must
either meet or improve upon.
• Remember that there are other criteria besides the validation
criteria. Cost effectiveness for example.
Day 2, 13:15 5
Preparing for the Study that will be Reported
in the CP. II.
• These documents should have been reviewed
before the development of the new method was
attempted.
• As a part of the design control/qualification for
the new method comparable information should
have been obtained prior to its development.
• In a method transfer, what information is
available to show that a successful transfer can be
accomplished?
Day 2, 13:15 6
Scenarios: 1. Alternative Analytical Procedures
A. • An alternative analytical procedure is an analytical
procedure that you use in place of the FDA- approved
analytical procedure. For an NDA or ANDA, you should
include any proposed alternate analytical procedures in the
application. You must include a description of the
procedure. After approval, for an NDA or ANDA, or for a
procedure approved in a BLA but not included in an FDA
regulation, the addition, revision, or deletion of an
alternative analytical procedure that provides the same or
increased assurance of the identity, strength, quality, purity,
or potency of the material being tested as the analytical
procedure described in the approved application, must be
documented in the next annual report.
Day 2, 13:15 7
Scenarios: 1. Alternative Analytical
Procedures B.
• For biological products, in rare cases an analytical procedure
may be included in an FDA regulation. If the analytical method
required is described by a regulation, however, and you want to
use an alternate method, you must submit the alternate method
for review and approval according to 21 CFR 610.9(a). You
must present evidence “…demonstrating that the modification
will provide assurances of the safety, purity, potency, and
effectiveness of the biological product equal to or greater than
the assurances provided by the method or process specified in
the general standards or additional standards for the biological
product.” Modification of such procedures requires FDA
approval during application review or in a postapproval
supplement.
Day 2, 13:15 8
Scenarios: 1. Alternative Analytical
Procedures C.
• You should identify the use of the alternative analytical
procedure (e.g., release, stability testing) and provide a
rationale for its inclusion, validation data, and
comparative data to the FDA- approved analytical
procedure. You should perform an analytical method
comparability study that demonstrates at a minimum that:
– The new method coupled with any additional control measures is
equivalent or superior to the original method for the intended
purpose.
– The new analytical procedure is not more susceptible to matrix
effects than the original procedure.
Day 2, 13:15 9
Scenarios: 1. Alternative Analytical
Procedures D.
• If new process-related or product-related variants
or any new impurities are discovered with the new
procedure, testing on retention samples from
historical batches should be performed to
demonstrate that the variants/impurities detected
by the new method are a result of an increase in
the sensitivity or selectivity of the new procedure
and not a result of a change to process-related
impurities.
Day 2, 13:15 10
Scenarios: 1. Alternative Analytical
Procedures E.
• If the procedure has stability-indicating properties:
• Appropriate samples should be included that allow a comparison of
the ability of the new and original method to detect relevant product
variants and degradation species.
• The number of batches analyzed for comparison should provide
sufficient statistical power.
• Equivalence, non-inferiority, or superiority studies should be
performed with appropriate statistical methods to demonstrate that
the new or revised methods performance is comparable or better than
the original method.
• The statistical analyses performed to compare product testing should
be identified
• All bias or differences between analytical procedures seen with
comparative results should be discussed with an explanation, as
appropriate.
Day 2, 13:15 11
Scenarios: 2. Analytical Methods Transfer
Studies.
• Analytical method transfer is typically managed under a transfer
protocol that details the parameters to be evaluated in addition to the
predetermined acceptance criteria that will be applied to the results.
Transfer studies usually involve two or more laboratories or sites
(originating lab and receiving labs) executing the preapproved transfer
protocol. A sufficient number of representative test articles (e.g., same
lot(s) of drug substance or drug product) are used by the originating
and receiving laboratories.
• The comparative studies are performed to evaluate accuracy and
precision, especially with regard to assessment of interlaboratory
variability. In cases where the transferred analytical procedure is also
a stability-indicating method, forced degradation samples or samples
containing pertinent product-related impurities should be analyzed at
both sites. The USP General Chapter <1224> Transfer of Analytical
Procedures provides additional guidance on this topic.
Day 2, 13:15 12
Reporting Postmarketing Changes to an
Approved NDA, ANDA, or BLA
• Postmarketing changes to analytical procedures must be
reported to the FDA in compliance with 21 CFR 314.70 or
21 CFR 601.12.24 Additional information on the
appropriate reporting category for various kinds of
postapproval changes for NDAs and ANDAs is provided in
the 483 FDA guidance for industry on Changes to an
Approved NDA or ANDA and Changes to an Approved NDA
or ANDA; Specifications – Use of Enforcement Discretion
for Compendial Changes. Similar information on
postapproval changes to BLAs regulated by CDER and
CBER is provided in the FDA guidance: Changes to an
Approved Application for Specified Biotechnology and
Specified Synthetic Biological Products.
Day 2, 13:15 13
Statistical Procedures
• The formal statistical procedures may be found in:
– USP <1010> Analytical Data – Interpretation and
Treatment
– ASTM E1488 Standard Guide for Statistical Procedures
to Use in Developing and Applying Test Methods.
– ASTM E2782 Standard Guide for Measurement Systems
Analysis.
– ASTM E2935 Standard Practice for Conducting
Equivalence Testing in Laboratory Applications.
– There are equivalent methods to be found in the
European Pharmacopeia.
Day 2, 13:15 14
15
DEMONSTRATING COMPARABILITY
• The analyst is confronted with two situations.
– The first situation arises when a new analytical procedure must be compared with a previous method.
– The second situation is when analytical methods are transferred to a new laboratory or location, or both.
• A linear association study is useful in this case.
– It is based on the idea that if two test methods perform in identical ways, a plot of one against the other will produce a straight line with a slope of 1.0.
16
LINEAR ASSOCIATION
• If the straight line has an intercept other than zero (the origin), then one method is biased versus the other.
• This is a bit different from the usual linear regression analysis because of the fact that the independent variable must be assumed to be just as variable as the dependent variable.
• In regression analysis the dependent variable is the result of some action on the independent variable, and the independent variable was assumed to be absolute.
• In this situation, each variable is the independent result of different actions on common samples.
– The common samples bind the tests methods together.
17
LINEAR CORRELATION ANALYSIS 1.
• y = a + bx A = est. a B = est.b
• Take samples large enough to make two measurements by method X and two measurements by method Y. Each of the measurements will be considered to be different runs. Thus you will have Xa1 and Xa2; and Ya1 and Ya2. These measurements will have been made on sample a.
• Take samples b, c, d, and e or more. These samples (a - e) should have concentrations covering the expected range of test results. There will be Xb1, Xb2; and Yb1, Yb2, etc.
• Actually, more than two measurements are often taken and will give more information on method variability.
– However the measurements should be in pairs.
18
LINEAR CORRELATION 3.
• Let d = the difference between the odd and corresponding even results. (i.e. Xa1 - Xa2 and Ye1 -Ye2) . Square the differences (d2
xa, d2xb….d2
ya, d2
yb, etc. ).
• Calculate the variances as:
pairs ofnumber the
2
2
22
22
n
n
nnn
Y
YY
YXX
XX
ds
ds
19
SLOPE ESTIMATION
• The equation is: Y = a + bX
• The estimate (b) of the slope is:
2
4
2
2
22
X
Y
XY
XYXYXY
S
S
SS
SSSSSSSSSSb
20
TERMS
• The sign of b is the sign of SSxy.
n
YXXYSS
n
XXSS
n
YYSS
XY
X
Y
22
22
21
SY•X
• SY•X is the standard deviation of y on x.
222
2
1XYXY SbS
n
nS
22
REGRESSION DATA
• METHOD X METHOD Y• #Run 1 Run 2 ave. dX Run 1 Run 2 ave. dY
• 1 22 24 23 -2 19 19 19 0• 2. 24 20 22 4 24 28 26 -4• 3. 15 17 16 -2 20 16 18 4• 4. 25 27 26 -2 28 20 24 8• 5. 38 42 40 -4 35 41 38 -6• 6. 26 28 27 -2 28 24 26 4• 7. 20 22 21 -2 29 31 30 -2• 8. 39 35 37 4 27 31 29 -4• 9. 18 18 18 0 31 25 28 6• 10. 33 37 35 -4 26 30 28 -4• 11. 31 32 32 -1 37 33 35 4• 12. 29 31 30 -2 39 35 37 4• 13. 24 26 25 -2 17 19 18 -2• 14. 25 23 24 2 31 25 28 6• 15. 31 33 32 -2 40 36 38 4
23
S2Y and S2
X
• These are calculated using the averages of the actual
data points, not the differences. So n = 15.
22
22
1
1
YYXX
Y
YY
X
XX
SSSS
n
SSS
n
SSS
24
CORRELATION PARAMETERS
1333.28 0.422 2.27 0.408
0495.33667.3
2667.10
2667.1030
308
3667.330
101 2
2
2
2
2
2
YYXX
S
S
S
Sn
dS
X
Y
Y
X
25
SUMS OF SQUARES
16.064,176 60.419
40.478,11 898,11
7340.639SS 40.684
512,12 782,11
2
Y
22
XYXY
X
SSSS
n
YXXY
SS
YX
26
Calculation of Run to Run Variation
• Note: This is not the same as the d calculation.
7598.6 6952.4514
7333.639
9918.6 8857.4814
4.684
2
2
YY
XX
SS
SS
27
SLOPE CALCULATION
7297.02.839
37.612
2.839
72.20593467.447,1
2.839
615.446,242,43467.447,1
2.839
14.214763447.209481208.208773.639
b
b
b
28
INTERCEPT AND TEST
• a = 28.1333 - (0.7297x27.20) = 8.2852
602.41781.21)6654.19(077.1
8857.485325.06952.4513
14
0 13.2 4331.0131.19
2852.8
282.17602.4
2852.8
40.684
0.782,11
15
1602.4
2852.80
15,2/05.0
XY
XY
S
XS
Att
t
29
Correlation Coefficient Calculation
X.in variations
by explained is Yin variation theof 40.2% So
4021.06341.0r
exists.n correlatiot significanA 514.0
13df 6341.0
267.872,110.512,126.097,110.781,11
40.478,11898,11
22
13,05.0
r
r
r
30
REFERENCES
• STATISTICAL INFORMATION CAME FROM
SEVERAL SOURCES, BUT THE PRIMARY SOURCE
WAS:
• “PRACTICAL STATISTICS FOR ANALYTICAL
CHEMISTS” by ROBERT L. ANDERSON
• Van Nostrand Reinhold CO., New York, 1987
• The table for the significance of r values is in:
• E.S. Pearson & H.O. Hartley, Biometrika Tables for
Statisticians, Vol. 1, pp. 138 (1962).