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E. DATA EVALUATION FOR RETEST PERIOD OR SHELF -LIFE ESTIMATION FOR DRUG SUBSTANCES OR PRODUCTS INTENDED FOR STORAGE BELOW “ROOM TEMPERATURE”

E. DATA EVALUATION FOR RETEST PERIOD OR SHELF -LIFE ESTIMATION FOR DRUG SUBSTANCES OR PRODUCTS INTENDED FOR STORAGE BELOW “ROOM TEMPERATURE”

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72



Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products



b.



Regression analysis is considered an appropriate

approach to evaluating the stability data for a quantitative

attribute and establishing a retest period or shelf life. The

nature of the relationship between an attribute and time

will determine whether data should be transformed for

linear regression analysis. Usually the relationship can be

represented by a linear or nonlinear function on an arithmetic or logarithmic scale. Sometimes a nonlinear regression can be expected to better reflect the true relationship.

An appropriate approach to retest period or shelf-life

estimation is to analyze a quantitative attribute by determining the earliest time at which the 95% confidence limit

for the mean around the regression curve intersects the

proposed acceptance criterion.

For an attribute known to decrease with time, the

lower one-sided 95% confidence limit should be compared

with the acceptance criterion. For an attribute known to

increase with time, the upper one-sided 95% confidence

limit should be compared with the criterion. For an

attribute that can either increase or decrease, or whose

direction of change is not known, two-sided 95% confidence limits should be calculated and compared with the

upper and lower acceptance criteria.

The statistical method used for data analysis should

take into account the stability study design to provide a

valid statistical inference for the estimated retest period

or shelf life. The approach described above can be used

to estimate the retest period or shelf life for a single batch

or for multiple batches when combined after an appropriate statistical test.



Significant Change at Accelerated Condition

for Products Intended for Refrigerated Storage

If significant change occurs between 3 and 6 months’

testing at the accelerated storage condition, the proposed

retest period or shelf life should be based on the real-time

data available at the long-term storage condition. No

extrapolation can be considered.

If significant change occurs within the first 3 months’

testing at the accelerated storage condition, the proposed

retest period or shelf life should be based on the real-time

data available at the long-term storage condition. No

extrapolation should be performed. In addition, a discussion should be provided to address the effect of short-term

excursions outside the label storage condition (e.g., during

shipping or handling). This discussion can be supported,

if appropriate, by further testing on a single batch of the drug

substance or product for a period shorter than 3 months.

2.



Drug Substances or Products Intended for

Storage in a Freezer



For drug substances and products intended for storage in

a freezer, the retest period or shelf life should be based

on the real-time data obtained at the long-term storage

condition. In the absence of an accelerated storage condition for drug substances or products intended to be stored

in a freezer, testing on a single batch at an elevated temperature (e.g., 5° ± 3°C or 25° ± 2°C) for an appropriate

time period should be conducted to address the effect of

short-term excursions outside the proposed label storage

condition (e.g., during shipping or handling).



REFERENCES

3.



Drug Substances or Products Intended for

Storage Below −20°C



For drug substances and products intended for storage

below −20°C, the retest period or shelf life should be based

on the real-time data obtained at the proposed long-term

storage condition and should be assessed on a case-bycase basis.



F.



GENERAL STATISTICAL APPROACHES



Where applicable, an appropriate statistical method should

be employed to analyze the long-term primary stability

data in an original application. The purpose of this analysis

is to establish, with a high degree of confidence, a retest

period or shelf life during which a quantitative attribute

will remain within acceptance criteria for all future

batches manufactured, packaged, and stored under similar

circumstances. This same method could also be applied

to commitment batches to verify or extend the originally

approved retest period or shelf life.



© 2004 by CRC Press LLC



1. Carstensen, J.T., “Stability and Dating of Solid Dosage

Forms,” Pharmaceutics of Solids and Solid Dosage

Forms, Wiley-Interscience, New York, 1977, p. 182–185.

2. Ruberg, S.J. and Stegeman, J.W., Pooling data for stability studies: testing the equality of batch degradation

slopes, Biometrics, 47, 1059–1069, 1991.

3. Ruberg, S.J. and Hsu, J.C., Multiple comparison procedures for pooling batches in stability studies, Technometrics, 34, 465–472, 1992.

4. Shao, J. and Chow, S.C., Statistical inference in stability

analysis, Biometrics, 50, 753–763, 1994.

5. Murphy, J.R. and Weisman, D., Using random slopes for

estimating shelf-life, Proc. Am. Stat. Assoc. Biopharm.

Sect., 1, 196–200, 1990.

6. Yoshioka, S., Aso, Y., and Kojima, S., Assessment of

shelf-life equivalence of pharmaceutical products,

Chem. Pharm. Bull., 49, 1482–1484, 1997.

7. Chen, J.J., Ahn, H., and Tsong, Y., Shelf-life estimation

for multi-factor stability studies, Drug Inf. J., 31,

573–587, 1997.

8. Fairweather, W., Lin, T.D., and Kelly, R., Regulatory,

design, and analysis aspects of complex stability studies,

J. Pharm. Sci., 84 (11), 1322–1326, 1995.



Guidelines for Evaluation of Stability Data in Retest Periods



73



APPENDIX A: DECISION TREE FOR DATA EVALUATION FOR RETEST PERIOD OR SHELF

LIFE ESTIMATION FOR DRUG SUBSTANCES OR PRODUCTS (EXCLUDING

FROZEN PRODUCTS)

Tabulate and/or plot

stability data on all

attributes at all storage

conditions and evaluate

each attribute separately



No extrapolation; shorter

retest period or shelf life

and data covering

excursions

can be called for; statistical

analysis if long-term data

show variability



Yes



Significant

change within

3 months?



No



Yes



Significant

change

at accelerated

condition?



Intended

to be stored in a

refrigerator?



Yes



Significant

change

at intermediate

condition?



No



No



Long-term

data show little or

no change over time

and little or no

variability?



No



Long-term

data amenable to

statistical analysis and

statistical analysis

performed?



No

to either



Yes to both



Accerelated

data show little or

no change over time

and little or no

variability?



No extrapolation; shorter

retest period of shelf life

can be called for; statistical

analysis if long-term data

show variability



Yes



No

to either



If supported by

supporting data:

Y = up to 1.25X, out not

exceeding X + 6 months



Yes to both



No

to either



Long-term

data amenable to

statistical analysis and

statistical analysis

performed?



No

to either



If supported by

statistical analysis

and supporting data:

Y = up to 1.5X, but not

exceeding X + 6 months



Yes to both



Y = Proposed retest period or shelf life

Statistical analysis

is normally

unnecessary



Y= up to 2X, but not

exceding X + 12 month;

or if refrigerated,

Y= up to 1.5X, but not

exceding X + 6 months



FIGURE 5.1



© 2004 by CRC Press LLC



X = Available long-term stability data



If supported by statistical

analysis and supporting

data: Y = up to 2X, but

not exceeding X =+ 12

months; or if refrigerated,

Y = up to 1.5X, but not

exceeding X + 6 months



If supported by supporting

data: Y = up to 1.5X,

but not exceeding X + 6

months: or if refrigerated,

Y = up to 1.25X, but not

exceeding X + 3 months



6



Skin Irritation and Sensitization

Testing of Generic Transdermal

Drug Products



To fully evaluate the equivalence of a transdermal product

for an abbreviated new drug application to a reference-listed

drug, skin irritation and sensitization should be assessed

because the condition of the skin may affect the absorption

of a drug from a transdermal system. More severe skin

irritation may affect the efficacy or safety of the product.

Transdermal products have properties that may lead

to skin irritation or sensitization. The delivery system, or

the system in conjunction with the drug substance, may

cause these reactions. In the development of transdermal

products, dermatologic adverse events are evaluated primarily with animal studies and safety evaluations in the

context of large clinical trials generally associated with

the submission of new drug applications. Separate skin

irritation and skin sensitization studies also are used for

this purpose. These latter studies are designed to detect

irritation and sensitization under conditions of maximal

stress and may be used during the assessment of transdermal drug products for abbreviated new drug applications.



I.



STUDY DESIGNS



Recommended designs for skin irritation and skin sensitization studies for the comparative evaluation of transdermal drug products for an abbreviated new drug application are delineated below. Other proposals for studies

may be suggested, but potential applicants are advised to

consult the Office of Generic Drugs about alternative study

designs before the initiation of such a study.



A. RECOMMENDATIONS

IRRITATION STUDY

1.



FOR A



CUMULATIVE SKIN



Sample Size



The sample size should be 30 subjects.

2.



Exclusion Criteria



Dermatologic disease that might interfere with the evaluation of test site reaction should be grounds for exclusion.

3.



Duration of Study



The study should last for 22 days.



4.



Study Design



The study should be a randomized, controlled, repeat

patch test study that compares the test patch with the

innovator patch. Placebo patches (transdermal patch without active drug substance) or high- and low-irritancy controls (e.g., sodium lauryl sulfate 0.1% and 0.9% saline)

can be included as additional test arms.

5.



Patch Application



Each subject applies one of each of the patches to be tested.

Test sites should be randomized among patients. Patches

should be applied for 23 hours (±1 hour) daily for 21 days

to the same skin site. At each patch removal, the site should

be evaluated for reaction and the patch reapplied.

Application of a test patch should be discontinued at

a site if predefined serious reactions occur at the site of

repeated applications. Application at a different site may

subsequently be initiated.

6.



Evaluations



Scoring of skin reactions and patch adherence should be

performed by a trained and blinded observer at each patch

removal, using an appropriate scale.

Dermal reactions should be scored on a scale that

describes the amount of erythema, edema, and other features indicative of irritations. (See Appendix A for an

example of a scoring system that can be used.) The percentage adherence of the transdermal patches should be

assessed using a 5-point scale (see Appendix B).

7.



Data Presentation and Analysis



Individual daily observations should be provided, as well

as a tabulation that presents the percentage of subjects

with each grade of skin reaction and degree of patch

adherence on each study day. The mean cumulative irritation score, the total cumulative irritation score, and the

number of days until sufficient irritation occurred to

preclude patch application for all the study subjects should

be calculated for each test product, and a statistical analysis of the comparative results should be performed (see

Appendix C).

75



© 2004 by CRC Press LLC



76



Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products



B.



RECOMMENDATIONS FOR A SKIN SENSITIZATION

STUDY (MODIFIED DRAIZE TEST)



1.



Sample Size



Two hundred subjects should be sampled.

2.



Exclusion Criteria



Exclusion criteria include

a. Dermatologic disease that might interfere with

the evaluation of the test site reactions

b. Use of systemic or topical analgesics or antihistamines within 72 hours of study enrollment or

systemic or topical corticosteroids within 3

weeks of study enrollment

3.



Study Design



The study should be a randomized, controlled study on

three test products: the test transdermal patch, the innovator patch, and the placebo patch (transdermal patch

without the active drug substance).

5.



6.



Data Presentation and Analysis



The individual daily observations should be provided, as

well as a tabulation of the percentage of subjects with each

grade of skin reaction and degree of patch adherence on

each study day. The mean cumulative irritation score and

the total cumulative irritation score for all the study subjects should be calculated for each test product, and a

statistical analysis of the comparative results should be

performed.

A narrative description of each reaction in the challenge phase should be provided, together with the opinion

of the investigator as to whether such reactions are felt to

be indicative of contact sensitization.



Duration of Study



The study should last 6 weeks.

4.



after patch removal. (See Appendix A for an example of

a scoring system that can be used.)



C. COMBINED STUDIES

Alternatively, the cumulative skin irritation study and the

skin sensitization study can be combined into a single study.

The study design would be identical to that described for

the skin sensitization study (see Section I.B), except that

patch application during the induction phase should be daily

for 23 hours (±1 hour) each day over 21 days.



Patch Application



Test sites should be randomized among patients. The study

is divided into three sequential periods.

a. Induction Phase

Applications of the test materials should be made to the

same skin sites three times weekly for 3 weeks, for a total

of nine applications. The patches should remain in place

for 48 hours on weekdays and for 72 hours on weekends.

Scoring of skin reactions and patch adherence should be

performed by a trained and blinded observer at each patch

removal, using an appropriate scale.

Dermal reactions should be scored on a scale that

describes the amount of erythema, edema, and other features indicative of irritation. (See Appendix A for an example of a scoring system that can be used.) The percentage

adherence of the transdermal patches should be assessed

using a 5-point scale (see Appendix B).

b. Rest Phase

The induction phase is followed by a rest phase of 2

weeks, during which no applications are made.

c. Challenge Phase

The patches should be applied to new skin sites for 48 hours.

Evaluation of skin reactions should be made by a trained

blinded observer at 30 minutes and at 24, 48, and 72 hours



© 2004 by CRC Press LLC



APPENDIX A

SKIN IRRITATION SCORING SYSTEMS

The following scoring system for irritation or sensitization

reactions is included as an example of a scoring system

that can be used for these studies. Other validated scoring

systems can be used in quantifying skin reactions. The

inclusion of this system should not be interpreted as an

endorsement of the system by the agency. It is provided

as an example only.

1. Dermal response:

0 = no evidence of irritation

1 = minimal erythema, barely perceptible

2 = definite erythema, readily visible; minimal

edema or minimal papular response

3 = erythema and papules

4 = definite edema

5 = erythema, edema, and papules

6 = vesicular eruption

7 = strong reaction spreading beyond test site

2. Other effects:

A = slight glazed appearance

B = marked glazing

C = glazing with peeling and cracking

D = glazing with fissures



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