2547

.. 2546 21 2546
120 19 7 2546 GMP
90

.. 2546 1
5 2547
4

4
1.
2.
3.
4.

4

2547

1
2
3
4

6
7
8
9
10

11

4.1
4.2 (Container Closure System)
4.3 (Specification)
4.4
4.5
4.6 Bracketing Matrixing

5.1
5.2 (Assay)
5.3
5.4
5.5
5.6 (Dissolution)
5.7 In-use stability study
5.8
5.9

10.1
10.2
10.3

1
1
4
5
5
5
6
7
7
10
11
11
11
11
12
13
13
13
14
14
14
15
16
17
18
18
18
18
20

1


(Distribution chain)

.. 2546

2
Accelerated Testing ()

Ambient Temperature
Bracketing




Climatic Zone 4
Zone I (Temperate)
Zone II (Sub-tropical)
Zone III
(Hot and dry)
Zone IV
(Hot and humid or tropical)
Controlled Room Temperature
mean kinetic temperature
30 c 2 c
Degradation Product

deamidation, photolysis, oxidation, hydrolysis, aggregation proteolysis
Expiration Date
specification

Impermeable Container

In-use Stability Study

Long Term Testing ()

Mass Balance
100%
Matrixing



Mean Kinetic Temperature


Arrhenius Equation J.D. Haynes (J. Pharm. Sci., 60:927-929, 1971)
USP 23 <1151> Pharmaceutical Dosage Forms
Pilot Scale Batch
solid dosage form 1 10
100,000 /

Primary Batch
(retest period)
primary batch
pilot scale pilot scale 2
1 primary batch production scale
Primary Container
Production Batch

Secondary Container
Semi-permeable Container
(absorption,
diffusion, desorption)
LDPE (low density polyethylene)
LDPE
Shelf Life (Expiration Dating Period)

Specification-Release

Specification-Shelf life

Storage Condition Tolerances

(stability
chamber)




24
Stability-indicating Method

Stress Test
(intrinsic
stability) -
Supporting Data

-
3
3.1 purity test (chromatographic
purity impurity) stress test
3.2
3.3
3.2 3.3
stress test hydrolysis
pH degradation pathway
(retest period)

ICH Q1A(R2) Q1B Q6A Q6B

4.1

2 - 3

. conventional dosage forms ( )

2 pilot scale
. critical dosage forms ( )

primary batch 3 2
pilot scale 1
primary batch

Bracketing Matrixing ( ICH Q1D)

1
stability profile 1 3 - 5

4.2 (Container Closure System)
primary secondary container

Bracketing Matrixing

(impermeable) ,
aluminium/aluminium blister, High Density Polyethylene (HDPE)
HDPE

Polyvinyl Chloride (PVC) blister,

Low Density Polyethylene (LDPE), HDPE polypropylene

permeability coefficient

4.3 (Specification)

stability-indicating method

(release specification) (shelf
life specification)


5


4.4 profile
3 6
3 2-3
6 0, 1, 3 6
3 0, 1 3

6
3 6
Bracketing
Matrixing ( ICH Q1D)
4.5
Long Term Testing Accelerated Testing
4.5.1

. .
4.1

Long Term Testing

Accelerated Testing*

30 c 2 c/ 75% RH 5% RH
25 c 2 c/ 60% RH 5% RH
40 c 2 c/ 75% RH 5% RH
45 c 2 c/ 75% RH 5% RH
45-50 c 2 c/ 75% RH 5% RH

6 ()
12 ()
6
4
3

.
.
* .
12




- potency 5%
-
-
resuspendability, delivery per actuation, caking, hardness
- pH
- 12 /
30 c 2 c / 75 % RH 5%RH
(1) (2)
(3)

4.5.2
(40 c 2 c / 75% RH 5% RH) 6 1

4.5.3
15 c

Long Term Testing

5 c 3 c

Accelerated Testing

25 c 2 c/ 60% RH 5% RH

: .
.

6 ()
12 ()
3 - 6 *


* 3-6
3

1 3
6
-20 c

Long Term Testing

-20 c 5 c

5 c 3 c
25 c 2 c/ 60% RH 5% RH

6 ()
12 ()
1

: .
.

-20 c

4.5.4 semi - permeable

semi-permeable

Long Term Testing

Accelerated Testing*

30 c 2 c/ 35% RH 5% RH
25 c 2 c/ 40% RH 5% RH
40 c 2 c 25% RH

6 ()
12 ()
6


: .
.
* 5 % 40 c 2 c
25% RH 3 semi-permeable
1 ml unit dose product

(water loss)

(100 - Reference relative humidity )/(100 - Alternative relative humidity)

Alternative relative Reference relative
Ratio of water loss rates
humidity
humidity
at a given temperature
60% RH
25% RH
1.9
60% RH
40% RH
1.5
65% RH
35% RH
1.9
75% RH
25% RH
3.0
75% RH
35% RH
2.6

Reference relative General testing condition Ratio of water loss rates

humidity
at the same temperature at a given temperature
25 c / 25% RH
25 c / 60% RH
1.9 = (100-25) / (100-60)
25 c / 40% RH
25 c / 60% RH
1.5 = (100-40) / (100-60)
30 c / 35% RH
30 c / 75% RH
2.6 = (100-35) / (100-75)
40 c / 75% RH
3.0 = (100-25) / (100-75)
40 c / 25% RH
4.6 Bracketing Matrixing

Bracketing
Matrixing ( ICH Q1D)

10

function test

5.1



accuracy, precision, specificity
5.2 (Assay)

accuracy precision
calibration curve
specificity impurities ()
excipients

(multidose parenterals) antioxidant
absorb adsorb

5.3
semi-quantitative
total impurities impurity
detection limit detection limit

11



chromatography
impurities degradation pathway
resolution detection limit

0.5%

5.4
5.4.1 dissolution rate profiles disintegration
( dissolution), appearance, odor, hardness, friability, moisture content, brittleness
( hard gelatin capsules) soft gelatin capsules /
pH fill medium
5.4.2 appearance, color, odor, pH, clarity (solutions), size
range of particulate contamination (large volume parenterals), particle size distribution (suspensions),
micelle size distribution (micellar solutions), resuspendability (suspensions), viscosity, moisture content
(powders for reconstitution), phase separation (emulsions)
/ (heating/cooling cycle) 4 c
45 c /

appearance, pH, dispersibility,

5.4.3 appearance, odor, viscosity, softening range, loss of water,

physical and chemical homogeneity, particle size distribution, particle formation, pH
5.4.4 freeze-dried
(reconstitute) appearance freeze-dried reconstituted material, pH, water content
(powders for reconstitution), rate of solution
5.4.5 leak tests, particulate contamination, valve function, weight loss,
metered dose aerosols uniformity of dose, number of doses per container,
metered dose aerosols pump actuated aerosols (particle size
distribution)

12


5.4.6 appearance, softening temperature (moulded products),
dissolution rate (compressed products)
5.4.7 appearance, in vitro release rate, peel adhesive forces
5.5
multidose microbial challenge test
primary batch 1
5.6 (Dissolution)

6 / (1, 3, 6.....)
dissolution profile
specification of finished product shelf life specification
Dissolution




5.7 In-use stability study

pH, clarity particulate matter

2 - 8 c 24

13


border-line solubility

5.8
polyvinyl chloride low density polyethylene
hydrolysis

density
5.9
5.9.1 impurities
semi-quantitative thin-layer
chromatography impurities

5.9.2

0.01 - 0.05%
0.05% detection limit
detection limit

14

6.1
6.2
6.3

dissolution
pass comply
6.4 In-use stability study
6.5

6.6
6.7

4.1


3

15

95%

slope
intercept 0 ( p value
0.25)

cubic function arithmetic

logarithmic scale goodness of fit degradation line curve

(extrapolate)

extrapolation
goodness of fit mathematical model

mass balance

16

24
-
4
-

-
24

9.1 30 c
9.2 25 c
9.3 2 c 8 c 8 c

9.4 - 5 c
9.5 - 18 c

9.6
9.7 65% RH
9.8
9.9 ambient condition
9.10

9.11
9.12
9.13 ()

17

10

10.1

10.1.1
impurity profile
pilot scale
1 3 3 6

pilot scale 2
3 solid dosage form
10.1.2
pilot scale 3
6


pilot scale 2 3

10.2
pilot scale 2
6
pilot scale 3 6

10.3

6

18


pilot scale 3

pilot scale 3 6

3
(Follow up Stability Study)

19

11

11.1 Draft Guidance for Industry, Stability Testing of Drug Substances and Drug Products,
Center for Drug Evaluation and Research, USFDA, June 1998.
11.2 Guidelines for Stability Testing of Pharmaceutical Products Containing Well Established
Drug Substances in Conventional Dosage Forms, WHO Technical Report Series, No. 863,
1996 Annex 5.
11.3 Note for Guidance on Stability Testing of Existing Active Substance and Related Product,
March 2004, The European Agency for The Evaluation of Medical Product (EMEA).
11.4 ICH Q1A (R2) Guideline on Stability Testing of New Drug Substances and Product, February
2003.
11.5 ICH Q1D Guideline on Bracketing and Matrixing Designs for Stability Testing of New
Drug Substances and Products, February 2003.
11.6 ICH Q1E Guideline on Evaluation for Stability Data, February 2003.
11.7 ICH Q1F Guideline on Stability Data Package for Registration Applications in Climatic
Zones III and IV, February 2003.
11.8 ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances, October 1999.
11.9 Guidelines on Stability Testing of Pharmaceuticals, Australian Guidelines for the Registration
of Drugs Vol.1, July 1994.
11.10 Note for Guidance on Declaration of Storage Conditions for Medicinal Products in The
Products Particulars, The European Agency for The Evaluation of Medical Product (EMEA).,
January 1998
11.11 Note for Guidance on In-use Stability Testing of Human Medicinal Products, The European
Agency for The Evaluation of Medical Product (EMEA), December 1999.
11.12 Guideline on Stability Testing for Applications for Variations to a Marketing Authorization,
The European Agency for The Evaluation of Medical Product (EMEA)., December 2003.

20