CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
Hold time study report of CDFF0213 (Tadalafil Orally Soluble Film 20mg)
Project No.
CDFF0213
Document ID
PD-PS1-00
Version ersi on No.
00
CTCBIO INC.
Jul. 29, 2013
page 1 / 8
CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
Revision History
Revision No.
Date of Revision
00
July 29, 2013
Details of Revision Initial issue
Revised by JunGi Kim
Comment Limit for the waiting period of half-finished products was established for each process.
Investigator Reviewed by Approved by
Jul. 29, 2013
Product research team Product research team Product research team
Junior researcher Chief researcher Senior researcher
JunGi Kim (Signature)
Date: Jul. 29, 2013
SuJun Park (Signature)
Date: Jul. 29, 2013
BongSang Lee (Signature)
Date: Jul. 29, 2013
page 2 / 8
CTCBIO INC. Confidential document
Tadalafil Orally Soluble Film 20mg
Hold time study
Contents
1. Summary ............................................................................................................................ 4 2. Purpose ............................................................................................................................... 4 3. Specimen ............................................................................................................................ 4 4.
Test Period and Schedule .................................................................................................. 4
5.
Test Item ............................................................................................................................. 5
6. Test Methods and Standards ............................................................................................ 5 7.
Results ................................................................................................................................7
8.
Conclusions ........................................................................................................................ 8
Jul. 29, 2013
page 3 / 8
CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
1. Summary Establishing the waiting period that is available for half-finished products in each process of CDFF0213 (Tadalafil Orally Soluble Film 20mg)
2. Purpose Limit for the waiting period of half-finished products in each process were established to ensure stability of half-finished products and effective production.
3. Specimen [Specimen] - Tadalafil Orally Soluble Film 20mg for lab scale up test - Lot No.: T002
4. Test Period and Schedule
Test date Jul. 08, 2013 Jul. 10
Jul. 29, 2013
Process Initiation of manufacturing film solution Transfer and coating
Duration - Initial film solution - Initial coating & drying
Jul. 13
-
- 3rd day film solution
Jul. 15
-
- 5th day film solution
Jul. 17
-
- 1st week coating & drying
Jul. 24
-
- 2nd week coating & drying
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CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
5. Test Item
Process
Test item 1. Content difference between the upper and lower layers by time and mean weight of the film 2. Increment of impurities by time 3. Microbial limit test by time (only on 3rd and 5th days) 1. Confirmation of content by time 2. Confirmation of film weight by time 3. Confirmation of loss on drying by time
Preparation of film solution
Coating & Drying
6. Test Methods and Standards [Film solution manufacturing process] (1) Collection of film solution for test More than 1kg of finished film solution was collected and put in a 1,000-mL measuring cylinder, covered the opening with plastic wrap and left for maximum 5 days at room temperature (25 ℃). (The initial data of film weight and content test are replaced by those of the initial sample in the coating & drying process.) (2) Sample collection at each time point For the content test on 3 rd and 5 th days, sample was carefully collected on the corresponding days at 5cm from the surface and approximately 5cm from the bottom using a pipette. Impurity test and microbial limit test were conducted using the sample obtained from the upper layer. (3) Drying the samples Base films placed on a glass plate was coated with the collected samples and then dried under the designated conditions for time and temperature. The coating and drying conditions are as follows. Coating thickness
460um
Drying temperature
80℃
Duration of drying
60 min.
(4) Sample analysis The dried films were evenly sliced and tested for the standard of ‘Tadalafil Orally Soluble Film 20m’ and for dosage form uniformity and impurity. Microbial limit test for the film solution was conducted following the Microbiological examination of Jul. 29, 2013
page 5 / 8
CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
nonsterile products: Microbial enumeration tests, USP <61> and the Microbiological examination of nonsterile products: Tests for specified microorganism, USP <62>. (5) Standards
Content test -
The content in the initial sample and samples at each time point should be 95-105%.
-
The content result at each time point should not be different by more than 2% compared with the result at the initial time point.
-
The content results between the upper and lower layers should not be different by more than 2% among the samples at each time point.
-
The mean weight difference among 5 sites of the upper and lower layers should not be more than 3mg among the samples at each time point.
Impurity test -
Impurity test results at each time point should be suitable, and the difference between the initial and each time point should not be more than 0.1% for individual unknown impurities and 0.2% for total impurities.
Microbial limit test -
Microbial limit test results should be suitable at each time point.
[Coating & Drying process] (1) Preparation of coating solution for test The manufactured film solution was dried under the condition described below and the base films were overlapped to the upper and lower surfaces. The packaging material that was identical to the one described in the manufacture order was used for packaging and then the samples were left for maximum 2 weeks at room temperature (25℃) (packaging performed separately for different time points). (2) Collection and analysis of samples at each time point Samples were collected at each time point and tested for the standard of ‘Tadalafil Orally Soluble Film 20m’ and for dosage form uniformity and impurity. (3) Standards
Contents -
Jul. 29, 2013
The result of content test at each time point should be 95-105%. page 6 / 8
CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
-
Hold time study
Difference between mean content at each time point and mean content at the initial time point should not be greater than 2%.
-
Difference in mean weight between each time point should not be greater than 3mg.
Loss on drying
-
Results of loss on drying of samples at each time point, including the initial sample, should be suitable.
-
Difference in the results of loss on drying between the initial and each time point should not be greater than 3%.
7. Results
[Film solution manufacturing process] Process
Initial
Time point 3rd day
5th day
Upper layer
99.94
99.99
99.85
Lower layer
99.76
99.78
99.63
Content difference (%)
0.19
0.21
0.22
Suitability
Suitable
Suitable
Suitable
Upper layer
120.84
120.24
120.58
Lower layer
120.38
119.74
119.82
Difference in mean weight (mg)
0.10
0.50
0.76
Suitability
Suitable
Suitable
Suitable
Individual known impurities
N.D.
N.D.
N.D.
Suitability
Suitable
Suitable
Suitable
Total impurities
N.D.
N.D.
N.D.
Suitability
Suitable
Suitable
Suitable
Microbial limit test
Not detectable
Not detectable
Not detectable
Suitability
Suitable
Suitable
Suitable
Test item
Content (%)
Mean weight of film (mg)
Manufacturing of film solution
Impurity
Jul. 29, 2013
page 7 / 8
CTCBIO INC.
Tadalafil Orally Soluble Film 20mg
Confidential document
Hold time study
[Coating & Drying process] Process
Coating & Drying
Initial
Time point 1 week
2 weeks
Content (%)
100.15
100.47
100.03
Suitability
Suitable
Suitable
Suitable
Film weight (mg)
120.48mg
119.10mg
119.92mg
Suitability
Suitable
Suitable
Suitable
Loss on drying (%)
8.78
8.71
8.86
Suitability
Suitable
Suitable
Suitable
Test item
8. Conclusions
In this hold time study for manufacturing process of film solution and coating & drying processes, the quality of half-finished products was not significantly reduced by 5 days after completing the manufacturing process of film solution and by 2 weeks after completing the coating & drying process.
These results indicate that the quality will be maintained up to the standard for 5 days after completing the manufacturing process of film solution and for 2 weeks after completing the coating & drying process. Therefore, the maximum storage time before proceeding to the next process shall be 5 days and 14 days, respectively, after the manufacturing process of film solution and after coating & drying process.
The maximum storage time after the coating & drying process refers to the period until just before the packaging process, and the slitting process shall be completed within the 14 days of maximum storage time.
Jul. 29, 2013
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