HOLD TIME STUDY PROTOCOL

Protocol No. HTP/001-00

Supersedes NIL
Batch Number
 PROTOCOL CONTENTS

Sr.
CONTENTS PAGE No.
No.

NA Protocol content 02

1.0 Protocol approval 03

2.0 Objective 04

3.0 Scope 04

4.0 Responsibilities 04

5.0 Brief description of process flow 05

6.0 Reference documents 05

7.0 Hold time study programme 05

8.0 Methodology 06

9.0 Environmental condition 06-08

10.0 Acceptance criteria 09

11.0 Sampling plan 10

12.0 Tests and Results 11-16

13.0 Deviation and Corrective Action Report 17

14.0 Summary, conclusion & recommendation 17

15.0 Abbreviation 18
1.0 PROTOCOL APPROVAL
INITIATED BY:

Designation Name Signature Date

QA Officer

REVIEWED BY:

Designation Name Signature Date

Manager Production

Manager QC

AUTHORIZED BY:

Designation Name Signature Date

Head QA
2.0 OBJECTIVE:
To establish the documented evidence to demonstrate the effect of temperature and relative humidity
on Lubricated Granules, Compressed Tablet and Coated tablets
.
 To ensure that the Lubricated Granules, Compressed Tablet and Coated Tablets of meet the
critical quality attributes & pre-determined acceptance criteria for three consecutive batches of
3.0 SCOPE:
 To establish documented evidence that whole process is capable of performing as per
specified acceptance criteria and is adequate to provide the assurance for which the process is
intended.
 The protocol is applicable for checking effect of storage on granules which is manufactured in
manufacturing area.

4.0 RESPONSIBILITY:
DEPARTMENTS RESPONSIBILITIES
 To prepare the protocol.
 To withdraw the samples as per sampling plan.
 Monitoring of the activities during study.
Quality Assurance
 Review and approval of the protocol and report.
 Compilation of data

 To perform the study as per the protocol.

 Temperature monitoring during hold time study.
Production
 Review the protocol and report.

 To analyze the samples as per specification.

Quality Control  Review of the protocol and report.
5.0 Brief description of process flow:
On completion of lubrication, compression and Coated Tablets of Acemed-Sera tablets
store the lubricated blend in IPC, compressed tablets in HDPE container & Coated tablets in
HDPE container in blend storage, compressed tablet & Coated tablets quarantine area
respectively at required temperature and humidity as per SOP for Environmental Monitoring
in Manufacturing Area.
The time taken for Hold time Study is as follows for Q.C. and Microbial purity.
5.1 Lubricated Granules: - Initial, 7th days, 14th days and 2st day shall be established and its
impact on the quality attributes shall be evaluated by drawing samples at defined
intervals based on sampling plan.
5.2 Compressed tablets (core tablet): - Initial, 15th days,30th and 45th days shall be
established and its impact on quality attributes shall be evaluated by drawing samples
at defined intervals based on sampling plan.
5.3 Coated tablets - Initial, 15th days,30th and 60th days shall be established and its impact
on quality attributes shall be evaluated by drawing samples at defined intervals based
on sampling plan.
Note :Initial sample is consider as the batch sample
6.0 Reference documents:
Sr.
Title of Document Document No./SOP No.
No.
Environmental Monitoring in
1
Manufacturing Area
Sampling of semi finished / finished
2
products

3 Compressed tablets specification

4. Coated tablets specification

7.0 Hold time study programme:

This includes the study,

7.1 Lubricated Granules: -
7 .1.1 Description
7 .1.2 LOD/ Moisture content
 7 .1.3 Assay
7.1.4 Microbial Purity
7.2 Compressed Tablet: -
7.2.1 Description
7.2.2 Disintegration Test
7.2.3 Assay
7.2.4 Microbial Purity
7.3 Coated Tablet: -
7.2.1 Description
7.2.2 Disintegration Test
7.2.3 Assay
7.2.4 Microbial Purity

8.0 METHODOLOGY:
Collect the composite sample from the blender for lubricated granules, composite sample for
compressed tablet & coated tablets as per respective SOPs. and store it in blend storage,
compressed tablet & coated tablets quarantine area respectively at required temperature and
humidity as per SOP for Environmental Monitoring in Manufacturing.
Note: Wear hand gloves while sampling at each stage.

9.0 ENVIRONMENTAL CONDITIONS:

Samples shall be stored at a temperature (0C) and RH (%) as per product requirement
Temperature (0C) ……………………………
RH (%)……………………………………. ..
The environmental conditions shall be monitored two times a day. Recording shall be filled in the
format as described.
9.1 For blend:
Equipment ID No. for Hygrometer:……… Storage Area:…………
Calibration Date:…………………… Calibration Due Date:………………
 Storage Limit: Temperature: ………….., Relative Humidity…………….
Date Time Dry Bulb Relative Recorded Time Dry Bulb Relative Recorded Remarks
Temperature Humidity By Temperature Humidity By

Remark:
________________________________________________________________________________
Checked By (Sign/Date) _____________ Reviewed By (Sign/Date) _____________
 9.2 For Compressed tablets:
Equipment ID No. for Hygrometer:………………….. Storage Area:………………………..
Calibration Date:………………………………… Calibration Due Date:………………
Storage Limit: Temperature: ………….., Relative Humidity…………….
Date Time Dry Bulb Relative Recorded Time Dry Bulb Relative Recorded Remarks
Temperature Humidity By Temperature Humidity By

Remark:
________________________________________________________________________________
Checked By (Sign/Date) _____________ Reviewed By QA (Sign/Date) ______
 9.2 For Coated tablets:
Equipment ID No. for Hygrometer:………………….. Storage Area:………………………..
Calibration Date:………………………………… Calibration Due Date:………………
Storage Limit: Temperature: ………….., Relative Humidity…………….
Date Time Dry Bulb Relative Recorded Time Dry Bulb Relative Recorded Remarks
Temperature Humidity By Temperature Humidity By

Remark:
________________________________________________________________________________
Checked By (Sign/Date) _____________ Reviewed By QA (Sign/Date) ______
10.0 Acceptance criteria:
10.1 For Lubricated granules (Blend):
10.1.1 Moisture content : - 1.50 to 2.50%
10.1.2 Assay : - 90 % to 110 %
10.1.3 Microbial Purity : - TBC- NMT 10000 CFU/ gm
TFC- NMT 100 CFU/ gm
Pathogen (E.coli, Salmonella, Ps. aeruginosa, S. aurous )
- should be absent / gm
10.2 For Compressed tablets (core tablet):
10.2.1 Description: - White colour, Elongated shaped, un-coated tablets with break line on
one side and plain on other side.
10.2.2 Disintegration test: - Not more than 15 minute.
10.2.3 Assay:-
10.2.3.1 For Paracetamol : 90.0% to 110.0 % of the labeled amount.
10.2.3.2 For Aceclofenac : 90.0% to 110.0 % of the labeled amount.
10.2.3.3 For Serratiopeptidase : 90.0% to 110.0 % of the labeled amount.
10.2.5 Microbial Purity: - TBC- NMT 10000 CFU/ gm
TFC- NMT 100 CFU/ gm
Pathogen (E.coli, Salmonella, Ps. aeruginosa, S. aurous)
- should be absent / gm
10.3 For Coated tablets
10.3.1 Description: - Orange colour, Elongated shaped, Film coated tablets with break line
on one side and plain on other side.
10.3.2 Disintegration test: - Not more than 30 minutes.
10.3.3 Assay:-
10.3.3.1 For Paracetamol : 90.0% to 110.0 % of the labeled amount.
10.3.3.2 For Aceclofenac : 90.0% to 110.0 % of the labeled amount.
10.3.3.3 For Serratiopeptidase : 90.0% to 110.0 % of the labeled amount.
10.3.4 Microbial Purity: - TBC- NMT 10000 CFU/ gm
TFC- NMT 100 CFU/ gm
Pathogen (E.coli, Salmonella, Ps. aeruginosa, S. aurous)
- should be absent / gm
11.0 Sampling plan:
SAMPLE REQUIRED
HOLD TIME FOR ANALYSIS
STAGE TESTS TO BE DONE
(IN DAYS) (collect in Duplicate for
each interval )
1. Description 1) Initial, 2 X 250 gm
2. LOD/ Moisture 2) 7th day
content 3) 14th day,
3. Assay 4) 21th day,
LUBRICATED
GRANULES
4. Microbial Purity 1. Initial, 2X150 gm
2. 7th day
3. 14th day,
4. 21th day,

1. Description 1. Initial,
2.Disintegration Test 2. 15th day
3.Assay 3. 30th day, 2 X 130 tablets
4. 45th day,
COMPRESSD
TABLET 4.Microbial Purity 1 Initial, 2X130 tablets
2 15th day
3 30th day,
4 45th day,

1. Description 1. Initial, 2X130 tablets

2.Disintegration Test 2. 15th day
3.Assay 3. 30th day,
4. 60th day,

4.Microbial Purity 1. Initial, 2X130 tablets

2. 15th day
3. 30th day
4. 60th day

 Keep duplicate sample in well closed IPC’s in respective quarantine area.

Prepared By: Checked By:

Date: Date:

12.0 Tests and Results:

 12.1 For Lubricated granules (Blend):
Results
Acceptance
Tests Batch No: Batch No: Batch No:
criteria

Initial Initial Initial

7th day 7th day 7th day

14th day 14th day 14th day

White color
Description
Powder
21st day 21st day 21st day

Mean Mean Mean

RSD RSD RSD

Initial Initial Initial

7th day 7th day 7th day
14th day 14th day 14th day
Moisture content 1.50 to 2.50%
21st day 21st day 21st day
Mean Mean Mean
RSD RSD RSD
Assay of- 90 % to 110 %
1. Paracetamol Initial Initial Initial

2. Aceclofenac
3.Serratiopeptidase 7th day 7th day
7th day
14th day 14th day

7th day 7th day

14th day
14th day 14th day

21st day 7th day 7th day

Mean Mean Mean

 RSD RSD RSD

Initial Initial Initial

7th day 7th day 7th day
TBC: NMT
14th day 10th day 10th day
10000
21st day 20th day 20th day
CFU/ gm
Mean Mean Mean
RSD RSD RSD
TFC: NMT 100 Initial Initial Initial
CFU/ gm th th
7 day 7 day 7th day
14th day 14th day 14th day
Microbial Purity
21st day 21st day 21st day
Mean Mean Mean
RSD RSD RSD
Pathogen Initial Initial Initial

should be 7th day 7th day 7th day

14th day 14th day 14th day
absent / gm
21st day 21st day 21st day
Mean Mean Mean
RSD RSD RSD

Remark:-

Prepared By: Checked By:

Date: Date:
12.2 For Compressed tablet:
Tests Acceptance criteria Results
Batch No: Batch No: Batch No:
 White colour, Initial Initial Initial
th th
Elongated shaped, 15 day 15 day 15th day
30th day 30th day 30th day
un-coated tablets
Description 45th day 45th day 45th day
with break line on
Mean Mean Mean
one side and plain on
RSD RSD RSD
other side
Initial Initial Initial
th th
15 day 15 day 15th day
20th day 20th day 20th day
Not more than 15
Disintegration 30th day 30th day 30th day
minutes.
45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD
Assay of-
1. Paracetamol Initial Initial Initial

2. Aceclofenac
3.Serratiopeptidase
15th day 15th day 15th day

30th day 30th day 30th day

90.0% to 110.0 % of
the labeled amount.

45th day 45th day 45th day

Mean Mean Mean

RSD RSD RSD

Initial Initial Initial

TBC: NMT 10000
Microbial Purity th
15 day th
15 day 15th day
CFU/ gm
30th day 30th day 30th day
 45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD
TFC: NMT 100 CFU/ Initial Initial Initial
gm
15th day 15th day 15th day
30th day 30th day 30th day
45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD
Pathogen- should be Initial Initial Initial
th th
absent / gm 15 day 15 day 15th day
30th day 30th day 30th day
45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD

Remark: -

Checked By: - Reviewed By:-

Date Date

12.3 For Coated tablet:

Results
Tests Acceptance criteria Batch No: Batch No: Batch No:

Orange colour, Initial Initial Initial

th th
Elongated shaped, 15 day 15 day 15th day
30th day 30th day 30th day
Film coated tablets
Description 45th day 45th day 45th day
with break line on
Mean Mean Mean
one side and plain on
RSD RSD RSD
other side
 Initial Initial Initial
th th
15 day 15 day 15th day
20th day 20th day 20th day
Not more than 15
Disintegration 30th day 30th day 30th day
minutes.
45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD
Assay of-
1. Paracetamol Initial Initial Initial

2. Aceclofenac
3.Serratiopeptidase
15th day 15th day 15th day

30th day 30th day 30th day

90.0% to 110.0 % of
the labeled amount.

45th day 45th day 45th day

Mean Mean Mean

RSD RSD RSD

Microbial Purity Initial Initial Initial

15th day 15th day 15th day
TBC: NMT 10000 30th day 30th day 30th day
CFU/ gm 45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD
TFC: NMT 100 CFU/ Initial Initial Initial
gm th th
15 day 15 day 15th day
30th day 30th day 30th day
45th day 45th day 45th day
Mean Mean Mean
 RSD RSD RSD
Pathogen- should be Initial Initial Initial
th th
absent / gm 15 day 15 day 15th day
30th day 30th day 30th day
45th day 45th day 45th day
Mean Mean Mean
RSD RSD RSD

Remark: -

Checked By: - Reviewed By:-

Date Date
13.0 Deviations and Corrective Action Report:
If any deviation observed fill the deviation form as per SOP for Deviation control.

14.0 Summary, conclusion & recommendation:

15.0 ABBREVIATION
HDPE : High Density Polyethylene
RSD : Relative Standard Deviation
CFU : Colony Forming Unit
LOD : Loss on Drying
TAC : Tablets and Capsules
QA : Quality Assurance
QC : Quality Control
NMT : Not More Than