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ISSUE HISTORY
Issue Description of Change Originator Effective Date
1 Initial Release Samuel Mengistu 27 Nov 2015

CONTENTS PAGE FOR DOCUMENT CONTROL

USE ONLY
1. PURPOSE 1
2. SCOPE 2
3. RESPONSIBILITY 2
4. MATERIALS AND EQUIPMENTS 3
5. SAMPLING AND SAMPLE STORAGE 3
6. PROCEDURE 4
7. ACCEPTANCE CRITERIA 19
8. REPORTING 19
9. EVALUATION 19
10. REVALIDATION 19
11. REFERENCES 20

1. PURPOSE

Hold time study is the determination of time period for which the product can be hold
at a particular stage and period during processing, under defined storage conditions.
Such study will support the maximum time period between various stages during the
manufacturing of the product so that storage have no any negative effect on the
processing, stability, safety, efficacy or quality of the materials, intermediate products
and bulk products prior to final packing. This protocol will provide the guideline to

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determine the hold time for different manufacturing stages so as meet the requirements
of current good manufacturing practice.

2. SCOPE

This protocol provides the guidance for determination of time limitation in stipulated
storage container at stipulated storage conditions up to which dispensed starting and
packaging materials used, intermediate, bulk and finished products of Ethiopian
Pharmaceuticals Manufacturing Share Company can be stored before taken for next
processing stage.

3. RESPONSIBILITY
QA is responsible for
 Preparing and approving the protocol
 Sampling as per the approved protocol
 Conducting analysis for the stipulated hold time as per the protocol
 Reporting and reviewing the report
 Making conclusion based on the analysis result and incorporates in the working
documents.
Production department is responsible to conduct the production activities as per the
stated procedure.

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4. MATERIALS AND EQUIPMENTS

Sufficient samples of drug products to be studied including all chemicals, solvents,

glass wares and instruments as stated in the individual monographs of the drug
products.

5. SAMPLING AND SAMPLE STORAGE

The hold time study for the product shall be carried out on three batches. The IPQA
shall collect the sample as per protocol during the manufacturing of the planned
batches. The representative sample product should be kept in respective quarantined
area in stainless steel container with PE bag inside at 25°C.

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6. PROCEDURE
6.1 Hold time study for Tablet
6.1.1 Hold Time Study Flow Chart for Tablet

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6.1.2 Hold time study plan

S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

N Hold Time frequency Quantity/ Criteria
sample
1 Binder 8 hours Initial, 12h, 100ml Appearance, viscosity, As per
24 h, 36 h, microbial test specification
48h, 72 h
2 Wet Granules 48 hours Initial,12 h, 100 gm Appearance, Microbial limit As per
24 h 36 h, specification
48 h, 72 h
3 Dried Granules 45 days Initial 100 gm Description, Water content/ As per
15 days Loss on drying, Assay, specification
30 days Related substances, Particle
45 days size distribution, Bulk and
tap density
4 Lubricated blend 45 days Initial 100 gm Loss on drying, Particle size As per
15 days distribution, Bulk and tap specification
30 days density, Blend uniformity,
45 days Microbial test
5 Core tablets 60 days Initial 100 tabs Description, Hardness, As per
15 days Thickness, Friability, specification
30 days Disintegration, Dissolution
45 days Assay, Related substances,
60 days Uniformity of dosage units,
Microbial test
6 Coating solution 72 hours Initial,12 h, 100 ml Physical appearance, As per
24 h, 36 h, Sedimentation, pH, Specific specification
48 h, 72 h gravity, Viscosity, microbial
test
7 Coated tablets 60 days Initial 100 tabs Description, Hardness, As per
15 days Thickness, Friability, specification
30 days Disintegration, Dissolution
45 days Assay, Related substances,
60 days Uniformity of dosage units,
Moisture content, Microbial
test

6.2 Hold time study for Capsules

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6.2.1 Hold Time Study Flow Chart for Capsule

6.2.2 Hold time study plan

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S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

N Hold Time frequency Quantity/ Criteria
sample
1 Granules 45 days Initial 100 gm Description, Water content/ As per
15 days Loss on drying, Assay, specification
30 days Related substances, Particle
45 days size distribution, Bulk and
tap density
2 Filled and 60 days Initial 40 Description, Water content/ As per
polished 15 days capsules Loss on drying, Assay, specification
Capsules 30 days Disintegration, Dissolution,
45 days Assay
60 days

N.B. Filled capsule at stage of filling or polishing shall be investigated for the total time period of
60 days

6.3 Hold time study for Oral Solutions

6.3.1 Hold Time Study Flow Chart for Oral solutions

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6.3.2 Hold time study plan

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S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

N Hold Time frequency Quantity/ Criteria
sample
1 Simple syrup 72 hours Initial 100 ml Description, MLT As per
12 hours specification
24 hours
36 hours
48 hours
72 hours
2 Bulk and filtered 72 hours Initial 200 ml Description, pH, Assay, MLT As per
medicated syrup 12 hours specification
24 hours
36 hours
48 hours
72 hours

N.B. Bulk and filtered medicated syrup shall be investigated for the total time period of 3 days

6.4 Hold time study for Oral powders

6.4.1 Hold Time Study Flow Chart for Oral powders
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6.4.2 Hold time study plan

S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

N Hold Time frequency Quantity/ Criteria
sample
1 Mixed powder 45 days Initial 100 gm Description, Water content/ As per
15 days Loss on drying, Assay, specification
30 days Particle size distribution,
45 days Bulk and tap density,
Reconstitution time, pH

6.5 Hold time study for Topical Preparation

6.5.1 Hold Time Study Flow Chart for Topical preparation
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6.5.2 Hold time study plan

S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

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N Hold Time frequency Quantity/ Criteria

sample
1 Mixed Semisolid 72 hrs Initial 100 gm Description, pH, Viscosity, As per
sample 12 hours Assay, MLT specification
24 hours
36 hours
48 hours
72 hours
2 Homogenized 72 hrs Initial 100 gm Description, pH, Viscosity, As per
semisolid 12 hours Assay, MLT specification
sample 24 hours
36 hours
48 hours
72 hours

6.6 Hold time study for Small volume parenterals (Ampoules)

6.6.1 Hold Time Study Flow Chart for Small volume parenterals (Ampoules)

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6.6.2 Hold time study plan

S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

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N Hold Time frequency Quantity/ Criteria

sample
1 Sterilized 72 hrs Initial 20 Sterility and Endotoxin As per
Ampoule 12 hours ampoules specification
24 hours
36 hours
48 hours
72 hours
2 Bulk prepared 72 hrs Initial 20 Description, pH, Assay, Bio- As per
Solution 6 hours ampoules burden, Endotoxin specification
12 hours
24 hours
36 hours
48 hours
72 hours
3 Filled Ampoules 72 hrs Initial 20 Description, pH, Assay, Bio- As per
before 6 hours ampoules burden, Endotoxin specification
sterilization 12 hours
24 hours
36 hours
48 hours
72 hours
4 Water for 72 hrs Initial 200 ml Description, pH, As per
Injection 6 hours Conductivity, Bioburden and specification
12 hours Endotoxin
24 hours
36 hours
48 hours
72 hours

6.7 Hold time study for Large volume parenterals

6.7.1 Hold Time Study Flow Chart for Large volume parenterals

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6.7.2 Hold time study plan

S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

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N Hold Time frequency Quantity/ Criteria

sample
1 Bulk prepared 72 hrs Initial 200 ml Description, pH, Assay, Bio- As per
Solution 6 hours burden, Endotoxin specification
12 hours
24 hours
36 hours
48 hours
72 hours
2 Filled Bags 72 hrs Initial 2 bag Description, pH, Extractable, As per
before 12 hours Assay, Bio-burden, specification
sterilization 24 hours Endotoxin
36 hours
48 hours
72 hours
3 Water for 72 hrs Initial 200 ml Description, pH, As per
Injection 12 hours Conductivity, Bioburden and specification
24 hours Endotoxin
36 hours
48 hours
72 hours

6.8 Hold time study for Dry powder parenterals for reconstitution

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6.8.1 Hold Time Study Flow Chart for Dry powder parenterals for
reconstitution

6.8.2 Hold time study plan

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S/ Stage Proposed Sampling Sample Tests to be Preformed Acceptance

N Hold Time frequency Quantity/ Criteria
sample
1 Sterilized Vial 72 hrs Initial 10 vials Sterility and Endotoxin As per
8 hours specification
12 hours
24 hours
36 hours
48 hours
72 hours
2 Sterilized Al cap 72 hrs Initial 10 rubber Sterility and Endotoxin As per
and rubber 8 hours 10 Al cap specification
stopper 12 hours
24 hours
36 hours
48 hours
72 hours
3 Filled vials 72 hrs Initial 10 vials Description, pH, Water As per
8 hours content /Loss on drying, specification
12 hours Assay, sterility, endotoxin,
24 hours
36 hours
48 hours
72 hours
4 Water for 72 hrs Initial 200 ml Description, pH, As per
Injection 8 hours Conductivity, Bioburden and specification
12 hours Endotoxin
24 hours
36 hours
48 hours
72 hours

7. ACCEPTANCE CRITERIA

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The acceptance criteria for all the tests should be same as per the hold time study
specification. If hold time study results are passing the 60 days time interval then 45
days limit will be taken as shelf life. In the same way if the stage is passing the 72 hours
interval then 48 hours limit will be taken as shelf life. Any significant change in the
result needs to be investigated and addressed properly.

8. REPORTING
 Results of hold time stability studies should be made available to QA Manager.
 A summary of all the data generated, including any interim conclusions on the
program, should be written and maintained.
 Out of specification or significant atypical trends should be investigated and
report shall be submitted to QA manager.

9. EVALUATION
The maximum period at which the observation for all the specified tests are within the
specification limits shall be the acceptable hold time for the respective intermediate.
Based on the generated results, evaluation and conclusion shall be made along with
established hold time period.

10. REVALIDATION

The hold time study shall be performed again in case of any major change in product
specification.

11. REFERENCES

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 WHO Technical Report Series No. 992, 49 th report, 2015, General Guidance on
Hold Time Studies, Annex 4.
 Mallu UR., Nair AK., Bandaru S., and Sankaraiah J. (2012). Hold Time
Stability Studies in Pharmaceutical Industry: REVIEW. Pharmaceut Reg Affairs.
1:4; 1-8.

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