This document outlines the process validation approach for manufacturing semi-solid dosage forms. It discusses pre-requisites like equipment and facility qualification. Critical process parameters identified include mixing speed, homogenization time, and storage conditions. The document proposes a prospective validation approach using 3 consecutive successful batches. It recommends sampling plans and acceptance criteria for validation including testing bulk and finished products for properties like viscosity, particle size, and content uniformity. An experimental plan is provided to validate the homogenization step focusing on achieving homogeneous bulk mixtures.

1. PROCESS VALIDATION
PREPARED BY
PRAJJWAL SHRESTHA
PRITY NEUPANE
RAJENDRA AYER
Semisolid

2. Introduction
 Semisolids are the topical dosage
form used for the therapeutic,
protective or cosmetic function.

3. SCOPE
 Covers process validation of
manufacturing of semi solid dosage
form

4. APPROACH
 Prospective Validation Approach

5. PRE-REQUISITE
 Equipment Qualification
 Calibration of equipment
 Preventive Maintenance for facilities and
utilities
 Raw material/ Components/Test methods
 Process Justification
 Documentation
 Change Control
 Training Operators
 Cleaning Validation
 Computer system qualified
 Understanding of CCP and documentation

6. Critical Process Parameter
 Mixing speed
 Homogenizing Speed and time
 Mixing Time
 Heating/Cooling Time
 Flow rate (Pumping speed)
 Filtration
 Filling
 Sealing & Labeling
 Storage Condition
Critical Manufacturing
Step
Dissolving Step
Melting Step
Homogenizing Step

7. Number of Runs
 During Performance Qualification, 3
consecutive successful batches
 During Process Validation, 3
consecutive successful batches

8. Product testing
 Validation testing of bulk and finished product
must be based on testing standard release
criteria and in process testing criteria
 Routine QC release testing should be
performed on a routine sample.
 These samples should be taken separately
from the validation samples.
 Validation sampling and testing typically is 3
to 6 time the usual QC sampling

9. Validation Batch :Bulk
Sampling
 Take 10 sample from the mixture, tank, or during
product transfer to the storage/filling vessel.
 The samples must represent the top, middle and
bottom of the vessel
 If sampling from the mixture/tank using an specific
equipment, samples should be taken immediately
adjacent to blades, baffles, and shafts where product
movement during mixing may restricted.
 The bottom of the tank and any potential dead spots
should be sampled and examined for unmixed material,
if possible.

10. Sampling Plan
Samples must be representative of each filling nozzle.
For single filling size
● Take a minimum of 3 fill containers from each of the
beginning, middle and end of the filling run.
● The total number of samples must be not less than
10.
● All samples must be tested.
Multiple filling size
Take minimum 3 samples each at the beginning and
end of the filling size

11. OTHER SAMPLING PATTERN
• Ten equidistant points across the filling
run
must be sampled.
 The beginning and end of filling must
be represented.
 Samples should be taken in triplicate.

12. PRODUCT PERFORMANCE
CHARECTERISTICS
1) Particle size Consideration
Control of particle morphology and
particle size are important parameters to
attain high quality drug product manufacture
and control procedure.
Particle size distribution for most
disperse system should be in the range of 0.2-
20 microns.

13. 2) Viscosity
The Viscometer- Calibrated to
measure the apparent viscosity of the
disperse system at equilibrium at a given
temperature to establish system
reproducibility.
Consistency
type
Approximat
e viscosity
in cps at
25°C
Pharmaceuti
cal example
Soft,
spreadable
100,000-
300,000
W/O, O/W
CREAM
Plastic flow,
spreadable
300,000-
1,000,000
Ointment

14. 3) Content Uniformity
Most important parameter governing
product stability and process control of
the disperse system.
In ointment/cream formulation are
more dependent on particle size, shear
rate, and mixing efficiency.

15. Monitoring
Output
Acceptance
Criteria
(n = 10)
Sampling Plan
Content
Uniformity
UPL & LPL
within 90
– 110% LA
3 – 4 units
from
beginning,
middle and
end
of filling cycle;
total = 10 units
RSD ≤ 4.2%
● The average result of 10 individual results must
meet the
release limit for assay.
● The usual sample size for testing ranges between

16. 4)Preservative
effectiveness
Microbial limit test into formal validation
of aqueous dispersion.
Determination of bio burden for
validation and production batches can
also be used to establish appropriate
validated cleaning procedure for the
facilities and equipment used in

17. 5) Dissolution Testing:
Quality control procedure to determine
product uniformity.
secondary as a means of assessing
the in vivo absorption of the drug in
terms of a possible in vitro/vivo
correlation.

18. KEY ACCEPTANCE
CRITERIA
All tests within specification
 Using standard ANOVA calculations,
there is no significant differences for
each individual run for each
parameter:
(1) between samples at the same
location
(2) between locations
(3) between 30 and 60 minute time
intervals

19. PART II : Experimental Plan
A. Aim
To consistently demonstrate homogeneity of bulk mixture before
packaging
B. Procedure
Homogenization of bulk mixture
C. Number of Experimental Runs
Minimum of 3
D. Process Variables
Homogenizers: Use Two homogenizers
Homogenizing Time: Set time 45 minutes
Speed: Set speed to HIGH (8000 rpm) and LOW (2000 rpm)

20. Experimental Plan Contd..
E. Experimental Details
F. Sampling Plan
Runs Homogenizer Speed
1 One Low
2 One High
3 Two Low
4 Two High
Sample Place of
collection
Time (Minutes) Quantit
y
Three from
each point
Outlets Start (0),15,30,45, End
(60)
1 gm

21. Experimental Plan Contd..
E. Process Measurement
Record of following information in Batch Record
1. Mill Identification
2. Name of Operators
3. Speed setting
4. Time of start and finish
5. Temperature of semisolid preparation after passing through
homogenizer
6. Space between rotor and stator (Usually 0.001 inch)
7. Flow rate
8. Pressure

22. Experimental Plan Contd..
F. Performance Parameters
Performance
Parameters
• Density
• Viscosity
• Particle Size
• Content Uniformity
• Dissolution Rate

23. Experimental Plan Contd..
G. Acceptance Criteria
1. All tests result must be within specification limits.
2. ANOVA test result, There is no significant (P=0.05) differences for
each runs for each parameter
 Between sample at same mill/tank
 Between mills
 At different time
Tests Acceptance Criteria
Particle size 0.2-20 µ
Viscosity 100,000-1,000,000 cps
Density 0.97-1.09 g/mL
Content Uniformity (n=10) UPL and LPL = 90-110%
Dissolution rate Drug release=90 % in 3 hours

24. References
 Lieberman H. A. , Rieger M. M. and
Banker G. S. “Pharmaceutical Dosage
Forms: Disperse System” ,vol.3;
Second Edition,473-511
 R. A. Nash and A. H. Wachter
“Pharmaceutical process validation”;
Third edition
 Agalloco James, Carleton J. Fredric
“Validation of Pharmaceutical
Processes”; Third edition,417-428