Process validation- This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes.

PROCESS VALIDATION
LIQUID DOSAGE
FORM
By;- Sanchit Dhankhar
1

WHAT IS PROCESS VALIDATION
?
It is the process of establishing,
through documented evidence,
a high degree of assurance that a
specific process will
consistently produce a product
that meets its predetermined
specifications and quality
characteristics.
2

WHY VALIDATE?
To conform Manufacturing to cGMP
regulations.
To avoid the possibility of rejected or
recalled batches.
To ensure the product uniformity and
quality.
3

PROCESS VALIDATION
PROTOCOL
Following protocol is suggested:
 Purpose and prerequisites for validation
 Presentation of whole process and sub processes
 Validation protocol approval
 Installation and operational qualifications
 Qualification reports including methods, procedures,
release criteria, etc.
 Product qualification test data from prevalidation batches
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Test data from formal validation batches
Evaluation of test data, conclusions, and
recommendations including the need for
requalification and revalidation
Certification and approval
Summary report of findings with conclusions
5

TYPES OF PROCESS VALIDATION
Main four types of process validation:
1. Prospective validation
2. Concurrent validation
3. Retrospective validation
4. Revalidation
6

WHAT ARE ORAL LIQUIDS?
 Oral Liquids are homogeneous liquid preparations,
usually consisting of a solution, an emulsion or a
suspension of one or more medicaments in a suitable
vehicle.
7

CLASSIFICATION OF LIQUID
ORALS
Two main types:
1.Monophasic liquids: 2. Biphasic liquids:
Solutions Suspensions
Elixirs Emulsions
Syrup
Liquid drops …etc
8

Test parameter Suspension Emulsion
Appearance yes
Specific gravity yes yes
Viscosity yes yes
PH yes yes
Content uniformity yes yes
Sedimentation yes No
Resuspendability yes No
Particle size yes yes
Release rate yes yes 9
Test parameters for emulsion and suspension

CONTINUOUS
PHASE
WATER
SURFACTANTS
OTHER
HELPING
AGENTS
PRESERVATIVES
MIXING
AQUEOUS SOLUTION
DISPERSE PHASE
FOR SUSPENSION FOR EMULSION
DRUG SOLUTION
IN OIL
MILLED DRUG
GRINDING OF
DRUG &
OTHER SOLIDS
DISSOLVED
DRUG IN OIL
Manufacturing of Biphasic liquids:
10

PRE – MIX
OR
CRUDE DISPERSION
HOMOGENIZE
FINE DISPERSE DELIVERY SYSTEM
OTHER ADDITIVES
(FLAVOURS,
COLOURING AGENT)
VOLUME ADJUSTMENT
pH ADJUSTMENT
Disperse
phase
Continuous
phase
11

12
Manufacturing of Monophasic liquids:

PROCESS VARIABLES
Process Equipmen
t
Process variables Properties
affected by
variables
Monitorin
g output
Mixing
of
liquid
Kettle &
Tank fitted
with
agitator
Capacity of unit,
Shape & position
of agitation
system,
Order of addition,
Rate of addition,
Fill volume,
Mixing speed of
agitator,
Temperature of
liquid,
Mixing time.
Appearance
of liquid,
Viscosity of
liquid.
Potency,
Appearanc
e, pH,
Viscosity,
Specific
gravity.
13

Process Equipment Process variables Properties
affected by
variables
Monitoring
Output
Mixing &
blending of
solids
Blade
mixers &
tumblers.
Capacity of unit,
Mixing speed of unit,
Shape of unit,
position of mixing
element within unit,
Product load.
Particle size
of solids,
Blending
uniformity.
Potency,
Particle size
analysis,
Content
uniformity of
active
component.
14

Process Equipment Process variables Properties
affected by
variables
Monitoring
output
Dispersing Homogenizer,
Colloid mill,
ultrasonic
device/
Bore opening/
clearance of rotor
& stator/power
setting,
Pressure/rotor
speed/power
consumption,
Feed rate,
Temperature,
Dispersion time,
Order of mixing.
Particle size
of solids,
Viscosity of
liquid.
Potency,
Particle size
Distribution,
Viscosity,
Specific
gravity.
15

Process validation concerns to following
operations:
 Raw material validation
 Monitoring outputs
 Filling and packaging validation
16

Raw material validation:
It includes mainly following tests
Particle size and size distribution
Particle shape or morphology
Microbial count
Rheology of solvent or vehicle
PH of the solvent or vehicle 17

Continue…
Raw materials are checked and validated for,
 Particle size and size distribution- Particle size
distribution range is 0.2-2microns for suspensions.
 Particle shape(Morphology)-It is also important to
consider because it affects the product appearance,
solubility, settling rates and drug stability.
 Microbial content-To prevent microbial growth on
the final product .
18

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 Rheology of solvent- It will determine how well
liquid will suspend the insoluble particles. Viscosity of
the External phase is generated by one or more of
following components:
 Suspended solids
 Blend of oils and waxes
 presence of polyols and polyoxyethylene derivatives
 High concentration of dispersed solids in water
 Dispersed clays, gums, cellulosic, and/or polymers
19

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 PH of the solvent-Solubility of the drug in the
solvent or vehicle can be markedly influenced by
the PH of the solvent.PH of the solvent is
important because large number of
chemotherapeutic agents are either weak acids or
weak bases so their solubility markedly affected
by the PH of the solvent.
20

Monitoring outputs
Some outputs to be monitored are as under,:
Appearance
pH
Viscosity
Specific gravity
Microbial count
Content uniformity
Dissolution testing 21

Appearance:
 Appearance of the final product is checked and
validated because it indicates the signs of instability
and degradation. For e.g. settling of solid particles
in case of suspension and turbidity in case of
emulsion.
 Time for mixing or agitation and temperature of
process can effect the appearance greatly.
22

PH value
PH of aqueous oral formulations should be taken at a
given temperature and only after equilibrium has
been reached in order to minimize the PH drift.
 Electrolytes , such as potassium chloride , may be
added to the aqueous external phase to stabilize their
PH drift.
23

 Viscosity is defined as the study of fluid flow. or
It is a measurement of the applied stress per unit area
to maintain a certain flow rate.
 The viscometer used for the measurement of
viscosity should be properly calibrated at
equilibrium at a given temperature to establish
system reproducibility.
24

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 Viscosity of the liquid oral dosage form is
important because it affects the settling rate of
suspended particles in suspension and of
globules of internal phase in emulsions and
also in case of oral solutions it affects the
overall appearance of the final product so it
must be measured and validated properly.
25

Specific gravity:
 Specific gravity is the weight of the product per unit
volume.
 For most of the liquid oral products it is 1gm/cube
centimeter.
 A decrease in specific gravity of the product like
suspensions indicates the presence of air within the
structure of the formulation.
 Hydrometer is used to measure the specific gravity
of liquid orals at a given temperature using well
mixed uniform solution. 26

Microbial count
 Microbial count for the final product is essential to
validate because by performing microbial count we
can select the preservative for the final product
storage.
 There are specifications for each liquid oral product
for the bioburden content.
27

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 Preservative system used in the formulation-
The use of small amounts of propylene glycol(5-
15%) or disodium edetate(about 0.1%) or
decrease in the PH of the disperse system have
often been use to increase the efficiency of the
preservative system.
28

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 Criteria for selection of preservatives:
 Must be effective against a broad spectrum of microorganisms.
 Must be chemically, physically, and microbiologically stable.
 It must be nontoxic, nonsensitizing, soluble and compatible with other
formulation components.
29

Content uniformity:
 In solution, suspensions and emulsions determination
of content uniformity affects the dose uniformity
in case of multidose formulations and also affects
the homogeneity of the drug within solvent system.
30

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 Content uniformity of suspension is affected by settling rate which is
governed by following factors,
 Particle size of the internal phase
 Particle density of the internal phase
 Density of the external phase
 Viscosity and structure of the external phase
31

Dissolution testing:
 There is not any official method for dissolution
testing of dispersed system , but the best way to
perform dissolution of suspension like system is to
place a small amount of formulation inside a secure
Durapore (polyvinylidene fluoride) membrane pouch
of suitable viscosity and suspend it in a suitable
dissolution medium using a USP method 1 paddle
apparatus.
32

33
Test parameters specific for suspension
Sedimentation rate
Resuspendibility
Particle size & particle size distribution
Zeta potential measurement
Test parameters specific for solution
Clarity of solution
Color of solution

Type of emulsion determination by
Dilution test
Conductivity test
Dye solubility test
COCl2 filter paper
Fluorescence test
34

Filling and packaging operation validation
 Following tests are performed mainly
Leakage test for filled bottle
Cape sealing test
Fill volume determination
Water vapour permeability test
35

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Some precautions to be taken while filling and packaging
Proper control of product temperature
Proper agitation in holding tanks and filling heads
Uniformity and homogeneity of active ingredient
Maintain stability in the primary container closure
system
36

PRACTICAL APPROACH FOR
MANAGING VALIDATION OF
EMULSION AND SUSPENSION
The validation of suspension and emulsion can be handled
in the same way, because their similarities rather than their
differences are subjected to validation
 Common similarities are
 Particle size distribution of the drug itself
 Homogeneity of the drug throughout the external phase
 Reproducibility and stability of the viscosity and/or
density in the final product
37

Continue…
 The primary focus of prospective validation is to identify the critical unit
operations, critical process variables, and control limits for these variables
in order to establish in process control of the manufacturing process. In
this connection, fractional, factorial designed experiments are used to
determine the critical process variables.
 In retrospective validation the objective is to establish and maintain
process control by demonstration of reproducibility of the various
manufactured batches primarily meeting their final product specifications.
This can be shown effectively by the use of quality control charts.
38

Processing
variables
Lower control
limit(LCL)
Upper control
limit(UCL)
Moisture content 5% 15%
Processing
temperature
50 degree Celsius 70degree Celsius
PH value 5.0 7.0
Processing time 2 hr 6 hr
Apparent viscosity 20,000cps 200,000cps
Blender speed 4,000rpm 20,000rpm
Avg. particle size 20 micron 40 micron
39
Limits of Process variables for factorial analysis

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
 The theory and practice of industrial pharmacy by Leon
Lachman, Herbert A. Liberman, Joseph L. Kanig; Third
edition
40

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