A

SEMINAR
ON

PROCESS VALIDATION OF
OINTMENT/CREAM
FORMULATION

Why need of process

validation for
ointment/cream?

Product bio burden high?

Multiple component?
More adequate preservative system?
All have Newtonian flow behavior?

History: Zinc oxide rash cream that was heated

to a relatively high temperature solely
by the action of rotating mixing plate.

Ointment

Cream

Soft,
semisolid
preparation intended for
application to skin and
mucus membrane.

Appearance: Opaque
Type: Oleaginous
Absorption
Emulsion
Water soluble

Viscous emulsion of
semisolid consistency
intended
for
application to skin and
mucus membrane.
Appearance: Translucent

bases
bases
bases
bases

Type: oil-in-water(o/w)
water-in-oil(w/o)

 Processes must be validated in

pharmaceutical
manufacturing are:
Cleaning
Sanitization
Fumigation
Depyrogenation
Sterilization
Sterile filling
Fermentation
Bulk production
Purification
Filling, capping, sealing
Lyophilization

Process Validation
Documented evidence, a high degree
of assurance that a specific process
will consistently produce a product
that
meets
its
predetermined
specification
and
quality
characteristics.

Process Validation Program

cont..

Process validation
WHY ENFORCE IT?
WHEN IS IT PERFORMED?
WHO PERFORMS IT?

Why?
Makes good engineering sense.
Results in fewer product recalls and
troubleshooting assignments in
manufacturing operations.
Results in more technically and
economically sound products and
their manufacturing processes.

When?
Development stage

Batch size

Product design

1X batch size

Product characterization

1X

Formula selection

1X

Process design

1X

Product optimization

10x batch size

Process characterization

10X

Process qualification

10x

Process demonstration

100X batch size

Process validation program

100x

Product / process certification

100x

Who?

Formulation development
Process development
Pharmaceutical manufacturing
Engineering
QA
QC
API operations
Regulatory affairs
IT operations

ORDER OF PRIORITY
A. Sterile products and their processes(High
Risk)
1) LVP
2) SVP
3) Ophthalmic, other sterile products and medical
devices

B. Non- sterile products and their

processes(Low Risk)
1)
Low dose/high potency tablets and capsules/
TDDS
2)
Drugs with stability problems
3)
Other tablets and capsules
4)
Oral liquids , topical ointment and cream
5)
Diagnostic aids

Validation Protocol
Written plan describing the process
to be validated, including production
equipment.
How validation will be conducted
Objective test parameter
Product characteristics
Predetermine specification
Factors affecting acceptable result

Protocol for validation of

manufacturing process
Purpose and prerequisite for validation
Presentation of the whole process and
sub processes including flow diagram and
critical step analysis
Validation protocol approvals
Installation and Operation qualification
Qualification reports including method,
procedure, release criteria, calibration of
test equipment, test data, summary of
result.

Cont..
Product qualification test data from
prevalidation batches
Test data from formal validation batches
Sampling plan - where, when and how the
samples to be taken
Evaluation of test data, conclusion
Any need for requalification and
revalidation
Certification and approval
Summary report of finding with conclusion
Copies of product stability

Components Included in cGMP

Process Validation
All should be validated.
Facility
Environment
People
Analytical laboratory
Raw materials
Equipment
Procedures
Process

Process Validation
Option
Prospective Process Validationperformed before the process is put into
commercial use
Retrospective Validation- done for
established products whose manufacturing
processes are considered stable
Concurrent validation- in process
monitoring of critical processing steps and
end product testing of current production

Revalidation
- change in critical component(raw material)
- change or replacement in a critical piece
of
equipment.
- change in a facility and/or plant
- significant increase or decrease in batch
size
- sequential batches that fail to meet
product
and process specifications

Semisolids manufacturing
consideration
1) Flow diagram
Combine
water soluble
ingredient in
auxiliary
kettle. Heat to
critical
temperature

Transfer water
phase by pump

Combine oil
soluble ingredient
in main kettle.
Heat to critical
temperature.
Counter sweep
agitation

Filling and
packaging
operation

Transfer
finished
product by
pump into
drum or tank

Homogenize or
pass thru colloid
mill while warm.
Cool slowly with
counter sweep
agitator

2) Unit Operation for

semisolid System
Five unit operation
1)Mixing of liquid
2)Mixing of solid
3)Mixing of semisolid
4)Dispersing
5)Milling and size reduction of
solid and semisolid

1. Mixing of Liquids
Equipment: Kettle and tank fitted with
Process
Properties
Monitoring
agitator
variables

affected by
variables

Output

Appearance
of liquid

Potency

Capacity of
unit
Shape and
position of
agitation
system
Order of
agitation
Rate of
addition
Fill volume

Appearance
Viscosity of
liquid

pH
Specific
gravity

2. Mixing and Blending

of Solid

Equipment: Blade mixture and

tumbler
Process
Property
Monitoring
variable

affected by
variable

output

Capacity of unit
Mixing speed of
unit

Particle size Potency

of solids

Shape of unit
and Position of
mixing elements
within unit

Blend
uniformity

Product load
Order of
addition of solids
to unit mixing

Particle size
analysis

Content
uniformity

3. Mixing and Blending of

semisolid
Equipment: Blade mixture and knider
Process
variable

Properties
affected by
variable

Monitoring
Output

Type and
capacity of unit

Potency

Shape of unit Homogeneity

and position of
mixing
elements within
unit

Content
uniformity

Product load

Viscosity

Temperature

Specific
gravity

4. Dispersing
Equipment: Homogenizers, Colloid mill, or
ultrasonic
device
Process
Properties
Monitoring
variables

affected by
variables

Bore opening/
power setting

output
Potency

Pressure/rotor
speed/power
consumption

Particle size of
solids

Particle
size
distribution

Feed rate

Viscosity of
liquid

viscosity

Temperature
Dispersion time
Order of mixing

Specific
gravity

5. Size Reduction of Solid

and Semisolid
Equipment: end-runner mill, hammer mill,
ball
mill, colloid mill,
micronizer
Process
Properties
Monitoring
variable

affected by
variables

Mill type

output
Potency

Mill size

Particle size

Particle size
analysis

Mill speed/air
pressure

Bulk density

Density/surface
area

Product load

Dissolution
rate of solid

Dissolution
rate/ flow rate
of solid

Feed rate

3) Filling and Packaging

Operation
The following critical aspects must be evaluated and
controlled
during
large-scale
validation
and
manufacturing runs
1. Proper control of product temperature to aid product
flow and maintain product consistency before and
during filling and packaging operations
2.
Proper agitation in holding tanks and filling heads in
order to main product uniformity and homogeneity
during filling and packaging operation
3. The use of air pressure and inert atmosphere to achieve
product performance and stability in the primary
container.

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.

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.

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

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.

Monitoring Output
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.

2) Viscosity
The Viscometer- Calibrated to
measure the apparent viscosity of the
disperse system at equilibrium at a
given temperature to establish system
reproducibility.
Consisten Approxim Pharmaceuti
cy type

ate
viscosity
in cps at
25C

cal example

Soft,
spreadabl
e

100,000300,000

W/O, O/W
CREAM

Plastic

300,000-

Ointment

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 in order to
attain and maintain uniformity of the
active drug component(usually the
internal phase).

Monitoring
Output

Content
Uniformity

Acceptance
Criteria
(n = 10)

Sampling Plan

3 4 units
UPL & LPL within from
90
beginning,
110% LA
middle
and
end
RSD 4.2%
of
filling
cycle;
total = 10
units

The average result of 10 individual results

must meet the

4) Preservative effectiveness
Incorporating a USP antimicrobial
preservative testing procedure or 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 manufacture of disperse system.

5) Dissolution Testing:
It is primary used as a 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.
For cream/ointments, the Franz in vitro
flow through diffusion cell has been modified
by using silicon rubber membrane barrier to
stimulate percutaneous dissolution unit for
testing purpose.

Validation Report
STANDARD FORMAT
1. Executive summary
2. Discussion
3. Conclusions & recommendation
4. List of attachment
Topic should be presented in the order in which they
appear in the protocol.
Protocol deviation are fully explained & justified.
The report is signed & dated by designated
representatives of each unit involved in water system
validation.

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

Thank You