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 • Viscous emulsion of
intended for application to semisolid consistency
skin and mucus membrane. intended for application to
skin and mucus membrane.

Appearance: Opaque Appearance: Translucent

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

Absorption bases water-in-oil(w/o)
Emulsion bases
Water soluble bases
● 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 Validation- performed
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 Combine oil soluble
soluble ingredient ingredient in main
Transfer water
in auxiliary kettle. kettle. Heat to critical
phase by pump
Heat to critical temperature. Counter
temperature sweep agitation

Homogenize or pass
Filling and Transfer finished thru colloid mill while
packaging product by pump warm.
operation into drum or tank 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 agitator
Process variables Properties affected Monitoring Output
by variables
▪ Capacity of unit
▪ Shape and ▪ Appearance of ▪ Potency
position of liquid
agitation system
▪ Order of agitation ▪ Appearance
▪ Rate of addition ▪ Viscosity of liquid ▪ pH
▪ Fill volume ▪ Specific gravity
▪ Mixing speed of ▪ Viscosity
agitator
▪ Temperature of
liquid and time
 2. Mixing and Blending of Solid
Equipment: Blade mixture and tumbler
Process variable Property Monitoring output
affected by
variable
▪ Capacity of unit
▪ Mixing speed of unit ▪ Particle size of ▪ Potency
solids
▪ Shape of unit and ▪ Blend ▪ Particle size
Position of mixing uniformity analysis
elements within unit
▪ Product load ▪ Content
uniformity

▪ Order of addition of
solids to unit mixing
time
 3. Mixing and Blending of semisolid
Equipment: Blade mixture and knider

Process variable Properties affected Monitoring Output

by variable
▪ Type and capacity ▪ Potency
of unit
▪ Shape of unit and ▪ Homogeneity ▪ Content
position of mixing uniformity
elements within
unit
▪ Product load ▪ Specific gravity ▪ Viscosity
▪ Temperature
▪ Agitation speed ▪ Viscosity ▪ Density
▪ Mixing time
 4. Dispersing
Equipment: Homogenizers, Colloid mill, or ultrasonic device
Process variables Properties affected by Monitoring
variables output

▪ Bore opening/ ▪ Potency

power setting
▪ Pressure/rotor ▪ Particle size of solids ▪ Particle size
speed/power distribution
consumption
▪ Feed rate ▪ Viscosity of liquid ▪ viscosity
▪ Temperature
▪ Dispersion time ▪ Specific
gravity
▪ Order of mixing
5. Size Reduction of Solid and Semisolid

Equipment: end-runner mill, hammer mill, ball

mill, colloid mill, micronizer
Process variable Properties affected Monitoring output
by variables
▪ Mill type ▪ Potency
▪ Mill size ▪ Particle size ▪ Particle size
analysis
▪ Mill speed/air ▪ Bulk density ▪ Density/surface
pressure area
▪ Product load ▪ Dissolution rate of ▪ Dissolution rate/
solid flow rate of solid
▪ Feed rate
▪ Inert atmosphere
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.
Consistency Approximate Pharmaceutical
type viscosity in example
cps at 25°C

Soft, 100,000- W/O, O/W CREAM

spreadable 300,000

Plastic flow, 300,000- Ointment

spreadable 1,000,000
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 Acceptance Sampling Plan
Criteria
(n = 10)

3 – 4 units from
Content UPL & LPL within 90 beginning,
Uniformity – 110% LA
middle and end
of filling cycle;
RSD ≤ 4.2%
total = 10 units
● The average result of 10 individual results must meet the
release limit for assay.

● The usual sample size for testing ranges between 0.5 and
1.5 g per sample assay.
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