A detailed presentation on "PROCESS VALIDATION OF AN OINMENT AND LIQUID ORALS"

1. Prepared by :
Neetu Vishwakarma
M.Pharm (Pharmaceutical Quality Assurance)
Submitted to:
Dr. Deepti Jain
Associate Professor & Director
School Of Pharmaceutical Sciences, RGPV Bhopal

2. Validation is a part of the quality assurance program and is fundamental to
an efficient production operation for building quality into the products.
Validation of the individual steps of the processes is called the process
validation.
The goal of validation is to ensure that quality is built into the system at
every step, and not just tested for at the end.
WHO – Validation is documented act of providing that any procedure,
process, equipment, material, activity or system actually leads to the
expected results.
INTRODUCTION:

3. Process Validation provides the flexibility and constraints in the
production process controls in the achievement of desirable qualities in the
drug product while preventing undesirable attributes.
USFDA – Establishing documented evidence which provides a high
degree of assurance that a specific process (such as the manufacture of
pharmaceutical dosage forms) will consistently produce a product meeting
its predetermined specifications and quality characteristics.
PROCESS VALIDATION:

4. STAGES OF PROCESS VALIDATION:
Stage 1 Stage 2
Stage 3
Design of Facilities
& Qualification of
Equipment and
Utilities
Process
Performance
Qualification
(PPQ)
Distribution Distribution
Evaluate/Confirm

6. Oral Liquids are homogeneous liquid preparations that usually consisting
of a solution, an emulsion or a suspension of one or more medicaments in
a suitable vehicle.
WHAT ARE LIQUID ORALS:

7. LIQUID DOSAGE CAN BE PREPARED:
1) By dissolving the active drug substance(s) in an aqueous or non-
aqueous (e.g. alcohol, ether, glycerine) solvent.
2) By suspending the drug in appropriate medium.
3) By incorporating the drug substance into an oil or water phase.

8. CLASSIFICATION OF ORAL LIQUIDS:
TWO MAIN TYPES
MONOPHASIC LIQUIDS BIPHASIC LIQUIDS
SOLUTIONS
ELIXIRS
SYRUP
LIQUID DROPS etc.
SUSPENSIONS
EMULSIONS

9. MANUFACTURING OF MONOPHASIC LIQUIDS:
Process Flow
Addition of Raw
Materials Active
Excipients
Mixing
Filtration
Filling
Control Variables
Mixing time
RPM
Temperature
Final Volume
Mesh Size
Filter Integrity
Filling Machine
Speed
Measured
Responses
Clarity
Viscosity
Assay
Clarity
Volume

10. MANUFACTURING OF BIPHASIC LIQUIDS:
WATER
CONTINUOUS
PHASE PRESERVATIVES
MIXING
SURFACTANTS
AQUEOUS
SOLUTION
OTHER HELPING
AGENTS

11. MANUFACTURING OF BIPHASIC LIQUIDS contd…
DISPERSE PHASE
FOR
SUSPENSION
MILLED DRUG DRUG SOLUTION IN OIL
FOR
EMULSION

12. MANUFACTURING OF BIPHASIC LIQUIDS contd…
Fine Dispersed
Delivery System
Other addictive (flavours
and colouring agents
Volume Adjustment
pH Adjustment
Homogenize
Continuous Phase Dispersed Phase
Pre-mix or Crude
Dispersion

14. OBJECTIVES OF PROCESS VALIDATION
FOR LIQUIDS:
 For a systematically process to assure the quality of the product.
 To ensure that the product is meeting with predetermined specifications.

15. VALIDATION OF LIQUID ORALS:
1) Equipment
2) Raw Materials
3) Compounding
4) Microbiological Quality
5) Oral Suspension Uniformity
6) Product Specifications
7) Stability
8) Packaging

16. TEST PARAMETERS FOR EMULSION AND SUSPENSION:
Test Parameter Suspension Emulsion
Appearance Yes 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

17. RAW MATERIAL VALIDATION:
It includes following important tests
 Particle size and size distribution.
 Particle shape or morphology.
 Microbial count.
 Rheology of solvent or vehicle.
 pH of the solvent or vehicle.
Raw materials are checked and validated for
 Particles size and size distribution – Particle size distribution range is
0.2 – 2 microns for suspension.
 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.  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.  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:
There are following outputs to be monitored
 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 affect 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:
 Viscosity is defined as the study of fluid flow. Or it is 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.
 Viscosity of the liquid oral dosage form is important because it affects
the settling rate of suspended particles in the suspension and of
globules of internal phase in emulsions and also in case of oral
solutions it affects the whole appearance of the final product, so it must
be measured and validated properly.

24. Proper Gravity:
 Specific gravity is the weight of the product per unit volume.
 For most of the liquid oral products it is 1gm/cube centimetre.
 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.

25. 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 bio burden
content.
 Preservation 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.
Criteria for selection of preservatives
 Must be effective against a broad spectrum of microorganisms.
 Must be chemically, physically and microbiologically stable.
 Must be nontoxic, non-sensitizing, soluble and compatible with other
formulation components.

26. Content Uniformity:
 In solution, suspensions and emulsions determination of content
uniformity affects the dose uniformity in case of multi-dose
formulations and also affects the homogeneity of the drug within
solvent system.
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.

27. 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.

28. NUMBER OF VALIDATION TRIALS:
 For new product, product transfer or having major changes generally at
least three consecutive successful batches are required.
1) One Right = Accident
2) Two Rights = Coincidence
3) Three Rights = Validated
SAMPLING FOR VALIDATION
 For solution, take at least 2 samples at top and bottom of the bulk.
 For suspension, take at least 2 samples at top, middle and bottom of the bulk.
 Finished Product Testing (Net content, Microbiology, Content Uniformity)

29. CRITICAL PARAMETERS:
Equipment
Manufacturing
Processing

30. ACCEPTANCE CRITERIA:
Dissolved Active Ingredient
Filtration
pH Adjustment
Final Mixing

31. FILLING & PACKAGING OPERATION VALIDATION:
There are following steps performed
 Leakage test for filled bottle.
 Cape sealing test.
 Filling volume determination.
 Water vapour permeability test.
 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.

32. LIMITS OF PROCESS VARIABLES FOR FACTORIAL
ANALYSIS:
Processing Variables
Lower Control Limit
(LCL)
Upper Control Limit
(UCL)
Moisture Content 5% 15%
Processing Temperature 50 Degree Celsius 70 Degree Celsius
pH Value 5.0 7.0
Processing Time 2 hrs. 6 hrs.
Apparent Viscosity 20,000 cps 200,000 cps
Blender Speed 4,000 rpm 20,000 rpm
Average Particle Size 20 microns 40 microns

33. VALIDATION REPORT:
 Validation team must prepare Validation Report.
 Validation Report must be reviewed and approved by Quality
Assurance.
 Written notification or either successful completion or failure must be
informed/issued to top management.
 In case of failure, an investigation must be completed and documented
prior to repeat the validation study.

34. CHANGES AND REVALIDATION:
 Change of any of the following may need revalidation.
1) Formula Composition
2) Raw Material Source
3) Manufacturing Location
4) All Equipment
5) Batch size
CHANGES:
 MINOR
 INTERMEDIATE
 MAJOR

36. INTRODUCTION:
Semisolid dosage forms include ointments and creams. Ointments are
preparations for external use, intended for application to the skin. Typically,
they have an oily or greasy consistency and can appear “stiff” as they are
applied to the skin. Ointments contain drug that may act on the skin or be
absorbed through the skin for systematic action. Many ointments are made
from petroleum jelly. Like many other.
Soft, semisolid preparation intended for application to skin and mucus
membrane.
Appearance: Opaque
Type : Oleaginous base, Absorption base, Emulsion base, Water-soluble Base

37. Processes must be validated in pharmaceutical manufacturing are:
 Cleaning
 Sanitization
 Fumigation
 Depyrogenation
 Sterilization
 Sterlilefilling
 Fermentation
 Bulk Production
 Purification
 Filling, capping, sealing
 Lyophilisation

38. 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 does / 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

39. SEMISOLIDS MANUFACTURING CONSIDERATION:
Combine Water
Soluble ingredient
in auxiliary kettle.
Heat to critical
temperature.
Combine oil soluble
ingredient in main
cattle. Heat to critical
temperature. Counter
sweep agitation
Transfer water
phase by pump
Filling and
packaging
Homogenize or pass
through colloid mill
while warm. Cool
slowly with counter
sweep agitation
Transfer finished
product by pump
into drum or tank
1) Flow Diagram

40. DISPENSING OF MATERIAL
1) Flow Sheet:
Q.C. APPROVAL
WATER PHASE PURIFIED
WATER HEAT ___MINS./SLOW
MIXING WITH ADDITON OF ACTIVE
INGRIDENT ___MINS./SLOW
FILLING, CAPPING & CODING
FINAL PACKING
OIL PHASE
___MINS./SLOW
ADDITION OF
EXCIPIENT
ADDITION OF
ACTIVE INGRIDIENT
1. ADDITIONAL
QUANTITY OF
WATER ADDED
2. TEMP.
3. SPEED (RPM)
1. MIXING TIME
2. TEMP.
3. SPEED (RPM)
1. MIXING TIME
2. TEMP.
3. SPEED (RPM)
1.WEIGHT
2. CRIPING
3. CODING

41. 2. UNIT OPERATION FOR SEMISOLID SYSTEM:
1) Mixing of semisolid
2) Dispersing
3) Milling and size reduction of solid and semisolid

42. 3. MIXING AND BLENDING OF SEMISOLID:
Process Variable
Properties affected by
variable
Monitoring output
 Type and capacity of
unit
 Potency
 Shape of unit and
position of mixing
elements within unit
 Homogeneity  Content uniformity
 Product load  Specific gravity  Viscosity
 Temperature
 Agitation speed  Viscosity  Density
 Mixing time

43. 4. DISPERSING:
Process Variable
Properties affected by
variable
Monitoring output
 Bore opening / power
setting
 Potency
 Pressure / rot or speed /
power consumption
 Particle size of solids
 Particular size
distribution
 Feed rate  Viscosity of liquid  Viscosity
 Temperature
 Dispersion time  Specific gravity
 Order of mixing

44. 5. SIZE REDUCTION OF SOLID AND SEMISOLID:
Process Variable
Properties affected by
variable
Monitoring output
 Mill type  Potency
 Mill size  Particle size  Particular size analysis
 Mill speed / air
pressure
 Bulk density  Density / surface area
 Product load
 Dissolution rate of
solid
 Feed rate
 Inert atmosphere

45. 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 operation.
2) Proper agitation holding tank sand 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.

46. PRODUCT SETTING:
 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.

47. 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 shaft where product movement during
mixing may restricted.
 The bottom of the tank and any potential dead spots should be sampled
and examined for unmixed.

48. SAMPLING PLAN:
Samples must be representative of each filing 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.

49. OTHER SAMPLING PATTERN:
 Ten equid is stand point across the filling run must be sampled.
 The beginning and end of filling must be represented.
 Samples should be taken in triplicate.

50. MONITORING OUTPUT:
1) Particle size consideration
Control of particle morphology and particle size important parameters to attain
high quality drug product manufactured and control procedure. Particle size
distribution for most dispersed system should 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 type
Appropriate viscosity in
cps at 25O
C
Pharmaceutical example
Soft, spreadable 100,000-300,000 W/O, O/W CREAM
Plastic flow, spreadable 300,000-1,000,000 Ointment

51. 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).
 The average result to 10 individual results must meet the release limit for
assay.
 The usual sample size for testing ranges between 0.5 and 1.5 per sample assay.
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%

52. 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 to
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.

53. IDENTIFICATION OF CRITICAL PROCESS VARIABLES/PARAMETER:
PROBABLE CAUSES THAT MAY EFFECT THE FINAL PRODUCT
DISPERSING OF
MATERIAL
OIL PHASE SOLUTION
DISPERSION
TUBE FILLING
WATER PHASE SOLUTION
DISPERSION
MANUFACTURING
SPEED
TEMPERATURE
LOAD SIZE
ACTIVE
EXCIPIENT
SPEED
WEIGHT / TUBE
LOAD SIZE
COOLING TEMPERATURE
pH
BOILING TEMPERATURE
TEMPERATURE
SPEED
SPEED
LOAD SIZE

54. CRITICAL PROCESS PARAMETERS:
# CRITICAL PROCESS VARIABLE RESPONSE PARAMETER REMARKS
1
Water Phase Solution Preparation
Water Phase Uniformity
Sequence of excipient addition Fixed order of addition
Water Boiling Temperature Fixed Boiling Temperature Range
Time Variation of time for boiling
Cooling Temperature Fixed Heating Temperature Range
Time Variation of time for cooling
pH Fixed limit of pH
Mixing Time Variation of mixing time (RPM)
2
Oil Phase Solution
Preparation
Oil Phase Uniformity
Sequence of excipient addition Fixed order of addition
Heating Temperature Fixed Heating Temperature Range
Time Variation of time for heating
Cooling Temperature Fixed cooling temperature range
Time Variation of time for cooling
Mixing Time Variation of mixing time (RPM)
3
Manufacturing
Active Ingredient Uniformity
Sequence of active addition Fixed order of addition
Mixing Time Variation of mixing time
Cooling Temperature Fixed temperature range
4
Filling
Filling, Cirmping & Cooling 1. Weight of tube
2. Crimping
Fixed machine speed, no variation
Filling Speed Fixed machine speed, no variation

55. CRITICAL PROCESS VARIABLE:
# PROCESS/VARIABLE
MACHINE SETTING
(CONTROL VARIABLES)
REMARKS
1
Water Phase Solution
Preparation
Quantity of water
Setting and conditions
as mentioned in the
batch manufacturing
record to be followed.
2
Oil Phase Solution
Preparation
Quantity of Paraffin & Wax &
Other Oil
3 Manufacturing
Mixing Time
Cooling Time
4 Filling Speed, Weight/Tube

56. SAMPLING, TEST PARAMETERS, ACCEPTANCE CRITERIA:
SAMPLING LOCATION:
MFG. TANK
BOTTOM VALVE
1. TOP-SAMPLE A1
2. MIDDLE-SAMPLE A2
3. MIDDLE-SAMPLE A3

57. STAGE/TEST
PARAMETER
EQUIPMENT
(SIZE/LOCATION/TIME)
ACCEPTANCE CRITERIA
Water phase solution
preparation
Determination on each sample, for
temperature, sample weight 10g.
 80 ± 5O
C
Oil phase solution
preparation
Determination on each sample, for
temperature, sample weight 10g.
 80 ± 5O
C
Manufacturing
ASSAY
pH
Sampling thief
 Assay 90% to 110%
 Rel. std:
FILLING
Appearance
Weight of Tubes
Weight of variation
Identification test
Visual inspection
Analytical balance
Analytical balance
H.P.L.C.
As specified in the BMR
___gm (__gm - ___gm)
___% of average weight.
Test should complies to its
specifications.
90% to 110%
Assay

58. VALIDATION REPORT:
STANDARD FORMAT
1. Executive summary
2. Discussion
3. Conclusion & 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.

59. REFERENCES:
1) P.P. SHARMA, “Validation in Pharmaceutical Industry Concepts
Apparatus & Guidelines”, 1st Edition; 2007, Vandana Publication
House.
2) Pavel Anthony, Grilti Anthony, De Santis Phil and Agalloco James,
“Handbook of Validation in Pharmaceutical Process”, 4th Edition; 2022
by CRC Press.
3) Agalloco James and Frederick J. Carleton, “Validation of
Pharmaceutical Process” 3rd Edition; 2008 by Informa Healthcare
USA.
4) Robert A. Nash and Alfred H. Wachter, “Pharmaceutical Process
Validation” 3rd Edition; 2003 by Marcel Dekker.
5) Process Validation of Pharmaceutical Dosage form; A review article by
Goyal Anju and Priyambada Pandey; Published in Biomedical Journal
of scientific & technical research; October 25, 2017.