1. A SEMINAR ON PROCESS VALIDATION OF OINTMENT, CREAM AND LIQUID ORALS

2. 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.

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

4. 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

5. Continue…. 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

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

7. 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.

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

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

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

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

12. Manufacturing of Monophasic liquids:

13. Properties affected by variables
Process Variables
Process
Equipment
Process variables
Properties affected by variables
Monitoring 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, Appearance, pH,
Viscosity, Specific gravity.

14. Properties affected by variables
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.

15. Properties affected by variables
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.

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

17. 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

18. 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 .

19. Continue….
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

20. Continue….
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.

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

22. 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.

23. 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.

24. Viscosity: 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.

25. Continue….
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.

26. 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.

27. 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.

28. Continue….
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.

29. Continue….
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.

30. 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.

31. Continue…
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

32. 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.

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

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

35. 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

36. Continue…. Proper control of product temperature
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

37. 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

38. 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.

39. 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
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

40. References:
Lieberman H. A. , Rieger M. M. and Banker G. S. “Pharmaceutical Dosage Forms: Disperse System” ,vol.3; Second Edition,
R. A. Nash and A. H. Wachter “Pharmaceutical process validation”; Third edition
Agalloco James, Carleton J. Fredric “Validation of Pharmaceutical Processes”; Third edition,
The theory and practice of industrial pharmacy by Leon Lachman, Herbert A. Liberman, Joseph L. Kanig; Third edition

41. THANK YOU