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

1. www.parasshah.weebly.com ASEMINAR ONPROCESS VALIDATIONOF OINTMENT, CREAM ANDLIQUID 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 fourtypes 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: 2. Biphasic liquids: Solutions Suspensions Elixirs Emulsions Syrup Liquid drops …etc

9. Test parameters for emulsion and suspension

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. 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. Process Variables

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-Solubilityof 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 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/cubecentimeter. • 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 parametersspecificfor 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…. 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

40. 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

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