1. 1 PILOT PLANT STUDY FOR LIQUID ORALS

2. 2 LIQUIDS ORALS Liquid pharmaceuticals encountered in the pilot plant are defined as non sterile solutions, suspensions or emulsions. Scale of each of these present a different set of processing concerns that must be considered Liquid orals are the liquid dosage formulations containing one (or) more active ingredients with (or) without additives dissolved in a suitable vehicle, meant for oral administration

3. 3 The physical form of a drug product that is pourable displays Newtonian or pseudoplastic flow behaviour and comforts to it’s container at room temperature. Liquid dosage forms may be dispersed systems or solutions. In dispersed systems there are two or more phases, where one phase is distributed in another. A solution refers two or more substances mixed homogeneously.

4. 4 TYPES OF ORAL LIQUIDS SOLUTIONS EMULSION SUSPENSION

5. 5 OBJECTIVE A formula is transformed into a viable robust product using reliable and practical method of manufacture that effects the orderly transition from lab to routine processing in a full-scale production

6. 6 STEPS INVOLVED IN PILOT PLANT FOR LIQUID ORAL Reporting responsibility Personal requirements Space requirements Review of the formula Raw materials Relevant processing equipments Production rates Process evaluation GMP consideration Transfer of analytic method to quality assurance

7. 7 Raw materials Weighing & Measuring Mixing Distilled water Filling Packing Finished Product storage Quality Assurance Pilot Plant Scale-Up Techniques for liquid orals

8. 8 General Consideration: I. Reporting responsibilities: The goal of pilot plant scale is to facilitate the transfer of a product from the laboratory in to production. The formulators continue to provide support to the production even after the transition in to production has been completed. There must be good relation between pilot plant and other departments.

9. 9 II. Personnel requirements:  Have good theoretic knowledge of pharmaceutics.  Practical experience in liquid orals manufacturing industry.  Chemical, physical, biochemical and medical properties of drugs.  Have the knowledge of computer, electronics.

10. 10 III. Space requirements: Administration and information processing area Physical testing area Standard pilot plant equipment floor space Storage area

11. 11 Administration and information processing area

12. 12 Physical testing area

13. 13 Standard pilot plant equipment floor space

14. 14 Storage area

15. 15 IV Review of formula: A thorough review of each and every steps of formulation is important The purpose of each ingredient and its contribution to the final product should be studied If any modification in formula, it should be done as soon as possible in phase III trials to allow time to generate meaningful long term stability in a support of a proposed new drug application

16. 16 V. Raw materials: One responsibility of pilot plant function is the approval and validation of the active ingredient and excipients raw materials used in the pharmaceutical products. The quality of the active ingredients needs to be verified.

17. 17 Formulation consideration:  Solvents  Preservatives  Antioxidants  Solubilizers  Organoleptic agents etc.

18. 18 SOLVENTS Water Alcohol Glycerol Polyethylene glycol Propylene glycol.

19. 19 Water Compared to ordinary drinking water, purified water USP is more free of solid impurities. When evaporated to dryness, it must not yield greater than 0.001% of residue. Purified water is obtained by distillation, ion-exchange treatment, reverse osmosis and other relevant method

20. 20 PRESERVATIVES Preservatives are added to prevent the microbial growth Preservative are necessary due to chances of microbial growth Raw material, processing containers & equipments, the manufacturing environment, operators, packing materials & the user. Phenol, chlorocresol, benzoic acid, etc.

21. 21 Antioxidants: ascorbic acid, sodium thiosulphate, sodium metabisulphate. Solubilizers: co-solvents and surface active agents Organoleptic agents etc: colour, flavor, sweetening agents

22. 22 VI. Relevant processing equipment: Almost all formulation development work is carried out on small, relatively simple laboratory equipment. The equipment that is most economical, the simplest, the most efficient should be selected Liquid pharmaceutical processing tanks, kettles, pipes, mills, filter housings, and so forth are most frequently fabricated from stainless steel. Of the three types commonly used in the industry (304, 308, and 316), type 316 is most often used because it is the least reactive. Ease of cleaning should be considered, if multiple products are to be manufacture in the same equipment.

23. 23 Stages of operations: 1.Tank selection Material of the tank must not be additive to the product The shape and size of equipment must be selected according to the batch size The tanks are usually constructed of polished stainless steel of different grades Teflon and glass lined tank. Adequate clean-up procedures developed.

24. 24 2.Mixing Simple mixing is essential to increase flow of liquids. If the liquid is of high viscosity, high electrical stirrer may be used. Addition of ingredients in proper order have vital important. At high viscosity the chance of air entrapment.

25. 25 Air entrapment Minimize:- By reducing agitator speed By caring out the mixing procedure in enclosed tank under vacuum The alternative procedure to the all is versator

26. 26 Versator

27. 27 3. Dispersion Suspensions and emulsions require considerably greater shear forces Laboratory formulation is difficult to duplicate at large scale Dispersion produced by colloidal mill or an immersion homogenizer Variety of equipment should evaluated for better results. Homogenizer Colloidal mill

28. 28 4. Filtration and clarification— Filtration procedure, requires careful evaluation to ensure that pilot scale-ups will exhibit the same degree of clarity as their laboratory counterparts. During the pilot run the clarity of the filtrate should be checked periodically, in order to establish schedule for changing pads, cake, or cartridges, depending on the type of filtration employed. In filtration, filter pads are used which is made up of asbestos and cellulose. Selection of filtration depends on The product viscosity Volumes Rate requirement

29. 29 5. Transfer and filling Filling – important parameter in the transfer of liquids from tank to tank and into containers. New batches should not be started until the previous batches are completely filled and the tanks are emptied. Bins and Piping

30. 30 Methods for filling of liquids:- The selection of equipment depends on characteristic of liquid such as, viscosity, type of packaging, surface tension. Gravimetric (specific weight) Volumetric (specific volume) Constant volume filling GravimetricVolumetric

31. 31 Containers and closures: Glass Plastic It is more important to store the final product in container until its expiration. Most oral liquids are packed in either amber or flint glass containers with plastic or metal caps.

32. 32 VII. Production rates:- The immediate and future market requirements - estimating the production rates, selecting the type and the size of the equipment needed. Determining the product loss in the equipment during manufacture. The time required to clean the equipment between batches. The number of batches that will need to be tested for release.

33. 33 VIII. Process evaluation:- Items that should be examined include the following- Mixing speed Mixing time Rate of addition of solvents, solutions of drug, slurries etc Heating and cooling rates Filter sizes Filling

34. 34 IX. Preparation of manufacturing procedures:- The processing directions should be precise and explicit. The batch records should include addition rates, mixing times, mixing speeds heating and cooling rates and temperature should be given. Finished product specification and release specification are set; they should be take into consideration.

35. 35 X. GMP considerations:- A check list of GMP items  Equipment qualification  Process validation  Regular process review and revalidation  Relevant written SOP  Adequate provision for training of personnel  A well defined technology transfer system  An orderly arrangement of equipments

36. 36 XI. Transfer of analytic method to quality assurance:- During the scale up new product the analytic test methods transferred to the quality department. The quality assurance staff should review the process to make sure that the proper analysis instrumentation is available and that personnel are trained to perform tests.

37. 37 Viscosity- It is the internal resistance (or) friction to the movement of molecules to “FLOW”. Agents which control viscosity E.g. Polyvinylpyrrolidine, alginates, carbomers, and various cellulose derivatives..

38. 38 Purpose to control Viscosity - 1. Improve pour ability. 2. Improve acceptability. 3. Improve palatability. Equipment used for this purpose are as followed- By OSTWALD VISCOMETER (Or) BY FALLING SPHERE VISCOMETER. OSTWALD VISCOMETER FALLING SPHERE VISCOMETER

39. 39 Preservative evaluation Preservative evaluation – should be done in addition to physical and chemical tests. Depending on the nature of the product and degree of protection required the surface of the product can be over lapped during filling or holding stages with carbon dioxide or nitrogen. Bacteriological testing should be done, to know if the concentration of preservative is to be increased in the formulation

40. 40 Stability studies:- Physical: Physical instability of liquid formulations involves the formation of precipitates, less-soluble polymorphs, and adsorption of the drug substances onto container surfaces, changes in product appearance. Chemical: Chemical instability of liquid formulation is mainly due to interaction between additives, oxidation or some due to interaction with containers. Microbiological: It is the most favorable condition for the growth of microorganism. So studies must me conducted for different microbiological test. Different preservatives are used to make product more stable.

41. 41 Type of changes: Contents: Viscosity, Texture, Color, Odour, pH Containers: a) Leakage, b) Corrosion, c) Stress d) cracking Glass container Plastic or metal cap

42. 42 REFERENCES: Leon Lachman, Liberman & Joseph.L, The theory & practice of industrial pharmacy. 3rd Ed., Vargese publishing house-1991, 466-75,681-84,703-706. James Swarbrick, encyclopedia of pharmaceutical technology Third Edition volume 5. Herbert A. Lieberman, Martin M. Rieger and Gilbert S. Banker, pharmaceutical dosage forms: Disperse system vol 1. Howard C. Ansel Introduction to pharmaceutical dosage forms, 4th edition. www.google.com

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