1.Validation Of Solid Dosage Forms. A.RAMYA PRIYA 13031S0312, M.PHARMACY, PHARMACEUTICS, CPS,IST,JNTUH. 1 2. 2 3. 3 4. CONTENTS- • INTRODUCTION • TYPES OF PROCESS VALIDATION • PRODUCT VALIDATION • PHASES OF VALIDATION • VALIDATION OF TABLETS • VALIDATION OF CAPSULES • CONCLUSION 4 5. • DEFINITION- • Validation is a key process for effective quality assurance. • “Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes.” 5 6. The major reasons for validation are: • Quality assurance: Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria. A successful validation provides high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch. • Economics: Due to successful validation, there is a decrease in sampling and testing procedures and there are less number of product rejections and retesting. This leads to cost-saving benefits. 6 7. • Compliance: For compliance to current good manufacturing practices, validation is essential. 7 8. • Prospective validation: -Conducted prior to market the product. - Documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product meeting its predetermined specifications and quality attributes. • Concurrent validation: Based on information generated during actual implementation of the process. Establishing documented evidence that the process is in a state of control during the actual implementation of the process. This normally performed by conducing in- process testing. Type of Process Validation- 8 9. • Retrospective validation: All the processes and subsystems should be validated ,which have been used for the production of batches of numerical data of both process and the end product testing of which are included in retrospective validation. 9 10. 10 • Product validation is associated with validation of the full- scale manufacture of numerous earlier aspects of product development that are critical to the subsequent phases of the process. product validation involves following steps: • validation of raw materials and excipients. • analytical methods of validation. • equipment and facility validation . • process variables and limits. PRODUCT VALIDATION 11. • VALIDATION OF RAW MATERIALS AND EXCIPIENTS • validation of raw materials is one of the major causes of product variation or deviation from specification. The API may represent the most uncontrollable component in the complete product . The validation process of solid dosage form begins with the validation of raw materials ,both API and excipients. preformulation is one of the critical step to be validated in product validation -Physical characters such as drug and particle size can affect material flow and blend uniformity. -Chemical characters like impurities can effect stability of drug. The hygroscopic nature is important in both handling and reproducibility of the manufacturing process. 11 12. • VALIDATION OF EXCIPIENTS- Excipients can represent less then 1% of a tablet formula Factors to be aware of are • The grade and source of the excipients • Particle size and shape characteristics and • Lot-to-lot variability Microcrystalline cellulose(MCC) used as diluents shows significant changes in the chemical composition, crystalinity, particle size b/w different lots. Differences in particle size of MCC can effect wet granulation/blend uniformity of tablet formulation. In direct compression formulations differences in particle size distribution b/w lots can result in • Non uniformity in initial mix • Materials segregate during compression. 12 13. • Accuracy of method: Ability of a method to measure the true value of a sample. • Precision of method: Ability of a method to estimate reproducibility of any given value • Specificity: Ability to accurately measure the analyte in the presence of other components • Repeatability: Does the precision and accuracy of the method change when conducted numerous times on the same day and repeated on a subsequent day? ANALYTICAL METHODS OF VALIDATION- 13 14. • Reproducibility: Repeat the precision and accuracy studies within the same lab using the same instrument but different analysts to challenge the reproducibility of the method. • precision: How will different instruments within the same lab run by the same analyst affect the accuracy and precision of the method. • Ruggedness: Will the precision and accuracy of the method be same between the development and quality control lab? 14 15. EQUIPMENT VALIDATION - Process equipment used in the development phase is assessed relative to its suitability for large scale manufacture. Alternate equipment s identified and evaluated and a final decision rendered. This protocol can be divided into • Design qualification • Installation qualification • Operation qualification • Performance qualification • Maintaince (calibration, cleaning, repair) qualification 15 16. • Design qualification (DQ): Documented verification of the design of equipment and manufacturing facilities. • Installation qualification (IQ): Documented verification of the system design and adherence to manufacturer’s recommendations. • Operational qualification (OQ): Documented verification of equipment or system performance in the target operating range. PHASES OF VALIDATION- 16 17. • Process performance qualification (PQ): Documented verification that equipment system operates as expected under routine production conditions. The operation is reproducible, reliable and in a state of control 17 18. 18 19. PROCESS VARIABLES AND LIMITS- • Process validation can be defined as means of challenging a process during devlopment to determine which variables can be controlled to ensure the consistency production of a product or intermediate. • It is based on the concept that the processed employed has been optimized, so that the data generated through the testing program may be considered credible and evaluated for consistency as well as relevance. 19 20. 20 21. Validation of tablets 21 22. 22 23. • INDUSTRIAL PROCESS OVERVIEW OF SOLID DOSAGE FORMS Steps &Process parameter are following- • MIXING OR BLENDING- material have similar physical properties will be easier to form a uniform mix or blend as compare to difference in properties. techniques-1.Diffussion(tumble) 2.convection(planetary or high intensity or fluid bed). Mixing and blending depends upon various factors- 1.Mixing speed- mixing of drug and excipient requires more intense mixing than adding the lubricant to the final blend. 23 24. 2.Mixing Time- depends on mixing technique and speed. 3.drug and excipient uniformity- handling of material is key in obtaining valid content uniformity results. Sample should be equivalent to the weight of a single tablet. 4.equipment capacity - the bulk density of material will affect the capacity of the equipment. 24 25. EQUIPMENTS- 25 26. what type of wet granulation to be used LOW SHEAR HIGH SHEAR wet granulation parameters are • Binder addition- should be added as a granulating solution • Binder conc- if the binder conc is high it is not rejected by the spray nozzle then the binder needs to be diluted • Amount of binder solution- too much binder solution can over wet the material and prolonged drying time. • Granulation end point- determined by ammeter and wattmeter equipment. WET GRANULATION- 26 27. EQUIPMENTS- 27 28. EQUIPMENTS- Does the wet granulation needs to break up the lumps and enhance the drying of granulation factors – • screen size – should be small enough to de lump the material. • mill speed- sufficient speed with out causing any staining to the equipment. • feed rate- is interrelated to screen size, mill size and speed WET MILLING- 28 29. EQUIPMENTS- 29 30. equipments Drying is a most important step in the formulation and development of pharmaceutical product. It is important to keep the residual moisture low enough to prevent product deterioration and ensure free flowing properties. factors- • Inlet/outlet temp- inlet temp is set to high to minize drying with out effecting physical/chemical parameters. • Airflow- insufficient air flow prolongs drying • Moisture uniformity- moisture content could vary in the granulation • Equipment capacity- high the load high moisture should be removed DRYING- 30 31. EQUIPMENTS- 31 32. 1.selection of lubricant- should compatible with other ingredient grade of lubricant used 2.amount of lubricant- too much lubrication will from hydrophobic layer resulting dissolution problems. 3.mixing time- if not mixed long enough problems like chipping, capping etc. LUBRICATION- 32 33. After the preparation of granules (in case of wet granulation) or sized slugs (in case of dry granulation) or mixing of ingredients (in case of direct compression), they are compressed to get final product. The compression is done either by single punch machine (stamping press) or by multi station machine (rotary press). factors- • compression speed- range of compression speed to determine the operating range of the compressor. • compression or ejection force- determined optimal compression force to obtain the desired tablet hardness. TABLET COMPRESSION- 33 34. EQUIPMENTS- 34 35. EQUIPMENT The following in-process tests should be examined during the compression stage- • Appearance • Hardness • Tablet weight • Friability-0.5-1% • Disintegration • Weight uniformity 35 36. Many solid pharmaceutical dosage mediums are produced with coatings, either on the external surface of tablets, or on materials dispensed within gelatin capsules. key areas – • equipment type- - coater will need to be selected. - convectional or perforated pan and fluid bed coaters are potential. • pan speed- interrelated with coating parameter like inlet temp, spray rate. • spray rate- too much spray rate leads to over wetting. THE TABLET COATING PROCESS- 36 37. EQUIPMENTS- 37 38. APPERANCE TEST FOR TABLET COATING- •cracking or peeling of the tablet •intagliation fill-in •color uniformity •coating efficiency should be determined for the coating operation 38 39. • Moisture content of dried granulation- usually less then 2% • Granulation particle size distribution • Blend uniformity • Individual tablet weight • Tablet hardness • Tablet thickness • Disintegration • Impurity profile IN PROCESS TESTS • Appearance • Assay • content uniformity • Tablet hardness • Tablet thickness • Impurity profile • dissolution FINISHED PRODUCT TESTS TESTS- 39 40. Validation of capsules 40 41. 41 42. CAPSULE COMPOSITION- 1.capsule shell provide –the reason for the presence of each ingredient in the capsule formulae. Justify the level and grade of each ingredient . Explain the selection of the capsule size and shape Discuss the need for capsule identification(color). 2. capsule shell contents- establish the compatibility of the capsule shell and the capsule contents. Determine the hygroscopic nature of the capsule formulation . For example, a hygroscopic formulation(API /excipients)can pull water from the capsule shell, which could effect the API stability. 42 43. EQUIPMENTS- 43 44. PROCESS EVALUATION AND SELECTION- The process to manufacture the contents of a hard gelatin capsule is the same as the tablet. It may required only a blending step, such as a direct compression tablet, or several unit operations, such as a wet granulation tablet (eg mixing, wet milling, drying, dry milling and blending).In either case, the materials are then encapsulated in a capsule shell. ENCAPSULATION- Encapsulation is a critical step in the production of capsules, similar to the compression for tablet dosage forms. The materials to be encapsulated will need to have good flow properties and a consistent density. 44 45. • Encapsulation speed- The formulation should be encapsulated at a wide range of speeds to determine the operating range of the encapsulator. 45 46. 46 Quality control tests are divided into PHYSICAL TEST • Disintegration test • Weight variation CHEMICAL TEST • Dissolution test • Assay • Content uniformity • Stability testing • Moisture permeation test 46 47. CONCLUSION- • Solid dosage form validation should be part of comprehensive validation program within an industry. • The multidisplinary validation team must identify the product and process characteristics that must be studied and incorporate specific validation tests to ensure that product will meet all quality, manufacturing and regulatory requirements. • Continuous awareness of validation will produce reproducibility. 47 48. REFERENCE- • http//www.pharmainfo.net/reviews/guidelines-general- principles-validation-solid-dosage. • www.google.com 48 49. 49 50. 50