Process Validation for solid dosage forms Process Validation Process Validation for solid dosage forms: Process

validation establishes the flexibility and constraints in the manufactur ing process controls in the attainment of desirable attributes in the drug produ ct while preventing undesirable properties. This is an important concept, since it serves to support the underlying definition of validation, which is a systema tic approach to identifying, measuring, evaluating, documenting, and re-evaluati ng a series of critical steps in the manufacturing process that require control to ensure a reproducible final product. USFDA defined process validation as establishing documented evidence which provid es high degree of assurance that a specific process will consistently produce a product meeting its pre determined specifications and quality characteristics. Despite the ongoing development of more sophisticated solid drug delivery system s, tablets are still by far the most prevalent solid dosage form. The emphasis will be on the practical inspectional requirement, rather than on a theoretical approach that does not reflect the practicalities (and problems) encountered whe n validating actual production operations. TYPES OF PROCESS VALIDATION: 1. Prospective Process Validation. Where an experimental plan called the valida tion protocol is executed (following completion of the qualification trials) bef ore the process is put to commercial use. Most validation efforts require some d egree of prospective experimentation in order to generate validation support dat a. 2. Concurrent Process Validation. Establishing documented evidence that the pro cess is in a state of control during the actual implementation of the process. This is normally performed by conducting in-process testing and/or monitoring of critical operations during the manufacture of each production batch. 3. Retrospective Process Validation. Where historic data taken from the records of the completed production batches are used to provide documented evidence that the process has been in a state of control prior to the request for such eviden ce. STRATEGY FOR INDUSTRIAL PROCESS VALIDATION OF SOLID DOSAGE FORMS: The following five points gives strategy for process validation: 1. The use of different lots of raw materials should be included. i.e., active drug substance and major excipient. 2. Batches should be run in succession and on different days and shifts (the la tter condition, if appropriate). 3. Batches should be manufactured in the equipment and facilities designated fo r eventual commercial production. 4. Critical process variables should be set within their operating ranges and s hould not exceed their upper and lower control limits during process operation. Output responses should be well within finished product specifications. 5. Failure to meet the requirements of the Validation protocol with respect to process input and output control should be subjected to process requalification and subsequent revalidation following a thorough analysis of process data and fo rmal discussion by the validation team. GUIDELINES FOR PROCESS VALIDATION OF SOLID DOSAGE FORMS: Numerous factors should be considered when developing and validating solid dosag e forms. As a means of providing a broad overview of these validation criteria, the following checklist/guideline as in Table 1, is provided for tablets and dry -filled capsules for inclusion in an in-depth validation program. Some of these unit operations will not be applicable for every solid dosage form (e.g., direct compression tablets and uncoated tablets). Table 1: Check list of Validation and Control Documentation Sr. No. Selection of cGMP Validation and control documentation 1 Introduction Establishing of QA & PV functions 2 Organization and personnel. Establishment and facility installation

and qualification 3 Buildings and facilities Plant and facility installation qualific ation Maintenance and sanitation Microbial and pest control 4 Equipment Installation and qualification cleaning methods. 5 Air and water quality Water treatment and steam systems air, heat, and vacuum handling. 6 Control of raw material, in-process material, product Incoming compone nts Manufacturing non-sterile products 7 Production and process controls Process control systems (instruments and computers) 8 Packing and labeling controls Depyrogenation, sterile packing, filling , and closing. 9 Holding and distribution Facilities 10 Laboratory controls Analytical methods 11 Records and reports Computer systems 12 Returned and salvage drug products Batch processing PROTOCOL FOR PROCESS VALIDATION: The protocol for process validation is given from the tables 2, 3, 4 & 5 as foll ows Table 2: Protocol for title page in industry Name of the company Process validation protocol Product: Page No. : 1 of . Protocol No. : Version No. : Product name : Label claim : Master Formula Record (MFR) No. : Batch Manufacturing Record (BMR) No.: Effective Date : Table 3: Protocol approval Prepared By Checked By Signature Date Name Department Quality Assurance (QA)/Research and development (R&D) Head QA Approved By

R & D

Production

Quality Control

Table 4: Table of contents Sr. No. Title Page No. 1. Protocol Approval Sheet 2. Table of contents 3. Objective 4. Scope 5. Validation term and responsibility 6. Steps for validation and acceptance criteria 7. Process flow chart 8. Procedure 9. Form A : Review of raw material/packing material 10. Form B : Evaluation of active raw material 11. Form C : Evaluation of inactive raw material 12. Form D : Qualification of equipment 13. Form E : Test instrument calibration 14. Form F : Dry mixing 15. Sampling point diagram of RMG

16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29

Form G : Wet mixing Form H : Drying Sampling point diagram of FBD Form I : Lubrication Sampling point diagram of RMG Form J : Compression Form K : Coating Form L : Bulk packing Re validation criteria Change control Stability Deviations Conclusion Report and Approval

Table 5: Validation team and Responsibilities Department Designation Responsibility Research and development (R&D) Executive/Officer To coordinate the entire validat ion process by scheduling meetings and discussions with production, quality cont rol and quality assurance. Preparation of preliminary validation protocol, master formula record, monitorin g the process, compiling and analyzing data and test results and preparing the f inal report. To review the preliminary validation documents. Quality assurance Officer To coordinate the entire validation process by s cheduling meetings and discussions with the team. Preparation of validation protocol, monitoring the process, Compiling and analyzing data and test results and preparing the final report. To review of validation documents. Production Officer To participate in performing the validation steps during manufacturing processes. To assist in collection of data. Quality control Officer To test and report the test results Quality assurance General manager Quality assurance To approve the process validation protocol and report. To review of validation documents. To approve the process. STEPS FOR VALIDATION AND ACCEPTANCE CRITERIA: The following steps (Table 6) are used in industry for validation of tablets in wet granulation process: Table 6: Steps for validation and acceptance criteria in wet granulation process Sr. No Steps Control Variable Critical Parameters to be checked Acceptance criteria 1 Dry mixing Time . Mixing time and speed Mixing time: min. 5RPM. Impeller speed: (slow/medium/high) Content uniformity :90%-110% RSD : 5% Impeller speed. 2 Binder preparation and addition Time Mode and time of addition Depending up on the formulation Temperature, solvent used 3 Kneading Time Mixing time and speed Impeller speed : (slow/medium/high) Chopper speed: (slow/medium/high) Depending up on the formulation.

Impeller speed & chopper speed 4 Drying Inlet/outlet temperature & time Inlet/outlet temperature & Drying time Initial drying:. C Drying time: min. Final drying: 0C 50C Loss on drying : .% below 3% or depending on formulation 5 Lubrication Time Mixing time and speed Mixing time: min. Speed: slow.rpm. Content uniformity: Physical parameters for information. Blender/granulator speed 6 Compression Pressure and turret speed Machine speed and compression pressure Average weight: mg 5%, 7.5%, 10%. Uniformity of weight mg : Thickness : .mm Hardness : ..KN or Kg/cm2 Disintegration time: NMT..min. Friability : NMT%w/w Assay : As per the label claim Dissolution % 7 Coating Pan speed and spray rate Pan speed Inlet & outlet temperature Spray rate Average weight:....mg 5% Weight of 20 tablets: ...mg Thickness : .mm Disintegration time: NMT..min. Assay : As per the label claim