EVALUATION SEMINAR PRESENTATION VALIDATION-DESIGN, DEVELOPMENT OF PROCESS VALIDATION, METHODS FOR PHARMACEUTICAL OPERATIONS INVOLVED IN THE PRODUCTION OF PHARMACEUTICAL DOSAGE FORMS. PRESENTED BY: P.SHARATH CHANDRA M.PHARM(SECOND YEAR) DEPT. OF PHARMACEUTICS KLE UNIVERSITY’S COLLEGE OF PHARMACY,BELGAUM

INTRODUCTION: The concept of Validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid 1970’s in order to improve the quality of Pharmaceuticals. USFDA Definition for Process validation:   Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics. The purpose of this work is to present an introduction and general overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing process with special reference to the requirements stipulated by the US Food and Drug Administration (FDA).. Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality levels.

General view of Process Validation End-product testing by itself does not guarantee the quality of the product. Quality assurance techniques must be used to build the quality into the product at every step and not just tested for at the end.

Why Is Validation Required ? It would not be feasible to use the equipments without knowing whether it will produce the product we wanted or not. The pharmaceutical industry uses expensive materials, sophisticated facilities & equipments and highly qualified personnel. The efficient use of these resources is necessary for the continued success of the industry. The cost of product failures, rejects, reworks, and recalls, complaints are the significant parts of the total production cost. Detailed study and control of the manufacturing process- validation is necessary if failure to be reduced and productivity improved. The goal of the validation is to ensure that quality is built into the system at every step, and not just tested for at the end, as such validation activities will commonly include training on production material and operating procedures, training of people involved and monitoring of the system whilst in production.

Responsible Authorities For Validation Department /Designation Responsibility Manager Production Responsible for manufacturing of batches and review of protocol and report. Manager QC Responsible   for   analysis   of   samples collected. Executive QC Responsible for samples collection and submission to QC. Manager Maintenance Providing utilities and engineering Support. Executive Production Responsible for preparation of protocol and manufacturing of validation batches. Manager QA Responsible for  protocol authorization and preparation of summary report.

Process validation timeline for a new process

Elements Of Validation Design Qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Design Qualification (DQ): - It is documented review of the design, at an appropriate stage of stages in the project, for conformance to operational and regulatory expectations. DQ Check Items: GMPs and regulatory requirements Performance criteria Facility air flow, movement flow & pressure regimes Reliability & efficiency Commissioning requirements Installation Qualification (IQ): - It is documented verification that all aspects of a facility, utility or equipment that can affect product quality adhere to approved specifications and are correctly installed. Important IQ considerations are: Installation conditions (wiring, utilities, and functionality) Calibration, preventative maintenance, cleaning schedules Safety features Supplier documentation, prints, drawings and manuals Software documentation Spare parts list Operational Qualification (OQ): - It is documented verification that all aspects of a facility, utility or equipment that can affect product quality operate to Intend throughout all anticipated ranges. OQ considerations include: Process control limits (time, temperature, pressure, line speed and setup conditions) Software parameters Raw material specifications Process operating procedures Material handling requirements Process change control Training Performance Qualification (PQ): - It is documented verification that all aspects of a facility, utility or equipment perform as intended in meeting predetermined acceptance criteria. PQ considerations include: Actual product and process parameters and procedures established in OQ Acceptability of the product Assurance of process capability as established in OQ Process repeatability, long term process stability.

Types Of Process Validation A) Prospective Validation (or Premarket Validation) B) Retrospective Validation C) Concurrent Validation D) Revalidation

A) Prospective validation: Validation conducted prior to the distribution of either a new product or product made under a revised manufacturing process. an experimental plan called the validation protocol is executed (following completion of the qualification trials) before the process is put into commercial use. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily: 1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements (completion of installation qualification) 2. The operators and supervising personnel who will be “running” the validation batch(es) have an understanding of the process and its requirements 3. The design, selection, and optimization of the formula have been completed 4. The qualification trials using (10 × size) pilot-laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have been provided 5. Detailed technical information on the product and the manufacturing process have been provided, including documented evidence of product stability 6. Finally, at least one qualification trial of a pilot-production (100 × size) batch has been made and shows, upon scale-up, that there were no significant deviations from the expected performance of the process. Prospective validation life cycle

B) Retrospective validation: Retrospective validation:Validation of a process for a product already in distribution based upon accumulated production, testing and control data. Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process. This approach is rarely been used today because it’s very unlikely that any existing product hasn’t been subjected to the Prospective validation process. It is used only for the audit of a validated process. Retrospective validation life cycle

C) Concurrent validation: Concurrent validation is used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual imputation of the process. This approach involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control. Concurrent validation life cycle

D) Revalidation: Revalidation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data. This approach is essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems. Change Control: Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process environment, processing site. All changes must be formally requested, documented and accepted by the validation team. Possible reasons for starting the revalidation process include: The transfer of a product from one plant to another Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality The necessity of periodic checking of the validation results Significant (usually order of magnitude) increase or decrease in batch size. Sequential batches that fail to meet product and process specifications. The scope of revalidation procedures depends on the extent of the changes and the effect upon the product. The likely impact / risk of the change on the product must be assessed and the need for the extent of re-validation should be determined

Validation Master Plan Validation Protocol A written plan stating how validation will be conducted, including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test results. Validation Master Plan A comprehensive document describing the applicable validation requirements for a given facility, and providing a plan for meeting those requirements. The VMP provides a “road map” for validation, to establish a sequence of events followed by facilities audits and inspections. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability and the manner in which the system will be tested. The protocol should list the selected process and control parameters, state the number of batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted. Validation Master Plan:A validation master plan is a document that summarizes the company’s overall philosophy, intentions and approaches to be used for establishing performance adequacy. The validation master plan should be agreed upon by management. The validation master plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP’s and validation protocols and reports.

Contents of Validation Protocol 1. Title  2. Objective & Scope  3. Responsibility 4. Protocol Approval 5. Validation Team  6. Product Composition   7. Process Flow Chart  8. Manufacturing Process 9. Review of Equipments / Utilities   10. Review of Raw Materials and Packing Materials  11. Review of Analytical and Batch Manufacturing Records 12. Review of Batch Quantities for Validation (Raw Materials) 13. Review of Batch Quantities for Validation (Packing Materials)    14. HSE Requirements  15. Review of Process Parameters 16. Validation Procedure    17. Sampling Location   18. Documentation 19. Acceptance Criteria   20. Summary 21. Conclusion

Content and Format of Validation Master Plan Introduction: Validation policy, Scope, Location and Schedule Organizational structure: Personnel responsibilities Plant/ process /product description: Rational for inclusions or exclusions and extent of validation. Specific process considerations that are critical and those requiring extra attention. List of products/ processes/ systems to be validated, summarized in a matrix format, validation approach. Re-validation activities, actual status and future planning. Key acceptance criteria Documentation format Reference to the required SOP’s Time plans of each validation project and sub-project.

Validation of Granulation process 1. Equipment validation 2. Process validation 3. Final Product (Granule) validation Validation of granulation process involves validation of equipments utilized in manufacturing of granulation and validation of operation carried out for granulation. It also validate final product for bulk density, moisture content, particle size distribution etc.

1) Equipment Validation Various equipment utilized in granulation process are 1) Mixer/Granulation 2) Dryer 3) Blender 4) Mills 5) Sieves In an ideal situation the equipment used to manufacture dosage forms would be selected based upon such factors asformulation,safety requirements,handling or production efficiencies and commercial demands.

Equipment validation steps Mixer/Blender Dryer Mills 1)Design qualification 1) Check extra paddle, choppers provided 2) Verify paddle is mounted to shaft properly. 3) Granulation end point detection system. 4) Options to introduce the granulating fluid (e.g. dump, meter, spray) 5) Verify automated charging of discharging system. 1) Cabinet with heater. 2) Check position of heaters. 3) Check fans provided. 4) Exhausting system. 5) Verify air handle. 6) Verify inlet or outlet system. 7) Explosion relief duct to avoid explosion. 1) Extra hammers, stationery knives are provided. 2) Verify the location and size of screen in mills. 3) Feeding and discharging system.   2) Installation qualification :1) Verify approved purchase order 2) Manufacturer and supplier. 3) Model and serial number. 4) Physical damage. 5) Confirm location and installation required per recommendation of manufacturer. 6) Required utilities. 7) Installation as per instruction provided in manual. 8)Ensure that all relevant documents are received -    User manual -    Maintenance manual & List of changed parts.

3)Operational Qualification 1) Perform calibration requirements. 2) Operate the equipment at low, medium and high-speed rate. 3) Verify all that switches and push buttons are functioning properly. 4) Establish procedure for operation, maintenance, and calibration. 5) Training program for staff. 1) Run three batches of each product and analyze for -Active ingredient uniformity -Moisture content. -Particle size distribution -Tap density.   Based on these data fixing a drying end point of process. (E.g. moisture content) 1) Run the mills at high, low, medium speed and determine -Range of units From this data set the time and speed of mills.

4)Performance Qualification Carry out operations for different samples and each product shall meet its predetermined characteristics. Carry out operations for different samples and determine drying temperature and time and characteristics of product. Determine milling time and speed for different products. - Particle size distribution of each sample at different time and speed.

2) Granulation process validation Validating a granulation process involves identification of critical parameters, which must be controlled to ensure the consistent production of granulation. Various operations carried out in granulation process are: 1) Mixing /Blending 2) Wet Granulation 3) Drying 4) Milling

Factors in creating uniform blending: -Mixing or blending technique I) Mixing/Blending: Factors in creating uniform blending: -Mixing or blending technique -Mixing/ Blending speed -Mixing time -Drug uniformity -Excipients uniformity. -Equipment capacity or load. II) Wet granulation: Parameters considered in wet granulation process are I) Binder addition II) Binder concentration III) Amount of binder solution or granulating solvent IV) Binder solution or granulating solvent addition rate V) Mixing time VI) Granulation end point Physical properties drugs and excipients like -   Bulk density -   Particle shape -   Particle size distribution -   Surface area

III) Milling: IV) Drying: To break up the lumps and aggregates and enhance drying of granules Factors to be considered Equipment size and capacity Screen size Milling speed Feed rate IV) Drying: Type of drying technique (Tray, Fluid, and Microwave) required for formulation needs to be determined and justified depending on drug formulation properties and equipment availability. High moisture contents can result in- 1) Final tablet picking and sticking to punch surface 2) Poor chemical stability due to hydrolysis.

Cont….. Parameters to be considered in drying 1) Inlet and outlet temperature: Inlet temperature is critical to drying efficiency of granules and should be set high enough to maximize drying without affecting chemical or physical stability of granules. 2) Air flow: Sufficient to ensure removal of moisture from wet granules 3) Moisture uniformity: 4) Equipment capability or capacity: Larger load will require more moisture to be removed on drying and will affect the drying time. Factors affecting moisture uniformity are -    Heat uniformity of the dryer -    Amount of granules per tray -    Incomplete fluidization of the bed.

3) Final product (granules) Validation: 1) Granule flow 2) Bulk density 3) Moisture content 4) Particle size distribution (Sieve analysis) 5) Granule compressive or crushing strength 1) Granule flow: Angle of repose is measured for determining the granule flow property. 2) Bulk density: Depends on particle packing and charges as the granules are compressed. Moisture conent of granules: Water is quantitatively measured by titration under anhydrous condition by the use of   reagent containing iodine, sulfur dioxide, pyridine and methanol. End point may be detected visually or preferably by the use of electrometric and automatic titration assembly.

Tablet Compression Tablet compression variables Factors to consider during compression are: Tooling Compression speed Compression/ejection force Tablet compression variables Fill volume Pre- and compression force Turntable speed Dwell time Granule size and feed Ejection force, lubrication Compression is a critical step in the production of a tablet dosage form. The materials being compressed will need to have adequate flow and compression properties. The material should readily flow from the hopper onto the feed frame and into the dies. Tooling: The shape, size, and concavity of the tooling should be examined based on the formulation properties and commercial specifications. For intagliated (embossed) tablets, factors such as the position of the intagliation on the tablet and the intagliation depth and style should be examined to ensure that picking of the intagliation during compression or fill-in of the intagliation during coating does not occur. Compression speed: The formulation should be compressed at a wide range of compression speeds to determine the operating range of the compressor. The adequacy of the material’s flow into the dies will be determined by examining the tablet weights. Is a force feeder required to ensure that sufficient material is fed into the dies? Compression/ejection force: The compression profile for the tablet formulation will need to be determined to establish the optimal compression force to obtain the desired tablet hardness. The particle size/size distribution or level of lubricant may need to be adjusted in order to have a robust process on a high-speed compressor. The tablet compression variables include: Fill volume: tableting and capsulation use a volumetric fill. A tableting press equipped with a pressure-transducer will help in collecting statistical data on the uniformity of die-fill and, therefore, on mass uniformity. Pre-compression force; compression force Turntable speed Dwell time Granule feed and uniformity. Granules made by the wet granulation method are less prone to de-mixing than dry granulation. This is critically important for microdose tablets (or capsules).

Tablet Coating Key areas to consider for tablet coating: Tablet properties Equipment type (Conventional or perforated pan and fluid bed coaters) Coater load Pan speed Spray guns Application/spray rate Tablet flow: Inlet/outlet temperature and airflow Coating solution (The concentration and viscosity of the coating solution) Coating weight (A minimum and maximum coating weight) Residual solvent level Tablet properties: Tablet properties such as hardness, shape, and intagliation (if required) are important to obtain a good film-coated tablet. The tablet needs to be hard enough to withstand the coating process. If tablet attrition occurs, the tablets will have a rough surface appearance. For tablet shape, a round tablet will be easier to coat than tablets will multiple sides or edges because of the uniformity of the surface. For intagliated tablets, the intagliation style and depth should be developed to prevent fill-in or chipping of the intagliation. Appearance testing of the tablets is critical during the coating operation…. Cracking or peeling of the coating Intagliation fill-in Surface roughness Color uniformity

Regulatory guidance on validation Guideline on General Principles of Process Validation http://www.fda.gov/cder/guidance/pv.htm Guidance for Industry: For the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. CDER CVM November 1994. www.fda.gov/CDER/GUIDANCE/cmc2.pdf Working Party on Control of Medicines and Inspections Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice Title: Qualification and validation http://pharmacos.eudra.org/F2/eudralex/vol-4/pdfs- en/v4an15.pdf ICH Q7a Section 12 on validation http://www.fda.gov/cder/meeting/ICH_Q7A/index.htm A WHO guide to good manufacturing practice (GMP) requirements. Part 2: Validation Chaloner-Larsson, G., Anderson, R., and Egan, A. 1997. World Health Organization, Geneva.

Conclusions Process validation is a requirement of cGMP regulation for finished pharmaceutical products. It is a key element in assuring that the quality goals are met. Successfully validating a process may reduce the dependence upon intensive inprocess and finished product testing. Validation of a new or existing product involves the efforts of scientists at various stages of the product development life cycle. Scientificinformation obtained during the preformulation stage can form the basis for a well-designed and comprehensive validation program.

References: 1)Nash RA., Wachter A.H., Pharmaceutical Process Validation, 3 rd Edition, Marcel Dekker publication, P.g, 173-182. 2) Lachman L., Lieberman H.A., Kania J.L., The Theory and Practice of Industrial Pharmacy, 3 rdedition, Varghese Publishing House, P.g.No. 318-320. 3) N. K. Jain & S. N. Sharma, A Text Book of Professional Pharmacy, VallabhPrakashan, P.g.no. -295-297 4) Haider S.I., Validation Standard Operating Procedures St. Lucie Press Publishers, P.g. No. 345-353.

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