Published on January 26, 2010
“Process Validation of Levofloxocin Hemihydrate Solid dosage form” : “Process Validation of Levofloxocin Hemihydrate Solid dosage form” Supervised by Submitted by Mr. Kaushal K. Chandrul Mr. Sandeep Jain Head Of Department,. M. Pharm IV sem. Department, of Q.A Quality Assurance Mentored By Ms. Suchitra Bhatnagar Head Q.A. Mecloids pharmaceutical Ltd. School of Pharmaceutical sciences, Jaipur National University , Contents : Contents 1. INTRODUCTION : 1. INTRODUCTION The goal of a quality system is to consistently produce products that are fit for their intended use. Process validation is a key element in assuring that these principles and goals are met. Phases Of Validation3 :The activities relating to validation studies may be classified into three phases: Phase 1: Pre-Validation Phase or the Qualification Phase, which covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability Slide 4: Phase 2: Process Validation Phase (Process Qualification phase) designed to verify that all established limits of the Critical Process Parameters are valid and that satisfactory products can be produced even under the "worst case" conditions. Phase 3: Validation Maintenance Phase requiring frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures. At this stage the Validation Team also assures that there have been no changes/ deviations that should have resulted in Requalification and Revalidation Reasons For Validation : Reasons For Validation Customer satisfaction: Non-conforming product can lead to lost customers. Customer mandated: Provision for securing new business Product liability: Conformance to product specifications must be maintained. Reduced production costs: PV leads to reduced inspections, testing, scrap and rework. Shifts costs from production to prevention. Supports improvements: Testing data can be used to support improvements in the process or the development of the next generation of the process. Regulatory requirement (CFR Title 21) Terms & Definitions : Terms & Definitions Validation: Ø Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled (820.3(z)). Process validation: Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes (CMI). Terms & Definitions : Terms & Definitions Types of Process Validation : Prospective validation :Validation conducted prior to the distribution of either a new product, or product made under revised manufacturing process, where the revision may affect the product’s characteristics. This type of validation are carried out at Laboratory scale and pilot trials. Critical parameters are challenged here. Materials can not be sold in market Concurrent validation :Concurrent process validation is done When process is validated (at laboratory and pilot scale).When validated process has been modified. When API batches are produce infrequently. Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API. Terms & Definitions : Terms & Definitions Retrospective validation : Batches selected for retrospective validation should be representative of all batches produced during the review period.Process must be established. No major changes in raw materials, equipment, system, facility and production process. Critical process and quality parameter must be identified. In process acceptance criteria must be established. There should not be significant batch failures. Batch failure due to equipment failure and operator error should not be considered. Validation of a process for a product already in distribution, based upon accumulated production, testing and control data. Terms & Definitions : Terms & Definitions Installation Qualification (IQ): Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer’s approved specification and that the recommendations of the supplier of the equipment are suitably considered (GHTF/SG3/N99-10:2004). Operational Qualification (OQ): Studies which are designed to challenge the process and process equipment, and establish objective evidence that the process meets predetermined requirements throughout all anticipated operating ranges (CMI) Performance Qualification (PQ): Studies conducted to demonstrate the process will consistently produce acceptable product under normal operating conditions. Challenges to the process should simulate conditions that will be encountered during actual manufacturing (CMI) Terms & Definitions : Terms & Definitions Validation protocol: A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results (FDA Guidance). The validation protocol should specify critical process steps and acceptable criteria as well as the type of validation to be conducted (e.g. retrospective, prospective, concurrent) and the number of process run. A validation report that cross references the validation protocol should be prepared, summarizing the results obtained, commenting on any deviation observed and drawing the appropriate conclusions, including recommending changes to correct deficiencies. Verification: Ø Confirmation by examination and provision of objective evidence that specified requirements have been fulfilled (820.3(aa) Terms & Definitions : Terms & Definitions Critical Process Parameter: Critical process parameters are parameter (condition) which affects the quality of product Specification: A list of test, references to analytical procedures, and appropriate acceptable criteria that are numerical limits, ranges or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. Conformance to specification means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria. In Process Control: Checks performed during production to monitor and, if applicable to adjust the process and\or to ensure that the intermediate or API conforms to its specifications. 2.LITERATURE REVIEW : 2.LITERATURE REVIEW 1. Gupta Vivek, Bonde C.G. have reported5 the Statistical Assurance of Process Validation By Analytical Method Development and Validation for Levofloxacin IR Tablets and Blend Statically tools of ANNOVA and Boneforri’s multiple tests were implemented on results of blend uniformity and content uniformity, done on process validation batches samples. 2. Guidance for Industry Process Validation:6 General Principles and Practices For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.. 3. MHRA, 2007, (sixth edition in 2002.)7 Rules and Guidance for Pharmaceutical Manufacturers and Distributors, (“Orange Guide”) Compiled by the Inspection and Standards Division of the Medicines and Healthcare products Regulatory Agency, The principles and guidelines of GMP are adopted by the European Commission. The objective of GMP is to ensure that products are consistently produced and controlled to particular quality standards. Slide 13: 4. Guide to Good Manufacturing Practice for Medicinal Products, (8) Part II. PIC/s Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme Contain text about the requirement of the Good Manufacturing Practice as per the updated version of the GMP PIC guide. 5. USFDA, Assessor checklist (9) Current Good Manufacturing Practices (cGMP), this check list present the criteria to be used in evaluating the facility as per regulatory cGMP requirements. The company’s policies and procedures must meet these requirements. Requirements that include the need for a process validation study 6. USFDA, September 2004,10 Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, This draft guidance is intended to help manufacturers that are implementing modern quality systems and risk management approaches to meet the requirements of the Agency's current good manufacturing practice (CGMP) regulations. Slide 14: 7. USFDA, September 2004,10 Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, This draft guidance is intended to help manufacturers that are implementing modern quality systems and risk management approaches to meet the requirements of the Agency's current good manufacturing practice (CGMP) regulations. 8. Leonard Steinborn, GMP/ISO Quality Audit Manual for Health care Manufacturers and Their Suppliers, 2003, (11) Sixth Edition, volume – 1, CRC press Boca Raton London New York Washington, D.C., contain the requirements and the basic tools for the structuring and planning of the various validation study like process validation study ,analytical method validation study, cleaning validation study. 9. ICH Harmonized Tripartite Guideline, (2003) ,(12) International Conference on Harmonization Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, stability testing of New drug substances and products Q1A(R2), 3.SCOPE AND OBJECTIVE : 3.SCOPE AND OBJECTIVE Scope: the scope of this project work is to conduct a process validation by which the quality of product increase and to produce the slandered testing procedure which are regulated by governing authority and the scope is minimize the chance of error in production process validation is also a regulatory requirement for ANDA submission to run the product in US market and also necessary for worldwide marketing. Objective: 21 The objective of this exercise is to validate the process and have documented evidence to ensure that Critical process variables are checked during validation. Also to demonstrate the process Capability of the product meets it’s predetermined specifications and quality Attributes. This protocol for the process validation of Levofloxacin hemi hydrate tablets 750 mg formulation defines the procedural aspects to be followed while carrying out Process validation activity that includes prerequisites before commencing the actual work like, Master formula and process, approved vendors and characteristics of raw materials. 4. MATERIALS AND METHODS : 4. MATERIALS AND METHODS The materials and methods used in the process validation of Levofloxacin Hemihydrate tablet are as follows- Master formula for process validation batch : The Master Formula is designed and Optimized by R&D unit (part of Process Validation Protocol ) and further the remaining part of Process Validation Protocol are designed as follows : Protocol Approval Sheet / Batches Under Validation Validation Team Introduction / Objective/ Scope / Validation Criteria/ Revalidation Criteria Product profile Master Formula Responsibilities of Validation Task Force Validation Task Force Slide 17: Sampling Procedure Manufacturing Procedure/ Calibration Methodology for Process Validation/ Acceptance Criteria/ Preparation Of A Scale Up Validation Report Equipment Record Sample Summary Flow Diagram (Process), Selection & Justification of Critical Process Steps Raw Materials – Rationale/ Wet Granulation – Rationale Blend Specifications Raw Material Specification Core Tablet Specification Finished Product Specifications Diagram of Bin Blender With Sampling Point Diagram of FBD With Sampling Point Standard Testing Procedure of Raw Material 5. RESULTS AND DISCUSSION : 5. RESULTS AND DISCUSSION The Validation of the process is performed as per the process validation Protocol and the result obtained are summarized in the tabular form as follows: Result of Raw Material (Active) Limit of assay of raw material (By HPLC, %w/w as C18H20FN3O4 on anhydrous basis) is Not less than 98.0% and not more than 102.0% and the results are under the limit Limit of Water(%w/w) By Karl Fischer is Between 2.0 and 3.0 and the results are under the limit So process is Validated. Slide 19: Manufacturing Process : Result of LOD at 80OC at IR moisture balance of Composite Sample (Dry Mix) 1.07 and the limit of LOD is not more then 4 Result of Bulk Density (Dry Mix) of composite sample is under the limit So Process is Validated Result LOD of Bulk Sample (Dried Granules) After Drying in FBD At different -2 Location and in Average is under the limit (2 to 4) so the process is validated Result of Milled Granules: Results of these densities (Bulk, tapped) and result of sieve analysis are for validation record for fulfillment of dossier requirement. And the results of LOD of milled granules is (1.0% - 3.0%) under the limit so process is validated. Result of Blend Uniformity – Lubrication The result of the assay of different sample for blend uniformity (lubrication) is (90 %-110%) under the limit and RSD is 1.4 which is also under limit so process is validated Slide 20: Result of compression stage are as follow : Individual In-Process Test Data (At Regular Intervals) Stage of Sampling: (Initial Stage/Full hopper) Stage of Sampling: (middle stage) Stage of Sampling: (End Stage/half hopper) Dissolution profile of composite sample (core tablets In process (Core) Analysis Result: the description of the core tablet in between and completion of granulation is complies with the specification, identification by HPLC is complies by the specification, average weight is(1029.0 – 1071.0) under limit, uniformity of weight is complies with specification, thickness of tablet during initial stage, middle stage, final stage is (6.3 to 6.9) under the limit, hardness during initial stage, middle stage, final stage is (140 – 260 ) is under the limit, friability during initial stage, middle stage, final stage is 0.05 is under the limit, disintegration time during initial stage, middle stage, final stage is 8 minutes 18 seconds is under the limit, dissolution during initial stage, middle stage, final stage is(Min 99.3% max 102.6% mean 101%) is under the limit, assay by HPLC of core tablet in % during initial stage, middle stage, final stage is (Not less than 95.0 and not more than 105.0) is under the limit so process is validated. Slide 21: Results of Finished (Coated) Tablet the description of the coated tablet at the end of coating lot 1 and 2 is complies with the specification, identification by HPLC is complies by the specification, average weight is(1058.4 – 1101.6) under limit, uniformity of weight is complies with specification, disintegration time at the end of coating lot 1 and 2 is 10 minutes 20 sec is under the limit, loss on drying value at the 105° for 3 hr of 1 gm sample at the end of coating lot 1 and 2 is 3.6 is under the limit, dissolution at the end of coating lot 1 and 2 is101% is under the limit, assay by HPLC of core tablet in % at the end of coating lot 1 and 2 is (Not less than 95.0 and not more than 105.0) is under the limit so process is validated. 6.References : 6.References Types of validation from WHO expert committee on specification for pharmaceutical preparation-WHO technical report series, no. 863-34th report (1996- 200pages) A WHO guide to good manufacturing practice (GMP) requirements Part 2: Validation Canada guideline for phase of process validation in which process validation is distributed indifferent phase’s pre validation phases, process qualification phases, maintenance phases. Statutory and Regulatory Requirements for Process Validation is taken from guideline for industry process validation Gupta Vivek, Bonde C.G. has reported the Statistical Assurance of Process Validation by Analytical Method Development and Validation for Levofloxacin IR Tablets, Vol.1, No.3, pp 921-924, July-Sept 2009. Guidance for Industry Process Validation: General Principles and Practices For purposes of this guidance, process validation November 2008 Current Good Manufacturing Practices (CGMP), United state Food and drug administration. Slide 23: 7) MHRA, 2007, (sixth edition in 2002.) Rules and Guidance for Pharmaceutical Manufacturers and Distributors, (“Orange Guide”) 8) Guide to Good Manufacturing Practice for Medicinal Products, 5 April 2007, Part II. PIC/s Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co- Operation Scheme; PE 009-6 (Part II). Geneva; p 1-55 9) Pharmaceutical Inspection Convention, 1 August 2006, Pharmaceutical Inspection Co-Operation Scheme; PE 009-5. 10) USFDA, September 2004, Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations USFDA, September 2004 11) Leonard Steinborn, 2003, GMP/ISO Quality Audit Manual for Health care Manufacturers and Their Suppliers, Sixth Edition, volume – 1, CRC press Boca Raton London New York Washington, D.C. 12) ICH Harmonised Tripartite Guideline, 6 February 2003, International Conference on Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human Use, Slide 24: ICH Harmonised Tripartite Guideline, 6 February 2003, International Conference on Harmonisation for validation of analytical procedure (Q2B), Pharmaceutical Inspection Convention, 3 August 2001, recommendations on validation master plan, EUROPEAN COMMISSION, November 2000, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Volume Quality Management Systems - Process Validation Guidance “Quality Management Systems – Process Validation Guidance”, originally finalized in 1999, is being Republished as “GHTF/SG3/N99-10:2004 (Edition 2) European regulation regarding pharmaceutical process validation in autumn 2001 has been the subject of much discussion. Vol.1 Page no. 368 autumn 2001. USFDA, May, 1997, Validation Master Plan, guideline on general principles of process validation, Slide 25: THANK YOU
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