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Updating on the latest developments in ich guidelines and applying learnings from recent experiences to speed up dmf filing process-final

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ICH Developments

ICH Developments

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  • 1. Our Motto “Start to FinishEvery Thing in Between” J. Ramniwas
  • 2. Our Motto : “Start to Finish, every thing in Between” Updating on the latest developments in ICH guidelines and applying learning from recent experiences to speed-up DMF filing processBy:J.RAMNIWAS ( CEO)SAI PHARMA SOLUTIONS INC. VADODARA(GUJARAT) INDIA 10/13/2012 J. Ramniwas 2
  • 3. Our Motto : “Start to Finish, every thing in Between” Outline  Introduction  Latest Development in ICH Guidelines  Speed up of DMF filing Process  Specific Analytical Method Validation Requirements in US  Challenging Areas in Analytical Validations  Effective Sourcing Strategies  Vendor Qualification Requirements  Method Transfer Requirements at various sites  Out of Trend and Out of specification issues  Conclusion10/13/2012 J. Ramniwas 3
  • 4. Our Motto : “Start to Finish, every thing in Between”INTRODUCTION  Evolutionary changes in ICH Guidelines  Science and Risk based Approach  Quality by Design(QbD) Design(QbD)  Question Based Review( QbR)  Paradigm shift in DMF filing  Harmonization in Regulatory Process  Pharmaceutical Development(ICH –Q8)  Quality Risk Management( ICH-Q9) ICH-  Pharmaceutical Quality System(ICH-Q10) System(ICH-  Development and Manufacture of Drug Substances(ICH -Q11) Substances(ICH-10/13/2012 J. Ramniwas 4
  • 5. Our Motto : “Start to Finish, every thing in Between” The 2003 ICH Quality Vision Industry parties and regulatory authorities of the ICH Quality met in Brussels in July 2003 and agreed on the ICH Quality vision “A harmonised pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to risk management and science”. In order to develop a modern pharmaceutical quality system, discussions on two topics, 1) Pharmaceutical Development (Q8) and 2) Quality Risk Management (Q9) started. The guidelines on the two topics were published in 2006 in the three ICH regions. (Pharmaceutical Quality System(Q10) reached final stage in June’2008)10/13/2012 J. Ramniwas 5
  • 6. Our Motto : “Start to Finish, every thing in Between”New vision and ICH Quality GuidelinesQ8~Q11 A harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to risk management and science Q8: Pharmaceutical Development Q9: Quality Risk Management Q10: Pharmaceutical Quality System Q11: Drug substance development and manufacturing (step 2)10/13/2012 J. Ramniwas 6
  • 7. Our Motto : “Start to Finish, every thing in Between” Expected Outcome For Industry o Establishment of Quality Management System from development to post-marketing For regulatory authority o Improvement of the approval review system by integration of the review and the GMP inspection oTo concentrate on higher risk products oThe establishment of effective, efficient and streamlined quality regulations10/13/2012 J. Ramniwas 7
  • 8. Our Motto : “Start to Finish, every thing in Between” Latest Development in ICH Guidelines Additional Q8/Q9/Q10 Points to Consider added on the ICH website (At Seville in November 2011, the ICH Quality Implementation Working Group ) 1. Criticality of Quality Attributes and Process Parameters 2. Control Strategy 3. Level of Documentation in Enhanced(QbD) Regulatory Submissions 4. Role of Models in Quality by Design (QbD); 5. Design Space 6. Process Validation/Continuous Process Verification10/13/2012 J. Ramniwas 8
  • 9. Our Motto : “Start to Finish, every thing in Between” Latest Development in ICH Guidelines Q3D : Guidelines for Metallic Impurities (Limiting metal impurities qualitatively and quantitatively in drug products and ingredients) (July ‘2009) The latest meeting of the group was in June 2011. Current status of the discussion: – The guideline will cover all products including biotech products, but will exempt herbals, radiopharmaceuticals and conventional vaccines. – The guideline will cover PDE and control strategy, but will not cover testing strategy and analytical methods. – The guideline will be applicable to new products, but will not be applied to existing products and clinical trials. – 2 sub-groups (safety assessment and control strategy) working simultaneously. – The guideline will cover more elements than the EMA guideline (about 30! In total) and intends to cover the general risk of c ontamination with metal impurities .  State 2 document expected for June 2012.  Adoption of the final guideline is not likely before 2014.10/13/2012 J. Ramniwas 9
  • 10. Our Motto : “Start to Finish, every thing in Between” Latest Development in ICH Guidelines Q10 Pharmaceutical Quality System ( June’2008 Final Guideline) Product Life Cycle 1. Pharmaceutical Development 2. Technology Transfer 3. Manufacturing 4. Product Discontinuation Quality System Elements: 1. Process performance and product quality monitoring 2. Corrective Action and Preventive Action( CAPA) 3. Change Management 4. Management Review of Process Performance and Product Quality10/13/2012 J. Ramniwas 10
  • 11. Our Motto : “Start to Finish, every thing in Between”Latest Development in ICH Guidelines Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) (May’2011) CTD sections 1. S 2.2 – Description of Manufacturing Process and Process Controls 2. S 2.3 – Control of Materials 3. S.2.4 – Control of Critical Steps and Intermediates 4. S.2.5 – Process Validation and or Evaluation 5. S.2.6 – Manufacturing Process Development10/13/2012 J. Ramniwas 11
  • 12. Our Motto : “Start to Finish, every thing in Between” Outlook• Preparation of an ICH API (chemical and biotechnological origin) guideline (Q11) taking into account the concepts and principles described in Q8R (Pharmaceutical Development). – enhanced/systematic development – establishment of design space – establishment of real time release testing• New Paradigm: combination of enhanced process understanding, formal use risk management tools and establishment of an efficient quality system10/13/2012 J. Ramniwas 12
  • 13. Our Motto : “Start to Finish, every thing in Between”Incremental steps Pharmaceutical Development (Q8) Changed Past: Data transfer / Variable output Paradigm Present: Knowledge transfer / Science based / Consistent output Quality Risk Management (Q9) Past: Used, however poorly defined Present: Opportunity to use structured process thinking Pharmaceutical Quality Systems (Q10) Past: GMP checklist Future: Quality Systems across product life cycle10/13/2012 J. Ramniwas 13
  • 14. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process References - Relevant Guidelines (API)• Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products• Q2R: Validation of analytical procedures• Q1A (R2): Stability: new active substances…….• Q3A (R2): Impurities Testing in new drug substances• Q3C: Impurities: Guideline for Residual Solvents• Q3D: Guidelines for Metallic Impurities 10/13/2012 J. Ramniwas 14
  • 15. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process 1. Planning aspects 2. Formatting and compilation aspects 3. Review aspects10/13/2012 J. Ramniwas 15
  • 16. Our Motto : “Start to Finish, every thing in Between”Speed up of DMF Filing Process 1. PLANNING ASPECTS  Deadline  Understanding Registration Requirements  Requirement listing  Sending Requirements to the respective departments10/13/2012 J. Ramniwas 16
  • 17. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process 2. FORMATTING AND COMPLIATION ASPECTS  Format  Compilation10/13/2012 J. Ramniwas 17
  • 18. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process 3. REVIEW ASPECTS  Recheck the information  Cross Verification  Use checklist10/13/2012 J. Ramniwas 18
  • 19. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process AVOIDING DEFICIENCIES:  Reporting Identification/ Quantitation thresholds of degradation impurities are not set as per ICH.  Stability Indicating nature of analytical method not proved  LOD/LOQ limits of impurities/ Degradants not specified  No adequate justification of proposed limits for impurities  No adequate justification of expiry date, retest period  No information on the type of polymorph  No complete characterization of impurities  Discussion on Chirality inadequate on chiral substances  Distorted Mass Balance( Sum of Assay & impurities) during stability study  Carry-over of impurities from starting materials in to the API 10/13/2012 Residual Solvents J. Ramniwas 19
  • 20. Our Motto : “Start to Finish, every thing in Between” Speed up of DMF Filing Process Key software skills for effective DMF management  Proficiency in MS office  Proficiency in Adobe Acrobat tools. (Especially useful in preparing eCTD ).  Proficiency in ISIS draw or Chem sketch software  training in the use of eCTD software.10/13/2012 J. Ramniwas 20
  • 21. Our Motto : “Start to Finish, every thing in Between”Speed up of DMF Filing ProcessOutlook• The pharmaceutical quality requirements for the API (AS) are very much guided by the harmonised ICH guidelines: Impurities, stability, analytical validation,………• From a pharmaceutical quality point of view there is no difference between new ASs and existing/known ASs.• The section on impurities is one of the most important section in an application file. Thorough preparation and presentation of this section is most helpful for the assessor.• During lifetime of the product, attention has to be paid to changes in the manufacturing process including change in suppliers of starting materials.• Impurities profile depends very much on the route of synthesis.!!10/13/2012 J. Ramniwas 21
  • 22. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US PRE-REQUISITES Suitability of Instrument • Status of Qualification and Calibration Suitability of Materials • Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst • Status of Training and Qualification Records Suitability of Documentation • Written analytical procedure and proper approved protocol with pre-established acceptance criteria10/13/2012 J. Ramniwas 22
  • 23. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US PURPOSE OF ANALYTICAL VALIDATION• Identification of Sources and Quantitation of Potential errors• Determination if Method is Acceptable for Intended Use• Establish Proof that a Method Can be Used for Decision Making• Satisfy FDA Requirements10/13/2012 J. Ramniwas 23
  • 24. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Verification Versus Validation• Compendial vs. Non-compendial Methods – Compendial methods-Verification – Non-compendial methods-Validation requirement10/13/2012 J. Ramniwas 24
  • 25. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Compendial Analytical Procedures• The Analytical procedures in the USP 25/NF 20 are legally recognized under section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory analytical procedures for the compendial items. The suitability of these procedures must be verified under actual conditions of use. When using USP 25/NF 20 analytical procedures, the guidance recommends that information be p r o v i d e d f o r t h e f o l l o w i n g characteristics: – Specificity of the procedure – Stability of the sample solution – Intermediate precision10/13/2012 J. Ramniwas 25
  • 26. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Regulatory and Compliance Requirement Review Validation of an analytical method is the process by which it is established, by laboratory studies, that the performance characteristics of the method meet the requirements for the intended analytical applications. USP 23 General Information <1225>10/13/2012 J. Ramniwas 26
  • 27. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Regulatory and Compliance Requirement Review The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may Be accomplished in accordance with 211.194(a)(2) 21 CFR PART 211 - CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS Subpart I-Laboratory Controls 211.165 Testing and release for distribution (e)10/13/2012 J. Ramniwas 27
  • 28. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Regulatory and Compliance Requirement Review• The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose ICH Guideline for Industry Q2A, Text on Validation of Analytical Procedures March 199510/13/2012 J. Ramniwas 28
  • 29. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Regulatory and Compliance Requirement Review In practice, it is usually possible to design the experimental work such that the appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: Specificity, Linearity, Range, Accuracy, and Precision. ICH Guideline for Industry Q2B, Validation of Analytical Procedures: Methodology10/13/2012 J. Ramniwas 29
  • 30. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US Today’s Validation Requirements ICH/USP GMPs (legal) FDA10/13/2012 J. Ramniwas 30
  • 31. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US ICH/USP Validation Requirements & Parameters USP ICH • Specificity  Specificity • Linearity  Linearity and Range • Range  Accuracy • Accuracy  Precision • Precision  Limit of Detection – Repeatability  Limit of Quantitation – Intermediate Precision  Ruggedness – Reproducibility  Robustness • Limit of Detection • Limit of Quantitation10/13/2012 J. Ramniwas 31
  • 32. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US 483 Observations There was inadequate method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from its impurities and degradation products. Specificity studies did not include the minimum stress conditions of acid and base hydrolysis, oxidation, thermal degradation and photolysis, degradation schematic for the active ingredient that identifies the major degradation products was not included for each product.10/13/2012 J. Ramniwas 32
  • 33. Our Motto : “Start to Finish, every thing in Between”Specific Analytical Method ValidationRequirements in US FDA Waning Letter On addition to the example of modifying both compendial methods and customer supplied methods, we also observed the use of unvalidated in- house methods as well as unvalidated modifications to in-house methods. A statement indicating that the method has not been validated in the particular formulation was included in the certificate of analysis for…use of this statement does not absolve…from using valid, accurate, and reproducible methods.10/13/2012 J. Ramniwas 33
  • 34. Our Motto : “Start to Finish, every thing in Between”Challenging Areas in Analytical Validations Man Machine Methods qualified calibrated characterised robust documented skilled qualified suitable Quality of the Reference analytical method Vibrations Time standards Irradi- Irradi- Analysts´ Analysts´ ations support Tempe- Tempe- Quality rature Humidity Supplies Material Milieu Management10/13/2012 J. Ramniwas 34
  • 35. Our Motto : “Start to Finish, every thing in Between” Effective Sourcing Strategies 1. Proactive Quality Assurance 2. Risk based Approach 3. Communicate Constantly 4. Release Product 5. Measure Capabilities 6. Qualify Supplier 7. Co-investigate Failures 8. Establish Milestones 9. Quality Agreements 10. Embrace Supplier Infrastructure 11. Customize Audits 12. Maintain Control 13. Manage Changes 14. Monitor through Surveillance Program10/13/2012 J. Ramniwas 35
  • 36. Our Motto : “Start to Finish, every thing in Between”Vendor Qualification Requirements Under 21 CFR 211.84, all lots of all components (API and excipient) must be tested before use for compliance with the predetermined specifications. The suppliers understanding of the GMP requirements The conditions under which the starting material is produced and controlled10/13/2012 J. Ramniwas 36
  • 37. Our Motto : “Start to Finish, every thing in Between”Vendor Qualification Requirements At least one test to verify the identity of each batch of material System in place to evaluate suppliers Manufacturer can consistently provide material meeting specifications. Full analyses should be conducted on at least three batches before reducing in-house testing Full analysis at appropriate intervals and compare with the Certificates of Analysis Reliability of Certificates of Analysis should be checked at regular intervals.  (ICH Guidelines)10/13/2012 J. Ramniwas 37
  • 38. Our Motto : “Start to Finish, every thing in Between”Vendor Qualification Requirements Quality Agreements 1. Applicable GMP Standard 2. Certificate of Analysis 3. Change Control 4. Right to Audit 5. Authority Inspections 6. Sub-contracting 7. Retention of samples (final SUBSTANCE) 8. Retention of records/documentation 9. Stability10/13/2012 J. Ramniwas 38
  • 39. Our Motto : “Start to Finish, every thing in Between”Vendor Qualification Requirements Quality Agreements 10. Complaints 11. Recall 12. Product quality review 13. Storage and distribution 14. Undesirable contaminants 15. HAPIs 16. Qualification / Validation 17. Reprocessing 18. Reworking10/13/2012 J. Ramniwas 39
  • 40. Our Motto : “Start to Finish, every thing in Between”Vendor Qualification Requirements Quality Agreements 19. Deviations / OOS (incl. stability) 20. Packaging 21. Labelling 22. Regulatory documents 23. Product release 24. Reference standards 25. Specifications 26. Analytical methods10/13/2012 J. Ramniwas 40
  • 41. Our Motto : “Start to Finish, every thing in Between”Method Transfer Requirements at various sites  Sending Unit (SU): Create the transfer protocol Execute training Assist in analysis Acceptance Criteria  Receiving Unit (RU): Qualified instrumentation Personnel Systems (Materials, Utilities, SOPs, etc) Executes the protocol10/13/2012 J. Ramniwas 41
  • 42. Our Motto : “Start to Finish, every thing in Between”Method Transfer Requirements at various sites METHODS TO BE TRANSFERRED Assay Impurities / Degradants Chiral Purity(If any) Identification Cleaning Validation Micronisation Microbiological10/13/2012 J. Ramniwas 42
  • 43. Our Motto : “Start to Finish, every thing in Between”Method Transfer Requirements at various sites Pre-transfer Activities  The RU should be provided with and review analytical methods prior to their transfer.  The SU and the RU should formally agree criteria for success before execution of the transfer protocol.  The SU should provide training to the RU. This should include a review of the methods and transfer protocol, as well as laboratory work, if possible. Training should be documented.10/13/2012 J. Ramniwas 43
  • 44. Our Motto : “Start to Finish, every thing in Between”Method Transfer Requirements at various sites Transfer Protocol  Objective  Scope  Responsibilities  Materials/Methods/Equipment  Experimental Design  Acceptance Criteria  Documentation  Deviations  References  Signature/Approval Page  Reference samples, actives, intermediates, and10/13/2012 finished products J. Ramniwas 44
  • 45. Our Motto : “Start to Finish, every thing in Between” Method Transfer Requirements at various sites Transfer Report Should include conclusions regarding the success of the transfer and confirm whether the receiving site is qualified to perform each analytical method. Any deviation should be discussed and justified in the transfer report.10/13/2012 J. Ramniwas 45
  • 46. Our Motto : “Start to Finish, every thing in Between”Out of Trend and Out of specification issues 1. No immediate information about OOS by outsourcing laboratories 2. Use of averaging? 3. Definition of reportable values? 4. Number of retests? 5. Second analyst? 6. Use of outlier testing? 7. What specification limits? 8. Defining testing into compliance?10/13/2012 J. Ramniwas 46
  • 47. Our Motto : “Start to Finish, every thing in Between”Conclusion  Keep pace with the latest regulatory developments  Learn, de-learn and re-learn de- re-  Revision in regulatory process  Rising awareness of quality, efficacy and safety  See today with the eyes of tomorrow  Reconfigure of review process to minimize delays  Risk Assessment  Doing things right first time  Short cuts can be a costly affair  Regulators understand guidelines, rules, laws and regulations only10/13/2012 J. Ramniwas 47
  • 48. Our Motto : “Start to Finish, every thing in Between” Thank you for your attention J.RAMNIWAS Founder & CEO SAI PHARMA SOLUTIONS INC. (Gateway to Regulatory Affairs, Quality & cGMP Compliance) Email: jramniwas@saipharmasolutions.com Phone No: +919558809128 Website: www.saipharmasolutions.com Our Motto" Start to finish, everything in between".10/13/2012 J. Ramniwas 48

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