Our Motto Our Motto “Start to Finish “Start to Finish
Every Thing in Between”Every Thing in Between”
J. RamniwasJ. Ramniwas
Our Motto : “Start to Finish, every thing in Between”
2J. J. RamniwasRamniwas10/13/2012
Updating on the latest developments in ICH guidelines and applying learning from recent experiences to speed-up DMF filing process
By:J.RAMNIWAS ( CEO)SAI PHARMA SOLUTIONS INC. VADODARA(GUJARAT) INDIA
Our Motto : “Start to Finish, every thing in Between”
3J. J. RamniwasRamniwas10/13/2012
Outline IntroductionIntroduction Latest Development in ICH GuidelinesLatest Development in ICH Guidelines Speed up of DMF filing Process Speed up of DMF filing Process Specific Analytical Method Validation Requirements in USSpecific Analytical Method Validation Requirements in US Challenging Areas in Analytical ValidationsChallenging Areas in Analytical Validations Effective Sourcing StrategiesEffective Sourcing Strategies Vendor Qualification RequirementsVendor Qualification Requirements Method Transfer Requirements at various sitesMethod Transfer Requirements at various sites Out of Trend and Out of specification issuesOut of Trend and Out of specification issues Conclusion Conclusion
Our Motto : “Start to Finish, every thing in Between”
4J. J. RamniwasRamniwas10/13/2012
INTRODUCTION Evolutionary changes in ICH GuidelinesEvolutionary changes in ICH Guidelines Science and Risk based ApproachScience and Risk based Approach Quality by Design(Quality by Design(QbDQbD)) Question Based Review( QbR)Question Based Review( QbR) Paradigm shift in DMF filingParadigm shift in DMF filing Harmonization in Regulatory ProcessHarmonization in Regulatory Process Pharmaceutical Development(ICH Pharmaceutical Development(ICH ––Q8)Q8) Quality Risk Management( ICHQuality Risk Management( ICH--Q9)Q9) Pharmaceutical Quality System(ICHPharmaceutical Quality System(ICH--Q10)Q10) Development and Manufacture of Drug Substances(ICHDevelopment and Manufacture of Drug Substances(ICH--Q11)Q11)
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5J. J. RamniwasRamniwas10/13/2012
The 2003 ICH Quality VisionThe 2003 ICH Quality VisionIndustry parties and regulatory authorities of the ICH Quality met inBrussels in July 2003 and agreed on the ICH Quality vision “Aharmonised pharmaceutical quality system applicable across thelifecycle of the product emphasizing an integrated approach to riskmanagement and science”.
In order to develop a modern pharmaceutical quality system,discussions on two topics, 1) Pharmaceutical Development (Q8) and2) Quality Risk Management (Q9) started. The guidelines on the twotopics were published in 2006 in the three ICH regions.(Pharmaceutical Quality System(Q10) reached final stage inJune’2008)
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6J. J. RamniwasRamniwas10/13/2012
New vision and ICH Quality Guidelines Q8~Q11
A harmonized pharmaceutical quality system applicable across the lifecycle of the product emphasizing an integrated approach to risk management and science
Q8: Pharmaceutical DevelopmentQ9: Quality Risk ManagementQ10: Pharmaceutical Quality SystemQ11: Drug substance development and
manufacturing (step 2)
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7J. J. RamniwasRamniwas10/13/2012
Expected OutcomeExpected OutcomeFor Industryo 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 inspectionoTo concentrate on higher risk productsoThe establishment of effective, efficient and streamlined
quality regulations
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8J. J. RamniwasRamniwas10/13/2012
Latest Development in ICH GuidelinesLatest Development in ICH GuidelinesAdditional 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 Parameters2. Control Strategy3. Level of Documentation in Enhanced(QbD) Regulatory
Submissions4. Role of Models in Quality by Design (QbD);5. Design Space6. Process Validation/Continuous Process Verification
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9J. J. RamniwasRamniwas10/13/2012
Latest Development in ICH GuidelinesLatest Development in ICH GuidelinesQ3D : Guidelines for Metallic Impurities(Limiting metal impurities qualitatively andquantitatively 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 contamination with
metal impurities .
State 2 document expected for June 2012. Adoption of the final guideline is not likely before 2014.
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10J. J. RamniwasRamniwas10/13/2012
Latest Development in ICH GuidelinesLatest Development in ICH GuidelinesQ10 Pharmaceutical Quality System
( June’2008 Final Guideline)
Product Life Cycle1. Pharmaceutical Development2. Technology Transfer3. Manufacturing4. Product DiscontinuationQuality System Elements:1. Process performance and product quality monitoring2. Corrective Action and Preventive Action( CAPA)3. Change Management4. Management Review of Process Performance and Product Quality
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11J. J. RamniwasRamniwas10/13/2012
Latest Development in ICH GuidelinesLatest Development in ICH GuidelinesQ11 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 Controls2. S 2.3 – Control of Materials3. S.2.4 – Control of Critical Steps and Intermediates4. S.2.5 – Process Validation and or Evaluation5. S.2.6 – Manufacturing Process Development
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Outlook• Preparation of an ICH API (chemical and biotechnological
origin) guideline (Q11) taking into account the concepts andprinciples described in Q8R (Pharmaceutical Development).– enhanced/systematic development– establishment of design space– establishment of real time release testing
• New Paradigm: combination of enhanced processunderstanding, formal use risk management tools andestablishment of an efficient quality system
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13J. J. RamniwasRamniwas10/13/2012
Pharmaceutical Development (Q8)Pharmaceutical Development (Q8)Past: Data transfer / Variable output
Present: Knowledge transfer / Science based / Consistent output
Pharmaceutical Quality Systems (Q10)Pharmaceutical Quality Systems (Q10)Past: GMP checklist
Future: Quality Systems across product life cycle
Quality Risk Management (Q9)Quality Risk Management (Q9)Past: Used, however poorly defined
Present: Opportunity to use structuredprocess thinking
Incremental steps
ChangedParadigm
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14J. J. RamniwasRamniwas10/13/2012
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
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Speed up of DMF Filing Process 1. Planning aspects
2. Formatting and compilation aspects
3. Review aspects
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16J. J. RamniwasRamniwas10/13/2012
Speed up of DMF Filing Process 1. PLANNING ASPECTS
Deadline
Understanding Registration Requirements
Requirement listing
Sending Requirements to the respective departments
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17J. J. RamniwasRamniwas10/13/2012
Speed up of DMF Filing Process 2. FORMATTING AND COMPLIATION ASPECTS
Format
Compilation
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18J. J. RamniwasRamniwas10/13/2012
Speed up of DMF Filing Process 3. REVIEW ASPECTS
Recheck the information
Cross Verification
Use checklist
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19J. J. RamniwasRamniwas10/13/2012
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 Residual Solvents
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20J. J. RamniwasRamniwas10/13/2012
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.
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21J. J. RamniwasRamniwas10/13/2012
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 nodifference between new ASs and existing/known ASs.
• The section on impurities is one of the most importantsection in an application file. Thorough preparation andpresentation of this section is most helpful for the assessor.
• During lifetime of the product, attention has to be paid tochanges in the manufacturing process including change insuppliers of starting materials.
• Impurities profile depends very much on the route ofsynthesis.!!
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22J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
PRE-REQUISITESSuitability 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 criteria
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23J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements 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 Requirements
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24J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Verification Versus Validation
• Compendial vs. Non-compendial Methods
– Compendial methods-Verification
– Non-compendial methods-Validation requirement
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25J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements 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 precision
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26J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Regulatory and Compliance Requirement Review
Validation of an analytical method is the process by whichit is established, by laboratory studies, that theperformance characteristics of the method meet therequirements for the intended analytical applications.
USP 23 General Information <1225>
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27J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Regulatory and Compliance Requirement Review
The accuracy, sensitivity, specificity, and reproducibility oftest 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 PHARMACEUTICALSSubpart I-Laboratory Controls 211.165 Testing and release for distribution (e)
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28J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Regulatory and Compliance Requirement Review
• The objective of validation of an analytical procedure ist o d e m o n s t r a t e t h a t i t i s s u i t a b l e
for its intended purposeICH Guideline for Industry Q2A, Text on Validation of Analytical ProceduresMarch 1995
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29J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Regulatory and Compliance Requirement ReviewIn practice, it is usually possible to design the experimentalwork such that the appropriate validation characteristicscan be considered simultaneously to provide a sound,overall knowledge of the capabilities of the analyticalprocedure, for instance: Specificity, Linearity, Range,Accuracy, and Precision.
ICH Guideline for Industry Q2B, Validation of Analytical Procedures: Methodology
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30J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
Today’s Validation Requirements
ICH/USP
GMPs(legal) FDA
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31J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements in US
ICH/USP Validation Requirements & Parameters
• Specificity• Linearity• Range• Accuracy• Precision
– Repeatability– Intermediate Precision– Reproducibility
• Limit of Detection• Limit of Quantitation
ICH
SpecificitySpecificity Linearity and RangeLinearity and Range AccuracyAccuracy Precision Precision Limit of DetectionLimit of Detection Limit of QuantitationLimit of Quantitation RuggednessRuggedness RobustnessRobustness
USP
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32J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements 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.
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33J. J. RamniwasRamniwas10/13/2012
Specific Analytical Method Validation Specific Analytical Method Validation Requirements in USRequirements 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.
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34J. J. RamniwasRamniwas10/13/2012
Challenging Areas in Analytical ValidationsChallenging Areas in Analytical Validations
Quality of theanalytical method
MManan MMachineachine
qualifiedqualified
calibratedcalibrated
robustrobust
qualifiedqualified
MMethodsethods
suitablesuitable
characterisedcharacterised
documenteddocumented
MMilieuilieuMMaterialaterial MManagementanagement
QualityQuality
ReferenceReferencestandardsstandards
TempeTempe--raturerature
AnalystsAnalysts´́supportsupport
skilledskilled
HumidityHumidity
VibrationsVibrations TimeTime
SuppliesSupplies
IrradiIrradi--ationsations
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35J. J. RamniwasRamniwas10/13/2012
Effective Sourcing StrategiesEffective Sourcing Strategies1. Proactive Quality Assurance2. Risk based Approach3. Communicate Constantly4. Release Product5. Measure Capabilities6. Qualify Supplier7. Co-investigate Failures8. Establish Milestones9. Quality Agreements10. Embrace Supplier Infrastructure11. Customize Audits12. Maintain Control13. Manage Changes14. Monitor through Surveillance Program
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Vendor Qualification RequirementsVendor 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 supplier's understanding of the GMP requirements
The conditions under which the starting material is produced and controlled
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37J. J. RamniwasRamniwas10/13/2012
Vendor Qualification RequirementsVendor 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)
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Vendor Qualification RequirementsVendor Qualification Requirements
Quality Agreements1. Applicable GMP Standard2. Certificate of Analysis3. Change Control4. Right to Audit5. Authority Inspections6. Sub-contracting7. Retention of samples (final SUBSTANCE)8. Retention of records/documentation9. Stability
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39J. J. RamniwasRamniwas10/13/2012
Vendor Qualification RequirementsVendor Qualification Requirements
Quality Agreements10. Complaints 11. Recall12. Product quality review13. Storage and distribution14. Undesirable contaminants15. HAPIs16. Qualification / Validation17. Reprocessing18. Reworking
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40J. J. RamniwasRamniwas10/13/2012
Vendor Qualification RequirementsVendor Qualification RequirementsQuality Agreements
19. Deviations / OOS (incl. stability)
20. Packaging
21. Labelling
22. Regulatory documents
23. Product release
24. Reference standards
25. Specifications
26. Analytical methods
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41J. J. RamniwasRamniwas10/13/2012
Method Transfer Requirements at various sitesMethod Transfer Requirements at various sites Sending Unit (SU):
Create the transfer protocolExecute trainingAssist in analysisAcceptance Criteria
Receiving Unit (RU):Qualified instrumentationPersonnelSystems (Materials, Utilities, SOP's, etc)Executes the protocol
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42J. J. RamniwasRamniwas10/13/2012
Method Transfer Requirements at various sitesMethod Transfer Requirements at various sitesMETHODS TO BE TRANSFERREDMETHODS TO BE TRANSFERRED
AssayImpurities / DegradantsChiral Purity(If any)IdentificationCleaning ValidationMicronisation Microbiological
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43J. J. RamniwasRamniwas10/13/2012
Method Transfer Requirements at various sitesMethod Transfer Requirements at various sitesPre-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.
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44J. J. RamniwasRamniwas10/13/2012
Method Transfer Requirements at various sitesMethod Transfer Requirements at various sitesTransfer Protocol
Objective Scope Responsibilities Materials/Methods/Equipment Experimental Design Acceptance Criteria Documentation Deviations References Signature/Approval Page Reference samples, actives, intermediates, and
finished products
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45J. J. RamniwasRamniwas10/13/2012
Method Transfer Requirements at various sitesMethod Transfer Requirements at various sites
Transfer ReportShould 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.
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46J. J. RamniwasRamniwas10/13/2012
Out of Trend and Out of specification issuesOut of Trend and Out of specification issues1. No immediate information about OOS by outsourcing
laboratories2. 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?
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47J. J. RamniwasRamniwas10/13/2012
Conclusion Keep pace with the latest regulatory developmentsKeep pace with the latest regulatory developments Learn, deLearn, de--learn and relearn and re--learnlearn Revision in regulatory processRevision in regulatory process Rising awareness of quality, efficacy and safety Rising awareness of quality, efficacy and safety See today with the eyes of tomorrowSee today with the eyes of tomorrow Reconfigure of review process to minimize delaysReconfigure of review process to minimize delays Risk AssessmentRisk Assessment Doing things right first timeDoing things right first time Short cuts can be a costly affairShort cuts can be a costly affair Regulators understand guidelines, rules, laws and Regulators understand guidelines, rules, laws and
regulations onlyregulations only
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48J. J. RamniwasRamniwas10/13/2012
Thank you for your attention
J.RAMNIWASFounder & CEO SAI PHARMA SOLUTIONS INC.(Gateway to Regulatory Affairs, Quality & cGMP Compliance)Email: [email protected] No: +919558809128Website: www.saipharmasolutions.comOur Motto" Start to finish, everything in between".