Updating on the latest developments in ich guidelines and applying learnings from recent experiences...

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



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



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)



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)



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)



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



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



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.



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



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



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



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



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



Speed up of DMF Filing Process 1. Planning aspects

2. Formatting and compilation aspects

3. Review aspects



Speed up of DMF Filing Process 1. PLANNING ASPECTS

Deadline

Understanding Registration Requirements

Requirement listing

Sending Requirements to the respective departments



Speed up of DMF Filing Process 2. FORMATTING AND COMPLIATION ASPECTS

Format

Compilation



Speed up of DMF Filing Process 3. REVIEW ASPECTS

Recheck the information

Cross Verification

Use checklist



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



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.



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.!!



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




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




Verification Versus Validation

• Compendial vs. Non-compendial Methods

– Compendial methods-Verification

– Non-compendial methods-Validation requirement




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




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>





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)





• 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




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




Today’s Validation Requirements

ICH/USP

GMPs(legal) FDA




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




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.




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.



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



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



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



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)



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



Vendor Qualification RequirementsVendor Qualification Requirements

Quality Agreements10. Complaints 11. Recall12. Product quality review13. Storage and distribution14. Undesirable contaminants15. HAPIs16. Qualification / Validation17. Reprocessing18. Reworking



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



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



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



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.



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



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.



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?



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



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".

Website: www.saipharmasolutions.com

Updating on the latest developments in ich guidelines and applying learnings from recent experiences...

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Transcript of Updating on the latest developments in ich guidelines and applying learnings from recent experiences...