Evolving Regulatory ParaphernaliaEvolving Regulatory Paraphernalia – Exciting opportunities

A.G. RaghuHead – Quality & Regulatory AffairsApotex Pharmachem India Pvt. LtdBangalore

US­FDA

ICH Japan

How to overcome…

TGAEDQMMHRA

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APRsOOS/OOT

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DeviationQualifications

Change controls

Validations

Major Markets

USAEuropeAustraliaCanadaJJapan

Increased– Increased Expectations

20th century….

Traditionally the pharmaceutical industry isa highly regulated environment withlittl fl ibilit i hi h l t hlittle flexibility in which regulators havetaken the responsibility for product quality.

Beginning 21st century….

Vision to move to a new desired state….

“A maximally efficient, agile, flexiblepharmaceutical manufacturing sector thatreliably produces high quality drugproducts without extensive regulatoryoversight”oversight

Janet Woodcock, M.D.

Chief Commissioner of Operations, FDA

Starting point……

August 2002: FDA launched the initiative“Pharmaceutical Current Good ManufacturingPharmaceutical Current Good ManufacturingPractices (cGMP) for the 21st Century: A RiskBased Approach”

Designed to evaluate and improve theagency’s approach to reviews and inspectionsrelated to the manufacturing of human andanimal drugs and biologicsanimal drugs and biologics.

Next……Brussels July 2003 (ICH)

D l h i d h i lDevelop a harmonized pharmaceuticalquality system applicable across the lifecycleof the product emphasizing an integratedof the product emphasizing an integratedapproach to quality risk management andsciencescience.

USFDA/EU/TGA/J

Harmonization of inspections

USFDA/EU/TGA/Japan

Rationalization of international GMPinspectors

Mutual Recognition Agreements (MRA) org g ( )Memorendum of Understandings (MOU)between regulatory authorities

Integration of policy guidelines byregulators across the worldregulators across the world

Exchange of inspection reports amongregulatorsregulators

July 2003: An ICH vision

The Regulatory

For companies with :1. Good design and Quality Risk

Management

Quality Risk Management

The Regulatory Quality System control strategies

2. Good Risk Management strategies

3. Good Quality Systems

Management (Q9)

Quality by Design(Pharmaceutical

Development)Quality

Quality by Design Reduced regulatory

b dQ ySystems

Quality

y g(Q8) burden:

• Reduction of submissions on changes/variationsI ti f litExisting Existing GMPGMP’’ss Quality

Systems (Q10)

• Inspection of quality systems

New approaches…

ICH Q11: Development and manufacture of ICH Q11: Development and manufacture of drug substances ­ Draft

US­FDA­Guidance for Industry ProcessValidation: General Principles andPractices

FDA Initiative: January 2007

Question based review (QbR) for Generic Drugs……g

Product quality and performance..‐ by effective designby effective design‐ Efficient manufacturing processes

Product specifications based on……‐ Mechanistic understanding of formulation and process factors impact on product performance

Ability of manufacturers to effect continuous improvement andcontinuous "real time" assurance of quality

Focus of regulators during Review & inspection

Process knowledge gained on variousStage of Product Life cycleScience based justificationRisk Based ApproachICH Q8/Q9/Q10 & Q11 (Draft)

Knowledge management during product lifecycle implementation

Process developmentProcess development….

Multivariate studies / InteractionUse of Statistical ToolsQuality Risk Management

Technology transfer

R&D Lab experimentsScale up challengesChallenges in process consistencyRisk based assessment

Routine Commercial production

P lid ti P fProcess validation – Process performancequalifications (PPQ)

Continued process verifications – Annualproduct quality review (APQR)product quality review (APQR)

Change ManagementChange Management

Increased focus on product and processunderstanding

Questions asked onQuestions asked on

Product designgCritical quality attributesCritical material attributesCritical process parametersLack of clear rationale behind setting specificationMi i l j ifi i lMinimal justifications on scale up process

Critical process parameters

Identified

Ranges are scientifically justified

Unidentified critical steps & process parametersmay be indicative of poorly controlledmanufacturing process High riskmanufacturing process – High risk

Higher assurance – Process is RobustgIncreased probability ofsuccessful scale up

Non-acceptance of advanced intermediates as starting material

Backward integrationorAssurance from vendor for supply of early stage raw materials

Vendor Selection

Commitment Consistent qualityConsistent supplySe ect o

QualificationAudit

pp yCGMP complianceData on requestChange intimation

Designing the process to achieve the parameters

Polymorphismy pParticle size distribution (PSD)Control of impurities in‐line with ICH Q3Ap QPotential Genotoxic impuritiesResidual solvent control in drug substanceResidual solvent control in drug substanceChirality of drug substance

Control of impurities

Tightening of total impurities based on the compendia..

Introduction of new impurities in the drug substancespecification

Process improvementsProcess improvements

Validation Impact – Analytical & Process

Stability impactStability impact

Etc.

Control of impurities

Process improvementsProcess improvements….

Challenge could be to modify the process toachieve the desired level or limit of the newlydd d i itadded impurity

Control of impurities

Validation Impact – Analytical validation

­ Need to re­validate the method­Method consistency and validation even at Key startingstages alsoS ifi M h d f d i d d i l i i i­ Specific Methods for detecting de­gradational impuritiesand method capabilities at QL level­ Degradation at Stress conditions and establishing the massbalancebalance

Validation Impact – Process validation

Need to re validate the process­ Need to re­validate the process

Control of impurities

Stability impact

Stability batches may not comply to thelimit of the added impurity.

Retract the shelf life.Retract the shelf life.

Inorganic catalysts

Need to demonstrate the control of residualinorganic catalysts such as Palladium (Pd)inorganic catalysts such as Palladium (Pd) ,Rhodium (Rh), Cadmium (Cd), Chromium(Cr) etc in final drug substance using(Cr), etc. in final drug substance usingvalidated analytical method by advancedtechnique; ICP‐OES (Inductively coupledtechnique; ICP OES (Inductively coupledplasma – Optical emission spectroscopy).

Manufacturing

Justification on the overages in the formulation bydemonstrating a similar in Referenced Listed Drugdemonstrating a similar in Referenced Listed Drug(RLD)

Why this excipient and why is this quantity

Granulation end point is subjective. Steps to be taken if ap j psuitable granulation is not formed by allocated time ofmixing and its effects on Quality of final Product.

Particle size distribution and its impact on thedissolution profile, content uniformity and Bio‐availabilityavailability

Excipients

API Compatibility ‐ Justifications based onmechanistic understanding of chemical interactionof drug substances and excipients andof drug substances and excipients andmanufacturing processes.

Possibility of degradation of API in presence ofPossibility of degradation of API in presence ofexcipients.

Significant reactive excipient impurities such asHydrogen Peroxide, Formaldehyde, Formic acid.

Suitability of analytical method to identifydegradant impurities formed by excipientdegradant impurities formed by excipientinteraction with API.

Low drug excipient ratio leads to higher risk ofLow drug excipient ratio leads to higher risk ofreaction.

Container Closure System

Moisture permeation data for the proposed BlisterPack Impact on

‐ Product Quality / Aesthetics‐ Product Stability / DegradationP d t I t it‐ Product Integrity

Extractable and Leachable Studies for proposedExtractable and Leachable Studies for proposedstoppers

‐ Impact on Product Qualityp Q y‐ Relationship to formulations (pH etc.)

Container Closure System

Specific Attributes – impact on Product quality ‐ Studyresults

Solid Oral Product Package driven by Stability issues‐ Light Sensitivity‐ Light Sensitivity‐ Moisture Protection‐ Inert Atmosphere‐ Tablet Integrity

How to overcome these challenges

ICH Quality trio Q8, Q9, Q10 will providesolution

­ Significant benefitsSignificant benefits‐ Guidance in demonstrating processand product Knowledgeand product Knowledge‐Accelerate continuous improvement

Throughout the product life cycle

Product life cycle: ICH Q10•Drug substance development

Pharmaceutical Development

Drug substance development• Formulation development•Manufacture IMP• Delivery development•Manuf. process development•Scale up• Analytical method development

Technology Transfer

• Analytical method development• New product transfer• Transfer marketed product between & within Manuf. & Test sites

Validations • Equipment• Analytical method • Process • Cleaning validations

Commercial Manufacturing

•Acquisition & control material• Facilities provision• Utilities & Equipment provisionCommercial Manufacturing Utilities & Equipment provision• Production• QC & QA• Release•Storage & Distribution

Product Discontinuation•Retention of documents• Sample retention• Continued product assessment and reporting

Objectives - ICH Q10Achieves Product RealizationAchieves Product Realization“Delivery of products with the quality attributes appropriate to

Meet the needs of patientsHealth care professionalsHealth care professionalsRegulatory authorities ”

Establishes and Maintains a State of Control“ ff i i i d l f“..effective monitoring and control systems for processperformance and product quality ..”

Facilitate Continual Improvementp“..implement, appropriate product quality improvements, processimprovements, variability reduction, innovations andpharmaceutical quality system enhancements ..”

Enablers‐ Knowledge Management‐ Quality Risk Management

Objectives - ICH Q10Knowledge Management Knowledge Management 

Product and process knowledge should bemanaged from development through theg f p gcommercial life of the product up to andincluding product discontinuation

Quality Risk Management 

‐ Quality risk management is integral to anQ y g geffective pharmaceutical quality system

‐ Proactive approach to identifying, scientificallyevaluating and controlling potential risks toquality

Pharmaceutical DevelopmentQuality by Design (QbD)

The development approach should be adapted based on the complexity andspecificity of product and process

Critical Quality attributes (CQA)Critical Process parameters (CPPs)Quality Target Product Profile (QTPP)

The information developed to determine CQAs and CPPs will help to:

Develop control strategy; p gy;Ensure quality of the product throughout the product lifecycle; Increase product and process knowledge; Increase transparency and understanding for regulators and industry; Evaluate changesEvaluate changes. 

Pharmaceutical Development

Control strategy

Initially implemented for Pilot scale batches re­definedInitially implemented for Pilot scale batches,  re­defined further in scale up and commercial lots

Acceptance criteriaAcceptance criteria

Analytical Methodology

Emphasis on process controlEmphasis on process control

The scientific justification of the proposed control strategy. gy

The scientific rationale for the studies conducted. 

Technology Transfer

Management of scale up issues

Risk associated on scale up

C t l t t t iti t i kControl strategy to mitigate risk 

Management of site change / Contract manufacturing (Regulatory impact)

P lid ti i d fi d th ll ti d l ti f d t f th

Process Validation

Process validation is defined as the collection and evaluation of data, from theprocess design stage through commercial production, which establishes scientificevidence that a process is capable of consistently delivering quality product.

The lifecycle approaches

Process improvement and innovation through sound scientific knowledge

Process Validation

Stage 1 – Process Design: The commercial manufacturingStage 1 – Process Design: The commercial manufacturingprocess is defined during this stage based on knowledgegained through development and scale‐up activities.

Stage 2 – Process Qualification: During this stage, theprocess design is evaluated to determine if the process iscapable of reproducible commercial manufacturing.capable of reproducible commercial manufacturing.

Stage 3 – Continued Process Verification: Ongoingi i d d i i d i h hassurance is gained during routine production that the

process remains in a state of control.

Commercial Manufacturing

Knowledge Management through review  ­ APQR

Response to assessment of data trends over time and otherk l d i dknowledge gained

Continual Improvement

CQAs and CPPs can evolve throughout the product lifecycle.

‐ Change of manufacturing process (e.g., change of synthetic route). 

‐ Subsequent knowledge gained throughout the lifecycle (e.g., raw q g g g y ( gmaterial   variability, pharmacovigilance, clinical trial  experience, and product complaints). 

How to overcome these challengesCommercial Manufacturing

Robust change Managementg g

Active knowledge Management at various stages of Productlife cycle translates to

Scientific Justification

‐ Selection of process, equipment, specification‐ Change of process, equipment, specification

P k l d ill d lProcess knowledge will grow and evolveduring product life cycle

Knowledge Management through  Product life cycle 

Process Development

Technology Transfer Changes

Qualification BatchesChanges

Changes

Stage­2: Process Qualification 

Process scale up / Q-Lots Stage­1: Process design

Process Validation

Changes

Commercial Manufacturing

Change Management

Changes

CAPAAnnual Product review

Stage­3: Process Verification

Challenges are overcome by

‐ Good design and control strategies‐ Good Risk Management strategiesg g‐ Good Quality SystemGood Knowledge management‐ Good Knowledge management

Effective implementation of ICH trio Q8,Q9 Q10Q9, Q10

US­FDAICH

EDQM

Japan

MHRA

aliano worries!!

i know the design!!

Good design with harmonized Quality systems

TGAEDQM

ICH Q8/ Q9 / Q10 / Q11

pher

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no worries!! i am ok for

any

design!!i have tools for any problems!!!

Development

Para

pyregulations

Qualifications

Validations

olvi

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Deviation/OOS

R&DQA

RA

Stability data

Evo

APRs

TT QC

Production Commercial

Stability data

Change management

Commercial

Acknowledgement

Thanks to my colleagues in Apotex

h k Thank youh @ iaraghu@apotex.co.in