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The Evolution of Chemistry, Manufacturing & Control (CMC) Systems during Product Development

Peter Lutwyche, Ph.D.Senior Vice President, Pharmaceutical Development

ASGCT Translational Science Training Course, Seattle, May 17th 2011

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Current Good Manufacturing Practice

• FD&C Act part 501 (a)(2)(B) [1938]

• Code of Federal Regulations Title 21 Parts 210 and 211“cGMP in Manufacturing, Processing, Packing, or Holding of Drugs”

• Regulations governing all aspects of manufacturing, packaging and testing of pharmaceutical products intended for human use

• “Failure to comply…shall render such product to be adulterated”

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The Tension Between CGMP and CMC Development

Preclinical Phase 1 Phase 2 Phase 3 Commercial

Knowledge of Product

CGMPGLP

• Knowledge of product increases during product development process

More lots; More Stability DataBetter Assays; Identification of ImpuritiesProven Acceptable Ranges for Manufacturing Process

• There are no “levels” of GMP; it either is, or it isn’t.

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FDA 1991 Guideline on Investigational New Drugs

• Reinforced the FDA’s position on CGMPs:

“When drug development reaches the stage where the drug products are produced for clinical trials…then compliance with the CGMP regulations is required”

• Some language allowing for early development:

“At early clinical stages…only limited process validation may be possible. In such cases, limited validation, especially for such critical processes as sterilization, should be derived…”

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FDA 2008 Final Rule: CGMP for Phase 1 Investigational Drugs

• Rule exempts most Phase I drugs from compliance with regulatory CGMP requirements

• But: FDA will continue to exercise oversight under FDA’s general statutory CGMP authority, and IND review

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FDA 2008 Guidance: CGMP for Phase 1 Investigational Drugs

• Adherence to CGMP in Phase 1 mostly achieved throughWell-defined, written proceduresAdequately controlled equipment, mfg environmentAdequately and consistently recorded data from manufacturing (including testing)

• Emphasis on hazards and risk assessment

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Phase 1 Production of a Parenteral: CMC Risks

SAFETY!• Sterility; Pyrogens

Generally, same standards for aseptic processing are used from Phase 1 to commercializationValidation of fill line by media fillsMicrobial monitoringSpecialized manufacturing environmentsDisposables; product contact

• Comparability of material to that used for IND-enabling toxicology studies

Impurity profile Method qualityManufacturing changes

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Quality Management

MANAGEMENT

QUALITY CONTROL

QUALITYMANUFACTURING

QUALITY ASSURANCE

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Role of Quality Functions During Preclinical to Phase 1 transition: Quality Control

• QC Function defined in 2008 Guidance• QC has a Central Role in Controlling Main Risks

• Preclinical Stage: Draft SpecificationsDose Solution AnalysisStability – obtain data for IND/retest dateAnalytical methods ready for QualificationMicrobial methods ready for ValidationStability-indicating methods

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• Phase 1 Clinical Stage:Testing for GMP Product ReleaseGMP Stability TestingApproved Specifications – “Change Control”Validation of Microbial MethodsQualification of other testsTesting of raw materials

Role of Quality Functions During Preclinical to Phase 1 transition: Quality Control

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Role of Quality Functions During Preclinical to Phase 1 transition: Quality Assurance for CMC

• PreclinicalHas input into draft Batch Record (BR) developmentHas input into specification developmentReviews analytical data, as required

• ClinicalProvides and documents trainingObserves ManufacturingApproves BR, reviews analytical dataIssues Certificate of Analysis and Certificate of ConformanceStores data in compliant manner

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Example: CMC Quality System for Phase 1 Clinical Production used by a Small Company

Drug Substance ConsumablesExcipients

Raw Materials Release

Drug Product Manufacture

Drug Product Testing

Container/closure

Release

Package/Distribute

Vendor Quality Systems, approved by Company Vendor Qualification Program

Company QC, Manufacturing Site, or CRO approved by Company Vendor Qualification Program

Company QC, Manufacturing Site, or CRO approved by Company Vendor Qualification Program

Most often CMO approved by Company Vendor Qualification Program

Can use GMP-trained company staff

Internal QA; CRO

CRO

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Example: siRNA LNP Drug Product Testing

• Selection of appropriate methods to ensure “the identity, quality, purity and strength/potency” of the Product

Description• appearance

Identity• ID of drug substance, functional excipients

Assay• Drug substance (API), functional excipients

Impurities• Related Substances, Residual Solvents, Heavy Metals

Physical Tests• Particle size, Osmolality, Particulate Matter

Safety• Sterility, Bacterial Endotoxins

Parenteral• pH, Osmolality, Particulate Matter

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Example: siRNA Stress Degradation – HPLC Method

AU

0.00

0.02

0.04

0.06

0.08

AU

0.00

0.02

0.04

0.06

0.08

AU

0.00

0.02

0.04

0.06

0.08

AU

0.00

0.02

0.04

0.06

0.08

Minutes4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00

45% 43%

38% 34%

27% 17%

40%43%

T = 0 hrs

T = 24 hrs

T = 6 hrs

T = 2 hrs

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Manufacturing Quality considerations

• PreclinicalWritten records“In the lab”

• ClinicalGMPTraining, documentationClassified manufacturing space Equipment cleaning procedures

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GMP LNP Manufacturing for Phase 1

Bulk product prior to fillCompounded in ISO6 room by Tekmira personnel

Sterile filtrationmanual fill/finish in ISO5 hood by CMO personnel

Sterile vialed final product

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Preclinical Phase 1 Phase 2 Phase 3 Commercial

CGMPGLP

CMC Development During Clinical Development

Process Development, Scaleup

ValidationAnalytical Development

Lock

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CMC Development During Clinical Development

Transition of manufacturing process from-

Small scale, one-off production by Scientists familiar with the product

To-

Large scale, routine production by manufacturing staff

Investment drastically , while clinical risk still high

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CMC Risks Change

• As process and testing become more routine, risk is associated more with mistakes or non-compliance with well-established procedures

• Much more emphasis on cost control, throughput

• FDA Report September 2004:“Pharmaceutical GMPs for the 21st Century: A Risk-Based

Approach”

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GMPs for the 21st Century

• Risk-based approach• Science-based regulation of Product Quality• Integrated Quality Systems• Facilitate introduction of latest innovations in

Pharmaceutical Engineering• Process Analytical Technology• Quality by Design• Electronic Batch Records

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Integrated Quality Systems & Quality by Design

• Design decisions based on Product and Process understanding

• A process to build in quality from inception to output

i.e. Not “Gatekeeper” QA

ICH Q8 “Pharmaceutical Development”

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Process Analytical Technology

• Enables real-time (on-line/in-line/at-line) control and decisions through measurement of Critical Process Parameters (CPP) affecting Critical Quality Attributes (CQA)

Image: nne pharmaplan

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Process Analytical Technology & Quality by Design

• Process DevelopmentEstablish Design SpaceBuild ModelsMonitor process to develop understanding

• ManufacturingProcess ControlFlexible operationExpedited release

• Continual ImprovementData tracking/trending

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Image: CAMO Software AS

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Summary

• Process understanding and product knowledge increases through the development process

• Focus on identification and mitigation of CMC risks, which may differ at different stages of development

• Let science and data guide development decisions

• Integrate quality

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