Biologics Drug Product Development using a Quality by ... · Galactosylation (%G1 + %G2) 0-5% Fucose content 2-13% Aggregate 0-5% Meets pharmacopoeial requirements for parenteral

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Biologics Drug Product Development using a Quality by Design approach –

Results from the CMC Biotech Working Group

Case Study

Satish K. SinghPfizer Inc.

01 March 2010

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Perform confirmatory formulation development study for A-mAb as we leverage the use of the prior knowledge gained from previous mAbsApply predictive mathematical models to compounding vessels to deliver a scale and equipment-independent process Establish a class-based sterile filtration process platform for X, Y, Z-mAb to build a knowledge set and apply it to a risk-based verification of the operating parameters for A-mAb as a “next in class” molecule

Apply a risk-based approach and the use of DoE to create a design space for the filling operation Use Fault Tree Analysis for a comprehensive risk assessment of the potential points of failure for the overall A-mAb drug product process and propose a mitigation strategy for highest assurance of process performance

Drug Product Case Study Intent

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Linking CQAs to Control StrategySpecifications are one element of

the Control StrategyBased on scientific understanding of

the Product and the Process

Specifications are linked to Clinical Relevance

1. What tests are included2. Acceptance limits3. Anal. Method requirements Product Stability

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Multiple Risk Assessments are used throughout Development Lifecycle

Repeat RA throughout development

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Control Strategy is Based on a Final Risk Assessment for each CQA

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Control Strategy Links all Unit Operations and Defines Testing Strategy

Product Quality Attribute C

QA

Prod

uctio

n B

iore

acto

r

Prot

ein

A

Low

pH

/VI

CEX

AEX

Nan

ofilt

ratio

n

UF/

DF

Com

poun

ding

Filtr

atio

n

Filli

ng, s

topp

er, c

ap

Test

ing

elem

ents

Aggregate Yes Form Remove Form Remove Remove Form Form LR

Deamidated isoforms No Form PM

Oligosaccharide Yes Form PM

CHO HCP Yes Form Remove Remove Remove Remove PM

DNA No Form Remove None

Protein A No Form Remove Remove None

Viral safety Yes Inact Clear Clear Biorx. IPC

CPPWC-CPP

KPP

Operation includes a parameter(s) that must be tightly controlled to achieve CQAsOperation includes a WC-CPP affecting a quality attributeOperation includes a KPP impacting a process attribute

IPCLRPM

In-process control testingLot releaseProcess monitoring

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Overview of DP Case• Based on well-established platform

(formulation, process)• Only verification of suitability of design

space is considered

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QTPP

2-13%HCP

0-5%Galactosylation (%G1 + %G2)

2-13%Fucose content

0-5%Aggregate

Meets pharmacopoeial requirements for parenteral dosage forms, colorless to slightly yellow, practically free of visible particles and

meets USP criteria for sub-visible particlesPharmacopoeial compliance

Below safety threshold, or qualifiedDegradants and impurities

Acceptable toleration on infusionBiocompatibility

Minimum 14 days at 25°C and subsequent 2 years at 2-8°C, soluble at higher concentrations during UF/DF

Compatibility with manufacturing processes

≥ 2 years at 2-8°CShelf life

20R type 1 borosilicate glass vials, fluro-resin laminated stopperContainer

Acceptable for manufacturing, storage and delivery without the use of special devices (for example, less than 10 cP at room temperature).Viscosity

IV, diluted with isotonic saline or dextroseMode of administration

25 mg/mLConcentration

10 mg/kgDose

500 mgProtein content per vial

Liquid, single useDosage Form

TargetProduct attribute

Table 5.2 Quality Target Product Profile (QTPP) for A-Mab

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A-mAb Formulation Design Space Strategy

Building on prior knowledge followed by verification of design space

Case study references: Fig. 5.2 - Formulation Verification, Figs. 5.3 and 5.4 – Formulation Characterization

Note: CQAs listed are only a sample of the relevant drug product CQAs considered in the study design

QTPPPrior Knowledge

Product UnderstandingProcess Understanding

Formulation Verification &

Characterization

Initial Risk Assessment

Comparison to previous mAbs

Design Space Verified

X, Y, Z-mAb commercial product development experience

COMPOSITIONConcentration of active, excipients

CONDITIONSTemp, light, shock, agitation, flow

STABILITYProcessing, packaging, transportation, storage, administration

CQAAggregation by SEC, sub-visible & visible particles

Final Risk Assessment

Product life-cycle, Control Strategy

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Formulation• Identified based on prior knowledge• Verification of suitability of design space

considered

CompendialSolventq.s. to final volume of 20 mLWFI

CompendialpH adjustmentq.s. to pH 5.3Sodium Acetate

CompendialSurfactant2 mg Polysorbate 20

CompendialBuffering agent20 mMAcetic Acid

CompendialIsotonicity agent1.8 gSucrose

In-house specificationActive ingredient500 mgA-mAb

Quality StandardFunctionAmountComponent

Table 5.3 Formulation Description

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DP Process and Unit Ops

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LowLowLowLowHCP

LowLowLowLowGalactosylation(%G1 + %G2)

LowLowLowLowFucose content

HighHighHighHighVisible particles

HighHighHighHighSub-visible particles

HighHighHighHighAggregate

Filling and stoppering

Sterile FiltrationCompoundingFormulation Composition

CQAsVariables and Unit Operations

Initial Risk Assessment connecting Formulation and Unit Ops

Assess Risk for Unit Op to have an impact on selected CQAs

Table 5.4 Initial Risk Assessment for Formulation and Unit Operations

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Risk Assessment: Formulation Composition and CQAs

Risk Assessment tool: Cause and Effect (C&E) Matrix

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Formulation Identification Strategy

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Formulation Verification

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Formulation Design SpaceFT Cycling and storage stab studies for DSDoE on composition including stability studies

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Compounding Unit Op

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Initial Risk Assessment Compounding Unit Op: C&E Matrix

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Mixing-Model guided Scale-Up for Dilution Tank

Model based on “similar mechanical stress” experienced by protein at all scales

Verification at scale

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Scaling Model based on Dimensional Analysis

Mixing power per unit volume (P/V) is calculated using vessel dimensions and fluid properties. The P/V constant is used for scaling across tank sizes to deliver equivalent mixing time, product stress and mixing characteristics

Scale-up for vessels of same configuration and scale-down for vessels of different configuration; does not address facility-dependent differences

Scale-down coefficient of less than 10 is applied to design a model used to generate data for power input, rotational speeds and examine stress on the product

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Confirmation of Hold-Times BDS, DP

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Compounding: Design Space and Control Strategy

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Final Risk Assessment; Compounding Unit Op

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Filtration Unit Op

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Initial Risk Assessment: Filtration Unit Op: C&E Matrix

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Establishment of Process Platform

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Filtration Process Platform

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Verification of Platform Process

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Filtration: Design Space and Control Strategy

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Initial Risk Assessment: Filling Unit Op (on Aggregation)

2: No (detectable) impact; 4 Minor (acceptable) impact; 8 Major (unacceptable) impact

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Recommended Process Characterization Studies

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Knowledge Space from Filling DOE Study

Size of green bubble is proportional to Aggregation

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Site-Specific FMEA

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Overall Drug Product Process Control Strategy

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Summary of DP Section• DP Section describes the formulation design,

compounding, filtering and filling steps, focusing on a limited set of critical quality attributes.

• The extensive prior knowledge of formulation and manufacturing processes for Mabs is such that it is possible to consider the product and its process to be essentially a platform process.

• Through risk assessments and targeted experimentation, it is shown that design space and proven acceptable ranges developed for other products can be re-used..

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Other Comments

• Variety of tools for Risk Assessment have been described– A Fault-tree analysis is also included for a

comprehensive risk assessment of potential failure points (not covered here)

• Rational approach to control strategy– Focus on control of CPPs

• Key is the Multivariate experimentation approach

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Expected Value of QbD Exercise

General• Increased product and process knowledge• Improved product quality and consistency• Faster and smoother development and

licensureSpecific (DP)• Easier site transfers and scale changes

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AcknowledgementsJoseph Phillips (Amgen)Michael Siedler, Hans-Jeurgen Krause (Abbott)Sherry Martin-Moe, Chung Hsu (Genentech)Joseph Rinella, Doug Nesta (GSK)Carol Kirchhoff (Pfizer)John Berridge, Ken Seamon, Sam Venugopal

and rest of CMC BWG. Also the team behind the representatives in the respective

companies

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Thank you

Satish K. [email protected]+1-636-247-9979