Quality by Design and Continuous Improvement as a basis for high product quality

CPHI WW 2019WEDNESDAY, NOVEMBER 6TH, 2019 AT 1:50PM

– Karin Schrooten, Lonza, Senior Director Quality

Our history: the legacy Capsugel business

Origins: Parker-Davis (early 1900s); Warner-Lambert

(1970); Pfizer (2000); KKR (2011)

Part of Lonza since July 2017

Capsule Delivery Solutions – CDS – a global business unit within the Lonza LPBN organization

Undisputed market leader in 2 piece hard capsules

An array of service additions, spanning formulation development and clinical trial stages to commercial manufacturing

Partnerships with more than 4,000 customers in more than 100 countries

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At the intersection of patient health

Patient Healthcare ConsumerPreventive Healthcare

Bioscience SolutionsBiologics DivisionChemical Division

Capsule Delivery Solutions

Biotechnology Fine Chemistry

AnalyticsRegulatory

Bioavailability

Delivering the Medicines of Tomorrow, Today™3

Lonza Capsugel® Value PropositionOur promiseHigh-quality excipients and formulations for the medicines of tomorrow. Through:

Broadest suite of offerings across formulation development, clinical trials and commercial manufacturing

A globally integrated supply chain

--A global quality organization

Unique combination of science, engineering, formulation and capsule expertise to optimize the bioavailability, targeted delivery and overall performance of customers’ products.

Tailor-made formulations to meet all new market needs

--Close to customers through regulatory, compliance and technical support

Made better. By science.™

LonzaGlobal network, global standards

Identical capsules, supplied from different Lonza manufacturing sites :

• Produced on proprietary equipment

• Globally approved raw material suppliers

• Global purchasing specifications and identical test methods for raw materials

• Standard capsule specifications, release criteria and test methods

• Globally aligned Quality Management Systems

• All sites comply with IPEC GMPs and are ISO 9001 certified

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Define desired product performance upfront and

identify product CQAs

Design the systems and processes to meet product

CQAs

Continually monitor and update process to assure

consistent quality

Identify and control sources of variability in the process

Understand impact of material attributes and process parameters on

product CQAs

Quality by design A systematic approach model

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QbD at Lonza/Capsugel®Product & process design and development

Process design / equipment: in house development of critical equipment (production and print equipment, metal detector, inspection systems...)

CTQ capsule attributes: disintegration, absence of impurities, defect levels, dimensions, microbial quality, flexibility, container ...

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QbD at Lonza/Capsugel®

Capsule Design Raw Material Sourcing

Equipment Process Control Continuous Improvement

Inspection Technologies

Risk Assessment and Control

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Capsule design Coni-Snap® features

Two aerodynamic air vents allow air to escape from the cap; critical when operating high-speed filling machines

Closely – matched locking ringsprovide full circumference leak-free closure

Six elongated dimplesMaintain precise round capsule diameter, improving filling machine performance

Tapered rim of the body, engages easily with thecap for problem-free filling

Capsule in closed positionThe full circumference locking rings of the cap & body interlock to form a secure leak-free closure

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Raw Material SourcingSupplier Qualification & Management

StringentRaw Material

Purchasing Specifications

Demanding Supplier Qualification Process

Long-term Supplier Partnership supported by continuous Performance Management

A Global Sourcing Strategy to ensure consistent quality

• Demanding Supplier qualification program

• Robust technical purchasing specifications

• Purity criteria aligned with global standardsEP, USP, JP, Chinese Pharmacopeia, Food, Chemical Codex, FAO/WHO Food Standards

• Updated to reflect current BSE / viral safety regulationsInternational OIE (World Organization for Animal Health) GuidelinesRegional food and medicinal product regulations

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Raw Material Sourcing

Supplier Qualification & Management

Supplier screening & investigation

Raw Material Quality Evaluation

Manufacturing Suitability Evaluation

On-site supplier audit

Scale-up & final approval

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Production environmentFocus on quality and contamination prevention

Equi

pmen

t

Cont

amin

atio

n pr

even

tion

EquipmentDesigned for quality

Own design & construction

Consistency across sitesContinuous

improvement

Contamination Prevention

Zoning conceptSeparate flows for raw

materials & finished goods

AutomationCIP and cleaning

procedures

Prod

uct S

afet

y

Product SafetyStainless steel / food

contact suitable materials

FiltersInline metal detectorStainless steel dipping

pins

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Hard Capsule ManufacturingProcess Control

• Manufacturing equipment – own design and built to global standard

• Standard automated processes, allowing for continuous real-time monitoring and control of critical manufacturing parameters

• Dimensional controls

• Close- loop optical inspection and metal detection systems

• Huge amount of real-time data

• Improved process control reduction in variation

• Specific improvement projects

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Consistent High QualityDefect trend

HCM Gen 1

Statistical Process Control

HCM Gen 2 CAQ

Advanced Quality Management System

Six Sigma Capability Improvement

Inline Metal Detection HCM

Gen 3 Electronic Inspection technology

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Setting new quality standards

Coni-Snap® Sigma Series for all printed capsules, including Vcaps® Plus

Launch of Coni-Snap®

Sigma SeriesRadial and rectified printed capsulesOpaque, hard gelatin capsules

Coni-Snap® Sigma Series for unprinted Hard Gelatin CapsulesPrinted transparent HGC

Coni-Snap® Sigma Series for unprinted Vcaps® PlusNew specifications for Coni-Snap® Sigma Series

2013-2014 2015 2016 2019

Standard Quality Sigma 2014 Sigma 2018

Visu

alDe

fect

s

Critical AOQL 0.029%290 ppm

5 σ233 ppm

5.4 σ50 ppm

Major AOQL 0.067%670 ppm

5 σ233 ppm

5.1 σ150 ppm

Minor AOQL 0.36%3600 ppm

4.2 σ3600 ppm

4.3 σ2500 ppm

Prin

t Def

ects

Critical AOQL 0.029%290 ppm

6 σ3.4 ppm

6 σ3.4 ppm

Major AOQL 0.11%1100 ppm

5 σ233 ppm

5 σ233 ppm

Minor AOQL 1.8%18000 ppm

4 σ6210 ppm

4 σ6210 ppm

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A Measurable Impact Throughout the Supply Chain

Incoming Inspection

• Reduced testing for visual and print defects

• Faster turn-around time for incoming processing

Consumer

• Reduction in consumer complaints

Encapsulation & Packaging

• Fewer in-process investigations for observation, reducing:

• Schedule interruptions• Paperwork and labor for

investigation• Loss of filled product batches• Sampling / product inspection

demands

Coni-Snap® capsules with superior visual and print quality characteristics resulting in:

Sigma 2019

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CTQ capsule attributes: disintegration, absence of impurities, defect levels,

dimensions, microbial quality, flexibility, ...

Process design / equipment : in house development of critical equipment

(production and print equipment, metal detector, inspection systems...)

Inspection EquipmentReal-Time Feedback Loop Improved

Process Control

Quality by design A systematic approach model

Internal TrendingM

arket FeedbackInte

rnal

Tren

ding

Mar

ket F

eedb

ack

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Drug product

One size fits all?

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QbD

Desired Product

Performance

Product Design

(Product Quality Attributes)

Product Design

(Process Parameters)

Product Design

(Product Quality Attributes)

Critical Quality Attributes

Risk Mitigating &

Customization

Continual Improvement

Control Strategy Design Space

Risk Assessment

EXCIPIENT

FRCFunctionality Related Characteristics

CQACritical Quality Attributes

QUALITYSAFETY

EFFICACY

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Capsule selectionSolid oral dosage form

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Capsule selectionApplication

Capsule formulation

HPMC (Vcaps® Plus)Hard Gelatin Capsule

HPMC (Vcaps® Plus)Vcaps® Enteric

Hard Gelatin Capsule

Enteric releaseImmediate release

HPMC (Vcaps® Plus)

HPMC (Vcaps® Plus)Hard Gelatin Capsule

HPMC (Vcaps® Plus)Hard Gelatin Capsule

Vcaps® Enteric

No X-linking Coating No Coating

HPMC (Vcaps® Plus)Hard Gelatin Capsule

HPMC (Vcaps® Plus)

Standard LOD Low moisture(customized LOD)

Standard weight range

Tighter weight range (customized)

Not Hygroscopic Hygroscopic

X-linking

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Capsule selectionApplication

Capsule formulation

Solid oral dosage form DPI (Dry-Powder Inhalation)

HPMC (Vcaps® Plus)Hard Gelatin Capsule

Coni-Snap® Sprinkle

Press®-Fit Licaps® HPMC (Vcaps® Plus)

HPMC(Vcaps®)

Hard Gelatin Capsule

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DPI - Critical Parameters and Performance

Capsule

• Polymer• Dimensions / weight• Powder retention /

residual lubricant content

• Water content• Mechanical resistance• Microbiologic

Powder Formulation

•Composition / Dose•Particle size distribution

and morphology•Chemical stability•Hygroscopicity•Ability to deagglomerate

Device

•Opening principle•Resistance•Patient handling•Powder retention

Critical Parameters

OptimalPerformance

Emitted doseAerodynamic particle size

distribution (APSD)

Fine Particle Mass (FPM)

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Start the dialogue!

ConclusionTarget Product Profile Critical to Quality Attributes Critical Material Attributes Capsule selection

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Quality by Design and Continuous Improvement as a basis for high product quality

CPHI WW 2019WEDNESDAY, NOVEMBER 6TH, 2019 AT 1:50PM

– Karin Schrooten, Lonza, Senior Director Quality