analytical sciences in biotechnology… opportunities … · capacity to regulate increasingly...

Analytical Sciences in Biotechnology… Opportunities and Challenges Wassim Nashabeh, Ph.D.

Global Head, Regulatory Policy

F. Hoffmann La-Roche, Basel, Switzerland

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Presentation Outline

• External Global Trends

• Role of Analytics in the Evolution of Regulations?

• Analytical Method: from University to QC??

• Hurdles to Innovation

• Our collective role in advocacy

2

Bio-Pharmaceutical Global Trends

• Increasing importance of biotherapeutics with conversion of the Pharmaceutical and Biotechnology industry

• Entry of biosimilars resulting in cost containment, pricing pressure and affordability, largely enabled by advances in Analytical Technologies

• Move towards personalized and targeted medicine

• Highly diversified and increasingly complex biologic molecular formats

• Internationalization and emerging markets

3

4

External Landscape: road to convergence…

• Interaction among regulators accelerating at tremendous paste, mostly through regional clusters – APEC/ASEAN, PANDRH, Gulf Cooperation….

• Formation of the “International Regulatory Forum” that brings together regulators across all continents

• ICH revamp of governance and scope to remain relevant…

• Increased interest in joining PIC/S (Inspection Cooperation Scheme) that will drive GMP harmonization of practices and reduce redundant inspections

Cooperation among global initiatives

ICMRA

ICH

APEC/PANDRA

IPRF

Strategic direction

WHO

Technical Operation

APEC Regulatory Harmonization Efforts

6

8


• WHO has expanded from its traditional focus on Vaccines to “Biotherapeutics” and now mandated by World Health Assembly to support developing countries in building regulatory capabilities

– Primary engine behind Biosimilars regulatory convergence

– WHO guidance on recombinant products will gradually shift emerging markets towards similar standards…

– More WHO guidance on Biotherapeutics are in the works….

• NGO’s expanding beyond communicable diseases…

• Rise of global industry association coalitions – IFPMA as primary link to WHO

– International Coalition of Biotechnology Associations (ICBA)

SIXTY-SEVENTH WORLD HEALTH ASSEMBLY (WHA)/A67 R20

9

To WHO DG

• to increase support and guidance for strengthening the capacity to regulate increasingly complex biological products with the focus on biotherapeutic products, blood products and associated in vitro diagnostics, and, where appropriate, on new medicines for human use based on gene therapy, somatic-cell therapy and tissue engineering;

SIXTY-SEVENTH WORLD HEALTH ASSEMBLY (WHA)/A67 R21

10

To WHA Member States:

• to develop the necessary scientific expertise to facilitate development of solid, scientifically-based regulatory frameworks that promote access to products that are affordable, safe, efficacious and of quality, taking note of the relevant WHO guidelines that may be adapted to the national context and capacity

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• Biggest gap is “knowledge”….Capacity building is key priority for regulators in EM – Formation of academic like “centers of excellence” has tremendous potential for influence and driving the right

scientific understanding

– Industry is welcome to support/develop training modules

– Focus on implementation/interpretation issues—the “how” not only the “what”

– Different work sharing models being explored—knowledge is pre-requisite

• Access to Medicines is on the mind of regulators and policy makers and will increasingly be core in decision making

– Striking a challenging balance between “access” and “quality/safety”

– Balancing local political/economic ambitions with scientific considerations


• External Trends



• Hurdles to Innovation


12

13

Regulatory Milestones

History of U.S. Biotech Regulations

ICH

PTC for Biotech

1986

80’s 90’s 2000

First Biotech Drugs •Insulin •Growth hormone

‘02 ‘03 ‘92 ‘97 ‘98

First Biotech Biologics

‘04

CBER/CDER

Inter-center

Agreement

CBER/CDER Integration

‘05 ‘06

REGO 1994-96 • *First WCBP Symposium

• Replaced PLA & ELA with BLA • Specified Products

• Eliminated Lot Release

‘94

Biosimilars

‘10-present

• Quality by Design/Risk-based Science

-ICH Q8, 9,10 and 11…

-CQA, CPP, DS

-Expanded Change Protocols

*Comparability

FDA—OPQ

2015

15

Comparability Over the Years….

Establishment of “Well-

Characterized

Biological” concept and

conference

TIMELINE: 15 YEARS

Development of regulatory

guidance (ICH) and study

design development of

“Comparability"

Extensive use of

Comparability for single site,

product changes with

regulatory relief

Expansion of comparability

applications to multiple simple

changes (component

simplification, bioreactor

family…)

Leverage QbD initiative to advocate for “expanded

Comparability/Change Protocols”

2011: First Approval of

2 eCP across multiple

facilities and products

Impact of external engagement: Significant regulatory relief (submission category downgrade and reduction in number of submissions required) achieved through advocacy in Scientific Conferences and Industry

Associations

Successful Global Approvals

• >20 drug substance site transfers

• 6 major process versions

2015: ICH Q12??

16

Release Tests

Extended Characterization

Process

Adapted from: S. Koszlowski & P. Swann (2006) Adv. Drug Delivery Revs. 58, 707-722

Product

Knowledge

Process

Understanding

How to manage heterogeneity and ensure that consistent product is made

Scientific Regulatory Concerns of the 1980’s

• DNA • Genetic Stability • Mutation • Host Cell Proteins • Endotoxins • Intrinsic Virus • Extrinsic Virus • Mycoplasma • Aggregates

• Glycosylation

• Immunogenicity

• Deamidation

• Use of Immortalized Cell Lines

• Analytical Characterization of Proteins

• Reproducibility of Process

• Stability

• Product Specifications

17

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Current Scientific Regulatory Concerns

• DNA • Genetic Stability

• Mutation

• Host Cell Proteins • Endotoxins

• Intrinsic Virus

• Extrinsic Virus • Mycoplasma

• Aggregates

• High order structure

• Glycosylation

• Immunogenicity

• Deamidation

• Use of Immortalized Cell Lines • Structure-function relationship

• Reproducibility of Process

• Stability • Product Specifications

• Particulates

• Leachables / Extractables

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Testing: Focus on what is important and it evolves

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HPLC: RP, IEC, HIC, SEC

SDS-PAGE (silver stain)

10’s of nmoles

Proteomics, genomics

Capillary electrophoresis

Higher order structure

Real-time analytics

10’s of pmoles

1976

1980’s

1990’s

2000+

Edman / amino acid analysis

SDS-PAGE (Coomassie)

100’s of nmoles

Mass spectrometry

hyphenated techniques

100’s of pmoles

Evolution of Analytical Methods: Example: Glycoproteins

Glycosylation Biological Relevnce: Then and Now

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1970’s 1980’s 2000’s

Solubility Solubility

+

Clearance

Solubility

+

Clearance

+

Bioactivity

21

Possible Mechanisms of Cell Killing

Apoptosis

ADCC

Phagocytosis

CDC complement binds to Fc --> cell lysis

FcgRI/II/III

Target cell

Complement

ADCC Fcg Receptor binds

to Fc --> cell lysis

CE Analysis of Neutral N-Linked Oligosaccharides from a Recombinant Antibody

22

G0-F Man5 Man6

G0

G1

G1’

G2

G-1 G1-1 G1’-1

Reproducible and Robust Assay

• Galactosylation variability is readily apparent

- fucosylation (e.g., G0-F) may also be important

Correlation of Bioactivity and Galactose Content in Rituxan™

50

60

70

80

90

100

110

120

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8

In V

itro

CD

C B

ioacti

vit

y

Moles Galactose Mole Heavy Chain

b- galactosidase treated

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• Non-fucosylated Fc glycans : ADCC correlation unknown 5 years ago

- very small differences may have significant in vitro effects:

When You Think You Know Everything...

0

1

2

3

4

5

0 1 2 3 4 5 6 7

Series1Rela

tive A

DC

C

% Non-Fucosylated IgG

Antibody Glycoengineering

Genetic engineering of CHO cell lines to produce antibody glycosylation variants with increased affinity to FcγRIII

receptors and enhanced ADCC

Overexpression of GnTIII and ManII glycosylation genes in mAb production cell lines leads to mAb glycoforms bearing complex, afucosylated oligosaccharides in the Fc region.

Enhancing ADCC of IgG1s via Fc glycoengineering

Humanized • Rodent VH and VL CDRs (ICR62) • CDRs grafted on human frameworks identical to germline

ADCC=antibody-dependent cellular cytotoxicity; CHO=Chinese hamster ovary.

Glycoengineered

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Complex Biologics

Highly diversified molecular formats and new therapeutic modalities

Bi/multi-specifics Pre-targeted radio immunotherapy

DNA vaccines Brain shuttle antibody fusion

Antibody drug conjugates

Alternative antibody scaffolds

Antibody cytokine fusion Cytolytic fusion protein

Thiomab Antibiotic Conjugate

Ocular drug delivery


• External Trends




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© 2009, Genentech

1981-1983 Initial Publication of “Zone Electrophoresis in Open Tubular Glass Capillaries” in Analytical Chemistry (81), followed by a paper in “Science” (83)—both widely credited with the launch of modern CE

1983-1988 Increased use in academic labs and few characterization or feasibility studies in industry (often in collaboration with academic labs)

1989 First international symposium HPCE (high performance capillary electrophoresis) held in Boston with

the introduction of first commercial CE instruments, indicating growing use within academic centers—First conference was chaired by Prof Barry Karger at Northeastern University

1997 Submission and approval by the FDA of two CE methods to be used as part of the control system QC

release for a MAB—cIEF (identity) and Glycan analysis

1999 First mention of “CE” in ICH Q6B in appendix 6.1.2 (c)

2001-2005 Advances in instrumentation continued with significant expansion in applications (including CE-MS for Characterization), imaged cIEF and the introduction of platform methods

2006-2010 Method becomes routine, with general chapters being developed in pharmacopeis

2010-present

ICH Q4B—Global Harmonization of the General Chapter on CE in USP, EP and JP (initial monographs 2006); expansion of routine use; coupling with orthogonal techniques

Development of Modern CE Applications for Biologics

CE-SDS / LIF: Silver Staining Sensitivity

Therapeutic rhuMAb

CE conditions: Fused silica capillary 50 µm x 24 cm; SDS run buffer (Bio-Rad); 20°C; reversed polarity, 15 kV; Argon-Ion laser, 480 nm excitation / 560 nm emission.

a. non-reduced b. reduced

G. Hunt and W. Nashabeh, Anal Chem. 1999, 71, 2390-2397.

S. Ma and W. Nashabeh, Anal Chem. 1999, 71, 5185-5192.

N-linked Oligosaccharides Analysis by CE

Excess APTS

Reagent IS

G0

G1

G2

APTS-glycan

adducts

IS = internal standard maltoheptaose

It Takes a Village to Develop CE into a Routine

Analytical Tool for Biologics

Strong Partnership between academics, industries (Instrument, Biopharmaceutical) and health authorities is key to success!

• Internal Management – Why change what is working…..

• Global Life Cycle Regulatory Management Process – Complexity of post-approval changes – Current global regulatory system favors status quo…

32

Key Challenges for Innovation


• External Trends




33

Global Life Cycle Management Problem Statement…

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Hinder innovation and continual improvement of process and product

Change classifications different or not available

Country-specific requirements (e.g., stability, raw data) CPP* needed for

submission?

Long/unpredictable approval timelines Backlog due to high review demand at Health

Authorities

Complex supply planning/ high bridging stocks

Drug shortage

Quality and safety

*CPP= Certificate of Pharmaceutical Product

Any change is a multiple year endeavor when it is executed globally

Wave 2: Non-CPP

Doc

Review 0-10 m

Doc Reviews 6-20 m

Wave 1: “ICH dossier” countries*

Review 6-24 m

0 12 24 36

Wave 3: CPP countries

CPP Data

4 2 Time (elapsed months)

Approved details differ from country to country after HA Q&A during approval

20

100

20

Approval

Approval

Change 1

Global convergence in action.....

WCBP, Jan.2013 DC, (Session: operating globally)

CMC forum Japan Dec. 2012 ( FDA asked for

challenges when filing globally)

CMC forum Japan Dec. 2013

CMC forum EU May 2014 (Session: Managing complex supply chain

and registrations

WCBP US Jan. 2014

(Session : Managing global complexity

CMC forum LATAM Aug. 2014

Challenges of global LCM

Ottawa, Oct. 2013

Seoul, Sept. 2013

APEC/WHO implementation workshops, Seoul,May 2014

First presentation of case studies

Middle East Regulatory Workshop, Nov 2014 Session:

Life-cylce-management

DIA Maghreb February 2015

Session: challenges of Global LCM

• Regulatory Dossier – A separate section in the dossier clearly listing the commitments linked to regulatory

change management

• Pharmaceutical Quality System – The greater the knowledge, the more flexibility a sponsor has in managing changes

internally through PQS

• Post-approval Change Management Plans/Protocols – Broader utilization of Change protocols globally

Connecting the Dossier and the Pharmaceutical Quality System

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ICH Q12: Life Cycle Management What We Want

ICH Quality Topics Proposed Timeline

2014 2015 2016 2017 2018 2019 2020

June Nov June Nov June Nov June Nov June Nov June Nov June Nov

Lifecycle Management

ICH Q12

API-Starting material

Quality Overall Summary

Enhanced Approached for

Analytical procedures

Continuous Manufacturing

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4. Enhanced Approaches for Development and Utilization of Analytical Procedures

• Problem Statement – Utilizing science and risk-based principles have not been fully considered

for analytical method design, development, validation, tech transfer and continuous improvement

– Lack of global acceptance of proposed enhanced approaches

• Desired State – Robust, fit for purpose, analytical methods that consistently

demonstrate and assure product & process quality throughout the product lifecycle

– New technologies are embraced

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Enhanced Approaches for Development and Utilization of Analytical Procedures

• Potential Elements:

– Analytical method development & validation, including: • Analytical Target Profile (fit for purpose), Risk Assessment, DoE, etc.

• Link to control strategy

• Contemporary and innovative methods and equipment i.e., NIR, XRPD, NMR, etc.

– Analytical method lifecycle • Based on enhanced approaches to analytical development and validation

• Aligned with proposed ICH Lifecycle Framework

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What We Need for Continued Success… - Embrace and implement Risk based approach for product development, analytical testing and

control with emphasis on patient risk/benefit - Continue to strive towards harmonized international regulatory policy with reduced regional or

local requirements • Implement spirit of ICH, and expansion of ICH adoption to all countries

- Open dialogue between industry, regulators and academics through professional forums that focus on science as a means of sound regulation

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Doing now what patients need next

© 2009, Genentech

Slide 44

History of CE in Biotechnology Industry

Slide 44

1989:

1st HPCE conference

1st PACE available Seminal paper on

CE in 1981

Mid 80’s – mid

90’s

Pioneering work on

CE applications for

biologics through

collaboration with

academia, with

applications

predominantly for

R&D purpose

80’s 90’s 2000 ‘03 ‘89 ‘99 ‘05 ‘06

1997 • First Mab control system incorporated CE assays for

ID and purity tests accepted by FDA for Rituxan

• Adoption of CE for all Mab products world wide since, including acceptance by various Pharmacopeia

15th CE Pharm

‘13

Continued realization of routine CE applications:

- Characterization

- QC testings

CE Pharm Launched

The 90s:

Significant advancements in commercial CE systems, reagents, applications

HPCE becomesMSB

Scientific Collaboration Between Industries, Academia

and Regulatory Agency is Key

WHO ICMRA ICH IPRF APEC/PANDRA

Purpose Standardization

of biological

products

Global

strategic

direction from

regulatory

heads

Harmonization

by common

regulatory

standards

Cooperation &

convergence at

Technical/

operational

level

Promote

convergence and

best practices

Roles Development

of international

guidelines

Implementation

workshop

Identification of

strategic areas

of shared need

or opportunity

Developmen

t of regional

guidelines

Regulatory info

sharing,

Support

implementation

of global

guidelines

Training,

Capacity building

Level of

task

Strategic

Operational

Strategic Operational Operational Operational

No of

members

194 20

(incl. WHO)

10 (SC incl.

WHO)

14 (GCG)

18 (incl. WHO) 21/31

Major global initiatives in biotherapeutics

analytical sciences in biotechnology… opportunities … · capacity to regulate increasingly...

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