Workshop 1 Title - European Directorate for the Quality of … · 2015-08-11 · 14 Questions to consider What is the type of biomolecule/product? antigen vs rec hormone, polysacharide

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EDQM Conference

Characterisation of biological molecules

Workshop 1

EDQM Conference

Characterisation of biological molecules

Workshop 1

14-15 October 2010Prague, Czech Republic

©2010 EDQM, Council of Europe, All rights reserved

Workshop 1Workshop 1

Dr Alan Fauconnier

Dr Hye Na Kang

Dr Anthony Mire-Sluis

Dr Martin Schiestl

©2010 EDQM, Council of Europe, All rights reserved

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FEDERAL AGENCY OF MEDICINAL AND HEALTH PRODUCTS

FAMHP/AFOctober 2010

Characterization of biomolecules: a regulatory perspective

Alan Fauconnier

Federal Agency for Medicines and Health Products (Belgium)

Prague, 14th October 2010



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Biomolecules

Several types of biomolecules -classified according to:

- chemical nature (e.g. proteins, nucleic acids..)

- mode of action (immunological, pharmacological…)

- manufacturing process (non-biotech vs biotech)

Insulin factory in 1946www.gettyimages.com/detail/JC7075-001/Hulton-Archive

Fermentation of E. coli expressing recombinant insulin

biomm.com/index.php?p=3,2

« One process – one product »

paradigm

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Biomolecules

Lung surfactantMiscellaneous

N/AN/ANucleic acids

Plasma derived MP

Extracted hormones/enzymes

toxoids(glyo)proteins

HeparinPolysacch. vaccinespolysaccharides

PharmacologicalImmunological

Pegylated rec proteinsMiscellaneous

�Plasmids exp. antigensNucleic acids

Rec hormones/enzymes

Monoclonal antibodies

Recombinant antigens(glyo)proteins

polysaccharides

PharmacologicalImmunological

� Synthetic oligonucleotides (e.g. siRNA) are not biological



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Concern of Regulatory Authorities (RA)

•To assure that the medicinal products to be put

on the market are safe and efficacious

•or, more pragmatically, that they display a

positive benefit/risk balance.

Benefit

Risk

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5

Characterization

The characterization of the biomolecules is thus aimed at

serving these safety and efficacy objectives.

In particular, the characterization should demonstrate that

the product to be put on the market:

- either is representative of the material used in clinical trials

- or is comparable to a reference product

- displays consistent quality (potency, impurities, stabilty …)

The characterization requirements of a given biomolecule

will depend on several factors.

dedicated exercice



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Factors affecting characterization

Chemical nature

polysaccharide monotonous

nucleic acids

proteins

glycoproteins highly complex

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Mode of action

Immunological

antigens: anyway, they will be processed

Pharmacological

MAb: biological activity relies on

the primary structure of paratope

Immunogenicity and/or PK depends

on glycosylation



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Biomolecule specificities

Ex1. mannose-terminated oligosaccharide chaines of

imiglucerase (Cerezyme®) are specifically recognised by

endocytic carbohydrate receptors on macrophages, the cells

that accumulate lipid in Gaucher disease.

Mannose residues

Mannose receptor

Macrophage

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9


Biomolecule specificities

Ex2. C. botulinum neurotoxin complex is… too complex for

extensive biochemical characterization



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Manufacturing process

Proteins extracted from human/animal material

vs

Recombinant proteins

The purity of recombinant proteins allows to go further in

their characterization, as compared to proteins extracted

from human/animal material where an inherent level of

inprocess impurities prevents in-depth analyses.

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Purified versus recombinant

The fact that the range and the depth of characterization requirements depend on the test feasability (instead of being strictly quality-driven) is questionable.

In other word, what is the rational for requesting more biochemical tests for characterizing a recombinant factor VIII as compared to a plasma derived factor VIII?



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Purified versus recombinant

Requesting more stringent testing for biotech products is both justified and unjustified.

Justified:

«Good old» purified products were clinically validated by several years of presence on the market whereas for recombinant proteins in new applications, clinical validation at the market scale is still awaited for.

Unjustified:

« natural » trend of RA to ask more and more.

If the test is feasible, just do it!

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Clinical validation

Clinical validation

- Inexistent: generics (not applicable to biologics)

- Partial: biosimilars

- Extensive: full dossier

Where (part of) the safety and clinical data are not

required, it will be necessary to conduct

comparability studies. Accordingly, thorough

characterisation studies will be needed.



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Questions to consider

What is the type of biomolecule/product?

antigen vs rec hormone, polysacharide vs glycoprotein…

What are the critical attributes of the biomolecule?

saccharide moieties working as a ligand…

How feasible is the testing, what are the technical

constraints limiting the characterization?

extracted protein versus recombinant protein, protein

complex…

How strong is the clinical validation of the product?

partial (biosimilar) versus extensive (full dossier)

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Characterization range

Toxoids in vaccines diphtheria and tetanus vaccinesproteinnon recombinanthuge market scale clinical experiencecritical attribute: absence of toxin

Fictitious imiglucerase biosimilar

glycoprotein

recombinant

No market scale clinical experience

limited premarketing clinical experience

posttranslational modifications identified as

critical attributes



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Regulator’s position

Based on both:

indisputable rational

subjective practice (possibly questionable)

Ideally, shoud result in a pragmatic position

Recommendations to the applicants:

- Wherever possible, rely on compendial and/or guidance document

- Make an assessment of the required level of characterization.

- Provide a justification.

- In case of doubt, ask for scientific advice.

1

Hye Na Kang | 14~15 October 20101 |

EDQM International ConferenceEDQM International Conference

WHO ASPECTS OF

SIMILAR BIOTHERAPEUTIC PRODUCTS:

from the Guidelines to the Implementation

Dr Hye Na Kang, WHO/FCH/IVB/QSS

Prague, 14~15 October 2010


OutlineOutline

� WHO Biological Standardization

� Concept of WHO guidelines for evaluation of SBPs

� Key principles for evaluation of SBPs

� Implementation of WHO Guidelines into regulatory and manufacturers' practice

� Challenges and WHO roles

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WHO norms and standards for biologicalsWHO norms and standards for biologicals

Global written standardsGlobal written standardsA tool for harmonization of specifications worldwide

Global measurementGlobal measurement standardsstandardsA tool for comparison of results worldwide

Essential elements for development, licensing and lot release


WHO written standardsWHO written standards

Global written standardsGlobal written standards Adopted guidelines by ECBSAdopted guidelines by ECBS

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Development of WHO guidelines on SBPs: key events in 2007 and 2008

Development of WHO guidelines on SBPs: key events in 2007 and 2008

� Mandated by ICDRA in 2006 and the Expert Committee on Biological Standardization (ECBS) in 2007

� WHO Consultation: 19-20 April 2007, Geneva (meeting report published:

http://www.who.int/biologicals/publications/meetings/areas/en/index.html )

� Drafting group meeting: March 2008, Bonn

� WHO Consultation: May 2008, Seoul

� ICDRA: Sep 2008, Bern

� ECBS: 13-17 Oct 2008, Geneva

� Seminar organized by NICPBP in Beijing, Dec 2008: ChineseRegulators (SFDA and NICPBP) and manufacturers


Consultations in 2009Consultations in 2009

1. Consultations in Tokyo: Feb 20091. Experience gained in Japan2. Meeting of the WHO drafting group

2. IABS/ Health Canada workshop: 13 - 14 July 2009

3. WHO Consultation: 15 - 16 July 20091. Focus on clinical evaluation of SBPs2. Review of the development of SBPs in the countries3. Comments received during the 1st round of public consultation

4. WHO drafting group meeting: 17 July 2009 1. Review of experience in countries where SBPs are under development2. Further improvements of the proposed guidelines.

5. Expert Committee on Biological Standardization: Oct 20091. WHO Guidelines on SBPs adopted by the Committee (The final version is available on

WHO Biologicals website: http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf)

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Concept of WHO GuidelinesConcept of WHO Guidelines

1) Provide key principles for evaluation of SBPs as a basis for setting national requirements;

2) Leave space to NRAs to formulate additional/ more specific requirements;

3) Living document that will be developed further in line with the progress in scientific knowledge and experience;

4) Assist with the implementation of the guidelines into regulatory and manufacturers practice through:

– Global, regional and national workshops involving regulators, manufacturers and other relevant experts

– Trainings, advisory groups

5) Consider guidance issued by other bodies – intention to complement them, not to create a conflict.


Important parts of the GuidelinesImportant parts of the Guidelines

scope

Key principles

RBPsProof ofsimilarityQ, NC, C

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Scope and key definitionsScope and key definitions

� Scope: Guidelines applies to well-established and well-characterized biotherapeutic products such as recombinant DNA-derived therapeutic proteins.

Vaccines and plasma derived products and their recombinant analogues are excluded from the scope of this document. WHO recommendations and regulatory guidance for these products are available elsewhere (http://www.who.int/biologicals/areas/en/).

� SBP is a biotherapeutic product which is “similar” in terms of quality, safety and efficacy (Q, S, E) to an already licensed reference biotherapeutic product (RBP).

� RBP is used as the comparator for head-to-head studies with SBP in order to show similarity in terms of Q, S and E. Only an originator product that was licensed on the basis of a full licensing dossier can serve as an RBP. It does not refer to measurement standards such as international, pharmacopoeial or national standards or reference preparations.


Key principles for the licensing of SBPsKey principles for the licensing of SBPs

� SBPs are not generic medicines and many characteristics associated with the authorization process and marketed use of generic medicines generally do not apply.

� Effective regulatory oversight: critical for assuring Q, S, E of SBPs

� Stepwise approach

- Demonstration of similarity of SBP to RBP in terms of quality is a prerequisite for the reduction of the non-clinical and clinical data set required for licensure.

- If major differences are found in the quality, non-clinical and clinical studies, the product should not be considered as "similar" and, therefore, other options for its further development should be considered (eg, stand alone).

Important to note that biotherapeutics which are not shown to be similar to a RBP should not be described

as "similar", nor called a "SBP".

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Reference Biotherapeuctic Product (RBP)Reference Biotherapeuctic Product (RBP)

� RBPs should have been marketed for a suitable duration and have a volume of marketed use.

� RBPs should be licensed based on a full Q, S and E data set.

� The same RBP used throughout the development of the SBP.

� An SBP should not be considered as a choice for RBP.

� The active substance of the RBP and the SBP must be shown to be similar.

� The dosage form and route of administration of the SBP should be the same as that of the RBP.

� NRAs may need to consider establishing additional criteria to guide the acceptability of using a RBP licensed or resourced in other countries.


QualityQuality

� Development of an SBP– Thorough characterization of a number of representative lots of the RBP

– Engineering a manufacturing process that will reproduce a product that is highly similar to the RBP in all critical product quality attributes

� The quality comparison showing molecular similarity between the SBP and the RBP provides the underlying rationale for predicting that the clinical safety and efficacy profile of the RBP should also apply to the SBP

– So that the extent of the non-clinical and clinical data required with the SBP can be reduced

� To evaluate comparability– The manufacturer should carry out a comprehensive physicochemical and biological characterization of the SBP in head-to-head comparison with the RBP

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Non-clinical evaluationNon-clinical evaluation

� General principles– Address pharmaco-toxicological assessment of SBP– Should be conducted with the final formulation intended for clinical use– Minimum: head-to-head comparative toxicology studies – Additional NC data depend of the specificities of a product

� In vitro studies– Methodology: Receptor-binding studies, cell-based assays, etc– Purpose: Establish comparability of biol/pharmacodynamic activity of SBP and RBP

� In vivo studies– General principles

• Comparative in nature• Performed in relevant species • Employ state of the art technology

– Endpoints • Biological/pharmacodynamic activity relevant to the clinical application• Non-clinical toxicity as determined in at least one repeat dose toxicity study

with a relevant species and including toxicokinetic measurements


Clinical evaluationClinical evaluation

� Designed to demonstrate comparable safety and efficacy of the SBP to the RBP

� Clinical comparability exercise: stepwise procedure; PK and PD studies followed by the pivotal clinical trials

� Efficacy studies

– No dose-finding studies

– Demonstrate in adequately powered, randomized, and parallel group clinical trial (ICH E9 and E10)

– Equivalence or non-inferiority studies may be acceptable for the comparison of efficacy and safety of the SBP with the RBP; equivalence/non-inferiority margins have to be pre-specified and justified

� Safety

– Usually, safety data obtained from the efficacy trials will suffice

– Comparison with the RBP should include type, frequency and severity of AEs

� Extrapolation– Prerequisites

• Similarity shown in a sensitive model• Mechanism of action/receptor the same• Safety and immunogenicity sufficiently characterized in the evaluated population

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ImplementationImplementation

� First implementation workshop in Seoul: 24~26 August 2010

� Focused on the implementation of the Guidelines into the regulatory and manufacturer practice at the global level

� Objectives– Discuss the application of the principles for assessing Q, S, E– Review experience in setting national requirements– Understand the principles of clinical designs and interpretation of clinical

data generated in CS

� Outcomes– Taken some pictures regarding current situations in 12 countries, i.e. Brazil,

Canada, China, Cuba, India, Iran, Japan, Jordan, Korea, Malaysia, Singapore, and Thailand

– Better understanding of the scientific basis for the clinical evaluation


Challenges (1)Challenges (1)

� Diversity of the national requirements for Q, N, C

– Brazil, Japan, Korea, Malaysia: full Q, reduced N and C with RBPs

– China: partial comparative data in Q for information, but the differences in Q are not relevant on the decision for approval; comparison with published data in C

– Jordan: non-comparative data in Q

– India: partial comparative data in Q, comparison with literature data in C

– Iran: partial comparative data in Q and N, comparative data in C

– Cuba: comparative data in Q, N, C, non-comparative data in C for Mab

� Most of the biotherapeutics that are currently subject of licensing belong to the category of known biological entity that undergoes through the stand alone pathway with reduced data package rather than through biosimilar pathway.

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Challenges (2)Challenges (2)

� Using the terminology

– Biosimilar (product)s: China, Iran, Jordan, Malaysia, Republic of Korea, Singapore

– Similar biological medicinal products: Singapore

– Biogeneric products: India, Thailand (will be changed to SBPs/ biosimilars)

– Follow-on biotherapeutic products: China

– Follow-on biologics: Japan

– Known biological products: Cuba

– Biological products: Brazil

– Subsequent entry biologics: Canada

� It was noted

– that biotherapeutics which are not shown to be similar to a RBP should not be described as "similar", nor called a "SBP",

– and that generic approach is not suitable for development, evaluation and licensing of SBPs;

– however, the terminology which has been used in developing countries can be shown the biosimilar pathway is not there yet.


WHO rolesWHO roles

� Proposed during the Workshop– Prequalification of SBPs at the global level– Standardization of biotherapeutics– Another implementation workshop in quality evaluation– Similar workshop in other regions/ countries (Arab, India)

� Planned for the next steps– Publication of the outcomes from the Workshop in 'Special issue' of

Biologicals– Collaborating Centres with the expertise in the evaluation of

biotherapeutics– Revision of the recommendations for biotherapeutics– Up-to-date information on the global development of SBPs/ Database

of RBPs and SBPs– Global map of the regulatory oversight of SBPs

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Regulations/ Guidelines for SBPsin selected countries (Aug 2010)Regulations/ Guidelines for SBPsin selected countries (Aug 2010)

R/Gd (1 country)

R/NG (2 countries)

Rd/Gd (1 country)

Rd/NG (4 countries)

R/G

No Data


Approved SBPs – Global Picture (Aug 2010)Approved SBPs – Global Picture (Aug 2010)

No Data

Yes (26 countries)

No (8 countries)

Ratiograstim, Filgrastim Ratiopharm, Biograstim, Tevagrastim, Zarzio, Filgrastim Hexal, Nivestim

Filgrastim

Silapo, RetacritEpoetin zeta

Binocrit, Epoetin alfa Hexal, AbseamedEpoetin alfa

Omnitrope, ValtropinSomatropin

ProductINN

Ratiograstim, Filgrastim Ratiopharm, Biograstim, Tevagrastim, Zarzio, Filgrastim Hexal, Nivestim

Filgrastim

Silapo, RetacritEpoetin zeta

Binocrit, Epoetin alfa Hexal, AbseamedEpoetin alfa

Omnitrope, ValtropinSomatropin

ProductINN

TevafilgrasFilgrastim

ProductINN

TevafilgrasFilgrastim

ProductINN

OmnitropeSomatropin

ProductINN

OmnitropeSomatropin

ProductINN

Clotinab

ProductINN

Clotinab

ProductINN

Epoetin alfa BS "JCR"Epoetin alfa

Somatropin BS "Sandoz"(=Omnitrope)

Somatropin

ProductINN

Epoetin alfa BS "JCR"Epoetin alfa

Somatropin BS "Sandoz"(=Omnitrope)

Somatropin

ProductINN

Scitropin A (=Omnitrope)

Somatropin

ProductINN

Scitropin A (=Omnitrope)

Somatropin

ProductINN

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Further information and contactFurther information and contact

Biological standardisation website:

www.who.int/biologicals

Immunization website: www.who.int/immunization

Contact details:

Dr Hye Na KANG

Email: [email protected]

10/19/2010

Amgen Corporate Template 1

An Innovator’s Perspective on the Characterization of Biosimilars

Tony Mire Sluis, Executive Director

Global product Quality and Quality Sciences

Biosimilars are not Generics - They are Larger & more Complex than Chemical Drugs and Thus Realistically they can only be Similar

Aspirin~180 daltons

Insulin51 amino-acids~5,800 daltons

Somatropin191 amino-acids~22,000 daltons

IgG1 antibody>1000 amino-acids~150,000 daltons

Images not to scale. Data sources: www.jtbaker.com, http://www.umass.edu/microbio/chime/antibody/abquests.htm and Genazzazi, AA et. al. (2007) Biosimilar Drugs: Concerns and Opportunities. Biodrugs 2007; 21 (6) ppg 351-356

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10/19/2010


Thus a Comparability Exercise is the only means of Determining ‘Biosimilarity’

• The Comparability process defines:– How to ensure whether process changes have not impa cted product

quality– How to determine that the process is still capable of meeting defined

requirements

Comparability demonstrates that:

• The product has highly similarquality attributes before and after process changes

• The process maintains or improves it capabilities

3

Comparability After a Process Change -Three Questions

1. Will the proposed process change alter the capability of the process to produce the same product?

2. Has the process change altered the product?

3. How would a change in product affect safety and efficacy?

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10/19/2010


Demonstrating Product Comparability is a Hierarchical Process

• The process of demonstrating product comparability involves a hierarchy of analysis:

• Analytical comparability• Pre-clinical comparability• Clinical comparability

• The majority of changes within a manufacturer are assessed solely by analytical comparability but it is dependant on the magnitude of the change

• For some changes, pre-clinical or clinical studies are expected by regulatory agencies (e.g., major drug product formulation changes)

• If analytical comparability cannot be shown (or risk to patient too high), pre-clinical and/or clinical studies may be required to show the safety and efficacy of the product has not been compromised. 5

The Nature of Manufacturing Changes Reflects the Amount and type of Supporting Data Required to Assure Comparability

Change filter supplier

Move equipment

within same

facility

Move to new

production facility (same

company)

Change cell culture media

New cell line

or major formulation

change

Nature of Process Change

Risk Factor & Data Requirements Low Risk

Commonly implemented- Analytical data- Process studies

Moderate Risk

- Analytical data- Process studies

- Stability data

High RiskLess commonly implemented

- Analytical data- Process studies

- Stability data- Clinical data

Biosimilars

Different:� Site of manufacture� Equipment� Cell-line, vector and culture media� Fermentation/culture conditions� Downstream processing/purification� In-process controls� Formulation and container/closure

BiosimilarsOut of scope of comparability guidance (ICH Q5E)

Innovator Process ChangeGoverned by comparability guidance (ICH Q5E)

6

10/19/2010


Comparability Studies Should Apply ‘Quality by Design’ Principles

• The most important element of a comparability study is the planning that goes ahead of the study

• One needs to develop a comparability plan/protocol (definition depends on whether a reduction in regulatory submission status is being sought, but protocol is the generally accepted term) that states up front what the intention of the study is and includes all elements of the study, including acceptance criteria and their justification

• A risk assessment is a valuable tool to understand the potential impact of any change

7

Comparability Protocols – The Manufacturing Process

• Process comparability• Development/Characterization data – what data on

process performance do you have to support the change (very important)

• What data to compare (IPC’s, operating parameters -what is key or critical etc.)

• How much (old process to new process, how many data points and why)

• Acceptance criteria and justification• Statistical plan

8

10/19/2010


The Manufacturing Process: Biosimilar Specific Issues• The level of understanding the process and showing

capability during development ideally should be the same between an innovator and a biosimilar process

• Most innovators invest in their process and learn more over time – remaining ‘c’ in cGMP

• The biosimilar manufacturer must also rely solely on end product testing of purchased material to assure similar lot to lot variability

• Thus, to what extent and how does a biosimilar compare:

• Process variability• Impact of non innovator source

raw materials• Impact of process on product

• ‘Design Space’• Unique to a process and not transferable

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Comparability Protocols – The Product

• Product comparability• Development data – what data do you have on

product parameters to support the change (very important) – need to understand what your ‘Critical Quality Attributes’ are but need more than just that

• What data to compare (lot release tests, characterization tests etc.)

• How much (old process to new process, reference standard, howmany data points and why)

• Acceptance criteria and justification• Statistical plan

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10/19/2010


Analytical comparability evaluations comprise several components

Process Comparability Batch Analysis Characterization

Assays

Stability and Forced

Degradation

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Analytical Comparability is Assessed using Multiple Techniques

• Includes analytical methods used for:• Lot release• Additional characterization methods• Stability studies

• Recommended storage temperature, accelerated and stressed conditions

• These studies may demonstrate that:• The structure and function of pre- and post-change

products are comparable within the capability of the assay.

• The impurity profiles of the pre- and post-change products are comparable.

Although analytical comparability may be shown, thi s does not necessarily mean the products are comparable

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10/19/2010


The Product: Biosimilar Specific Issues

• Biosimilar companies need to have dual comparability programs - within biosimilar product development, and against innovator product at each stage of development

• What material to use for innovator comparability?• Drug substance not available• Drug product would have to be purified if appropriate

data can not be directly provided (e.g. too dilute orconfounded by excipients)

• What does purification do to the innovator product?

• How many individual innovator lots?• How can biosimilars tell what they are?• Variability is greatest during clinical development

• Without fully understanding CQAs or having clinical exposure to ranges of attributes from multiple lots to understand impact to safety and efficacy, it is hard to assess the importance of product differences should they exist

13

Points to Consider for Forced Degradation Studies

• Choose conditions (temperature, container, pH) to give reproducible and significant degradation

• Include a protease-friendly temperature (37 ºC) if there is a risk of changes in process-related impurities

• Ensure methods are qualified for degraded samples

• Challenge a panel of reference lots and develop appropriate statistical criteria

• Degrade and test reference and conformance lots side-by-side

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10/19/2010


Statistical Comparisons of Profile data can be Challenging Without an Appropriate Level of Historical Data

ANCOVA (p-value) approach

• Test for differences in mean slopes

• Rewards noisy data, punishes precision

• Frequent “failures” observed due to small (but practically insignificant) differences in slopes

Equivalence

• Test for equivalence in mean slopes

• Rewards replicates and precision

• Requires significant upfront analysis to establish acceptance criteria

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Equivalence acceptance

criteria

p-value = 0.0485

What does this mean for Comparability Protocols? - Immunogenicity

• Immunogenicity• Comparability and assessment of immunogenicity

during development relies heavily on analytical characterization, the design of the assays used to detect and characterize antibodies and the design of preclinical and clinical studies:• Assay format (RIA, ELISA - bridging or direct etc.)• Assay sensitivity and specificity• Assay positive control• Positivity criteria• Timing and number of samples• Patient population

• multiple indicationsGoogle.www

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10/19/2010


Immunogenicity: Biosimilar Specific Issues

• A Biosimilar will have the same challenges as the innovator to show comparable rates during development, but much more difficulty comparing against the innovator data unless in extensive head to head clinical studies

• How will they know the details of the innovator assays:• Assay format (RIA, ELISA - bridging or direct etc.)• Assay sensitivity and specificity• Assay positive control (standard)• Positivity criteria (e.g. cut point)• Timing and number of samples• Patient population

• Multiple indications(if going into licensure with only one)

• What would a difference in rate for theinnovator product mean in these studies?

Google.www

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Comparability Protocols – The Methods

• Method comparability• Development data – what data do you have on method

development/validation and the suitability to assess comparability

• What data to compare – do you have sample retains? Can you use old data?

• Acceptance criteria and justification –do your methods have the correct data evaluation in their SOP’s/method descriptions to support comparability? (e.g. conforms to standard, visually similar etc.)

• Statistical plan

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Google.www

10/19/2010


The Methods: Biosimilar Specific Issues

• The biosimilar does not have access to the exact methods used by the innovator, who may have tailored current methodology specific to the product over many years of investigation – using state of the art technology has to be undertaken with product knowledge

• Pharmacopoeia method monographs are rarely specific enough for biological products and are specifically tailored to a particular molecule during development

• Thus one needs to assure that the results used in comparability studies between innovator and biosimilar using biosimilar developed methods can pick up all relevant quality attributes (role of the regulators?)

• Comparison of data can be confoundedby how the assay is optimized with process specific reagents, for example assays for host cell proteins

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Risk Assessments are an Essential Component for Understanding the Relevance of a Comparability Study

• Risk Assessments can drive the right questions:• How well do you understand the relationship

between product characteristics and safety and efficacy

• Patient Population - disease state (oncology?)• Therapeutic window• Treatment regimen• Ability to characterize product• Process impact on product (‘Design Space’)• Impacts of immunogenicity

20

10/19/2010


Conclusions1. Biosimilars should be highly similar, not identical to the

innovator – differences are expected2. Understanding what are critical attributes of a product is

essential to show if differences in attributes are impactful to patients

3. Given the complexity of biotech products and their respective manufacturing processes, the identification of product/process specific CQAs can only be achieved in association with clinical data

4. Appropriately designed clinical studies are the only reliable means of identifying clinically meaningful differences in efficacy, safety and immunogenic potential of originator biotech products and biosimilars, when significant manufacturing changes are made

21

Acknowledgements

• Gino Grampp• Andrew Fox• Geoff Eich• Art Chirino• Bob Kuhn

22

1

Target Directed Development of Biosimilar Products

EDQM Conference, Prague, 14 – 15 October 2010

Martin SchiestlScientific and Regulatory AdvisorSandoz Biopharmaceuticals

All trademarks used for this presentation are the property of the respective owners

2 | Martin Schiestl, EDQM Conference, Prague 14-15 October 2010

Biosimilar concept

• Complete stand alone manufacturing process development

• Demonstrated comparability at following levels

- Quality (physicochemical and biological)

- Non-clinical

- Clinical (safety and efficacy)

Justifies certain reduction in non-

clinical/clinical data package

Complete comparability exercise is the basis for extrapolation to other indications of the reference product

2


Define target

Confirmation: Final comparability

exercise

Development of Manufacturing process

Target directed approach

Biosimilars are systematically engineered to match the reference product

Characterize multiple lots of the Reference Product

Iterative optimization of all process steps using sophisticated analytical characterization to achieve biosimilarity


Current experience with Biosimilars/SBPs

� EMA approved Biosimilars have been proven to be safe and effective medicines since the first launch in 2006

� Non glycosylated proteins

• Somatropin

• Filgrastim

� Complex glycosylated proteins

• Erythropoietin

� Currently in development

• Monoclonal antibodies

• Others

3


Year 1 2 3 4 5 6 7 8

PhI/II Dev.

PhI/II supply

PhIIIDev.

PhIII supply

Process Charact.

Process Validation

Tox. wk Tox study

Proof of Concept read out

Phase II study Phase III study

PhII read out

CellLineDev.

Innovative biopharmaceutical (example)

PoC / Phase I study

Originator product characterisation

Cell Line Dev.

Pre-clin.

PhI/III Dev.

PhIsupply

PhI study PhIII study

Process Charact.

SubmissionQuality Proof of Similarity

Biosimilar (example)

PhIII supply/ Validation

What is the difference between innovative and Biosimilar/SBP development?

Longer manufacturing process development to achieve similarity

Shorter preclinical and clinical development if similarity is achieved


Upcoming biosimilar monoclonal antibodies

� EMA is currently drafting a guideline on similar biological medicinal products containing monoclonal antibodies

• Concept paper released October 2009

• Publication of draft guideline expected by end of 2010

� How evaluate the comparability regarding quality?

• Use comprehensive toolbox of physicochemical and biologic methods

• Supported by published clinical and technical experience

• Big amount of published information available for mAbs according to the importance of this class of products

4


Which quality attributes to consider?Example IgG1 type mAb

Effector functions- Complement interaction- Fc Receptor interaction

CH 2

CH 3 H

eavy

cha

in- S - S -- S - S -

Biological Characteristics Physico-chemical Characteristics

N-Terminal heterogeneityPyroglutamate formationOther modifications

Amino acid modificationsDeamidation, Oxidation, Glycation, Isomerization

OligosaccharidesFucosylation, Sialylation, Galactosylation,...

C-terminal heterogeneityLysine processing, Proline amidation

FragmentationCleavage in hinge region, Asp-Pro

Disulfide BondsFree thiols, disulfide shuffling, thioether

-CO

O-

SS

SS

Fab

Fc


Physicochemical and biological characterization of biopharmaceuticals (selection)

Parameter Attribute Methods for control and characterization

IdentityPrimary structure

Sum formula: Mass of intact molecule and individual peptide chains

LC-ESI-MS

Amino acid sequence Peptide map with UV detectionOrthogonal peptide maps with high resolution MS and MS/MS sequencingEdman sequencing

Disulfide bridging Non-reducing Peptide Map

Higher order structure

Secondary and tertiary structure CD spectroscopy, NMR, H-D-Exchange, FT-IR, NMR

In vitro assays, in vivo assay

Mixed mode parameter

Effective charge IEF, CIEF, CE, AEX

Size SDS-PAGE, SEC

Hydrophobicity RP-HPLC

Glycosylation Glycan isoforms NP-HPLC-ESI-MS of 2AB-labeled glycans, exoglycosidase digestion, MALDI TOF/TOF, LC MS/MS

Sialic Acids incl. NGNA NP-HPLC, WAX, HPAEC; RP-HPLC (DMB-label)

Aglycosylated SDS-Gel-CE, Peptide map

Glycanmapping HPAEC-PAD, NP-HPLC

Biologic activity Specific biologic activity In vitro assays (cell based functional assays)

In vivo assay (animal PD model)

5


Physicochemical and biological characterization of biopharmaceuticals (selection)

Parameter Attribute Methods for control and characterization

PurityProduct related variants

C- and N-terminal truncation IEX, Peptide Map, RP-HPLC

Oxidation RP-HPLC, Peptide map

Deamidation IEX, CE; Peptide map

Aggregation SEC, FFF, MALLS, DLS; imaging, particle counter

Post-translational modification CGE, CE, IEX, SDS-PAGE, SEC, RP-HPLC

Process related impurities

Host cell proteins Quantitative immunoassay

Residual DNA Q-PCR, Treshold

Solvents GC

Endotoxin LAL

Contaminants Viruses Virus tests (validated at small scale)

Bioburden Bioburden count

Endotoxin LAL

Potency Quantitative biological activity In vitro assays (cell based functional assays)

In vivo assay (animal PD model)

Content Protein mass Photometry, SEC, RP-HPLC, amino acid analysis, protein determination


Bioassays addressing multiple MoAs

Target cell

Effector cell(NK cells)

FcγγγγRIIIa

C1

PCDProgrammed cell death (apoptosis )

ADCCAntibody dependentcellular cytotoxicity

CDCcomplementdependentcytotoxicity

Membrane attackcomplex

Target cell


FcγγγγRIIIa

C1





Blocking/ Inhibiting RB

Target cell


FcγγγγRIIIa

C1





Target cell


FcγγγγRIIIa

C1





Blocking/ Inhibiting RBDimerization / Shedding / Internalization

6


• Proteins can be well characterized up to the complexity of monoclonal antibodies

– Primary structure determined from recombinant DNA sequence and fully accessible to analytical verification

– Set of orthogonal analytical methods available to characterize the identity and amount of related variants with high sensitivity

– Glycosylation profile can be comprehensively determined with regard to identity and content of individual glycans with high sensitivity

– Accurate and relevant bioassays for pivotal biological functions available

Capabilities of current analytical tools


* Different samples, different scaling

Column Particle size

Analysis time Usage

HILIC Amide 80

5 µm 42 min until 2008

HILIC Amide 80

3 µm 60 min 2008 –2009 (1)

HILIC BEH glycan 1.7 µm 40 min

since 2010

Case Study: Detectability of glycan variantsCQAs require adequate analytical methods

� Improving HILIC glycan analysis for reliable detection and quantification glycosylation CQAs

� Essential for targeted process development, process characterization, validation, and the design of the control strategy

(1) Melmer et al., Anal.Bioanal.Chem., 398 (2010) 905-914

7


What can we learn from the variability in the quality attributes of the reference product?

� The characterization of the reference product plays the pivotal role in the definition of the Quality Target Product Profile (QTPP*) for the biosimilar development

• Requires analysis of multiple batches of the reference product

• The QTPP is updated throughout the development and used for the targeted and prioritized development of the Biosimilar product

� Changes in the reference product over time, e.g. caused by batch to batch variability and manufacturing process changes, provides a distribution of acceptable variants

� Since originators change their molecules by process changes over time, if the biosimilar quality is within the range of the old and new originator molecule, extrapolation is warranted as in comparability exercises made to evaluate manufacturing process changes

*) QTPP as defined in ICH Q8R


Originators may exhibit changes in quality attributes

14 18 22 26 30

Pre-Shift batch

Post-Shift batch

Acidic Variants

Basic Variants

Cation Exchange Chromatogram

Retention Time [min]

Example A: Monitoring batches of MabThera®/Rituxan® (rituximab):

Shift in the identity profile measured by cation exchange chromatography

• Separation of differently charged variants, e.g. basic N-terminal glutamine and C-terminal lysine variants

• Indication of a change in the manufacturing process?

0,0

10,0

20,0

30,0

40,0

50,0

60,0

08.2007 12.2008 05.2010 09.2011Expiry Date

Basic Variants[% of total]

Pre-Shift batches

Post-Shift batches

8


0,0

0,4

0,8

1,2

1,6

2,0

08.2007 12.2008 05.2010 09.2011Expiry Date

Unfucosylated G0[% of glycans]

60

80

100

120

140

08.2007 12.2008 05.2010 09.2011Expiry Date

ADCC Potency[% of reference]

Post-Shift

Pre-Shift

Pre-Shift

Post-Shift

Example B: Monitoring batches of MabThera® /Rituxan® (rituximab):

Shift in glycosylation profile and ADCC potency

• Differences/shift in glycosylation pattern results in different potency in cell-based assays

• Product label remained unchanged – indicating comparable quality

Originators may exhibit changes in quality attributes


What if originator changes quality attributes?e.g. due to process manufacturing changes

Development of a biosimilar – time axis

Complete quality range for claiming biosimilarity

range for control of Biosimilar product (specification limit)

� Manufacturing process changes are tightly regulated (see ICH Q5E)

� Change of quality attributes only acceptable if they do not alter safety/efficacy

� For demonstrating biosimilarity it is therefore acceptable to use the upper and the lower limit of the pre and post shift material

� However, the Biosimilar/SBP release specification should be as tight as the current originator specification but need not to be the same values

9


Cel

llin

es

Pools Pools Clones Clones Clones SelectedClone

Hundreds Thousands Hundreds Tens One

Pro

cess

Dev.

96/24/6 well plates Shake flask Lab-scale bioreactor

Targeted cell line development: Drilling down!


ParentalCell Line

Pools

ClonesCell Line X

Pool A

ClonesCell Line X

Pool A

ClonesCell Line X

Pool B

Final CloneCell Line X

Pool B

0

2

4

6

8

10

Qua

lity

Attr

ibut

e [%

]

Target≤ 2 %

Screening of bioreactor conditions

� Target defined as comparability range

� Generate and use diversity

� Choose the right stage to target a quality attribute:

– Cell line

– Bioreactor

– Down stream process

– Drug Product

� Cell line, process and product understanding is key

Case Study: Using diversity for targeted cell line development

� Screening cell lines, pools and clones to meet quality target

10


0,0 0,2 0,4 0,6 0,8 1,0 1,2 1,40,0

0,5

1,0

1,5

2,0

Media Component A

Med

ia C

ompo

nent

B

32,6

43,8

55,0

66,2

77,4

Case Study: Targeting glycosylation in the bioreactor process development

� Glycosylation of mABs is determined by the cell culture process

� May impact safety & efficacy

� Definition of media components resulting in desired glycosylation state in dose-dependent manner

� Example: targeting galactosylation by multivariate DoE

� Also mannosylation and fuscosylation can be set to target

Chromatogram of oligosaccharides from 3 different samples

G0F G1F G2F

Galactosylation


Case study: Adjusting charge variants of a mAB in the bioreactor

0

2

4

6

8

10

12

14

Media Components

Cha

rge

Var

iant

(%)

7.2 7.0 6.80

20

40

60

80

Cha

rge

varia

nt (%

)

Target Range

Target Range

Targeting a charge variant via pH in bioreactor

Targeting a charge variant via media components in bioreactor

� Charge-variants are typical product-related impurities or variants for mABs:

• acidic variants (e.g. de-amidation of Asn)

• basic variants (e.g. amidation of Pro)

• pyroglutamate/gln at N-terminus

• Lys-variants at C-terminus

• mAb fragments

� Adjustment in the down stream process is partially possible, but reduces yield

� Charge-variants can be adjusted in the bioreactor by optimization of

• process parameters, e.g. pH

• media components

11


Conclusion

� Today's analytical technologies enable state of the art biotech companies to develop and manufacture biosimilar products

� Changes in the reference product over time offers a distribution of product attributes that can be used to judge similarity and to extrapolate for safety and efficacy just as in a comparability exercise made to evaluate a manufacturing process change

� Modern concepts of developing manufacturing process facilitate the target directed development of biosimilars

• Quality by design approaches including multivariate design of experiments

� Current technology allow the development of biosimilar monoclonal antibodies

Documents

Workshop 1 Title - European Directorate for the Quality of … · 2015-08-11 · 14 Questions to consider What is the type of biomolecule/product? antigen vs rec hormone, polysacharide