Module 9 2024

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products Date: 9 th – 11 th September 2024 Module: 9 of the TOPRA MSc Data Management and Digitalisation in Regulatory Affairs Module Leader: Rhydian Howells

©The Organisation for Professionals in Regulatory Affairs 2024 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products

Date: 9 - 11 September 2024

LOCATION: TOPRA OFFICE, LONDON, UK / ONLINE

Module Leader: Rhydian Howells

Date: Monday 9 th September 2024

Time

Activity

Speaker

10.30 – 10.45

Welcome & Introduction to the Module

TOPRA & Rhydian

Lecture 1: Overview of Regulation of Biologicals

Rhydian Howells, ProPharma Group

10.45 – 12.00

12.00 – 13.00

Lunch

Alison Wolfreys, UCB Celltech

13.00 – 14.15

Lecture 2: Preclinical Testing of Biologicals

Lecture 3: Clinical Development of Biopharmaceuticals

Tara Hutton, Biogen Idec

14.15 – 15.30

15.30 – 15.45

Refreshment Break

Isabelle Cludts, MHRA

15.45 – 16.45

Lecture 4: Immunogenicity Issues

16:45 – 17:00

Review of Day 1 and Close

All

Version: 1

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products

Date: 9 - 11 September 2024

Date: Tuesday 10 th September 2024

Time

Activity

Speaker

Zabin Younes, Scendea

09.00 – 11.00

Lecture 5: Quality/CMC Considerations

11.00 – 11.15

Refreshment Break

Lecture 6: Module 3 Guideline Requirements

Richard Keane, Biogen Idec

11.15 – 12.30

12.30 – 13.30

Lunch

Case Study 1 – Specification Setting and Comparability.

Module Leader + Speakers

13.30 – 15.00

15.00 – 15.30

Refreshment Break

15.30 – 16.30

Lecture 7: Bioassays

Paula Urquhart Covance

16.30 – 17.00

Review of Day 2 and Close

All

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Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products

Date: 9 - 11 September 2024

Date: Wednesday 11 th September 2024

Time

Activity

Speaker

Cecil Nick, Parexel

09.00 – 10.15

Lecture 8: Regulation of Biosimilars

10:15 – 10.30

Refreshment Break

Andrew Deavin, GSK Vaccines

10.30 – 11.45

Lecture 9: Regulation of Vaccines

12.00 – 12.45

Lunch

Lecture 10: Regulation of Gene and Cell Therapy Products

Sergio Fracchia, Novartis

12.45 – 14.00

14.00 – 14.30

Refreshment Break

14.30 – 16.00

Case Study 2

All

16.00 – 16.30

Review of Course and Close

All + TOPRA

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03/09/2024

Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products

Introduction to Biologicals and Biotech Regulation

Rhydian Howells, VP Regulatory CMC, ProPharma Group

09 September 2024

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals i Regulatory Affairs

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Definition of Biotech Products - USA

USA (District of Columbia) Virus Serum and Toxin Act 1902

‘Viruses, serums, toxins and analogous products’

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Definition of Biotech Products - USA

USA (District of Columbia) Virus Serum and Toxin Act 1902

‘Viruses, serums, toxins and analogous products’

FDA published a final rule that, effective March 23, 2020, amends the regulatory definition of “biological product” consisten t with the statutory definition under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as amended by the Further Consolidated Appropriations Act, 2020 (FCAA) ‘A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings” (see section 351( i)(1) of the PHS Act).

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Definition of Biotech Products - USA

USA (District of Columbia) Virus Serum and Toxin Act 1902

‘Viruses, serums, toxins and analogous products’

FDA published a final rule that, effective March 23, 2020, amends the regulatory definition of “biological product” consisten t with the statutory definition under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as amended by the Further Consolidated Appropriations Act, 2020 (FCAA) ‘A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, protein (except any chemically synthesized polypeptide), or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings” (see section 351(i)(1) of the PHS Act).

Protein further defined : defines "protein" as "any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size." (See 21 CFR §600.3(h)(6)).

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Definition of Biotech Products - USA

USA (District of Columbia) Virus Serum and Toxin Act 1902

‘Viruses, serums, toxins and analogous products’

FDA published a final rule that, effective March 23, 2020, amends the regulatory definition of “biological product” consisten t with the statutory definition under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as amended by the Further Consolidated Appropriations Act, 2020 (FCAA) ‘A virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product or analogous product, protein (except any chemically synthesized polypeptide), or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings” (see section 351(i)(1) of the PHS Act).

Protein further defined : defines "protein" as "any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size." (See 21 CFR §600.3(h)(6)).

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Definition of Biotech Products - EU

EU Definition of Biological Medicine

According to Part I of Annex I of Directive 2001/83/EC (as amended by directive 2003/63/EC),

a biological medicinal product is a product, the active substance of which is a biological substance.

A biological substance is a substance that is produced by or extracted from a biological source

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Definition of Biotech Products - EU

EU Definition of Biological Medicine

According to Part I of Annex I of Directive 2001/83/EC (as amended by directive 2003/63/EC),

a biological medicinal product is a product, the active substance of which is a biological substance.

A biological substance is a substance that is produced by or extracted from a biological source

AND that needs for its characterisation and the determination of its quality a combination of physico chemical-biological testing together with the production process and its control.

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Implication of these different definitions

Peptides >40 amino acids are now regulated as a biological in both the USA and EU.

e.g. Insulin (51 amino acids) is now regulated under the PHS act meaning it also falls under biosimilar pathways

However,

Low molecular weight heparin, FD&C act in USA, biological in the EU

And for Peptide Based Cancer Vaccines - in the US theses are regulated as biologicals regardless of size but in the EU, if synthetically manufactured they are small molecules

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A biological substance is a substance that is produced by or extracted from a biological source

Insert vector into host cells (transfection)

Chinese hamster ovary cells (CHO)

Plasmid

Apply selection pressure

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A biological substance is a substance that is produced by or extracted from a biological source

Apply selection pressure

Evidence of clonality required by regulatory authorities

‘for recombinant products, the cell substrate is the transfected cell containing the desired sequences, which has been cloned from a single cell progenitor) (Q5A)

Methods include - Limited dilution (two rounds)

Cloning

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A biological substance is a substance that is produced by or extracted from a biological source

Cloning

Looking for:

High or suitable levels of expression Desired product characteristics Desired growth profiles

Screen clones

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A biological substance is a substance that is produced by or extracted from a biological source

Screen Clones

Stability Studies on 3 stocks

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A biological substance is a substance that is produced by or extracted from a biological source

Under cGMP conditions manufacture a Master Cell Bank (MCB) ~300 vials

Under cGMP conditions manufacture a Working Cell bank (WCB) ~300 vials

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A biological substance is a substance that is produced by or extracted from a biological source

Key learnings

• The cell bank is our starting material for a biological such as a monoclonal antibody • It is manufactured in preparation for preclinical TOX material and must last the entire life cycle of the product. (~12 years of development, 20 years of commercial production or more!) • The cells in the bank are clonal, as our gene integrates into the genome of the cell and minor differences in cell can impact on product quality.

• Reading ICH Q5D and ICH Q5A

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needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing…

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needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing… Purity for a small molecule

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needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing… Purity for a biological

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needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing… Purity for a biological

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needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing… Purity for a biological

ICH Q6B - The manufacturer should define the pattern of heterogeneity of the desired product and demonstrate consistency with that of the lots used in preclinical and clinical studies.

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Modifications

• Deamidation

• Phosphorylation

• Disulphide bond scrambling

• Oxidation

• Succinylation

• Sequence variants

• Aggregation

• Sulfation

• Truncation

• Fragmentation

• Carbamylation

• Denaturation

• Glycosylation

• Methylation

• Sialylation

• Hydroxylation

• N-terminal pyroglutamation

• Citrullination

• Glycation

• Nitrosylation

• Lysine clipping

• Acetylation

• Proline amidation

• Cysteinylation

• Alkylation

• Trisulphide bonds

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Purity - Charge Heterogeneity Example Method: cIEF/IEX Acidic Basic

Deamidate d

Major Chemical Degradation Pathways

Effect

Species Formed

Sialylation

COOH addition

Acidic

Deamidation

COOH formation Acidic

C-terminal lysine clipping

Loss of NH2

Acidic

Adduct formation

COOH formation or loss of NH2

Acidc

Succinimide formation

Loss of COOH

Basic

Methionine, cysteine, lysine, histidine, tryptophan oxidation

Conformational change Conformational change

Basic

cIEF = capillary electrophoresis IEX – ion exchange chromatography

Disulphide-mediated

Basic

Asialylation (terminal galactose)

Loss of COOH

Basic

Khawli et al, Mabs 2;6 1-12 2010

C-terminal lysine and glycine amidation

NH2 formation or loss of COOH

Basic

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Purity – Aggregates (HMWs) Example Method: SE-HPLC

- Aggregates are defined as immunity- provoking factors in the FDA Guidance ‘Immunogenicity Assessment for Therapeutic Protein Products’ (Aug 2014).

- The WHO recommends ‘Generally, not less than 95 % of the immunoglobin present should be in form of molecular monomers and dimers.

- Typically for a mAb aggregates are quantitated by Size exclusion (SEC) HPLC method

- In Europe an orthogonal aggregate determining method such as light scatter or Analytical ultracentrifugation should be included (AUC).

Monomer

HMWS Aggregat e

LMWS Fragment

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Purity – Intact Example Method: CE-SDS

Non reduced

Covalent Aggregat e

Heavy Chain

Light Chain

Reduced

Aglycosyl Heavy Chain

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Purity – Glycosylation Example Method: NP-HPLC

- Glycosylation plays a key role in effector function, PK, and is an indicator of process consistency and control - PNGase F used to release N-linked glycans from protein. Oligosaccharides are labelled with the fluorophore 2 aminobenzamide (2-AB) used for identification against standards. - Orthogonal methods – Intact glycoproteins (ESI-MS), glycopeptides (LC-MS, MALDI), released glycans (underivatized – MALDI-TOF, HPAE-PAD) and monosaccharide analysis.

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Impact of Glycosylation Heterogeneity

Neu5Gc and α gal Non human or non

G0F

G2F Terminal galactose key in complement dependent cytotoxicity (CDC). CDC increases proportionally to galactose content

G0 Afucosyl glycans show

Man-5 High mannose species demonstrate faster clearance via

G2-NeuAc Sialic acids linked to increased circulating lifespan by covering galactose and preventing clearance via the hepatocyte asialo glycoprotein

increased affinity to FcyRIII

mammalian glycans, can cause immune reactions,

and be targets for antidrug antibodies (ADAs)

which is the key receptor for NK mediated ADCC

mannose receptors

expressed by macrophages

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needs for its characterisation and the determination of its quality a combination of physico-chemical biological testing…

Key learnings

• Biologics are complex, multicomponent, often large, labile

• Cannot be characterised by a single method

• Product of a biological system: heterogeneity

• We hope to show batch to batch consistency in the pattern of heterogeneity.

• Reading ICH Q6B,

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Example Drug Substance FIH Specification

Quality Attribute

Test Method

Acceptance Criteria

Appearance (Colour)

Ph. Eur. 2.2.1

Not more intensely coloured than Y3

Appearance (Clarity)

Ph. Eur. 2.2.2

Less than reference standard 4 (30NTU)

Appearance Visible Particles

Ph. Eur. 2.9.20

Report result

pH

Ph. Eur. 2.2.3, USP<791>

x.x ± 0.5 pH units

Protein content

In house

x.x ± 10% mg/ml

Identity

Method choice (PMAP, IEX, ELISA)

Comparable to reference standard

Monomer Purity Total Aggregates

In house – SEC HPLC

% Monomer ≥90.0 % % Aggregate ≤5.0 %

Purity (Reduced)

In house – Reduced CE-SDS

≥90.0 % as heavy and light chains

Purity (Non-reduced)

In house – Non-Reduced

≥85.0 % as Intact IgG

Charge Heterogeneity

In house – (e.g IEX, icIEF)

Profile comparable to reference Report % acidic, basic, main isoforms

Potency (Binding ELISA)

In house

50 – 150 % relative to reference

NP-HPLC (glycosylation)

In house

Report rel. % of major glycans

rDNA

In house

Not more than xx ppb Complies with WHO limit 10ng/dose

rPrA

In house

< x ppm

rHCP

In house

< x ppm

Bacterial endotoxins

Ph. Eur. 2.6.14, USP<85>

Not more than x.x EU/mg Refer to Ph. Eur for calculation

Bioburden

Ph. Eur. 2.6.12, USP<61>

Not more than x CFU/x ml (1 CFU / 10ml or 10 CFU/100 ml)

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Example Drug Substance Specification

Quality Attribute

Test Method

Acceptance Criteria

Appearance (Colour)

Ph. Eur. 2.2.1

Not more intensely coloured than Y3

Appearance (Clarity)

Ph. Eur. 2.2.2

Less than reference standard 4 (30NTU)

Appearance Visible Particles

Ph. Eur. 2.9.20

Practically free from visible particles

Sub-visible particles

Ph. Eur. 2.9.19, USP<788>

≥10 µm: ≤6000 particles/vial ≥25 µm: ≤600 particles/vial

pH

Ph. Eur. 2.2.3, USP<791>

x.x ± 0.5 pH units

Quantity - Protein content

In house – UV, gravimetric

x.x ± 10%

Identity

In house - PMAP, IEX, ELISA

Comparable to reference standard

Extractable volume

Ph. Eur. 2.9.17 and USP<1>

≥ X.X mL

Uniformity of Dosage Units

Ph. Eur. 2.9.40 and USP<40>

Conforms

Monomer Purity Total Aggregates

In house – SEC HPLC

% Monomer ≥90.0 % % Aggregate ≤5.0 %

Purity (Reduced)

In house – Reduced CE-SDS

≥90.0 % as heavy and light chains

Purity (Non-reduced)

In house – Non-Reduced

≥85.0 % as Intact IgG

Charge Heterogeneity

In house – (e.g IEX, icIEF)

Profile comparable to reference Report % acidic, basic, main isoforms

Potency (e.g Binding ELISA)

In house

50 – 150 % relative to reference

Bacterial endotoxins

Ph. Eur. 2.6.14, USP<85>

Not more than x.x EU/mg Refer to Ph. Eur for calculation

Sterility

Ph. Eur. 2.6.1, 71

Sterile

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…together with the production process and its control

Upstream

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…together with the production process and its control

Downstream

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…together with the production process and its control

Key learnings

• The upstream process is where our product is made

• Upstream conditions impact on product titre, product quality and impurities and conditions must be controlled. Link between process parameters and quality attributes • Downstream process is necessary to remove process impurities, cell matter, cell DNA and proteins, process reagents (antifoam)

• Steps included in the downstream process to also remove PRODUCT related impurities, aggregates, undesired charged/hydrophobic variants, viruses

• The process must be validated prior to marketing authorisation to show consistent production of the desired product

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You might be forgiven for thinking that

‘The

Process Is The ProducT’

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Biotech Regulation

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Two centuries ago

Edward Jenner, 14 th May 1796

• Pustular material from cowpox lesion (Sarah Nelms, a milk maid)

• Inoculated 8 year old boy (James Phipps)

• Boy inoculated with smallpox 6 weeks later

No infection occurred

•

If Jenner’s clinical trial and investigation product had been constrained by a competent authorities and ethical oversight, would vaccines have started here?

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One century ago

• Further vaccines: rabies (Pasteur, 1885), cholera (1892), typhoid (1898), tuberculosis (1921), pertussis (1923), mumps (1949), polio (1954), etc.

• Antitoxins: diptheria (1894), tetanus (1927)

• Blood products: plasma fractions (cohn), serum albumin for shock WW2, insulin (Banting & Best 1923)

• Antibiotics: penicillin (Fleming 1928), started in 1939

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Smallpox Vaccine Manufacture 1891

• “A red heifer calf about two months old, in good flesh and health, is placed upon a bench in a special operating room and strapped on its side with one hind leg fastened vertically against the back of the bench. The area between the thighs, covering about ten inches square and including the teats, is shaved and washed with soap and water, with hydrogen peroxide solution, and finally with sterilized water and then dried with sterilized absorbent cotton. On the area so prepared, one hundred spots are then scarified, each from a quarter to half an inch square. The blood is washed away with sterilized water, and when the bleeding has entirely ceased virus is rubbed on each spot very thoroughly for some minutes; the calf is then returned to its stall. It is examined on the third and following days, and when the vesicles are seen to be at the proper stage of development, which is usually on the sixth day, the calf is again placed upon the bench and the whole shaved area washed twice with sterilized water and once again with peroxide of hydrogen solution. All macroscopic dirt and crust is removed and every scarification is cleansed as thoroughly as possible; then with a sterilized curette each scarification is scraped and every particle of pulp removed into a sterilized glass dish. The pulp taken is weighed, comminuted, and mixed with a measured amount of chemically pure glycerin*, by being passed between glass rollers on which the glycerin flows. There is thus produced a brown syrupy homogeneous emulsion, which is then drawn by a filter pump into sterilized glass tubes, which when full are sealed in a flame at both ends. Each of these tubes holds about 20 cubic centimeters .”

•

* glycerin acted as a preservative

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Why have we come here?

Hazards of biological

• 13 children die in 1901 St Louis diptheria epidemic tragedy

– Tainted diptheria antitoxin serum produced from horses.

– Traced to C.tetani infection in one horse

• 207 children in 1930 Lubeck incident contract TB (72 deaths)

– BCG substitution with virulent strain

• 600 children infected in 1948 Kyoto-shimane tragedy (84 deaths)

– Incompletely detoxified diptheria toxoid

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Hazard of blood products – Virus Safety

1980s: HIV infected donated blood

•

• 1980s/90s – In 2,772 male US heamophilia patients

– 30 % +ve for HBC

– 64 % +ve for HCV

1990: HAV from Factor VIII

•

– Solvent detergent treatment inadequate, difficult to eradicate (non-enveloped)

– >80 cases 1991

– Clusters of infection into the late 90’s e.g. in Germany in 1997

• 2001: product withdrawals from donors exposed to tick-borne pathogens

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Hazard of biotech products

• rHu Erythropoietin (various): variations in potency

• rHu Erythropoietin (Eprex): red cell aplasia

• rHu factor VIII; suspected penicillium contamination

PEG-rHu MGDF: thrombocytopenia

•

• Gene therapy: Gelsinger, X-linked SCID trials

• mAb TGN1412: CD28 agonist, Phase 1 cytokine storm

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Hazard of biotech products

• rHu Erythropoietin (various): variations in potency

• rHu Erythropoietin (Eprex): red cell aplasia

• rHu factor VIII; suspected penicillium contamination

PEG-rHu MGDF: thrombocytopenia

•

• Gene therapy: Gelsinger, X-linked SCID trials

• mAb TGN1412: CD28 agonist, Phase 1 cytokine storm

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What happened on the journey?

Early on, it dawned on us that:

Manufacturing technology was facile

•

– Extraction with little or no processing

– Collection and fractionation

– Expansion/culture and modification

• High dependence on facility and raw materials

Minimal analysis

•

• Inconsistency/quality attributes not detectable

Manufacturing errors unchecked

•

• Biological activity/potency determined utility

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Early in the journey

Consequential conclusions

• Realisation of attributes of biological products and their variability

Awareness of serious hazards

•

• Importance of consistency in manufacture through analysis

• Recognition of need for controls on raw materials, process and facility to reduce risk

• Concept of Quality; using well-controlled ingredients to manufacture a product of consistent standard

regulation

Concept of oversight: the birth of

•

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Consequences of advances in technology

New hazards become apparent

Contaminants in starting materials

•

– With biological/pathogenic activities - viruses – New agents – TSE

• Very difficult to test at low levels due to insensitivity of bioassays

– Endogenous viruses – Adventitious agents

• Raw material control becomes critical

– Provenance, traceability (geographical origin) – Testing, validation

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Consequences of advances in technology

• Need to demonstrate process capability

• Inactivation/removal of viruses

• Beyond the likelihood of reaching the patient

Effects of process inconsistency

•

• Changes in product attributes

– Post-translation changes

– Impact on potency → efficacy

– Consequences for safety → immunogenicity

– Product = process …

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Regulators

United States •

•

1930 National Institute of Health 1972 FDA Bureau of Biologics

•

1987 FDA CBER

•

• 2001 onwards CDER/CBER – CDER gained mAbs, proteins for therapeutic use, cytokines, enzymes etc, • CBER, Cellular products, gene therapy products, vaccines, plasma derived products, blood and blood components, human cells, tissues and cellular and tissue based products and others. • United Kingdom • 1925 Therapeutic Substances Act – State testing laboratories – Licensing of premises • 1968 Medicines Act (Medicines Control Agency) • 1975 Biological Standards Act (NIBSC) – Substances whose quality or potency cannot be adequately tested by chemical and physical means • 2003 Medicines and Healthcare products Regulatory Agency • 2013 MHRA and NIBSC merge

European Union • 1995 European Medicines Evaluation Agency • 2004 European Medicines Agency

•

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Harmonisers

Two principle harmonisers

• A coalition of regulators and manufacturers to satisfy each others’ needs and ends

• International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (1990)

• Tripartite agreements representing consensus between 3 regions

• US, EU and Japan (+ observers)

• Each contribute authority and industry representatives

Dedicated function

•

• A global organisation supported by governments to provide minimum standards for the world

World Health Organisation

•

• Little industry involvement (mostly philanthropic)

Many other functions

•

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What is it like here?

We are heavily regulated

•

• This is a good thing, but expensive

• Extensive technical guidance is available

Guidance is harmonised

•

Advice is easily accessible

•

• We understand established development and regulatory pathways

• Industry and regulators can collaborate

• Regulators are proactive in the face of advancing technology

• Unmet clinical needs can be addressed

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• ICH (ICH Official web site : ICH) • ICH Q2(R1) Validation of Analytical Procedures • ICH Q5A(R1) Viral Safety Evaluation of Biotechnology Products • ICH Q5C Stability Testing of Biotechnology Products (additional to Q1A) • ICH Q5D Derivation and Characterisation of Cell Substrates (i.e. host cells, cell banks) • ICH Q5E Comparability of Biotechnology/Biological Products • ICH Q6A Specifications : Test Procedures and Acceptance Criteria • ICH Q8, Q9, Q10 Quality risk management • Regional (EMA) • Community Directives • 2001/83/EC Medicinal Products for Human Use • 2003/94/EC Guidelines of Good Manufacturing Practice in respect of medicinal products for human use and investigational medicinal products for human use. • Guidelines • Guideline on development, production, characterisation and specification for monoclonal antibodies and related products (europa.eu) • Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission • Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMA/410/01 rev.3 • Guideline on Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials (Jan 2022) Types of Guidance’s Relevant to Biologicals

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Types of Guidance’s Relevant to Biologicals

• Reflection Papers • Statistical methodology for the comparative assessment of quality attributes in drug development • Q&A • Quality of medicines questions and answers: Part 1/Part 2 • Pharmacopeia • Ph. Eur. 2031 (monograph) – Monoclonal Antibodies for human use

• Ph. Eur. 2.9.20 - PARTICULATE CONTAMINATION: VISIBLE PARTICLES,

• Cell-based assay for potency determination of TNF-alpha antagonists (2.7.26)

• Ph. Eur. 3.2.1 – Glass containers for pharmaceutical use

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Types of Guidance’s Relevant to Biologicals

• Regional (US) • Guidance for Industry (FDA’s interpretation of policy on a regulatory issue) • Bispecific Antibody Development Programs – May 2021 • Inspection of Injectable Products for Visible Particulates – December 2021 • Process Validation: General Principles and Practices January 2011 Rev 1 • cGMP for Phase 1 Investigational Drugs – July 2008 • 21 CFR (Code of Federal Regulations, Title 21 Reserved for Rules of the FDA) • 21 CFR Part 600 Biological Products • USP • USP<1151> Pharmaceutical Dosage Forms • USP<1295800> Glycine • USP<791> General chapter on pH • International • WHO – Technical Report [1998] “Requirements for the use of animal cells as in vitro substrates for the production of biologicals” – Residual DNA levels 10 ng/dose (<200 Da) • International Society for Pharmaceutical Engineering (IPSE) / Parental Drug Association – Industry perspective on matters e.g. visible partlcles in parentals

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For biologicals in particular

• Regulatory authorities’ concerns are similar to those for “traditional” pharmaceuticals

Risk : benefit evaluation

•

Safety

•

• Quality (purity and potency)

Efficacy

•

Biopharmaceuticals

•

• Greater emphasis on assessment of manufacture and control of the product

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Preclinical Testing of Biologicals

Day 1: Lecture 2

With

Dr. Alison Wolfreys

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Pre-Clinical Testing of Biologicals

• Safety testing of biologicals is inevitably complicated by the common mismatch between test article specificity, selection of test species, dose, route of administration, duration of exposure, immunogenicity and so on

• Another perfect example of the case by case basis applies here in a situation where guidance can really only aim to be indicative rather than definitive

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Clinical Development of Biopharmaceuticals

Day 1: Lecture 3

With

Tara Hutton

The Organisation for Professionals in Regulatory Affairs

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Clinical Development

• A milestone step in translational science is to transform the scientific discoveries into therapeutic applications • The clinical development of biologicals and its regulation has a variety of product specific aspects which need to be carefully navigated • It is necessary to summarise clear quality and preclinical safety information for clinical trial regulators in order to address the critical benefit risk evaluation, particularly for FIH studies.

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Immunogenicity Issues

Day 1: Lecture 4

With

Dr Isabelle Cludts

The Organisation for Professionals in Regulatory Affairs

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Immunogenicity Assessment

• With the exception of vaccines, the immunogenicity of a biological product is potentially an undesirable attribute

• All therapeutic proteins, even those that share a common structure sequence with endogenous human proteins have an intrinsic potential to induce undesirable immunogenicity in human subjects. • Potential clinical consequences of an unwanted immune response include loss of efficacy, serious acute immune effects such as anaphylaxis. evaluated in the context of its potential or actual impact on both product potency and safety in preclinical and clinical studies • Subtle changes in product quality can have far reaching immunological effects which might (and in some cases have) radically alter the benefit/risk balance adversely • It must be fully characterised and its consequences

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Immunogenicity Lessons Learned

• First therapeutic insulins products in the 1920s were of bovine/porcine origin – leading to fatal anaphylactic reactions. Linked to other contaminating proteins. • Human growth hormone (hGH) derived from pituitary glands of cadavers used to treat children suffering from hypopituitary. For the early products, 50% children developed immune reaction – risk lowered by removing significant presence of aggregated hGH • Humanization of monoclonal antibodies has significantly decreased immunogenicity risk, observed with early murine antibodies. • Patients treated with early gene therapy products suffered severe immune reactions to the viral vector (Gene’s Delivery Vehicle)

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Immunogenicity Lessons Learned

Murine 100% mouse

Chimeric 33% mouse

Humanised 10% mouse

Human 0% mouse

Immunogenicity

Still immunogenic but less so: Allotypes vary within and between populations

Human: 0% mouse

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Quality / CMC Considerations

Day 2: Lecture 5

With

Zeb Younes

The Organisation for Professionals in Regulatory Affairs

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Problem Statement

Biotechnology and Biological products and processes are complex, subject to variability and inevitably will be changed pre- and post- approval.

How do we assess the impact of these changes?

How do we determine what attributes are critical and could have an impact on Product Safety and Efficacy

What are the regulatory concerns?

How can we be proactive about change?

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Module 3 Guideline Requirements

Day 2: Lecture 6

With

Richard Keane

The Organisation for Professionals in Regulatory Affairs

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Module 3

• The Q, S & E data requirements for product approval submissions are presented in harmonised regulatory procedural guidance for the Common Technical Document, acceptable now in essentially all regulatory jurisdictions

• The ICH CTD guidance describing the core of a MAA or BLA dossier has clearly defined requirements for:

Structure

•

Format

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Content

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Granularity

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• Relationships between sections

• The expectations of regulatory reviewers must be carefully matched, regardless of product class, and a successful filing is contingent on a clear understanding of how the file is put together

• An awareness of common deficiencies, notably for biological product submissions, is a first step in getting it right

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Development of Bioassays

Day 2: Lecture 7

With

Paula Urquhart

The Organisation for Professionals in Regulatory Affairs

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Potency of Small Molecules Versus Biologicals

• Small Molecules – Low molecular weight and simple chemical structures. Typically tested in animal and human studies to determine Potency. • Biologicals – Large, complex often with a complex mode of action, the structure of biologics does not prove potency.

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Definition of Potency (ICH Q6B)

‘Potency (expressed in units) is the quantitative measure of biological activity based on the attribute of the product which is linked to the relevant biological properties, whereas, quantity (expressed in mass) is a physicochemical measure of protein content.

Mimicking the biological activity in the clinical situation is not always necessary.

A correlation between the expected clinical response and the activity in the biological assay should be established in pharmacodynamic or clinical studies’

Biological Assay / Potency assay / Bioassay terms can be used interchangeably

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Analytical Methods Maturing Through Clinical Development

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Potency Strategy Linked to MoA

Start by understanding the mode of action of the protein and the processes involved in potency…..

Example 1 rituximab

Mode of Action: Antibody binds to the target antigen (CD20) present on B cells. It binds via the Fab region of the antibody. However it also recruits the immune system via binding sites present in the Fc region next to the large sugar (glycosylation), this sugar stabilises the binding domain where the immune cells bind (e.g. phagocytes, macrophages, NK cells, complement proteins).

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How Does a Monoclonal Work - rituximab

B Cell

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How Does a Monoclonal Work - rituximab

NK NKT

B Cell

B Cell Aptosis

Complement Activation

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03/09/2024

How Does a Monoclonal Work - rituximab

NK NKT

B Cell

B Cell Aptosis

Complement Activation

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Potency Strategy Linked to MoA

Example 2: Bevacizumab (Avastin)

Binds to target VEGF via the Fab region to prevent the tumor developing blood vessels to support its growth, but as it is binding soluble VEGF it does not crucially also recruit the immune system as part of its potency, it simply binds VEGF and removes it.

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How Does a Monoclonal Work - bevacizumab

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Regulation of Biosimilars

Day 3: Lecture 8

With

Cecil Nick

The Organisation for Professionals in Regulatory Affairs

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Biosimilars

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Biosimilars

Companies manufacturing biosimilars do not have access to the originators CELL BANK or PROCESS DESCRIPTION. If process was the product then biosimilars would not be possible. Through state of the art analytical characterisation and improvements in product and process understand, possible to produce a biosimilar with acceptable safety and efficacy profile to the Innovator product

•

•

•

Generics: Must demonstrate active ingredient is the same as the in the reference listed drug Biosimilars: Must demonstrate highly similar to the reference product with only minor differences allowed

Proposed biosimilar must have similar variations compared to the reference product

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Biosimilars

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Regulation of Vaccines

Day 3: Lecture 9

With

Andrew Deavin

The Organisation for Professionals in Regulatory Affairs

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03/09/2024

Regulation of Vaccines – Complex Biologicals

Vaccine technology is now largely unrecognisable compared to its 18th century antecedents, although the underlying mechanisms are no different This has been the longest journey of any product class, and probably the most important one for global public health Regulation of product quality, safety and efficacy is required to take into account the need for rapid availability against an emerging infectious agent strain and for population vaccination programmes Quality, Safety and Efficacy Must be Assured as usually administered to healthy peoples including infants.

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Regulation of Cell and Gene Therapy Products

Day 3: Lecture 10

With

Sergio Fracchia

The Organisation for Professionals in Regulatory Affairs

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Complexities of Advanced Therapies

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Complexities of Manufacturing Advanced Therapies

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Common CMC Deficiencies

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Evolving Regulation with Industry

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What is it like here?

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And now we are here….

• Thank you for your attention • Enjoy the course!

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Module 9: Registration of Biological, Biotechnology and Advanced Therapy Products

Preclinical Testing of Biologicals

Dr Alison Wolfreys

Nonclinical Safety Evaluation, UCB Biopharma UK

09 Sept 2024

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals i Regulatory Affairs

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“Biologics” used to include a broader range of modalities… but some now have own guidelines….

Monoclonal antibodies & related formats

This talk will concentrate on mAbs and related formats

Recombinant proteins or

New Biological Entity (NBE)

Synthetic peptides & nucleotides

“natural” peptides

Gene and cell therapy

Vaccines

Gene & cell therapy

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Preclinical Testing of Biologicals – Sept 2024

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03/09/2024

Monoclonal antibodies (mAbs) are typically an IgG • IgGs are comprised of 4 main types → IgG1, IgG2, IgG3 and IgG4 • IgG1 and IgG4 are the most commonly used formats for biotherapeutics

Antigen binding site

Parameter

IgG1

IgG2

IgG3

IgG4

Heavy chain

Molecular Mass (kD)

146

146

170

146

Complement activation (C1q binding)

++

+

+++

-

Light chain

Fc γ R1*

6500

-

6100

3400

Fc γ R2a*

520

45

89

17

Fc Region

Fc γ R2b*

12

2

17

20

Fc γ R3a*

200

7

980

25

* = Binding in uM; Table modified from Yu et al (2020) J Hematol Oncol, 13: Article 45

• IgG1 has highest affinity for all FcγRs → Potent activator of ADCC and ADCP • IgG4 has high affinity for FcγRI but not others → Weak activator of ADCC and ADCP Which IgG is chosen depends on MoA and whether ADCC and ADCP are desirable or not

ADCC = antibody dependent cell mediated cytotoxicity; ADCP = antibody dependent cellular phagocytosis

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Preclinical Testing of Biologicals – Sept 2024

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Monoclonal antibody related formats – some examples • Variable and becoming more exotic…. • Design dependent on many factors, e.g. target organ accessibility, potential structure-related toxicities and MoA

Antigen binding site

Heavy chain

Light chain

Fc Region

Bispecific antibody

Figure modified from Schweizera et al (2014). European Journal of Pharmaceutics and Biopharmaceutics, 88, Pages 291-309

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Preclinical Testing of Biologicals – Sept 2024

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