www.cordenpharma.com

Experts taking care.

Drug Product Development and Industrialization for Peptides and Oligos: A CDMO Perspective

Tides Europe Conference, AmsterdamNovember 12th, 2019

Injectables

Platform

www.cordenpharma.com

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Your Full-Service CDMO Partner

CordenPharma Overview

Supply Chain Positioning

CordenPharma covers the full GMP supply chain of pharmaceutical custom manufacturing (raw materials and non-GMP pharmaceutical intermediates partially sourced from WeylChem)

API manufacturing accounts for c.62% of net sales and usually have a shorter ramp-up phase than respective Drug Product projects

Raw Materials Non-GMP Intermediates

GMP Intermediates APIs DPs Pharma

Logistics

Lifecycle Positioning

CordenPharma focuses on all stages of a drug lifecycle with competitive advantages in clinical development and commercial production

Preclinical12 months

Phase I12-18 months

Phase II24 months

Registration12 month Commercial GenericPhase III

36 months

Value Chain Positioning

CordenPharma Manufacturing Sites >From Drug Substance to Drug Product

Peptide Drug Substance Sites• CordenPharma Bergamo• CordenPharma Boulder (US)• CordenPharma Brussels (BE)• CordenPharma Chenôve (FR)• CordenPharma Colorado (US)• CordenPharma Frankfurt (DE)• CordenPharma Liestal (CH)

Injectable Drug Product Sites• CordenPharma Caponago (IT)• CordenPharma Latina (IT)• CordenPharma Plankstadt (DE)

Injectables - Your Development Life Cycle Journey is Our Commitment

Preclinical12 months

Phase I12-18 months

Phase II24 months

Registration12 month CommercialPhase III

36 months

Clinical Supply(at any Scale & Stage of Drug Product)

PharmaceuticalFormulationDevelopment

Validation & CMC Dossier Registrations Globally

Commercial Injectable Drug Product Manufacture & Supply

Secondary Packaging, Labeling, Kit Assembly & Serialization

Clinical Trial Material Management & Distribution

SmallMolecules

Peptides

Lipids & Carbohydrates

Oligonucleutides

Sterile Liquids

Sterile PowderLyophilized Vials

Pharma Packaging& Logistic

Injectables – Our Capabilities

Sterile Drug Products (Aseptic or Terminally Sterilized)

Sterile Emulsion Technology

Small & Large Molecules, incl. Peptides, Oligonucleotides & Biologics

Clinical Trial Services

Packaging & Labeling

CordenPharma Caponago

Formulation & Packaging of Parenteral Dosage Forms

Sterile Emulsion Technology

Pre-filled Syringes & Cartridges

Formulation Development

Clinical Trial Drug Kits Distribution & Logistics

Formulation & Analytical Development

Approved by FDA, EMA, Anvisa, TGA, ISO-14001 & ISO 45001

Location: Caponago, Milan, Italy Acquisition: June 2009 Employees: 400+

Core Competencies• Formulation, Terminal Sterilization,

Aseptic Fill & Finish, Inspection & Packing of Parenterals

• Filling of Ampoules, Vials, Lyophilised Vials & Syringes in 1 – 100 ml range

• Extended Analytical & Micro-biological Tests, Stability Studies

Originator Liraglutide > medication used to treat diabetes mellitus type

2 and obesity (sold under the brand name Victoza among others)

Liraglutide > a fragment of the naturally occurring human glucagon-like peptide-1 sequence position 7-37 with 97% homology and a lipophilic substituent for prolongation of half-life. A modified polypeptide of 31 amino acid residues with a covalent linkage at γ-position of N-palmitoylglutamic acid to the ε-amino group of Lys.

Liraglutide > reduces meal-related hyperglycemia (for 24 hours after administration) by increasing insulin secretion (only) when required by increasing glucose levels, delaying gastric emptying, and suppressing prandial glucagon secretion.

Liraglutide > a multi-dose parenteral combination product (Drug - Device Combination Product, DDC)

Regulatory Background

505(j) Abbreviated NDA (ANDA, i.e., duplicate of a previously approved drug product)

Must refer to a listed drug (i.e., a reference listed drug [RLD]), contain information to demonstrate therapeutic equivalence, and may not be submitted if studies are necessary to establish the safety or effectiveness of the proposed drug product.

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Equivalence

Equivalence ConceptsPharmaceutical Equivalence (PE) Same active ingredient(s) Same dosage form Same route of administration Same strengthBioequivalence (BE) No significant difference in rate and extent of the active ingredient at the site of action

Therapeutic Equivalence (TE) of Generic Product Generics must demonstrate PE and BE to the RLD Generics rely on the safety and efficacy of the RLD TE products can be substituted freely

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Q1/Q2 Requirement for Generic Parenteral Products

21 CFR 314.94 (a)(9)(iii) – Inactive ingredient changes permitted in drug products intended for parenteral use.

Generally, a drug product intended for parenteral use must contain the same inactive ingredients (Q1) and in the same concentration (Q2) as the reference listed drug.

However, an applicant may seek approval of a drug product that differs from the reference listed drug in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product.

Liraglutide 6mg/mL

Batch formula of Liraglutide 6 mg/ml solution for injectionIngredient Concentration (mg/ml)

Liraglutide 6.000Disodium-phosphate diihydrate

1.420

Phenol 5.500Propylene glycol 14.000Hydrochloric acid sol 0.1 N q.s. target pH 8.15

Sodium hydroxide sol 0.1 N q.s. target pH 8.15

Water for injection q.s. 1.000 ml

Substitution of an excipient, propylene glycol (isotonic Agent), present in the RLD with Mannitol or Glycerol.

The originator developer used mannitol as an isotonic agent during the clinical development that led to Victoza® NDA approval. Novo Nordisk, used the excipient, mannitol in Phase 1, 2 and 3a of the clinical. The phase3 clinical trial, NN2211-1311, concluded that Liraglutide formulations containing mannitol and propylene glycol are bioequivalent. Moreover, glycerol is already used in a formulation containing Liraglutide and Insulin Degludec, which is approved in EU, Xultophy and it is under evaluation by the FDA agency.

A glycerol based formulation has been successfully developed supported by stability, safety and robustness data

Our Experience

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Q1/Q2 Assessment

Q1: identity of an inactive ingredient. An applicant should provide detailed information on the chemistry and grade of each inactive ingredient, and characterization data, if needed for inactive ingredients.

Q2: determine the difference (%) of an inactive ingredient in the Test (T) and Reference (R) products (i.e., [(T-R)/R] x100). The difference should not exceed 5%. Formulation robustness studies recommended

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Formulation Robustness

Risk Assessment(Literature and previous knowledge assessment)

Formulation Robustness Studies(Impact of formulation components levels on the CQAs @ bench scale through DoE)

Short Term Stability(Lead Prototype Selection)

Manufacturing Implementation (Scale Up and –Risk Control & Control Strategy)

Registration Batches Manufacture(Risk review –Continuous Improvement)

Analytical Methods Development & Validation

Risk AssessmentFormulation development initial risk assessment - Cause & EffectMatrix

Formulation Robustness: Initial Screening

Formulation Initial Screening

Select filter membrane Evaluate comparability with RLD Draft Drug Product specifications Acquire data on formulation stability through accelerated

stability study Identify design of space to deepen explore during robustness

study Identify critical process parameters, if any Identify lab scale formulation manufacturing process

Formulation Robustness: DoE

Run Order CenterPt Excipient 1 Excipient 2 Excipient 3 pH1 1 110 110 110 82 1 90 110 110 8 Red high value 3 1 110 110 90 8 Green central value 4 1 90 90 90 8 Blu low value 5 1 110 110 110 66 1 90 90 110 67 0 100 100 100 78 1 110 90 90 69 1 90 110 90 8

10 1 90 110 90 611 1 90 90 90 612 1 90 90 110 813 1 110 90 90 814 1 110 110 90 615 1 110 90 110 816 1 110 90 110 617 1 90 110 110 618 0 100 100 100 719 0 100 100 100 7

On the base of screening results the design of space to be explored has been reduced

The number of factors to be explored allowed us to run a full factorial design with three replicates of the center points (19 runs)

Integrated Development

The development & commercialization of Combo Drug Products require strict collaboration of multiple stakeholders & Sponsors.

Drug Subst. Manufacturer

Drug Product Manufacturer

Device Manufacturer

Sponsor

CordenPharma provides integrated CMC solutions through strong project management & thorough technical collaboration across sites.

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Analytical Challenges

Analytics in generics development can be a limiting factor conditioning the overall development and hence ANDA submission timelines.

Analytical method development is driven by the API isolation of process and degradation impurities. DP analytical methods using the API methods as a starting point.

To expedite and streamline analytical activities for development and validation, some methods were outsourced to GMP-qualified CordenPharma preferred partners.

Full-Service CDMO Organized under 5 Technology Platforms

€ 311 Million Total Sales (2018)

9 Manufacturing Facilities in Europe / US (8 GMP Plants, 1 R&D Laboratory)

1,375 Employees

Analytical Streamline

An extensive research of GMP accredited and FDA certified contract laboratories supplementing a large inventory of analytical instrumentation in support of development and validation of a wide range of methods in accordance with international pharmacopoeias (Ph. Eur. USP) and other pharmacopoeias (BP, JP etc.) was done.

An intense networking communication with all parties involved in different countries was created in order to maximize and facilitate the performance of laboratory work in line with the expectation of the customer and deadlines.

Drug Product

Glass Cartrige

Nest & Tub

Autoinjector

Drug Product - Challenges Scale up of the drug product manufacturing might

reveal issues that have been under estimated during the bench scale development batches. Through the manufacturing of several technical

engineering batches the whole fill & finish process has to be challenged to assess the relevant process parameters.

• Compounding Process (mixing times, Mixing speed, holding times)

• Filling parameters• Plunger placement settings

CordenPhama’s Drug Substance revealed to be prone to generate foam during Compounding and Filling at commercial scale

This phenomenon that can severly impact the plunger placement process has been controlled through the determination of all the critical process parameters generating foam during filling, including the shape of the filling needles, the filling speed and the extension of filling needles insertion within the cartrige

Combo Drug Product - Challenges

The manufacture of this type of combination products (DDC) has to be designed as such that The final filled cartrige should comply to the requirements of the final

autoinjector Plunger position Air bubble minimization / avoidance

The final combination product has to be characterized according to ISO11608-1:2014 (requirements and test methods for needle-based injection systems (NISs)

Conclusions

Development of a generic represents a worst case for analytical development that could represent a bottleneck for the overall development timeline.

Drug Product development should take into consideration the formulation as well as the manufacturing process and the device requirements (autoinjector).

CordenPharma gained relevant experience in the development and manufacture of combination products and the challenges that come along with it.

www.cordenpharma.com

Experts taking care.

Umberto RomeoR&D ManagerCordenPharma CaponagoUmberto.Romeo@cordenpharma.comM: +39 347 4564263

Inquirieswww.cordenpharma.com/contact-us/

THANK YOU!