Manufacturing of nanomedicines a GMP perspective-2017-11-16 · Manufacturing of nanomedicines: a...

Manufacturing of nanomedicines: a GMP perspective

Dr. Steliyan Tinkov, MBA, PMPBasel

Oct 24, 2017

© 2017 Novartis Pharma AG

Biologics Technical Development and Manufacturing


Disclaimer

- These slides are intended for educational purposes onlyand for the personal use of the audience. These slidesare not intended for wider distribution outside theintended purpose without presenter approval.

- The content of this slide deck is accurate to the best ofthe presenter’s knowledge at the time of production.

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Topics list1. Introduction

2. Manufacturing process design

3. Definitions

4. Technology readiness

5. Practical examples• Complex CQAs

• Consumables

• Microbiology

• Visual inspection

6. Outlook and readings

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Introduction

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“Nanomedicinal products may exhibit a complex mechanismof action, combining mechanical, chemical, pharmaco-logical, and immunological properties [1].“Critical determinants of the in vivo behavior are highlysensitive to small changes in the manufacturing process [2].

[1] EMA, 2006: Reflection paper on nanotechnology-based medicinal products for human use[2] Ehmann F. et al., 2013: Next generation nanomedicines and nanosimilars: EU regulators` initiatives

Complexity, characterization,manufacturing

controls

Therapeutic comparability

First generation nanomedicines

Second generation

nanomedicinesNanosimilars


Manufacturing process design

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Purification & Buffer Exchange

Remote Drug Loading

Phospholipid Blending

Raw Liposome Formation

Size Reduction Sterile Filtration

Aseptic Fill and Finish

Lipids dissolution in an organic solvent

High-pressurehomogenization

Solvent -antisolvent precipitation

Ammonia gradient

Tangential flow filtration

Validatedcombination ofproduct, filter & parameters

At-line IPCDynamic light scattering and turbidimetry

Isolator technology


Definitions (1)

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Critical Process Parameter (CCP):“a limited subset of operation parameters, whichsignificantly affect critical quality attributes when variedoutside a meaningful narrow, or difficult to control,operational range [3].

[3] PDA Technical Report 15 Validation of Tangential Flow Filtration

Critical Quality Attribute (CQA):“product attributes, which affect product safety, identity,quality, and purity [3].


Definitions (2)

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Process Step or Operation Critical Process Parameter Related

Critical Quality Attribute

High-pressurehomogenization

Homogenization pressure Particle size (mean average, D10, D90)

Product temperature Degradation by-products

pH adjustment pH gradient (inside / outside liposomes)

Drug uptake,Zeta potential

Weighing Liposomes / drug ratio Drug uptake

Drug loading incubation

Incubation temperature

Drug uptake,In-vitro release profile

Incubation timeHeating & cooling rampsParticle size (D10, D90)

Sterile filtrationTransmembrane pressure (∆P) Product sterility

Particle size (D90) Product filterability


Technology readiness (1)

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Critical Process

Parameters

Critical Quality

Attributes

Pharmaco-kinetics

Pre-clinicalSafety

Proof of Concept

Therapeutic Profile

Manufacturing Controls

Quality Control

Pre-Clinical and Phase I-III Clinical Studies or Market

Keep your manufacturing process in control…

…otherwise process gaps will backfire in later phases.

For nanomedicines, CPPs are closely related to CQAs and, furthermore - to a multitude of in-vitro and in-vivo attributes of the product.


Technology readiness (2)

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[4] Eaton MA, Levy L, Fontaine OM, Delivering nanomedicines to patients: a practical guide (with modifications)

Market

Phase II&IIIPhase I / Pilot

ClinicalDevelopment

Preclinical / Process

development

Research

Idea Early research

PoC1

PoC2

Research project

accepted

Therapeuticproject

Nanomedicine candidate- Precise NM structure

- Manufacturing process,

scale up, and transferability

Development portfolio

First-in-man

- First GMP batch (CCPs)

- Product characterization

(CQAs)

1 2 3 4 5 6 7 8 9

1 2 3 4 5

Stage-gate decision points

Increasing regulatory attention and scientific advice


Practical examples


How complex are your CQAs?

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“Particle size distribution: a list of values or a mathematical function that

defines the relative amount of particles present according to size [5].

[5] Jillavenkatesa A, Dapkunas S J, Lin-Sien Lum, Particle Size Characterization, NIST Special Publication 960-1, 2001

What size are those particles?

Chi-Square?

Particle size distribution cannot be thoroughly expressed,

using a single numerical value:

• Direct comparison of values is intricate

• Acceptance limits are difficult to define


Do you know your consumables well? (1)

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Membrane extrusion:

• Commonly used approach for particle size reduction

• Liposomes are pressed through narrow, uniformly sized pores

• Repetitive passes through descending pore size membranes

• Process temperature above the phase transition of phospholipids

Process pressure

Extrusion membrane

Processed liposomes


Do you know your consumables well? (2)

SEM micrographs of track-etched extrusion membranes [6]

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Typical quality attributes (CoA, CoQ):

• Average pore size (0.1 µm, 0.2 µm, etc.)

• Average pore density (cm-1)

• Membrane thickness (approx. 5-15 µm)

[6] Apel, P., Track etching technique in membrane technology , Radiation Measurements 34 (2001) 559–566 (with permission)

Extrusion membranes:

Not reflected attributes (non-exhaustive):

• Types of pore geometry: “regular” cylindrical and “atypical” e.g. cross-linked,

cigar-like, conical, and bow-tie pores [6].

• Ratio of “regular” vs. “ atypical” pores (batch-wise)


Are you on the safe side of microbiology?

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TFF may lead to germ accumulation in the bulk product:

100L product bulk @ 3 CFU/100 mL +

10 x 100L TFF buffer @ 2 CFU/100 mL =

100 L processed bulk @ 23 CFU/100 mL

(acceptance limit: ≤ 10 CFU/100 mL) [7]

Tangential Flow Filtration:

• Most common approach for

purification & buffer exchange

• Membrane MW cut-off

• Trans-membrane pressure

• Differential pressure

[7] CPMP/QWP/486/95 and EMEA/CVMP/126/95


Visual inspection (1)

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• USP <790> and <1790>: Parenteral drug products must be

„essentially free of visible particles“

• Detection of visible particles is probabilistic

Classification of visible particulates:

• Extrinsic: from outside the process e.g. insect parts, hair, paint

• Intrinsic: from within the process e.g. stainless steel, glass,

rubber, silicone

• Inherent: part of the formulation e.g. agglomerates, crystals


Visual inspection (2)

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Nanomedicines are generally rendered

„difficult to inspect“ finished dosage forms due to their

intrinsic turbidity / opalescence.

Recommended inspection approach:

• sampling plan

• destructive treatment to reduce or remove turbidity

• focused visual inspection for visible particulates


Outlook and readings (1)

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Cooperation networks between academia, investors,industry, and regulatory agencies must be fosteredthrough knowledge exchange and performance-drivencooperations.

The cross-linking between research (academia) anddevelopment (industry) must be further strengthened.

Nanomedicine innovation may be wasteful and unethical,unless candidates have the cutting edge to gain enoughmarket share and significantly improve patients` lives.


Outlook and readings (2)

Business Use Only18

Gaspar, R.S., Florindo, H.F., Silva, L.C., Videira, M.A., Corvo, M.L., Martins, B.F., Silva-Lima, B., (2014). Regulatory Aspects of Oncologicals: Nanosystems Main Challenges, Advances, Delivery Science and Technology pp 425-452

Hodge, G.A., Bowman, D.M., Maynard, A.D. (2010). International handbook on regulating nanotechnologies. Edward Elgar Publishing Ltd.

Ehmann, F., Sakai-Kato, K., Duncan, R., Hernán Pérez de la Ossa, D., Pita, R., Vidal, J.M., Kohli, A., Tothfalusi, L., Sanh, A., Tinton, S., Robert, J.L., Silva Lima, B., Papaluca Amati, M., (2013). Next-generation nanomedicines and nanosimilars: EU regulators’ initiatives relating to the development and evaluation of nanomedicines, Nanomedicine 8:5, pp 849-856

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