Manufacturing of nanomedicines: a GMP perspective
Dr. Steliyan Tinkov, MBA, PMPBasel
Oct 24, 2017
© 2017 Novartis Pharma AG
Biologics Technical Development and Manufacturing
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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Biologics Technical Development and Manufacturing
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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Biologics Technical Development and Manufacturing
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
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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
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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].
Biologics Technical Development and Manufacturing
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
Biologics Technical Development and Manufacturing
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.
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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
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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
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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
Biologics Technical Development and Manufacturing
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)
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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
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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
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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
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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.
Biologics Technical Development and Manufacturing
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