An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Methods
2.2.1. Elements of the QbD Design
Development of the Knowledge Space and Determination of the QTPP
Determination of the CQAs, the CMAs and the CPPs
Risk Assessment
Design of the Experiments
2.2.2. Preparation of Liposomes and Process of Lyophilisation
2.2.3. Characterisation of the Liposomes
Vesicle Size and Zeta Potential Analysis
Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) Investigations
Fourier-Transform Infrared (FT-IR) Spectroscopy Measurements
Atomic Force Microscopy (AFM) Measurements
Residual Ethanol Measurements via Gas Chromatography-Mass Spectrometry (GC-MS)
2.2.4. Statistical Analysis
3. Results
3.1. Development of the Knowledge Space, the Definition of the QTPP and the Identification of the CQAs, CMAs and CPPs
3.2. Risk Assessment
3.3. Characterisation Results of the Liposomal Products
3.3.1. Effects of Using Different Temperature Values
3.3.2. Effects of Using Different Ratios of Wall-Forming Agents
3.3.3. Effect of Using Different Concentrations of PEGylated Phospholipid
3.3.4. Effect of Using Different Types of Hydration Media
3.3.5. Effect of Using Different Types of Cryoprotectants
3.4. Residual Ethanol Measurements via Gas Chromatography-Mass Spectrometry (GC-MS)
4. Discussion
4.1. Development of the Knowledge Space, the Definition of the QTPP and the Identification of the CQAs, CMAs and CPPs
4.2. Risk Assessment and Design of Experiment
4.3. Characterisation Results of the Liposomal Products
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AFM | atomic force microscopy |
API | active pharmaceutical ingredient |
CH | cholesterol |
CMAs | Critical Material Attributes |
CPPs | Critical Process Parameters |
CQAs | Critical Quality Attributes |
DLS | dynamic light scattering |
DoE | Design of Experiments |
DPPE-PEG2000 | 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt) |
DS | Design Space |
DSC | differential scanning calorimetry |
DSPE–PEG2000 | 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (ammonium salt) |
dTG | derivative thermogravimetry |
EMA | European Medicine Agency |
FT-IR | Fourier-transform infrared spectroscopy |
ICH | International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use |
LUV | large unilamellar vesicles |
PBS | phosphate-buffered saline |
PC | L-α-phosphatidylcholine |
PdI | Polydispersity Index |
PE | phosphatidylethanolamine |
PEG | polyethylene glycol |
QbD | Quality by Design |
QTPP | Quality Target Product Profile |
R&D | Research and Development |
RA | Risk Assessment |
Tc | gel to liquid-crystalline phase transition temperature |
Tg | glass transitions temperature |
TGA | thermogravimetric analysis |
Tm | phase transition temperature |
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Compositions | Phosphatidylcholine–Cholesterol Liposomes | ||||
---|---|---|---|---|---|
Phospholipid:Cholesterol Mass Ratio | |||||
100:0 | 90:10 | 80:20 | 70:30 | 60:40 | |
PC (w/w%) | 100 | 90 | 80 | 70 | 60 |
cholesterol (w/w%) | - | 10 | 20 | 30 | 40 |
solvent of the stock solution | |||||
EtOH 96% | + | ||||
hydration media | |||||
saline solution (mL) | 100 |
Compositions | PEGylated Liposomes | ||||||||
---|---|---|---|---|---|---|---|---|---|
PC:DPPE-PEG2000:Cholesterol Mass Ratio | |||||||||
55:5:40 | 50:10 | 40:20:40 | |||||||
PC (w/w%) | 55 | 50 | 40 | ||||||
DPPE-PEG2000 (w/w%) | 5 | 10 | 10 | ||||||
cholesterol (w/w%) | 40 | 40 | 40 | ||||||
solvent of the stock solution | |||||||||
EtOH 96% | + | ||||||||
hydration media | |||||||||
saline solution (mL) | 100 | - | 100 | 100 | - | 100 | - | 100 | - |
PBS pH 5.6 (mL) | - | 100 | - | - | - | - | - | - | 100 |
PBS pH 7.4 (mL) | - | - | - | - | 100 | - | 100 | - | - |
cryoprotectant | |||||||||
glucose (%) | 5 | 5 | - | 5 | 5 | 5 | 5 | - | 5 |
sorbitol (%) | - | - | 5 | - | - | - | - | - | - |
trehalose (%) | - | - | - | - | - | - | - | 5 | - |
(A) Sample Name | Composition (m/m%) | Hydration Media | Cryoprotectant (5% of Total PPL. Mass) | |||||
PC | CH | |||||||
PPL-CH-60-40/50-SS | 60 | 40 | saline solution | - | ||||
PPL-CH-60-40/60-SS | 60 | 40 | saline solution | - | ||||
PPL-CH-70-30/60-SS | 70 | 30 | saline solution | - | ||||
PPL-CH-80-20/60-SS | 80 | 20 | saline solution | - | ||||
PPL-CH-90-10/60-SS | 90 | 10 | saline solution | - | ||||
PPL-CH-100-0/60-SS | 100 | 0 | saline solution | - | ||||
PPL-CH-60-40/70-SS | 60 | 40 | saline solution | - | ||||
(B) Sample Name | Composition (m/m%) | Hydration Media | Cryoprotectant (5% of Total PPL. Mass) | |||||
PC | DPPE- PEG2000 | CH | ||||||
PPL-CH-55-5-40/60-SS+G | 55 | 5 | 40 | saline solution | glucose | |||
PPL-CH-55-5-40/60-PBS7.4+G | 55 | 5 | 40 | pH 7.4 PBS | glucose | |||
PPL-CH-50-10-40/60-SS+G | 50 | 10 | 40 | saline solution | glucose | |||
PPL-CH-50-10-40/60-PBS7.4+G | 50 | 10 | 40 | pH 7.4 PBS | glucose | |||
PPL-CH-40-20-40/60-SS+G | 40 | 20 | 40 | saline solution | glucose | |||
PPL-CH-40-20-40/60-PBS7.4+G | 40 | 20 | 40 | pH 7.4 PBS | glucose | |||
PPL-CH-40-20-40/60-SS+T | 40 | 20 | 40 | saline solution | trehalose | |||
PPL-CH-40-20-40/60-PBS5.6+G | 40 | 20 | 40 | pH 5.6 PBS | glucose | |||
PPL-CH-55-5-40/60-SS+S | 55 | 5 | 40 | saline solution | sorbitol |
Critical Factors | Investigated Levels or Parameters | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
C P P | working temperature | 50 °C | 60 °C | 70 °C | ||||||||||||
C M A | Phosphatidylcholine:cholesterol mass ratio | 100:0 | 90:10 | 80:20 | 70:30 | 60:40 | ||||||||||
PEGylated phospholipid content PC:DPPE-PEG2000:cholesterol mass ratio | 5% 55:5:40 | 10% 50:10:40 | 20% 40:20:40 | |||||||||||||
quality of hydration media pH ionic strength | saline solution pH 5.5 0.15 M | PBS pH 5.6 pH 5.6 0.40 M | PBS pH 7.4 pH 7.4 0.16 M | |||||||||||||
quality of cryoprotectants | glucose | sorbitol | trehalose |
QTPP Factors | Details | Comments/Justifications |
---|---|---|
dosage form/ appearance | lyophilised powder |
|
physical attributes | morphology, large unilamellar structured, liposomes (LUV), optimal particle size, proper zeta potential |
|
stable structure | in aqueous solution |
|
in freeze-dried powder form | ||
homogeneoussystem | homogenous formulation |
|
CQAs | Details | Comments/Justification |
type of liposomes | conventional, cationic, immune, bioresponsive, magnetic | determine the quality of the lipids |
targeted delivery compatibility | knowledge about the possible administration route | formulation needs to be suitable for the requirements of the later API |
size of the vesicles | mean particle size: 100–200 nm | large vesicles (LUV) |
number of lamellas | 1 lamella | unilamellar vesicles (LUV) |
morphology | shape and structure | spherical unilamellar vesicles |
polydispersity index (PdI) | acceptable: below: 0.3 | monodisperse system |
zeta potential | the higher in absolute value, the more stable the formulation | indicates stability |
surface modifications | attachment of polyethylene glycol (PEG) chains, monoclonal antibodies, antibody fragments peptides, nucleic acids, carbohydrates or small molecules | maintain targeted delivery |
specific surface area | surface area-to-volume ratio | determines the properties of the later drug release |
phase transition temperature (Tm) | working temperature is recommended to be higher than Tm | different value for each composition |
sterility | meets the microbiological requirements | depends on the chosen administration route |
stability | stable under given circumstances | in aqueous solution/in freeze-dried powder form |
Compositions | Phosphatidylcholine–Cholesterol Liposomes (Mass Ratio: 60:40) | |||||
---|---|---|---|---|---|---|
50 °C | 60 °C | 70 °C | ||||
mean | SD | mean | SD | mean | SD | |
vesicle size (nm) | 154 | 14 | 152 | 28 | 166 | 18 |
PdI | 0.24 | 0.02 | 0.18 | 0.08 | 0.21 | 0.04 |
zeta potential (mV) | −9.6 | 2.0 | −10.3 | 1.8 | −8.1 | 1.6 |
TG% | 2 | 3 | 2 | |||
sample name | PPL-CH-60-40/50-SS | PPL-CH-60-40/60-SS | PPL-CH-60-40/70-SS |
Compositions | Phosphatidylcholine–Cholesterol Liposomes (60 °C) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Phosphatidylcholine:Cholesterol Mass Ratio | ||||||||||
100:0 | 90:10 | 80:20 | 70:30 | 60:40 | ||||||
Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
vesicle size (nm) | 135 | 24 | 149 | 18 | 176 | 30 | 200 | 34 | 152 | 20 |
PdI | 0.24 | 0.02 | 0.25 | 0.03 | 0.26 | 0.03 | 0.30 | 0.08 | 0.18 | 0.08 |
zeta potential (mV) | −9.6 | 1.3 | −9.3 | 0.7 | −8.7 | 1.5 | −8.9 | 0.7 | −10.3 | 1.8 |
TG% | 4 | 3 | 4 | 2 | 3 | |||||
sample name | PPL-CH-100-0/60-SS | PPL-CH-90-10/60-SS | PPL-CH-80-20/60-SS | PPL-CH-70-30/60-SS | PPL-CH-60-40/60-SS |
Compositions | Cryoprotectant: Glucose; 60 °C | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
PC:DPPE-PEG2000:Cholesterol Mass Ratio | ||||||||||||
55:5:40 | 50:10:40 | 40:20:40 | ||||||||||
Hydration Media | ||||||||||||
Saline Solution | PBS pH 7.4 | Saline Solution | PBS pH 7.4 | Saline Solution | PBS pH 7.4 | |||||||
Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
vesicle size (nm) | 103 | 4 | 109 | 8 | 152 | 44 | 138 | 23 | 104 | 6 | 117 | 15 |
PdI | 0.25 | 0.05 | 0.20 | 0.02 | 0.27 | 0.01 | 0.27 | 0.07 | 0.29 | 0.07 | 0.26 | 0.06 |
zeta potential (mV) | −2.5 | 0.5 | −3.6 | 1.1 | −2.0 | 1.2 | −2.8 | 0.6 | −1.3 | 0.5 | −1.6 | 0.7 |
TG% | 4 | 4 | 5 | 6 | 5 | 7 | ||||||
sample name | PPL-CH-55-5-40/60-SS+G | PPL-CH-55-5-40/60-PBS7.4+G | PPL-CH-50-10-40/60-SS+G | PPL-CH-50-10-40/60-PBS7.4+G | PPL-CH-40-20-40/60-SS+G | PPL-CH-40-20-40/60-PBS7.4+G |
Compositions | Phospholipid:Cholesterol Mass Ratio 60:40 Liposomes; Saline Solution; 60° | |||
---|---|---|---|---|
PC: Cholesterol 60:40 | PC:DPPE-PEG2000: Cholesterol 55:5:40 | |||
Mean | SD | Mean | SD | |
vesicle size (nm) | 152 | 28 | 103 | 5 |
PdI | 0.18 | 0.08 | 0.25 | 0.05 |
zeta potential (mV) | −10.3 | 2.0 | −2.5 | 0.5 |
TG% | 3 | 4 | ||
sample name | PPL-CH-60-40/60-SS | PPL-CH-55-5-40/60-SS+G |
Compositions | PC:DPPE-PEG2000:Cholesterol Mass Ratio 40:20:40; Cryoprotectant: Glucose; 60 °C | |||||
---|---|---|---|---|---|---|
Hydration Media | ||||||
Saline Solution 0.154 M | PBS pH 5.6 0.40 M | PBS pH 7.4 0.16 M | ||||
Mean | SD | Mean | SD | Mean | SD | |
vesicle size (nm) | 104 | 7 | 110 | 5 | 117 | 15 |
PdI | 0.29 | 0.07 | 0.33 | 0.05 | 0.26 | 0.06 |
zeta potential (mV) | −1.3 | 0.5 | −2.3 | 1.2 | −1.6 | 0.7 |
TG% | 5 | 15 | 7 | |||
sample name | PPL-CH-40-20-40/60-SS+G | PPL-CH-40-20-40/60-PBS7.4+G | PPL-CH-40-20-40/60-PBS5.6+G |
Compositions | Hydration Media: Saline Solution; 60 °C | |||||||
---|---|---|---|---|---|---|---|---|
PC:DPPE-PEG2000:Cholesterol Mass Ratio | ||||||||
55:5:40 | 40:20:40 | |||||||
Glucose | Sorbitol | Glucose | Trehalose | |||||
Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
vesicle size (nm) | 103 | 4 | 130 | 5 | 104 | 7 | 103 | 3 |
PdI | 0.25 | 0.05 | 0.30 | 0.05 | 0.29 | 0.07 | 0.29 | 0.03 |
zeta potential (mV) | −2.5 | 0.5 | −4.1 | 0.8 | −1.3 | 0.5 | −3.2 | 0.9 |
TG% | 4 | 25 | 5 | 6 | ||||
sample name | PPL-CH-55-5-40/60-SS+G | PPL-CH-55-5-40/60-SS+S | PPL-CH-40-20-40/60-SS+G | PPL-CH-40-20-40/60-SS+T |
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Németh, Z.; Pallagi, E.; Dobó, D.G.; Kozma, G.; Kónya, Z.; Csóka, I. An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development. Pharmaceutics 2021, 13, 1071. https://doi.org/10.3390/pharmaceutics13071071
Németh Z, Pallagi E, Dobó DG, Kozma G, Kónya Z, Csóka I. An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development. Pharmaceutics. 2021; 13(7):1071. https://doi.org/10.3390/pharmaceutics13071071
Chicago/Turabian StyleNémeth, Zsófia, Edina Pallagi, Dorina Gabriella Dobó, Gábor Kozma, Zoltán Kónya, and Ildikó Csóka. 2021. "An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development" Pharmaceutics 13, no. 7: 1071. https://doi.org/10.3390/pharmaceutics13071071
APA StyleNémeth, Z., Pallagi, E., Dobó, D. G., Kozma, G., Kónya, Z., & Csóka, I. (2021). An Updated Risk Assessment as Part of the QbD-Based Liposome Design and Development. Pharmaceutics, 13(7), 1071. https://doi.org/10.3390/pharmaceutics13071071