Transcript Implementation of QbD Paradigm In Sterile Dosage Form

Hemant N. Joshi, Ph.D., MBA
Tara Innovations LLC
www.tarainnovations.com
October 17, 2011
Quality by Design
QbD is a systematic approach to development that
begins with predefined objectives and emphasizes
product and process understanding and process
control, based on sound science and quality risk
management.
Design space is the multidimensional combination and
interaction of input variables (e.g., material attributes)
and process parameters that have been demonstrated
to provide assurance of quality. Working within this
design space is not considered as a change.
Sterile Dosage Form Routes of Administration






Intravenous (IV)
Intramuscular (IM)
Subcutaneous (SC)
Intradermal (ID)
Intrathecal
Epidural
Other routes of administration
 Inhalation
 Intranasal
 Ophthalmic
 Wound cleaning solutions
Types of Sterile Formulations
1. Solutions ready for injection.
2. Powders
 Soluble, combine with a vehicle to form a solution
 Insoluble, combine with a vehicle to form a
suspension
3. Suspensions - ready for injection.
4. Emulsions
5. Liquid concentrates – Diluted prior to
administration
Another way to classify sterile dosage forms
 Large volume
 Small volume
Functions of Packaging Materials
Following are the key functions of packaging in
sterile dosage forms
 Protection : Physico-Chemical
 Protection : Microbiological
 Presentation : Appealing to patients
 Identification/differentiation
 Convenience of administration
 Ease of storage and transportation
Packaging concerns with drug products
° of Concern
with route of
Administration
Likelihood of packaging component – dosage form
interaction
High
Medium
Highest
Inhalation
Aerosols and
solutions;
Injectables – Solns.
and suspensions
Sterile powders,
powders for
injection,
inhalation
Powders
High
Ophthalmic pdts.,
Nasal sprays and
transdermal
ointments/patches
Low
Topical and oral
products
Low
Topical and oral Oral tablets and
powders
capsules
FDA’s Guidance for Industry, Container Closure Systems for Packaging Human Drugs & Biologics,
May 1999.
Primary packages of sterile formulations
Prefilled syringes
As Is
In an Auto-injector
2. Vials
 Glass
 plastic vials sealed with a rubber closure
3. Ampoules
4. Plastic bags
5. Inhalers
6. Ophthalmic drop bottles
1.


Secondary packaging
 Cartons – vials, ampoules, bottles
 Auto-injectors – Prefilled syringes
Steps in Quality by Design
 Pharmaceutical Product Profile
 Critical Quality Attributes
 Risk Management
ICH Guidance
Q8 - Pharmaceutical Development
Q9 - Quality Risk Management
Q10 - Pharmaceutical Quality Systems
Critical Quality Attributes and Effects of
Primary Packaging
Assay
2. Uniformity of dose
3. pH
1.
4. Sterility
4.
5. Endotoxins/pyrogens
5.
1.
2.
3.
Adsorption issue
Accuracy of delivery
Variation of pH during
storage in vials
Exposure to air during
multiple usage
Leaching of plastic
components from
sterile bags, rubber
closures
Critical Quality Attributes and Primary
packaging
6. Particulate matter
6. Precipitation, leachables
7. Water content and
penetration
8. Antimicrobial
preservative content
9. Antioxidant preservative
contents
7. Mainly for non-aqueous
formulations
8. Adsorption to the plastic
9. Permeability to oxygen,
heavy metal leaching in
vials
Critical Quality Attributes and Primary
Packaging
10. Extractables and
Leachables
11. Functionality of delivery
systems
12. Osmolarity
13. Particle size
distribution
10. Different dosage forms
11. Syringeability, pressure,
seal integrity and piston
travel etc.
12. Mainly important for
the release of product
13. Induce crystallization
Critical Quality Attributes and Primary
Packaging
14. Redispersability
15. Reconstitution time
14. Shape of primary
packaging
15. Transparency of
primary package
QbD Applications in Packaging
Quality can be designed in the product at two
levels
1. By selecting appropriate packaging design.
2. By adopting an appropriate packaging process.
Case Study 1
Extractable/Leachables Assessment – Establishing a
design space
Design space boundaries –
1. Aqueous drug products, pH 2 to 8, no polarity
impacting agents
2. Same packaging system
3. Fill volume – 50 to 1000 mL
4. Subjected to terminal sterilization and stored at 24°C
Applied to over 12 products. When operated within the
design space, the leachable profile was predictable.
Ref.: Dennis Jenke, PDA J. Pharm. Sci. Tech. 64 : 527 – 535 (2010)
Case Study 2
QbD: Prediction of Lyophilization cycle parameters
 Here lyophilization is considered as a packaging step
 There are three critical steps in freeze-drying : 1.
Freezing of drug solution in partially stoppered vials,
2. Primary drying to produce a cake, and 3. Desorption
phase for secondary drying.
 Nucleation temperature is affected by several
formulation and process factors.
 Primary drying step – Temperature should not go
beyond eutectic temperature, else the cake can
collapse
Mockus et. al. , AAPSPharmSciTech 12 : 442 – 448, 2011
Case Study 2
QbD: Prediction of Lyophilization cycle parameters
 Composition of formulation, pressure differential,
rubber stopper resistance for water vapor release, and
heating rate etc . could be some of the factors affecting
the primary drying.
 # of temperature gauges and their correct placement is
critical to determine the exact primary drying end
point.
 The design space is generally different for different
products.
Case Study 3
Syringes – Syringeability, and Injectability
Syringeability – ease of withdrawal, clogging, foaming
tendency and accuracy of dosing
Injectability – Force required for injection, evenness of
flow and freedom from clogging
Force-displacement plot – Plunger-stopper break loose
force, maximum force during injection and dynamic
glide force
Ref.: Cilurzo, F. et al., Injectability Evaluation : An Open Issue, AAPS
PharmSciTech 12 : 604 – 609 (2011)
Case Study 3
Needle
Gauge
Needle
length, mm
PBF (mPa)
Fmax (mPa)
DGF (mPa)
30
67
91
72
40
70
107
84
50
77
114
93
16
73
92
73
25
86
115
90
30
91
127
100
24
25
99
135
113
25
25
104
156
128
26
12
121
171
143
22
23
Ref.: Cilurzo, F. et al., Injectability Evaluation : An Open Issue, AAPS
PharmSciTech 12 : 604 – 609 (2011)
Plunger-stopper Break Force, Maximum force, and Dynamic glide force
Case Study 4
Silicone oil in syringes
 The stability of 3 protein formulations – 1. the
recombinant protective antigen for anthrax , 2.
Abatacept, and 3. an antistaphylococcal enterotoxin
monoclonal antibody was assessed in siliconized,
uncoated and BD-42 coated prefilled syringes.
 All three formulations showed subvisible and visible
particles in siliconized syringes. Except Abatacept,
other two formulations showed silicone oil droplets
Ref.: Majumdar et al., Evaluation of the effect of syringe surfaces on protein
Formulations, J. Pharm. Sci. 100 : 2563 – 2573 (2011)
Case Study 5
Comparison of cumulative radiation dose between ground and space flight
Payload
# days
Radiation dose,
Control, mGy
Radiation dose,
Space flight, mGy
1
0
4.54
1.93
2
353
4.84
44.12
3
596
5.06
74.53
4
880
5.45
110.70
Ref.: Du, B. et. al., Evaluation of physical and chemical changes in pharmaceuticals
Flown on space missions, The AAPS Journal, 13 : 299-308 (2011)
Case Study 5
Formulations failing chemical potency requirements, # out of 33 formulations
Payload (# days)
Control (%)
Space Flight (%)
1 (0)
0 (0)
1 (3)
2 (353)
2 (6)
11 (33)
3 (596)
8 (24)
17 (52)
4 (880)
16 (48)
24 (73)
Ref.: Du, B. et. al., Evaluation of physical and chemical changes in pharmaceuticals
Flown on space missions, The AAPS Journal, 13 : 299-308 (2011)
Case study 6
 Generation of Glass flakes in the injectable liquids
 Three model drugs – carboxylic acids
 Three types of glasses – A. Type I treated with
ammonium sulfate to reduce surface alkalinity, B. Type
I uncoated, and C. Type I coated with SiO2
 Depyrogenation temperature – 250 and 350°C/4 hrs
 Terminal sterilization cycles – 0 or 2
 Storage conditions – 5°C, 25°C, 40°C and 60°C
Iacocca, R.G. et al., AAPS PharmSciTech 11: 1340 – 1349 (2010)
Case study 6
Results
 pH dropped due to glass degradation
 ICP-OES analysis showed higher amounts of silicon
dissolved in A vials and more at 60°c compared to 40°C
 SEM analysis showed breakage of flakes from A.
 More # of particles were observed in A and at 60°C
compared to those generated at 40°C (Spectrex data).
 A decrease in glass durability could be explained by
the combination of the anionic nature of the drugs and
the pH of the solution
Case Study 7
Situation - Filling of a solution in the vials
Issue – During filling, the solution was foaming and
coming out of vials
Solution – Increased the needle diameter and decreased
the filling rate of vials to solve the issue.
Packaging waste
 Contaminated and un-contaminated
 Contaminated packaging is often incinerated
To protect environment, we should  Reduce unnecessary packaging
 Recycle – even glass can be recycled
 Incineration with caution – Burning of
polyvinylchloride is controversial (increase in dioxin
level)
Conclusions
 Packaging aspects must be considering during the
development of Sterile Dosage Forms.
 The packaging process parameters may affect the final
product quality
 During the development of packaging for sterile
products, understand the impact of material attributes
and process parameters on CQAs.
 Identify and control the sources of variability. For best
quality, continue to monitor these throughout the
lifecycle of the product.