Hemant N Joshi PhD MBA Tara Innovations LLC wwwtarainnovationscom 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 q ID: 411828
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Slide1
Implementation of QbD Paradigm in Sterile Dosage Form Packaging – Some Practical Considerations
Hemant N. Joshi, Ph.D., MBATara Innovations LLCwww.tarainnovations.com October 17, 2011Slide2
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. Slide3
Sterile Dosage Form Routes of Administration
Intravenous (IV) Intramuscular (IM) Subcutaneous (SC)
Intradermal
(ID
)
Intrathecal
Epidural
Other routes of administrationInhalation Intranasal Ophthalmic Wound cleaning solutionsSlide4
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. Emulsions5. Liquid
concentrates
– Diluted prior
to administrationSlide5
Another way to classify sterile dosage forms
Large volume Small volume Slide6
Functions of Packaging Materials
Following are the key functions of packaging in sterile dosage formsProtection : Physico-ChemicalProtection : Microbiological
Presentation :
Appealing to patients
Identification
/differentiation
Convenience
of administrationEase of storage and transportationSlide7
Packaging concerns with drug products
° of Concern with route of Administration
Likelihood
of packaging component – dosage form interaction
High
Medium
Low
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
Topical and oral powdersOral tablets and capsules
FDA’s Guidance for Industry, Container Closure Systems for Packaging Human Drugs & Biologics,
May 1999.Slide8
Primary packages of sterile formulations
Prefilled syringesAs IsIn an Auto-injector
2.
Vials
Glass
plastic
vials sealed with a rubber closure
3. Ampoules4. Plastic bags 5. Inhalers
6. Ophthalmic
drop bottlesSlide9
Secondary packaging
Cartons – vials, ampoules, bottlesAuto-injectors – Prefilled syringesSlide10
Steps in Quality by Design
Pharmaceutical Product ProfileCritical Quality AttributesRisk Management
ICH Guidance
Q8 - Pharmaceutical Development
Q9 - Quality Risk Management
Q10 - Pharmaceutical Quality SystemsSlide11
Critical Quality Attributes and Effects of Primary Packaging
AssayUniformity of dosepH
Sterility
Endotoxins/pyrogens
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 closuresSlide12
Critical Quality Attributes and Primary packaging
6. Particulate matter7. Water content and penetration8. Antimicrobial preservative content9. Antioxidant preservative contents
6. Precipitation, leachables
7. Mainly for non-aqueous formulations
8. Adsorption to the plastic
9. Permeability to oxygen, heavy metal leaching in vialsSlide13
Critical Quality Attributes and Primary Packaging
10. Extractables and Leachables11. Functionality of delivery systems12. 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 crystallizationSlide14
Critical Quality Attributes and Primary Packaging
14. Redispersability15. Reconstitution time
14. Shape of primary packaging
15. Transparency of primary packageSlide15
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.Slide16
Case Study 1
Extractable/Leachables Assessment – Establishing a design spaceDesign space boundaries –Aqueous drug products, pH 2 to 8, no polarity impacting agents
Same packaging system
Fill volume – 50 to 1000 mL
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)Slide17
Case Study 2
QbD: Prediction of Lyophilization cycle parametersHere lyophilization is considered as a packaging stepThere 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, 2011Slide18
Case Study 2
QbD: Prediction of Lyophilization cycle parametersComposition 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.Slide19
Case Study 3
Syringes – Syringeability, and Injectability Syringeability – ease of withdrawal, clogging, foaming tendency and accuracy of dosingInjectability – 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)Slide20
Case Study 3
Needle Gauge
Needle
length, mm
PBF (mPa)
Fmax
(mPa)
DGF (mPa)
22
30
67
91
72
40
70
107
84
50
77
114
93
23
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
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 forceSlide21
Case Study 4
Silicone oil in syringesThe 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)Slide22
Case Study 5
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
4880
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)
Comparison of cumulative radiation dose between ground and space flightSlide23
Case Study 5
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)Formulations failing chemical potency requirements, # out of 33 formulationsSlide24
Case study 6
Generation of Glass flakes in the injectable liquidsThree model drugs – carboxylic acidsThree types of glasses – A. Type I treated with ammonium sulfate to reduce surface alkalinity, B. Type I uncoated, and C. Type I coated with SiO2Depyrogenation 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)Slide25
Case study 6
ResultspH dropped due to glass degradationICP-OES analysis showed higher amounts of silicon dissolved in A vials and more at 60°c compared to 40°CSEM 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 solutionSlide26
Case Study 7
Situation - Filling of a solution in the vialsIssue – 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.Slide27
Packaging waste
Contaminated and un-contaminatedContaminated packaging is often incineratedTo 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)Slide28
Conclusions
Packaging aspects must be considering during the development of Sterile Dosage Forms.The packaging process parameters may affect the final product qualityDuring 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.