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Implementation of QbD Paradigm in Sterile Dosage Form Packa Implementation of QbD Paradigm in Sterile Dosage Form Packa

Implementation of QbD Paradigm in Sterile Dosage Form Packa - PowerPoint Presentation

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Implementation of QbD Paradigm in Sterile Dosage Form Packa - PPT Presentation

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

quality packaging study primary packaging quality primary study case space vials sterile design dosage process formulations 2011 force ref

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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.