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 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 powders

Oral tablets and capsules

FDA’s Guidance for Industry, Container Closure Systems for Packaging Human Drugs & Biologics, May 1999.

Primary packages of sterile formulations

1. 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

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

1. Assay

2. Uniformity of dose

3. pH

4. Sterility

5. Endotoxins/pyrogens

1. Adsorption issue

2. Accuracy of delivery

3. Variation of pH during storage in vials

4. Exposure to air during multiple usage

5. Leaching of plastic components from sterile bags, rubber closures

Critical Quality Attributes and Primary packaging

6. Particulate matter

7. Water content and penetration

8. Antimicrobial preservative content

9. 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 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)

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 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

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)

Comparison of cumulative radiation dose between ground and space flight

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 formulations

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.