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Implementation of QbD Paradigm in Sterile Dosage Form Packaging – Some Practical Considerations

Implementation of QbD Paradigm in Sterile Dosage Form Packaging – Some Practical Considerations. Hemant N. Joshi, Ph.D., MBA Tara Innovations LLC www.tarainnovations.com October 17, 2011. Quality by Design.

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Implementation of QbD Paradigm in Sterile Dosage Form Packaging – Some Practical Considerations

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  1. Implementation of QbD Paradigm in Sterile Dosage Form Packaging – Some Practical Considerations Hemant N. Joshi, Ph.D., MBA Tara Innovations LLC www.tarainnovations.com October 17, 2011

  2. 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.

  3. 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

  4. 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

  5. Another way to classify sterile dosage forms • Large volume • Small volume

  6. 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

  7. Packaging concerns with drug products FDA’s Guidance for Industry, Container Closure Systems for Packaging Human Drugs & Biologics, May 1999.

  8. 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

  9. Secondary packaging • Cartons – vials, ampoules, bottles • Auto-injectors – Prefilled syringes

  10. 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

  11. Critical Quality Attributes and Effects of Primary Packaging • Assay • Uniformity of dose • pH • 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 closures

  12. 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

  13. 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

  14. Critical Quality Attributes and Primary Packaging 14. Redispersability 15. Reconstitution time 14. Shape of primary packaging 15. Transparency of primary package

  15. 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.

  16. Case Study 1 Extractable/Leachables Assessment – Establishing a design space Design 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)

  17. 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

  18. 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.

  19. 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)

  20. Case Study 3 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

  21. 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)

  22. Case Study 5 Comparison of cumulative radiation dose between ground and space flight Ref.: Du, B. et. al., Evaluation of physical and chemical changes in pharmaceuticals Flown on space missions, The AAPS Journal, 13 : 299-308 (2011)

  23. Case Study 5 Formulations failing chemical potency requirements, # out of 33 formulations Ref.: Du, B. et. al., Evaluation of physical and chemical changes in pharmaceuticals Flown on space missions, The AAPS Journal, 13 : 299-308 (2011)

  24. 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)

  25. 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

  26. 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.

  27. 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)

  28. 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.

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