Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products

A practical and science–based approach for addressingtoxicological concerns related to leachables and extractablesassociated with inhalation drug products

Packaging and device components of Orally Inhaled and Nasal DrugProducts (OINDP) such as metered dose inhalers, dry powderinhalers, and nasal sprays pose potential safety risks fromleachables and extractables, chemicals that can be released ormigrate from these components into the drug product. Addressing theconcepts, background, historical use, and development of safetythresholds and their utility for qualifying leachables andextractables in OINDP, the Leachables and Extractables Handbooktakes a practical approach to familiarize readers with the recentrecommendations for safety and risk assessment established througha joint effort of scientists from the FDA, academia, and industry.Coverage includes best practices for the chemical evaluation andmanagement of leachables and extractables throughout thepharmaceutical product life cycle, as well as:

Guidance for pharmaceutical professionals to qualify andrisk–assess container closure system leachables and extractables indrug products

Principles for defining toxicological safety thresholds that areapplicable to OINDP and potentially applicable to other drugproducts

Regulatory perspectives, along with an appendix of key terms anddefinitions, case studies, and sample protocols

Analytical chemists, packaging and device engineers, formulationdevelopment scientists, component suppliers, regulatory affairsspecialists, and toxicologists will all benefit from the wealth ofinformation offered in this important text.

Acknowledgements.

Dedication.

Preface.

Part I. Development of Safety Thresholds, Safety Evaluation,and Qualification of Extractables and Leachable in Orally InhaledNasal Drug Products.

1. Chapter 1. Overview of Leachables and Extractables in OrallyInhaled and Nasal Products (Douglas J. Ball, Daniel L. Norwood,Lee M. Nagao).

2. Chapter 2. A General Overview of the Suitability for IntendedUse Requirements for Materials Used in Pharmaceutical Systems(Dennis Jenke).

3. Chapter 3. Concepts and Application of Safety Thresholds inDrug Development (David Jacobson–Kram and Ronald D.Snyder).

4. Chapter 4. The Development of Safety Thresholds forLeachables on Orally Inhaled and Nasal Drug Products (W. MarkVogel).

5. Chapter 5. The Analytical Evaluation Thresholds (AET) and itsRelationship to Safety Thresholds (Daniel L. Norwood, James O.Mullis, Scott Pennino).

6. Chapter 6. Safety Thresholds in the PharmaceuticalDevelopment Process for OINDP: An Industry Perspective (DavidAlexander and James Blanchard).

7. Chapter 7. The Chemistry and Toxicology Partnership:Extractables and Leachables Information Sharing Among the Chemistsand Toxicologists (Cheryl L. M. Stults, Ronald Wolff, Douglas J.Ball).

8. Chapter 8. Use of Safety Thresolds in the PharmaceuticalDevelopment Process for OINDP: US Regulatory Perspectives(Timothy J. McGovern).

9. Chapter 9. The Application of Safety Thresholds to QualityLeachables from Plastic Container Closure Systems Intended forPharmaceutical Products: A Regulatory Perspective (KumudiniNicholas).

Part 2. Best Practices for Evaluation and Management ofExtractables and Leachables in Orally Inhaled and Nasal DrugProducts.

10. Chapter 10. Analytical Best Practices for the Evaluation andManagement of Extractables and Leachables in Orally Inhaled andNasal Drug Products (Dan Norwood, Cheryl Stults and LeeNagao).

11. Chapter 11. Chemical and Physical Attributes of Plastics andElastomers: Impact on the Extractables Profile of Container ClosureSystems (Michael A Ruberto and Diane Paskiet).

12. Chapter 12. Pharmaceutical Container Closure System Selection & Qualification of Materials (Douglas J. Ball,William P. Beierschmitt, and Arthur J. Shaw).

13. Chapter 13. Analytical Techniques for Identification ofExtractables and Leachables (Dan Norwood, Thomas N. Feinberg,James O. Mullis, and Scott Pennino).

14. Chapter 14. Extractables The Controlled ExtractionStudy (Thomas N. Feinberg, Daniel L. Norwood, Alice T. Granger,and Dennis Jenke).

15. Chapter 15. Extractables Case Study of a SulfurElastomer (Daniel L. Norwood, Fenghe Qiu, James Coleman, JamesO. Mullis, Alice T. Granger, Keith McKellop, Michelle Raikes, JohnRobson, David Olenski, John Hand, Sr., Melinda K. Munos, TianjingDeng, Xiaochun Yu, Derek Wood, Shauang Li, Song Klapoetke andXiaoya Ding).

16. Chapter 16. Extractables Case Study of aPolypropylene (Diane Paskiet, Laura Stubbs, and Alan D.Hendricker).

17. Chapter 17. Leachables Analytical Leachables Studies(Andrew D. Feilden and Andy Rignall).

18. Chapter 18. Development and Optimization of Methods forRoutine Testing (Cheryl L. Stults and Jason M. Creasey).

19. Chapter 19. Critical Component Quality Control andSpecification Strategies (Terrence Tougas, Suzette Roan, andBarbara Falco).

20. Chapter 20. Inorganic Leachables (Diane Paskiet, ErnestL. Lippert, Brian D. Mitchell, and Diego Zurbriggen).

21. Chapter 21. Foreign Particulate Matter (James Coleman,John A. Robson, John A. Smoliga, and Cornelia B.Field). 

DOUGLAS J. BALL is a board–certified toxicologist (Diplomateof the American Board of Toxicology) and currently employed byPfizer Inc. as a Research Fellow in drug safety R&Dspecializing in regulatory strategy and compliance. He chairs theExtractables and Leachables Safety Information Exchange (ELSIE)Board of Directors, and the Toxicology Team of the Product QualityResearch Institute (PQRI) Leachables and Extractables Working Groupfor both OINDP and parenteral and ophthalmic drug products.

DANIEL L. NORWOOD is a Distinguished Research Fellow inAnalytical Development at Boehringer Ingelheim and has more thanthirty–five years of professional experience. He chaired the PQRILeachables and Extractables Working Group and is a thirty–two–yearmember of the American Chemical Society (ACS). Dr. Norwood is amember of the ELSIE Board of Directors.

CHERYL L. M. STULTS is a Senior Fellow at NovartisPharmaceuticals Corporation, focusing on materials analysis andcharacterization. She chairs the International PharmaceuticalAerosol Consortium on Regulation and Science (IPAC–RS) Materialsand Leachables and Extractables Working Groups and is a member ofthe ELSIE Board of Directors. Dr. Stults is a thirty–three yearmember of the ACS.

LEE M. NAGAO is a Senior Science Advisor in thePharmaceutical Practice Group at Drinker Biddle & Reath LLP. Asa member of the IPAC–RS Secretariat, Dr. Nagao supports theConsortium′s initiatives in materials quality, leachables andextractables, supplier quality, and foreign particles. She was amember of the PQRI OINDP Leachables and Extractables Working Groupand serves as Science Advisor and Secretariat to the ELSIEConsortium. Dr. Nagao is a member of the ACS and the AAAS.

However, since this handbook provides clear, relevantinformation across both toxicology and pharmaceuticalanalysis/development, it is probably most useful for practicingtoxicologists or chemists, providing both a detailed reference todip into and a means of better understanding the requirements andcontributions of colleagues working in the otherdiscipline.   (British Toxicology Society, 1 July2013)

However, the book is extremely well written and is acompelling read.  The book accomplishes its goal to provide astate of the art review with respect to mercury . . . The bookserves as an excellent educational resource.  ( International Journal of Toxicology, 31 May 2012)