All materials chosen for use in a disposable (single-use) bioprocess must pass the specifications in USP 27, monograph c88:
Biological Reactivity Tests, In Vivo: Classification of Plastics, Class VI. If the disposable materials require a very long holding time, those materials may need to meet the requirements set forth
in ISO 10993–1:2003, Biological Evaluation of Medical Devices Part 1: Evaluation and Testing or in the FDA Blue Book memorandum, Required Biocompatibility Training and Toxicology Profiles for Evaluation of Medical Devices. In addition, materials used in a disposable bioprocess should be fully evaluated in terms of extractables profiles and potential
leachables. Routine QC extractables methods should be developed and validated to qualify incoming material components of the
Extractables and leachables studies are only one of many aspects of qualifying materials. Other aspects such as impurity,
potency, and mechanical properties, etc., should also be evaluated to ensure that materials used in a disposable bioprocess
are compatible with drug product formulations and manufacturing process parameters.
Product quality control can be achieved through well-designed process development, evaluation, and characterization, which
begin with the selection of materials used in a manufacturing process. In this article, a roadmap has been presented for a
comprehensive extractables and leachables evaluation to establish the suitability of materials used in a disposable bioprocess.
Different analytical technologies used to support extractables and leachables studies have their own capabilities and limitations.
Depending on the materials used in the disposable bioprocess, specific requirements are needed for the E/L study designs to
support the manufacturing process qualification and validation from an E/L perspective. Furthermore, disposable containers
designed for low-temperature storage, holding, and processing such as plastic bags made from ultra-low temperature film used
in the freeze-and-thaw cycling process-can be evaluated, characterized, and quantified, as demonstrated in the case studies.
New global regulations such as ICH Q8, Q9, and Q10 are steering the pharmaceutical and biopharmaceutical industries to move
toward the new paradigm of QbD. The study design approach presented here is based on the importance of a scientific understanding
of compounds that could be extracted or leached from disposable materials that make contact with a drug product during manufacturing
and product use; the approach is, thus, a means of incorporating quality by design into a disposable biopharmaceutical manufacturing
The authors wish to acknowledge the support of their employer, PPD, Inc., and to acknowledge, in particular, Magdalena Mejillano,
Tom Rosanske, Donald F. DeCou, Bert Kittner, Louise Caudle, and Joel Galang for their productive input.
Xiaochun Yu is a senior research scientist, Derek Wood is a laboratory manager, and Xiaoya Ding is the director of scientific and technical affairs, all at the cGMP laboratory, PPD, Inc., Wilmington, NC, 910.558.7585,
1. Product Quality Research Institute. Safety thresholds and best practices for extractables and leachables in orally inhaled
and nasal drug products. Arlington, VA; 2006.
2. International Conference on Harmonization. Q7, Good manufacturing practice guide for active pharmaceutical ingredients.
Geneva, Switzerland; 2000.
3. International Pharmaceutical Excipient Council. Good manufacturing practices guide for bulk pharmaceutical excipient.
Leidschendam, the Netherlands; 2001.
4. International Organization for Standardization. Biological evaluation of medical devices: Evaluation and testing; Framework
for identification and quantitation of potential degradation products; Tests for systematic toxicity; Establishment of allowable
limits for leachable substances; and Chemical characterization of materials. Geneva, Switzerland; 2003, 1999, 2006, 2002,
5. US Food and Drug Administration. Blue Book Memorandum #G95-1. Required biocompatibility training and toxicology profiles
for evaluation of medical devices. Rockville, MD; May 1995.
6. International Conference on Harmonization. Q8, Pharmaceutical development. Geneva, Switzerland; 2005.
7. International Conference on Harmonization. Q9, Quality risk management. Geneva, Switzerland; 2005.
8. International Conference on Harmonization. Q10, Pharmaceutical quality systems. Geneva, Switzerland; 2007.
9. Bio-Process Systems Alliance. Component quality test matrices. Washington, DC; Apr–May 2007.
10. Deng T, Yu X, Cliff H, Rude D, Ding X. Identification of Irganox 1010 and Irgafos 168 degradation products by LC-MS and
GC-MS. Pittcon 2005 Meeting; Orlando, FL. 2005 Feb 27–Mar 4.