Case Study

Extractables And Leachables Studies Support Single-Use Systems

By Aryo Nikopour, Senior Vice President, Scientific & Technical Services, Nitto Avecia Pharma Services

Extractables And Leachables Studies Support Single-Use Systems

Single-use systems have gained a surprisingly strong foothold in the drug manufacturing market thanks to improved extractables and leachables studies.

Not long ago, concerns about leachables were expected to restrict adoption of single-use systems.

2015 Survey Found Limited Interest in Disposable Systems

One of the most widespread concerns in the biopharmaceutical industry in 2015 was plastics and their additives, by-products, and other non-fully-polymerized polymer and formulated plastics’ leachables affecting bioprocessing and related products.1

The 2015 BioPlan Report and Survey of Biopharmaceutical Manufacturers found three-quarters of respondents agreed or strongly agreed that this concern limited their adoption of single-use systems.

Yet three years later, the same annual survey found high adoption rates for these disposable systems. It appears the worries had vanished.

2018 Survey Showed Dominance of Single-Use Systems

According to the 2018 BioPlan report, pre-commercial bioprocessing was dominated (approximately 85 percent) by single-use systems.2 The report provides a composite view and trend analysis from 222 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations in 22 countries.

Nitto Avecia Pharma Services Conducts E&L Studies of Single-Use Bioprocess Bags

Nitto Avecia Pharma Services has contributed to the growing adoption of single use system by providing successful extractables and leachables services.

In one case, the company investigated disposable bioprocess bags for a small molecule drug substance. The bags were made of an advanced medical-grade film — a five-layer 14 mil cast co-extruded polyolefin film. The outer layer was a polyester elastomer co-extruded with an EVOH barrier layer and an ultra-low-density polyethylene product contact layer.

The layers of the film also included co-polyester ether, a blend of maleic anhydride modified and unmodified polyethylene, ethylene vinyl alcohol, and an ethylene alpha olefin material.

Commercial bag sizes can vary from less than 1 liter to more than 1,500 liters.

These E&L studies examined two types of 100 mL disposable bioprocess bags.
Nitto Avecia Pharma Services used the following analytical techniques in this case:3

  • Ion chromatography to quantitate inorganic and organic acids in the bags
  • Analysis of headspace volatile organic compounds and Soxhlet solvent extractables for semi-volatile organics
  • Analysis of Soxhlet IPA/Heptane/H2O extractions for polar, non-polar and aqueous extractables.

Here are the model extraction conditions:

  • All samples stored at 60°C for zero, one, two, three, and four weeks
  • Model extraction solution analyzed by IC, GC/MS, and LC/MS

Here are the results:

The controlled extraction study found the following 20 potential leachables.

  • four low molecular weight (MW) acids: acetic, boric, citric, and formic acids
  • three long chain aliphatic carboxylic acids: palmitic, stearic, and myristic acids
  • five low MW non-antioxidant aromatic compounds: dibutylphthalate; dibutyl phthalate, 2; 4-di-tert-butylphenol, 1; 3-di-tert-butylbenzene, and 2,2’-bipyridyl
  • four amides: erucamide; hexadecanamide; octadecanamide; oleamide
  • three antioxidants: Irganox 1010, Irganox 1076, and Irganox 168
  • one siloxane: decamethylcyclopentasiloxane

Unknown Peak Creates Study Obstacle

The biggest challenge of the Nitto Avecia Pharma Services study was determining the structure of an unknown peak on the MS/MS scan. This was found to be an Irgafos 168 degradant called bis(2,4-di-tert-butylphenyl) phosphate. The study team had to synthesize the degradant because there was no authentic standard.

It conducted synthesis, characterization, method development and validation, and quantitation of the sample in the bioprocess bags throughout the shelf-life studies. The outcome was a report giving the client more confidence to use the disposable system for its drug substance.

Clearly, advances in manufacturing quality such as those achieved by Nitto Avecia Pharma Services are bringing renewed interest in single-use systems. Future data from Bioplan and other market research firms may show expanding adoption of disposables.

References
1. Eric Langer. Leachables And Extractables In Single-Use: Trends and Expectations Over Plastics Innovation. Bioprocess Online, March 5, 2015.
2. Ronald A. Rader, Eric Langer. Fifteen Years of Progress: Biopharmaceutical Industry Survey Results. PharmTech.com, July 2, 2018.
3. Best practices guide for evaluating leachables risk from polymeric single-use systems used in biopharmaceutical manufacturing. Biophorum Operations Group, April 2017.