Not only the primary packaging of a final drug product may leach undesirable compounds which may present safety risks for the patient, leachable impurities may also be introduced upstream in the (Bio)pharmaceutical production process. These impurities may be introduced into the product stream through contact with filters, filter housings, tubings, disposable bioreactors, storage bags, mixing systems, disposable lyophilization trays, impellers, connectors, chromatographic columns and column housings etc.

During the process validation of single-use technology, the assessment of extractables and potential leachables for disposable systems has become a substantial part of the validation documentation. However, no specific standards or guidelines make references to extractables and leachables from single-use disposable bioprocessing materials.

The FDA-Guidance “container closure systems for Packaging Human Drugs and Biologics” was not intended to describe the information that should be provided about packaging operations associated with the drug product manufacture. However, impurities – potentially introduced upstream in the production process – may also contribute to the adulteration of a drug. This makes the general approach of the FDA-Guidance (i.e. the classification of the risk based upon the route of administration) also relevant for the impact disposable/single-use systems may have on the purity of the final drug product.
In the US, a better guidance for the process validation of single-use technology may be given by the cGMP for finished pharmaceuticals. In the 21 CFR part 211.65, it is stated that “Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug product shall not be reactive, additive or absorptive so as to alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements...”

In Europe, although the EMEA Guideline on plastic immediate Packaging Materials is limited to packaging materials intended to come into contact with either the active substance or the medicinal product, it provides a framework on how to increase the level of documentation and what kind of information may be relevant to be included in a process validation file for single-use technology. Similar to the US cGMP, the European GMP-guideline states that: “Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive and absorptive to such an extent that it will affect the quality of the product and thus present any hazard...”.

Other regulatory guidelines which were used in the past to address the E/L issue for single-use technologies are the ICH Q3A, ICH Q3B(R), ICH Q3C, Ph.Eur. 5.4 and the similar USP <467> on residual solvents.

It is clear that all the above regulatory guidelines, compendial tests and other isolated initiatives – so far – did not lead to a harmonized approach to address the potential risk for introduction of impurities into the production stream. New initiatives, such as the BioProcess Systems Alliance (BPSA) are trying to provide a better and harmonized guidance in how both the vendors and the BioPharma Industry can work together in meeting the Regulatory Requirements, when addressing the qualification of disposable components.The BPSA has developed a decision tree on how to approach the validation of single-use systems, taking into account the information that is already available or that should be provided in a validation dossier.
Although the BPSA is an industry group (representing suppliers of disposable process components, systems and services to the biopharmaceutical industry) with no regulatory representation, it is expected that the conclusions of the BPSA will have a considerable impact on how process validations of single-use components will be approached in future.

Nelson Labs Europe is specialized in qualifying container closure systems for all disposable applications, starting from the typical compendial EP and USP testing up to a high level of Extractable/Leachable studies.

Because of our vast experience in qualifying disposable single-use systems for the Biopharmaceutical Industry, Nelson Labs Europe has built a broad expertise in developing testing programs which require a combination of state-of-the-art analytical techniques, such as Headspace GC/MS, PTV-GC/MS, GC/MS, LC/MS, LC/MS/MS, ICP, IC... In addition, Nelson Labs Europe can offer its assistance in the elucidation of structural information for critical compounds, using GC-ToF, LC-ToF, FT-MS or NMR.

Nelson Labs Europe works together with a broad base of container closure manufacturers in order to develop and qualify their products, as well as with pharmaceutical companies to give guidance in developing a strategy to comply with the regulatory requirements and to assist in their worldwide Regulatory Submissions.

If you would be interested to find out more about our services and testing programmes, please feel free to contact us at InfoEurope@nelsonlabs.com or call us at ++32 (0)16 400.484. 



Recommendations for Extractable/Leachable testing, Part 1; Bioprocess International, December 2007, pg 36-44.
Recommendations for Extractable/Leachable testing, Part 2; Bioprocess International, December 2008, pg 44-52.

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