Extractables, leachables and QbD
Written by Dr. Paolo Biffignandi, Advisory Board member of the pan-European pharmaceutical regulatory affairs organisation ELC Group and former President of TOPRA (The Organisation for Professionals in Regulatory Affairs), and Lini Subin, Head of Regulatory Affairs at ELC Group.
Extractables and leachables are increasingly becoming a cause of major concern for both the pharmaceutical industry and regulatory bodies. The development of unique packaging, novel formulations and drug-coated medical devices has exacerbated this issue. The FDA is demanding more and more information about every packaging component and its potential to interact with the final product. Furthermore, the increasing popularity of single-use disposables — such as filters, tubing and bags for biopharmaceuticals — can introduce unwanted extractables into the final product.
Extractables are chemical species mostly generated by interaction between products and their packaging (gaskets, stoppers, storage bags, cartridges and prefilled syringes) over time, usually under extreme conditions, e.g., in the presence of strong solvents or elevated temperatures. Leachables are compounds that leach into the drug or biological product from the container-closure system. Leachables are typically a subset of extractables and they generate as a result of direct contact with the formulation under normal conditions of use.
In the case of plastic containers, typical extractables and leachables are additives and processing aids such as antioxidants and other stabilisers, plasticisers, emulsifiers and colourants but also monomers and oligomers of the plastic polymer and all kinds of reaction products. Useful information can often be obtained from vendors regarding the formulation of the polymer packaging but the issue remains complex as the full manufacturing chain from raw materials all the way to a plastic container involves different specialised manufacturers and full traceability is hard to obtain. Quite generally, containers meant to protect a drug from environmental contamination are themselves a source of contamination.
In the pharmaceutical industry, it is not only containers that are a source of leachables. Combination products such as inhalers and pens or even more sophisticated medical device equipment like insulin pumps and implants may all leach unwanted chemicals.
The regulatory perspective on safety qualification of extractables and leachables is an ever-green issue impacting on:
• Efficacy, e.g., leachable interacting with an active ingredient, resulting in a loss of activity.
• Safety, e.g., toxicity, immunogenicity and endocrine disruption.
• Quality, e.g., impact on the manufacturing process, product stability and interference with drug assays/medical diagnostic tests may increase the impurity level of a drug product, etc.
An area of increasing concern and scrutiny for the US FDA’s Center for Drug Evaluation and Research (CDER) is the potential adulteration of drug products by extractables and leachables that enter a drug from a container, closure system, disposable or device.
From a manufacturing point of view, a crucial evaluation is the assessment of their place in the process stream (e.g., upstream vs. downstream). Typically, risks are greater as production moves closer to the finished product. The surface-to-volume ratio, contact time and type of polymeric material are further important points to consider and risk should often be assessed on a case-by-case basis.
The Regulatory guidances on extractables and leachables are:
• Federal Food Drug And Cosmetics Act.
• Good Manufacturing Practices — 21 CFR (CFR 211.94 — Drug Product Containers and Closures and CFR 211.160 — General requirements).
• EU Directives.
• CDER Guidance Documents for Industry.
• EMA and Health Canada Guidelines.
• Standard compendia — USP/EP/ICH Q4 (Annexures), Q6A, Q8.
It can be challenging to effectively design a programme that will adequately address and evaluate the extractable/leachable issues associated with the container closure system, delivery devices and processing equipment.
The concept of Quality by Design (QbD), originating from the platform principles outlined in the ICH, Q8R, Q9 and Q10 guidelines, reflects the current global regulatory thinking related to pharmaceutical products. QbD will ideally lead to better-understood products and manufacturing processes that will be subject to less variability in quality. A cornerstone of the QbD paradigm is the concept of a design space, a multi-dimensional combination of input variables and process parameters that have been demonstrated to provide the assurance of product quality. It has been proposed that this concept can be applied to the safety (leachables) assessment of drug products manufactured and stored in packaging systems.
For an extractables and leachables evaluation to be meaningful and successful, QbD must be a collaborative approach on the part of the drug manufacturer, component vendor, analytical laboratory, toxicologist and regulatory agency. Each party has critical input and is a significant contributor to the overall process.
Dr. Paolo Biffignandi, paolo@elc-group.com.