Observed trends in regulatory expectations for the qualification of pharmaceutical container/closure systems from an extractables and leachables perspective
A first observation you bring to the table is that – from a regulatory perspective – there is still a strong bias towards concerns about the quantitative aspect of E&L studies. Can you elaborate a bit more on this?
When assessing the impact of extractables or leachables from a safety perspective, there are two important pieces of information that will allow completing an in-depth toxicological assessment: the compound’s identity and its concentration or dose to the patient. The compound’s correct identification allows making the link to relevant toxicological information (e.g. literature). Alternatively, it can also be derived from in silico information (e.g. QSAR) if no relevant literature is available. Armed with this toxicological information, PDE’s or other relevant toxicological thresholds can be derived. In a second step, you can verify the impact for the patient by confirming if the patient’s exposure is above or below this PDE value, or you can calculate “Margin of Safety” values. While it is a valid concern that a “screening methodology”, often used for the discovery, identification, and quantification of extractables and leachables may only lead to estimated or semi-quantitative results, the obtained concentration “estimates” can still be used, in combination with well-defined uncertainty factors, which account for the lack of accuracy of the result. However, only a few questions are asked about the correctness of the identification of the compound, while identifications – e.g. based upon “mass spectral matching” – can lead to flawed identities, which will irreversibly compromise the overall risk assessment.
Continuing on the same theme of “compound identification”, are the regulatory requirements for fully elucidating the leachable structure above the associated Analytical Evaluation Threshold also a recent development?
Indeed, for parenteral drug products, for instance, there is a regulatory requirement to identify fully every leachable compound, present in a drug product, at levels that are at or above the AET level corresponding to a dose of 5 μg/day for non-chronic treatments or 1.5 μg/day for chronic applications. While that appears to be a valid requirement – you can only assess a compound if its identity has been determined unequivocally – it comes with a second observation that has all to do with how leachable studies are designed. This requirement comes with the inherent expectation that the drug product will not only be analyzed for target leachables identified as compounds of concern during the preliminary round of extractable investigations. You can only come across “unidentified” compounds if a leachable investigation also includes a “screening” step, assessing every single compound that is present in the drug product as a result of a prolonged container/closure contact. It also means that more efforts will be needed to identify these leachable compounds, which will inevitably result in the use of high-end analytical instrumentation, such as high-resolution accurate mass HRAM mass spectrometers.
One of the frequently reoccurring discussions is about the need or necessity to perform E&L studies on lyophilized drug products, as the interaction between a solid drug product and the container closure system is expected to be low. What is your viewpoint on this?
It is indeed true that E&L standards such as the USP<1664> standard on “Leachables” classify lyophilized/freeze-dried products in the low interaction category. It is expected that the interaction between a solid phase drug product and it’s container/closure system will not lead to any substantial leachables accumulation levels which – eventually – could be harmful to patients. However, you need to understand that the mechanism of interaction between the lyophilized (lyo) cake and its container/closure system is not through direct contact; rather it is a result of an “outgassing” mechanism of the lyo stopper with a subsequent adsorption step onto the lyo cake. Depending upon the quality of the rubber – and its corresponding impurities profile – volatile and semi-volatile compounds may, or may not, be released from the stopper through evaporation to the inner volume of the lyo vial. These “gas phase” leachables are then adsorbed onto the lyo cake. Taking into account that a lyo-cake is extremely dry and porous (with a high surface area), it becomes an extremely efficient adsorbent for all gas phase leachables, released from the rubber through evaporation. Accumulation levels of leachables during the shelf life of the drug product may therefore be substantially higher than you would expect from a low “direct contact” logic.
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Do you also see a growing interest in understanding how leachables may interact with therapeutic proteins, which is reflected in the FDA Guidance “Immunogenicity Assessment for Therapeutic Protein Products” (2014)?
The reactivity of leachables with the drug product or its ingredients (API, API-degradants, excipients…) is indeed a relatively new field in extractables & leachables research, although the impact of this phenomenon cannot be underestimated. Especially for (lyophilized) therapeutic proteins and peptides there is a substantial risk that some of the nucleophilic functional groups of the composing amino acids in proteins and peptides may interact with certain leachables with electrophilic functionalities. This may lead to (covalent) adduct formation, which may affect the quality and safety of the biologic drug product. One well-known historical example is the EPREX case where a direct “link” between the selection of primary packaging materials for the drug product and the occurrence of an immune response (PRCA) was clearly established. However, it is only in the last 5 years or so that a growing awareness that the immune response, observed with EPREX, may have led to a decrease of the red blood cell count, potentially caused by leachable protein adduct interactions. Therefore, if you want to develop an E&L evaluation strategy for biologics, not only is the “direct” toxicological information of the leachable relevant, you may also need to take into account the reactivity of a leachable as a predictor of concern with regard to potential immunogenicity issues.
Is the ability to correlate the extractables results with the analytical observations during a leachable assessment one of the new themes frequently requested by authorities?
While monographs in the USP with a number above 1000 are considered to be informative in nature, different aspects of what is the UPS <1663> (Extractables) and USP <1664> (Leachables) tend to be considered as a requirement when submitting for a marketing authorization in the US. One item in both the USP <1663> and USP <1664> is the advice to have correlating extractable and leachable information for the container/closure system you are developing for your drug product. While, at first, it may look a bit overdone - after all, it is only the leachable identities and respective doses that determine the risk to the patient – it is considered as a kind of Quality Control check if all extractable and leachable studies were well designed and performed with sufficient scrutiny. Leachables which were not detected as extractables in the composing parts of a container/closure system of concentrations or leachables which are substantially higher than the corresponding concentrations of the compound during the extractable investigation, for instance, may be an indication that one (or both) studies may have been ill designed.
Are you noticing that health authorities tend to request more information on the impact of Secondary Packaging on the drug product safety and quality?
Indeed, although secondary packaging has been in scope for the qualification of pharmaceutical container/closure systems since the release of the original FDA Guidance document, “Container/Closure Systems for Packaging Human Drugs and Biologics” (1999), the impact of secondary packaging on the leachable profile of a drug product is not always well understood. This includes labels, ink, pouches, overwraps, cardboard boxes etc. To determine if the secondary packaging needs to be taken into consideration, you need to evaluate the physical properties of the primary packaging as well. For instance, for semi-permeable, flexible materials (e.g. eyedropper bottles, nasal sprays or IV-bags) the risk of secondary packaging migration is obvious as some of the outer surfaces of these containers are almost completely covered with a label (e.g. eyedropper bottles). Also, blowfill-seal containers, produced for different applications and routes of administration, may be prone to migration of secondary packaging. In those cases, it is likely that an accumulation of leachables from the over pouch will be detected in the drug product. For example, additional information on the secondary packaging has recently been requested for more rigid polymer materials, which are used in the manufacture of SVP containers.
Piet Christiaens received his Ph.D. from the Analytical Chemistry Department of the University of Leuven (Belgium) in 1991. From 1992 to 1997, he was Lab Manager in two Analytical Contract Laboratories.
From 1997 to 2000, he worked as an independent consultant with Shell Chemical Company in Houston, TX (US) where he conducted research on a new hydrogenation catalyst system for Hydrogenated Triblock Copolymers (Kraton Polymers).
From 2001 onwards, Mr. Christiaens held the position of Scientific Director with Toxikon Europe where he developed analytical methods and protocols for both extractables and leachables studies for the Medical and Pharmaceutical Industries. In his current role at Nelson Labs Europe, Mr. Christiaens supports the Strategy and Global Business Development for Extractables and Leachables Service Offerings for Pharmaceutical and Medical Applications.