Identification of Unknown Extractables and Leachables Using Mass Spectrometry: Identification With Confidence?

Abstract
Extractable and Leachable (E&L) studies on materials used in the manufacturing process and container closer systems of drug products and drug substances are commonly used to assess the risk for patient exposure. Most often LC-MS or GC-MS is used to detect, identify and then quantify extractables and leachables as part of evaluation of safety and quality. In general, an analytical evaluation threshold or reporting threshold is set based on a calculated patient exposure. Substances above the set threshold required further investigation if patient exposure exceeds this. Substances need to be accurately identified to enable a toxicological risk assessment which considers the risk of patient exposure. However, how confident are we when we identify a substance using spectral libraries? A match with mass spectral libraries, data from orthogonal techniques, fragmentation data and availability of a reference standard can increase the level of confirmation. We will discuss an approach for different levels of identification possible and how to increase the level of confidence of identified extractables and leachables.

Introduction
Regulatory authorities require extractable and leachable (E&L) studies on components used in the manufacturing process, medical devices and container closure systems (CCS) to assess the risk for patient exposure to potential leachables in drug products (DP)1. Ideally, the drug substance (DS) and DP contain only intentionally added ingredients. However, during the manufacturing process the DS and DP are in contact with manufacturing components. Substances from the manufacturing components can enter the manufacturing process stream and end up in the final DS or DP. In a similar way, substances from the CCS and medical devices which are in contact with the DP can potentially leach to the DP.
Extractable studies are performed on components used in the manufacturing process, CCS or medical device which are in contact with the DS and DP to identify substances to which a patient might be exposed to. Leachable studies are performed on the DP to identify substances to which the patient is exposed to. Leachables in the DP can potentially impact the quality and safety for the patient of the DP. Therefore, leachables must be profiled in the DP to assess the quality and safety for patients and to trace the sources of leachables present in the DP, extractable studies can support this.
Due to the wide variety of components used in the manufacturing process, CCS and medical devices and the great number of substances with different chemical properties used in these components, comprehensive screening is required using hyphenated analytical techniques.
In extractable studies, the aim is to extract a wide range of substances with different chemical properties, therefore the solvent and extractions conditions should be carefully considered. This may mean an exhaustive extraction or a more selective extraction aiming to simulate a particular formulation or set of conditions.
In leachables studies, analysis of the drug product (and the drug substance) can confirm the presence of substances detected through any extractable study, the key difference being that substances detected and quantified represent a closer estimate to patient exposure.
Organic extractable and leachable substances are generally categorized and analysed based on their volatility; Volatile substances can be detected, identified and quantified using head-space GC-MS, semi-volatile substances by liquid injection onto a GC-MS and non-volatile substances by liquid injection into a LC-MS. These three hyphenated analytical techniques cover a wide range of substances with different polarities. Inorganic extractables and leachables are generally detected using ICP-MS. To assess the potential impact of leachables substances on the safety to patients a threshold for detected substances is set based on calculated patient exposure. This same threshold can then be applied to extractable studies. If a leachable substance exceeds the set threshold a toxicological assessment is required to assess the risk for patient exposure. For a toxicological risk assessment, the identity and level of the substance is required. The increased availability of high-resolution mass spectrometry and spectral libraries has dramatically improved the identification of extractable and leachable substances. However, confidence of the identification can vary between analytical techniques due to mis-identification using spectral libraries, availability of reference standards or confirmation via complementary methods. Protocols and methods have been developed for E&L studies including identification and toxicological risk assessment2, but clear definition of levels of confirmation of their identity are generally missing and are not addressed fully in regulatory guidance. Confidence in the identity of detected extractables and leachables is necessary to accurately assess the risk for patients. We will focus on identification and confirmation of extractables and leachables using LC-MS and GC-MS and propose an approach for identification and confidence levels for extractables and leachables.

Identification of extractables and leachables using mass spectrometry
Profiling extractables and leachables includes; detecting the substances, establishing their identities and determining their concentrations3. Approaches to identify small molecules using mass spectrometry have been described and are widely used for non-targeted screening to identify a great number of substances4,5,6. For E&L studies a detection threshold should be set based on the dosing regimen for the medicine under study and only substances which exceed this threshold need to be identified and quantified. In addition, for E&L studies, prior knowledge of components used in the manufacturing process, CCS or medical devices can be beneficial to predict the identity of detected extractables and leachables, this prior knowledge might provide information about materials and substances added to the components. Nevertheless, comprehensive screening methods should be used to cover a wide variety of substances with different chemical properties.
Most commonly, GC-MS is used to analyse volatile and semi-volatile extractables and leachables, whereas LC-MS is used for identification of non-volatile extractables and leachables. With electron impact (EI) ionisation in GC-MS most often characteristic fragments of molecular ions of the substances are detected. Whereas, the soft ionisation techniques (Electrospray and Atmospheric-Pressure Chemical Ionisation (ESI and APCI)) commonly used in LC-MS impart less energy resulting in a protonated or deprotonated molecular ion containing few or no fragmentation ions. Additionally, the type of mass analyser also has a major impact on the detection limits and spectral information available and therefore identification of the substance. There are several kinds of commercially available mass analysers which can be broadly divided into low resolution and high-resolution systems. Low resolution MS generates nominal mass which can aid in both elucidation and identification of a substance and has the advantage of being relatively cheap and easy to use. In addition, high resolution MS allows prediction of a molecular formula from an accurate mass of the molecular ion or further aids elucidation from fragment ions but comes with added complexity of operation and is more expensive to purchase.
Depending on the ionisation techniques and mass analyser, the number of fragment ions and the corresponding signal intensity can vary between substance specific spectra. EI GC-MS spectra are more consistent compared to LC-MS spectra. LC-MS/MS spectra can vary greatly depending on the collision energy. A variety in collision energies for LC-MS/MS is commonly used to give further insight in fragmentating ions.

Deconvolution of GC-MS and LC-MS signals
Deconvolution is a mathematical algorithm designed to simplify a complex signal; separating MS ions of interest from within a convoluted chromatographic signal to improve the quality of a derived mass spectrum by selective enhancement of the relevant information from the chromatographic signal and removal of interference.
Raw data acquired with GC-MS and LC-MS need to be processed before it can be analysed and interpreted. In order to successfully identify a substance, the peak purity of a chromatographic peak is of major importance. If the derived spectrum from a chromatographic peak is a mixture of two or more components, then probability of successful identification is reduced. Therefore, effective deconvolution of LC-MS and GC-MS signals to ensure purity of spectrum prior to interpretation is a necessary step where purity of the chromatographic data cannot be assured, which is nearly always the case with complex trace analysis. Deconvolution of mass spectra is used to correlate retention time, peak width, peak shape and ion abundance to create a pure spectrum for each substance and to reveal peaks in poorly resolved spectra. Deconvolution software is available online or can be included in the software package provided by the vendor of the MS instrument. Several algorithms for deconvolution have been described and shown to be successful in the identification of substances, however false positives and negatives are also reported7,8,9,10. Deconvolution software provided by vendors from MS instruments usually do not provided information about the algorithm, which can limit the understanding on how the data is processed and effect the accuracy of the output.
Control blanks should be included to ensure extractables and leachables do not arise from sample preparation or analysis. During deconvolution, background interferences (e.g. column bleed and noise) are discarded because they do not show a chromatographic peak shape. In GC-MS generally 70 eV is used for ionisation, LC-MS spectra are generally recorded at a range of energy levels to include not only the molecular ion but also information on fragment ions. Spectra obtain with different energy levels are grouped together when they show an identical retention time and peak shape resulting in a list of candidates for identification.
Most software package contain an option to generate a molecular formula from the spectrum of the peak of interest. The spectral interpretation to generate a molecular formula is based on whether the data is acquired in positive or negative mode, accurate mass, isotope ratio, minimum and maximum number of potential elements included by the user and generates a list of potential elemental compositions.

Spectral libraries
A number of computer-assisted mass spectral library search procedures have been developed over the last decades11 and the number of published spectral libraries is increasing. A range of public and commercially available spectral libraries for LC-MS and GC-MS have been reviewed and discussed6,12. Most of these spectral libraries are developed for specific compound classes or mass analysers. Comparing obtained spectra with commercially or publicly available spectral libraries is currently the fastest approach to identify substances, but care must be taken to avoid mistakes. In the field of extractables and leachables, the NIST GC-MS database is probably the most commonly used library to identify substances detected with GC-MS due to its great number of spectra and its wide application range. Identification of substances through the use of public or commercial libraries detected with LC-MS tends to be less successful and more problematic than GC-MS. MS spectra derived from LC-MS are subject to large variation due to lack of uniformity in how the spectra are created with a variety of ionisation types and variation within ionisation type due to no universal standards and the diversity of mass analysers. In GC-MS, the near universal use of electron (impact) ionisation at 70eV, allows much easier comparison of reference spectra.
Due to a limited number of LC-MS spectral libraries commercially available and varying specific spectra based for substances depending on the ionisation technique and mass analyser, in-house spectral libraries are commonly created. These in-house spectral libraries mainly contain substances of interest for a specific class or group of compounds. Mueller et al developed an LC-MS library on an enhanced product ion scan at three different collision energies in positive mode to be able to identify 301 drugs13. An in-house library, containing 174 additives, was successfully created and used to identify leachables in vaccine, however due to this limited number one peak could not be assigned14.
Some mass spectrometry vendors sell spectral library as optional software package with their instruments. The advantage is that these spectral libraries are instrument specific, but they contain a limited number of spectra which can only be updated by the vendor and these spectral libraries are generally expensive. It is becoming more common for vendor software package to allow the integration of on-line data sources and import libraries from multiple sources6. This allows users to access a larger number of libraries.
To be able to build a spectral library, high quality mass spectra are required. High quality spectra can be obtained from a reference material or preferably certified reference material; however these reference materials are not always available. Reference compounds can be synthesised, but the purity and identity of the compound synthesis must be confirmed with additional analytical techniques (e.g. MS, NMR, FTIR). Improper data acquisition methods can hinder compound identification based on spectral comparison. For example, using a high fragmentor or cone voltage can result in loss of the parent ion due to in source fragmentation, leading to MS/MS data acquired on fragmentation ions instead of the parent ion. Therefore, high quality spectra require expert evaluation. One of the limitations is that spectral library files are often built in different formats making it difficult to share spectral libraries and compare spectral library searches.
As an alternative to manual interpretation of mass spectrum it is increasingly possible to use in-silico fragmentation software to suggest potential fits to observed fragmentation patterns15. These fragments can then be compared to a growing number of online databases. These in-silico predictions can be a useful tool in supporting structure elucidation, however the identity of the structure should be confirmed using a reference standard and experimental data.
The reliability of a spectrum match with the library spectrum can differ for several reasons. Useful spectral information can get lost due to settings used to process the spectrum. Frequently the molecular ion is not the most prominent ion and can be absent all together in GC-MS due to the high energy used for EI resulting in fragmentation. This can result in identification of a fragment of the extractable or leachable instead of the molecular structure. Stereo-isomers can have identical spectra and structural information of functional groups cannot be assigned from MS spectral information. Although there are a great number of compounds in spectral libraries, not all compounds have been added to spectral libraries. If a substance does not give a match with a spectral library the question whether the substance is actually in the library should be considered.
To our knowledge, complete spectral libraries for extractable and leachable studies are not available. Most libraries contain some extractables and leachables. Whereas in the field of metabolomics, proteomics and environmental sciences it is very common to share spectral library information16,17, spectral information about extractables and leachables and impurities in DS and DP is lacking and infrequently shared.
The best hit from the spectral library is often reported as the most likely candidate however, false positives and negatives can arise from this process18. A false negative can occur when a substance has not been assigned, because the substance has been discarded due to settings used in the workflow to identify substances. False positives can occur when substances are positively matched against the wrong candidate. Therefore, it is crucial to evaluate the probability of mis-identification before posing a scale of confidence for the identification of extractables and leachable substances and to understand the processes by which a spectral library hit is assigned.

Levels of identification
A reference material is essential for confirmation of the identity of the substance. A reference material is defined as a “Material, sufficiently homogeneous and stable with respect to one or more specified properties, which has been established to be fit for its intended use in a measurement process”19. This reference standard can then be used to provide support to any mass spectral library. For commercial or public spectral libraries, it would confirm the spectral match is correct and it will also offer the orthogonal confirmation of identity required through a chromatographic retention time match and the opportunity to generate supporting data such as a molecular formula or FTIR or NMR spectrum which in turn can be compared under some circumstances. Without the availability of the reference material the reliability is only on a spectral match which can result in a mis-identification18.
USP<1663> provides an example of a frame work for the identification of extractables and leachables19. Additionally, parameters to be considered for identification are compound composition, and isomeric possibilities, molecular weight and mass defect, matrix and its clean-up, chromatography, and detection specificity including mass accuracy and mass resolution17. We propose the following workflow and levels for identification of extractables and leachables using mass spectrometry which builds on to the USP framework:

Level 1: Confirmed
A reference standard is available from which the following information has been gathered:

(a) An accurate mass
(b) A retention time on the same chromatographic system
(c) Other spectroscopic information to confirm identity (e.g. fragmentation data, collision cross section)

The above data has been compared to confirm the identity of substance of interest. The suggested requirement here is that the proposed structure has been confirmed by a reference standard with retention time, MS spectrum and MS/MS spectrum. A strategy of combining hyphenated techniques (e.g. LC-MS, GC-MS) and organic synthesis (to derive the reference standard) was successfully used to identify and confirm extractables from rubber closures used21. It should be noted, mass spectrometry is not able to distinguish between isomers, and isomers are not always separated using GC or LC. Spectral information from orthogonal techniques can be used to confirm the identified substance and provide confidence of the structural information.

Level 2: Confident
No reference standard is available. Able to propose a structure which has little or no ambiguity in position of functional groups on molecule.
The following information is available:

(a) A spectral match (above predefined criteria) to a commercial library or internal library. Match made on the basis of characteristic fragment ions or molecular ion.
(b) Retention time information in library or equivalent.
(c) Proposed molecular formula is a good match.

A reference standard is not available, but it is possible to propose a structure with a high probability that this structure is correct. This may be based on a good spectral library match but is very often supported with range of other information. Care must be taken when searching for spectra in spectral libraries. It is a mistake to consider the highest-ranking score as the identified substance, other hits should be considered as well together with elemental composition followed by database search and mass fragment tools could help to elucidate the structure of substances that could not be identified by using libraries14. The match is supported by characteristic fragment ions or molecular ion. The proposed molecular formula is a good match with the accurate mass observed in the spectrum of the molecular ion or fragment ions. Data from orthogonal techniques (e.g. NMR, FTIR) or other analytical techniques (e.g. UV, deuterium exchange, ion mobility) can be used to support the proposed structure.

Level 3: Tentative
No reference standard available. Proposal for structure can be made but confidence that it is the only viable structure in lacking; e.g. alternative structures might be suggested from data available. The following information in available:

(a) Spectral match is poor or incomplete to a commercial or internal library, perhaps the match can suggest a compound class or some functional groups, but there is insufficient structural information available.
(b) Multiple empirical formula match to available data but allows a structure to be proposed.

Substances are classified as tentative identified when a spectral match with a spectral library is poor or incomplete and/or multiple empirical formulas match to available data. A molecular formula can be assigned based on spectral information (e.g. isotope ratio, adduct or fragmentation information), however there is insufficient structural information. If the substance is only observed in extractable studies and not found in leachable studies a toxicological risk assessment is not needed. But the molecular formula provides information and can be presented as it can be traced in future studies.

Level 4: Unknown
No reference standard available. No proposal for a structure can be made from available data.

(a) Only nominal mass or accurate mass available with a retention time which cannot be matched to any spectral library information.
(b) Accurate mass does not give information which allows a proposal for molecular formula

The exact mass of an E&L substance is determined, however there is insufficient information about the molecular formula. If the substance is only observed in extractable studies and not found in leachable studies a toxicological risk assessment is not needed. But the molecular formula provides information and can be presented as it can be traced in future studies.

Orthogonal techniques and supporting information for confirmation
MS information alone provides insufficient information for structural elucidation and identification of extractables and leachables. Orthogonal techniques or supporting information from other analytical techniques can and should be used to determine the correct structure and are capable of producing compound specific data which are complementary to mass spectrometry. Additional structural information can be obtained from separation methods (e.g. ion mobility, chromatography), detection methods (e.g. NMR, IR, UV) or chemically (e.g. H/D exchange, chemical derivatisation). A major issue to overcome in the structural identification of any small molecules is the ability to isolate compounds in high purity and in reasonable quantities for identification and confirmation as many studies rely on multiple chromatographic purification steps to increase yield and purity. Another common issue is the stability or instability of the isolated compound.
NMR and IR techniques can support the structural information; however these techniques require generally a few milligrams to elucidate the structure. Since extractable and leachables are usually present at trace levels, the substance needs to be isolated from the sample and concentrated for successful NMR or IR analysis. IR spectroscopy is a powerful tool for identifying different functional groups in a molecule. IR measures infrared absorption and emission spectra of pure compounds and/or mixtures of compounds and takes advantage of the fact that molecules absorb specific frequencies that are characteristic for their structure (i.e. bond type, and presence of specific moiety). The advantage of IR over NMR and MS is that it is relatively quick, simple and non-destructive. IR is a powerful spectroscopic technique that provides insight into functional groups as well as the chemical composition. Photodiode array detectors and UV detectors are non-destructive detector and can easily be coupled to LC-MS. The absorption of UV light and/or visible region of the electromagnetic spectrum depends on the conjugated π-electron system present in an organic compound, the UV spectrum provided additional structural information4. After isolation and enrichment, NMR, UV and IR can be powerful techniques to further confirm the molecular structure of unknowns after identification with MS22.
Ion mobility incorporated with MS is a recently developed technique which can be used to separate and identify ionised molecules in the gas phase based on their mobility in a carrier buffer gas and can be used to provided information on size and shape of gas phased ions. Ion mobility high-resolution mass spectrometry may offer possibilities for applications where reference standards are not available. An orthogonal ion mobility based filter can remove multiple charged ions as well as noise and artefact and significantly reduces the false positives and hardly increase false negatives22. In ion mobility, an additional separation of incoming unfragmented ions occur before the ions reach the detector which result in a drift time separation of ions. Drift time filtration can reduce the list of candidate components. Peak deconvolution alone removes a lot of noise, while drift time filtering is capable of further removing fragments not related to the investigated precursor ion resulting in a reduced list of potential candidates10.
Hydrogen/deuterium (H/D) exchange and/or chemical derivatisation can be used when different structures are proposed. Hydrogen atoms bound to atoms such as oxygen, nitrogen and sulfur are exchange by a deuterium and the mass difference by exchanged deuterium can be easily detected using mass spectrometry. H/D exchange can provide additional structural information when the proposed structures contain a different number of exchangeable hydrogen atoms. With chemical derivatisation the physicochemical properties of the molecule are changed to provide knowledge of the number of certain functional groups that can be derivatised and therefore structural information.

Conclusion
The complexity of identification and confirmation of extractables and leachables poses a significant challenge and requires significant expertise for successful E&L studies. We presented an approach for levels of confidence for identified extractables and leachables which can be modified and improved in the future. The purpose of this approach is to provide guidelines for confirmation of identified extractables and leachables and is a step forwards to improve quality and safety of DS and DP. Data-sharing can give a boost to promoting the wider use of mass spectral libraries for extractable and leachable studies.

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Author Biographies
Petra Booij obtained a PhD in analytical chemistry from the VU University in Amsterdam, The Netherlands. She is currently working in GSKs E&L team based in Stevenage (UK). Her work focusses on trace level analysis, identification and confirmation of E&L using mass spectrometry, and risk assessments of E&L within biopharma and cell and gene therapy. She is a member of the ELSIE leachable team and involved in harmonising approaches for leachable testing.

Jason Creasey is a graduate Analytical Chemist. He has recently setup as an independent consultant providing advice in the area of extractables and leachables, after working for GSK in the area of extractables and leachables since the mid 1990’s.
Over that time, he has seen demand in this area grow exponentially and Jason has held roles of increasing seniority relating to the support that GSK has given to extractables and leachables (E&L). Before setting up Maven E&L Ltd, he was the director of a team of analytical chemists who are responsible for GSK’s global R&D support for E&L activities across a wide range of product types and modalities. This included; biopharmaceutical and small molecules including Inhalation, Parenteral and Cell & Gene Therapy use. He has had the pleasure of commenting on PQRI guidelines on E&L for GSK, the E&L section in EMEA guidelines on inhalation and nasal products and co-authoring a chapter within a book entitled “Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products”.
Jason has been a member of several external groups concerned with the development of best practice guides for extractable and leachables issues these include; the IPAC-RS material working group, BPOG and continues as a scientific advisor to Extractable and Leachable Safety Information Exchange otherwise known as ELSIE. Currently he is working and commenting on risk- based approaches to E&L requirements, which he hopes will form part of an ICH guidance in the not too distant future.



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