The risks posed by extractables and leachables (E&Ls) on product quality and patient safety is an ongoing challenge for the pharmaceutical industry. In this roundtable discussion, industry experts provide insight on E&L testing using a risk-based approach, including how acceptance limits are set. The participants were Diane Paskiet, director, Scientific Affairs, West Pharmaceutical Services, and chair of the Product Quality Research Institute (PQRI) Parenteral and Opthalmic Leachables and Extractables Working Group; Andreas Nixdorf, team manager, Extractables & Leachables Testing, and Chris Harbach, CSci CChem FRSC, manager, Chemical Services, both at the laboratory services division of SGS Life Science Services; and Karl Abele, project manager, Extractables & Leachables Testing, Solvias AG.
Common sources of E&Ls
PharmTech: What are the common sources of E&Ls and what measures can you take to reduce such risk?
Nixdorf (SGS): Any material in direct contact with a drug solution could potentially cause contamination through leaching. This change in the product’s composition can impact its therapeutic effectiveness—E&Ls may reduce stability, alter impurity profiles, inactivate the active ingredient, alter the smell, taste or color of the product, and cause it to fail quality-control assays. Regulations in both the United States and the European Union state that production equipment should not introduce hazards to the product. In addition, chemical compatibility (regarding E&Ls) of packaging and product must be evaluated. Production equipment, such as filters, single-use bags, and tubes, have large contact surfaces, and the materials used to make them must be carefully tested for suitability. There is, however, often a lack of extractables data from materials manufacturers, and without detailed knowledge and control over all the ingredients, obtaining a reliable E&Ls profile is difficult. The selection of a good supplier is as important as the selection of a good material.
Harbach (SGS): Polymers are the most common source, whether plastics or rubbers, but they can also arise from glass, metal, adhesives, printing inks, and cardboard packaging. The supply chain is the main problem given that the materials are processed in several locations with additives added at each stage, and full composition information is often not available to the end-user. In the past, additives were included to impart specific properties with no consideration of E&L potential. This issue is compounded by the fact that the pharma sector only uses a tiny amount of worldwide production volumes.
Risk can be reduced if there is good communication throughout the supply chain, and the end-user is informed of all changes. Ideally, the end-user will develop a close relationship with a polymer supplier who specializes in pharmaceutical container/closure systems, and will be aware of the issues around E&Ls, and supply extractables profiles. Non-polymer-related risks can be reduced, for example, by using high-quality glass, avoiding problematic ink formulations, and selecting adhesive with low E&L potential.
Paskiet (West): Materials that come into direct or indirect contact with a drug or biologic product have the potential to leach substances into the final pharmaceutical product. Substances that may leach can originate from various materials at any point in the pharmaceutical supply chain and throughout the product lifecycle. Constituents that leach from primary packaging into the final product when manufactured and stored under its normal conditions are referred to as leachables. Typically, leachable compounds are found in trace amounts but can have a negative impact on pharmaceutical quality with potential to compromise patient safety. Any component used during drug or biologic manufacture, storage, shipping, and administration to the patient can be implicated as a source of E&Ls.
Manufacturing and delivery systems consist of multiple components. In addition to being compatible with the drug product and safe for patient use, suitable materials must protect the drug product, as well as perform and function properly. Primary classes of materials used to manufacture and store drugs and biologics include rubbers, plastics, glass, metal, and paper components. A pharmaceutical product can be affected by leached substances with distinct outcomes—for instance, the leachable entity can be toxic, or the leached substance can react with the APIs or excipients to form a new chemical entity or affect the stability of the final pharmaceutical. The risk to the patient needs to be assessed and mitigated based on understanding the potential for leaching, and this is accomplished by designing systematic studies to identify and quantitate extractable substances.
Component profiles have many levels of complexity, which may become more varied once the component is formed, washed, sterilized, and assembled. Common sources of extractables include residuals and by-products from the material. Processing aids and additives, such as stabilizers, antioxidants, lubricants, curatives, and breakdown products, are all examples of species contributing to the chemical profile.
An extractable study will establish the chemical profile, which reflects risks relative to potential toxicity and incompatibility. Toxicity will depend on the leachable concentration in the final product and patient total daily intake. Incompatibility is fundamentally dependent upon the pharmaceutical matrix and conditions of use. Compatibility issues are often manifested by different end points such as pH shift, degradation, oxidation, aggregation, foreign articles, and other impurities that become evident over time.
All materials will leach to some degree under certain conditions. The goal is to provide evidence that the materials are suitable for intended use by understanding how risk for leaching correlates to patient harm and eliminating or mitigating that risk.
Designing E&L studies
PharmTech: What are the key considerations when designing E&L studies? Can you describe a risk-based approach to E&L testing?
Paskiet (West): An E&L strategy consists of multiple steps in which voluminous information is acquired and builds until the final drug product stability studies are completed. It can span a period of five years or more from discovery to confirmation. Formal risk assessment tools such as flow diagrams, control charts, risk ranking/filtering or hazard analysis, and critical control points can add value, although these tools are not required.
The objective of an E&L study is to identify risk by conducting controlled extractable studies, which can be correlated to drug/biologic safety and quality. The first step in designing a study is to identify the various components to be evaluated and the degree of evaluation. Criticality should be assessed based on the likelihood of component interaction with the drug/biologic product during manufacture, storage, or when in contact with a patient.
Once the components are deemed critical for evaluation, the chemical make-up of each material should be understood. This chemical profile will feed into the component sampling, preparation of extracts, and analysis techniques. Multiple solvents that encompass organic as well as aqueous solutions should be employed to explore a comprehensive chemical profile. Multiple analytical techniques that are orthogonal are recommended to detect and confirm a wide range of extractable species with a wide range of sensitivities. Analytical methods should be fit for purpose--that is, having a system capable of detecting certain predetermined targets at specified levels as well as detecting unexpected extractables.
A material’s chemical profile should be generated using aggressive solvents under exaggerated conditions to indicate the basic chemical characterization; however, this approach is often not indicative of actual leachables. Understanding the chemical profile is necessary because trace leachables are easily masked and difficult to detect in a complex matrix. Spiking and recovery studies are necessary to confirm the presence or absence of target compounds. In certain applications, it can be an advantage to simulate or mimic the final product subjected under exaggerated conditions to better define targets. The purpose of extractable studies is to provide comprehensive data to indicate risk for leaching and guide a leachables assessment. Correlation of the component extractables with confirmed leachables under worst-case conditions will lead to the necessary control strategy.
Harbach (SGS): The key consideration when designing an E&L study is patient safety. For small-molecule pharmaceuticals, the concern is over leachables from the container/closure system. For biopharmaceuticals, an additional concern is any interaction of leachables with the biopharmaceutical product that can adversely affect its potency and efficacy, or cause immunomodulatory effects. These attributes should be monitored in addition to any leachables.
When designing an E&L study, there is no ‘one-size-fits-all’ approach. In a risk-based approach, due consideration should be given to the nature of the drug product, the dosing regimen, the container/closure system, and the nature of the treatment. Risk/benefit should also be considered; higher levels of leachables would be acceptable in a drug used for the treatment of cancer than in, for example, aspirin.
Extraction solvents for controlled extraction studies should be chosen to mimic, as closely as possible, the nature of the drug product. While a controlled extraction study should be designed for the worst-case scenario, it should not use overly harsh solvents compared with those in the drug product. For example, an aqueous-based drug product could be mimicked with water at varying pH values and a water/isopropanol mixture. On the other hand, for a drug product, such as an oral or nasal spray with an organic propellant, solvents such as n-hexane and dichloromethane would be more appropriate.
Contact time and temperature are also key considerations when designing a controlled extraction study. PQRI recommendations give appropriate extraction methods, temperatures, and times for orally inhaled and nasal drug products (OINDP), such as reflux and Soxhlet extraction. For parenteral and ophthalmic drug products (POPD) with water-based extraction solvents, methods such as autoclaving and migration (e.g., 55 °C for 72 hours) are more appropriate.
The resulting extracts should be concentrated and analyzed by a wide range of analytical techniques in an attempt to detect all potential leachables. It is important to ensure that any extractables (and potential leachables) can be detected down to an appropriate level--the PQRI recommends 0.15 µg per day for OINDPs (1), while a level of 1.5 µg per day can be used for POPDs (2). These values need to be converted into an analytical evaluation threshold (AET) (e.g., µg/mL) using information on amount dosed, doses per day, and doses per container/closure system. Allowance (usually 50%) should also be made for analytical uncertainty. If the drug product is to be given over a shorter period than a lifetime, then the stepped thresholds described in ICH M7 may be used (3).
Once extractables (potential leachables) have been identified and quantified, an experienced toxicologist should review the data and recommend which compounds are of sufficient concern that they should be monitored as leachables in the stability trial samples of the drug product. The choice of potential leachables to monitor is dependent on their toxicity at the maximum dose likely to be received by the patient. These leachables should then be analyzed using validated methods (ICH Q2) (4). It is important that an end-of-shelf-life sample is monitored as part of this process. Following the leachables analysis, the data should again be reviewed by a toxicologist to ensure none of the leachables are at a level that would have an adverse effect on a patient.
Nixdorf (SGS): The key quality criterion is the absence, or a minimal level, of extractables that become leachables. Common sense implies that selecting component materials based on extractables profiles is very difficult without comprehensive data, and controlled extractables testing and toxicological assessment of observed extractables is essential.
When designing studies, solvent and extraction parameters such as time and temperature should not be so harsh they damage the polymer, and vendor information about the additives a polymer contains is a good starting point for determining decomposition pathways.
It is advisable to start a risk-based E&L assessment program based on a comprehensive knowledge of the process, including R&D studies, process descriptions, batch records, standard operating procedures (SOPs), technical reports, batch testing, data trending, and operating parameters. A list of product contact materials should include any material with the potential to migrate into the product at any point in the process. For each material, risk factors (scoring of risk should be documented) include material compatibility, location in the process, nature of the product, surface area, contact temperature and time, and pre-treatment steps.
Multiple analytical techniques must be selected to ensure no E&Ls are missed, and any that are found can be identified. Results should be assessed by a toxicologist. The route of patient administration and whether the product is for acute or chronic use should be included in the assessment because the risk levels differ—the concentration of a leachable in the drug product is less important than the amount accumulated by the patient.
Abele (Solvias): Principally, two different E&L strategies are currently being used. The classical approach is based on defining the targets expected by conducting an analysis of the materials used in the device tested. In particular, non-volatile compounds, which are not accessible by gas chromatography-mass spectrometry (GC–MS), are monitored by simple liquid chromatography with diode-array detection (LC–DAD) or LC–triple-quadrupole target methods, with a limited number of target compounds. As the material information provided by manufacturers is often incomplete, this approach has a significant risk of missing toxicologically relevant compounds.
The advances in analytical technology (in particular, the improved availability of LC/MS/MS systems with accurate mass capability) have opened up an alternative route, which is based on non-target analysis of larger additives (e.g., bisphenol A diglycidyl ether-type coatings, pentathiaethylenethioglycol oligomers, and hindered-amine light stabilizer-type additives). At Solvias, we have developed a database (EXLEA) comprising accurate mass LC/MS/MS data of nearly 6000 polymer additives and their degradation products.
We perform target analysis for all EXLEA compounds by monitoring all extracted ion chromatograms (extracted ± 5 mDa) above a defined threshold, thus increasing the sensitivity for compounds in our database by typically three orders of magnitude compared to visual inspection of base-peak chromatograms (BPCs). In addition, BPCs are manually inspected for compounds currently not contained in our database. Our approach typically results in the identification or semi-quantification of 20–50 hits per extract, which would have been missed using a simpler, target-based study layout without accurate mass LC/MS/MS screening.
Planning an extractables study starts with the definition of the reporting threshold for extractables related to the device tested, which will be based on considerations such as the route and frequency of the drug product administration and the dose applied to the patient. After this, a study protocol will be defined (which includes device definition, reporting threshold of the study planned extractions, screening methods for volatiles, semi-volatiles, non-volatiles, and inorganic compounds).
The extractables study report will contain identification and semi-quantification of any extractables detected above the reporting threshold. Additionally, we may include a toxicological assessment in the study report, which evaluates the complete list of compounds detected by using a software-based quantitative structure activity relationship (QSAR) approach. Compounds classified by the software as Cramer Classes III–V will be further examined by our toxicological experts.
Based on the extractable study report and the toxicological assessments, target compounds for the leachables study will be defined. For these targets, quantitative methods will be developed and validated according to ICH Q2(R1) (4). In most cases, GC/MS/MS and LC/MS/MS target methods will be used. In parallel, stored drug samples will be analyzed with screening methods to monitor secondary leachables (e.g., reaction products of target compounds with the drug formulation).
Setting acceptance limits
PharmTech: How do you set acceptance limits? What guidance has regulators provided on this issue?
Nixdorf (SGS): Setting acceptance limits involves the extrapolation of agent-induced health effects in animals to human risks. For drug development, the methodologies for threshold-associated exposures are discussed in ICH Q3C (5). This guideline discusses a method for calculating a permissible daily exposure (PDE) for a solvent, although calculating PDEs for mutagens and carcinogens is more complex. Toxicological data are often required to do a risk assessment that can be obtained from rodent lifetime bioassays for example. The data, however, are rarely available for impurities found in drug products, and it is impractical to test all potential carcinogens this way. As a result, toxicologists devised the concept of TTC that represents a level of exposure for a chemical below which there is no appreciable risk to human health. The PQRI’s Leachables and Extractables Working Group has also developed various thresholds and analytical methods for E&Ls to help establish whether testing is necessary.
Harbach (SGS): The extractables analyses conducted at SGS M-Scan for OINDPs are based on PQRI recommendations, which have been used for submissions to US, European, and Canadian regulators. The recommendations suggest the use of a safety concern threshold (SCT) of 0.15 µg per day for patient exposure (1).
Extractables analyses for other drug products (e.g., PODP) are usually based on the EMA genotoxic limit of 1.5 µg per day for patient exposure (6). The latest information from the PQRI suggests that they will also adopt this level for PODP. FDA, however, recommends particular limits for potential leachables within ophthalmic products and these limits will need to be followed when submitting ophthalmic data to FDA.
Paskiet (West): There are limits in various compendia for certain materials used in the pharmaceutical and medical-device industries; however, these limits are considered a starting point to identify materials that might be acceptable. The final drug or biologic product will influence appropriate specifications and acceptance criteria. Acceptance criteria should be set based on the observed range of variation according to FDA and ICH guidance—Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products (Q6A) and Biological Products (Q6B) (7, 8). The guidance establishes the criteria to which a drug and biologic product should conform to be considered acceptable for its intended use. There is a provision for control of extractables from container/closure systems in which parenteral products are considered significantly important. The guidance indicates that where development and stability data show evidence that extractables are consistently below levels demonstrated to be acceptable and safe, the elimination of this test can be accepted but should be reinvestigated if the container/closure system or formulation changes. The guidance also recommends that data should be collected for components as early in the development process as possible. This recommendation is consistent with quality guidelines ICH Q8, ICH Q9, and ICH Q10 (9-11).
Acquiring appropriate evidence to demonstrate suitability of materials is necessary for each pharmaceutical product. Extractables are a function of the material chemical make-up, physicochemical properties, configuration of the component, various environments, and length of exposure. Risk variables include component proximity to the final product, area of direct contact, dosage form, and conditions of use throughout material processing, manufacturing, filling, and storing. Risk for leachables can be indicated based on identifying those extractable compounds with the highest propensity to leach into the final product. The extraction and analysis methods should be tailored to substantiate that leachable levels are below quality and safety concerns. This approach allows risk of toxicity or poor quality to be identified and mitigated. It is not practical to assume that a standard method, or even suite of methods, can provide the essential evidence. A strategic approach for demonstrating safety thresholds and best practices for E&Ls in OINDPs has been demonstrated by PQRI and is currently in process for PODPs. Recent United States Pharmacopeia (USP) guidelines <1663> Assessment of Extractables Associated with Pharmaceutical Packaging and Delivery Systems and <1664> Assessment of Leachables Associated with Pharmaceutical Packaging and Delivery Systems were published in USP Pharmacopeial Forum 39 in September 2013 and are consistent with PQRI approaches (12, 13).
To set acceptance criteria for E&Ls, relevant data must be collected and assessed. It is important to justify specifications based on impact to the final product and the patient. Control points can be considered early on, but the nature of leaching often occurs over a period of time. Variability will exist from component to component as well as the extractables’ propensity to leach. Control points are not easily derived until there are multiple lots of components representing full shelf-life stability studies. Once an analytical target profile is established for leachables, methods should be optimized and measurements fully validated. Statistically relevant data are necessary to establish acceptance criteria.
PharmTech: What analytical techniques are used in the identification and quantification of E&Ls?
Paskiet (West): Identification and quantification of E&Ls covers a broad range of extraction and analytical techniques. The overall goal of the study is to detect and measure leachables and interpret the data with regard to safety risk based on total daily exposure and alerts for incompatibility. The scope of a leachable study includes understanding materials, which begins with an extractable study.
The objective of an extractable study is to provide evidence to support leachables assessments. Depending on the intended outcome, different methods will be fit for different purposes. The material should be characterized to confirm chemical make-up and establish suitable methodology. The output would indicate general compatibility and potential for a material to leach. In this case, aggressive extraction techniques using multiple solvents of varying polarity are generally employed. Extraction techniques can also be designed to simulate worst-case conditions relative to the actual product or a placebo to indicate probable leachables. If the extraction media is complex, extractables can be masked and method optimization may be necessary. Extractions using complex media for discovery of extractables are not recommended unless known targets for spiking and recovery have been justified. Extractions should not be so mild that information is insufficient, or so overly aggressive that it leads to misleading extractables data. Extractability is influenced by variables of extraction techniques as related to time, temperature, solvent/media, sample surface area, static versus dynamic with consideration of the polymer properties, and diffusion/migration characteristics.
Solvent-extraction methods include standard Soxhlet, reflux apparatus, shakers, and sonication equipment. Instrument-based extraction techniques include microwave, accelerated solvent extraction (ASE) or supercritical fluid extraction (SFE). A host of methods for volatile organic extraction exist such as headspace samplers, dynamic headspace, thermal desorption, solid-phase microextraction (SPME), stir bar sorptive extraction (SBSE), and thermal desorption techniques. The extraction techniques should be optimized, and in some cases, method development for extractions techniques will be necessary.
Once the extract is generated, it is possible that dilution, concentration, or solvent exchange is warranted. Depending on chemical species of interest and analytical technique, isolation of trace compounds in complex mixtures or derivitization to increase volatility can be considered.
There is not a single analytical technique capable of detecting all volatile and non-volatile organics, or inorganic E&Ls. GC or LC techniques are generally employed to separate mixtures of organic compounds. Many chemical species that are likely to migrate are amenable to GC due to the mobility of low molecular weight volatile compounds. High-performance liquid chromatography (HPLC) can separate diverse species with a wide range of molecular weight, polarity, or conductivity. Typically, chromatographic techniques are paired with MS. This method will measure the molecular mass of charged ions providing molecular structure of chemical entities, and is the mainstay of extractable identification.
Organic compounds can be targeted for quantitative analysis based on results of a basic extractables screen. Some materials have known safety or quality targets to be investigated. There are multiple detectors to consider depending on the intended outcome. MS is compound specific, but there could be a need to measure a specific type of compound with low sensitivity or wide/narrow ranges of concentrations. Different options include: flame-ionization detector, which has a linear response across a wide range; electron-capture detector, which is more suitable for detecting halogenated compounds; and photoionization detector for low level volatile organics. Often LC employs a photodiode-array detector to obtain ultraviolet (UV) and visible spectra. The value depends on specific needs and examples noted are not implied to be all-inclusive.
Extractable screening studies typically produce numerous unknown and known organic compounds. Equally as important are screenings for inorganics. Even though the number of inorganics is limited to the periodic table, there are unique challenges. Trace levels can interact with drugs or biologics, and in some cases, may be toxic. There is potential for elements to leach, but some of these elements already exist in drug-product excipients whereas others are ubiquitous and difficult to trace to the source. It is the accumulation of all elements in the system that will impact the final dosage form. Most inorganics from component materials are not readily soluble and should not be a significant contributor to the end product but should be realized. A semi-quantitative screen of extracts across the periodic table of the elements is commonly performed using inductively coupled plasma mass spectroscopy (ICP–MS) or atomic emission spectroscopy (ICP–AES). The plasma will atomize/excite atoms that are ionized and detected by MS or, in the case of AES, the photons are detected by optical methods. In certain cases, such as mercury, arsenic, or chromium, speciation may be warranted and may require other excitation and detection techniques. Once a comprehensive list of extractables is derived, selecting the critical extractable is the next challenge. Methods should be robust and have the capability to detect the unexpected E&Ls.
Modern analytical technology offers a wealth of tools in various combinations. Critical to establishing the extractable profile are the extraction solvents/media and technique. Only the chemicals extracted will be detected, so worst-case scenarios must be considered. An example of detailed extractable protocols can be found at www.PQRI.org.
The totality of the extractable data will lead to the leachable analytical target profile. Leachable methods often will use the same techniques as those used for extractables. In most case, the techniques need to be optimized to eliminate interferences and achieve appropriate sensitivities.
Accurate and reliable measurements that are fully validated are necessary to provide leachable data. Accelerated leachable data can be useful but will not take the place of shelf-life stability studies. The stability of the final pharmaceutical product over the shelf life should be observed for unexpected leaching resulting in poor quality, which can be in the form of an impurity, particle, or degradants. The multiple and diverse tools of modern analytics provides a means for thorough E&L evaluation. The analytical techniques are abundant but the challenge is choosing an appropriate methodology for the relevant information to link the acquired knowledge to product quality and patient safety.
Harbach (SGS): Extraction from container/closure systems is carried out using a range of techniques including Soxhlet extraction, reflux, ultrasonication, autoclaving, and migration testing in ovens for extended periods. These extracts are concentrated and/or solvent exchanged to provide suitable aliquots for analysis.
At SGS M-Scan, we typically performed our analyses using one of more of the following major pieces of equipment:
- Triple-quadrupole mass spectrometer fitted with an atmospheric pressure chemical ionization (APCI) ion source and incorporating a HPLC system with a variable wavelength UV detector for the analysis of fluorinated compounds from polytetrafluoroethylene-coated seals.
- Single-quadrupole mass spectrometers fitted with a combined electrospray/APCI ionization (ESCi) source and a ultra-performance liquid chromatography (UPLC) system with a diode-array detector (UV) for the analysis of non-volatiles and more polar species.
- Triple-quadrupole mass spectrometer fitted with an ESCi source and a UPLC system with a diode-array detector (UV) for the analysis of non-volatiles and more polar species.
- GC–MS system with headspace autosampler for the analysis of volatile organic compounds.
- GC–MS systems with liquid injection for the analysis of semi-volatile organic species amenable to this method.
- GC–MS system with a pyrolyzer for the analysis of polymeric and oligomeric compounds.
- LC–UV system for analyzing mercaptobenzothiozole (MBT) from rubber components.
- ICP–MS system for the analysis of elements particularly heavy metals.
- GC–NCD for the analysis of nitrosamines from rubber components.
- GC–MS for the analysis of polycyclic aromatic hydrocarbons from rubber components.
Nixdorf (SGS): Numerous analytical techniques are used to detect, identify, and quantitate E&Ls. A combined analytical approach is preferable, using at least two different techniques. HPLC, for example, is a universal separation tool for organic compounds, and can accommodate multiple detection techniques such as UV diode array and mass spectrometry. GC is used for semi-volatile and volatile analytes, and can be used alongside high-resolution mass spectrometry and flame-ionization detectors, among others. GC plus headspace sampling analyzes vaporized volatiles, useful if residual solvents are likely to be present. Inductively coupled plasma spectroscopy screens for a wide range of metals. Nuclear magnetic resonance (NMR) spectroscopy may also be used if identification is required.
PharmTech: Have advances in technology have improved E&L testing? What advances do you wish to see in the near future?
Harbach (SGS): Advances in technology continue to improve testing for E&Ls. Many OINDPs contain a large number of doses in a relatively small volume, and hence have high AETs. However, some PODPs, particularly those dosed intravenously or those used for dialysis, can have extremely low AETs. The continuing advances in the sensitivity of mass spectrometers are vital to the successful analysis of such drug products. Despite these advances, some AETs in large volume parenterals are still beyond the reach of modern analytical instruments, and alternative approaches are required.
New chromatography techniques also contribute to advances in E&L testing. For example, the use of UPLC rather than HPLC has substantially reduced the time taken for LC–MS analysis of extractables from controlled extraction studies and leachables in drug products.
Ensuring patient safety through sound science is the goal of any E&L study. Newly emerging analytical techniques should be employed where they can advance the detection, identification, and quantitation of E&Ls.
Nixdorf (SGS): It is not possible to precisely identify all substances extracted from polymers under harsh conditions. A confirmation must be grounded on fact or a confident attribute to be deemed ‘reliable.’ For this reason, rules are required to specify what constitutes a reliable confirmation. In cases where an authentic reference substance is not available, data must be collected from multiple analytical techniques for a plausibility check.
For example, a UV spectrum might provide some information about a conjugated double bond or aromatic system. Data from electron ionization (EI)–GC/MS could provide spectral information by matching the pattern of two or three substances in a library of spectra. Accurate mass assignments could predict the elemental composition of the peak of interest, and double bond equivalents can be predicted. This is the degree of saturation, and allows for the sum of the number of rings, double bonds, and triple bonds present in the molecule to be determined. The final structure can be verified with the use of NMR, MS, and infrared (IR), as well as a qualitative inspection of all the data.
Paskiet (West): A wide range of sophisticated analytical technologies can be employed for E&L testing. While all-purpose methods can be a starting point, these methods will not address distinct applications. Pertinent information is acquired by understanding the materials and intended use to enable specific extraction and analytical methodology to be justified. There continues to be a move to green chemistry, which will influence future use of chemicals and analytical instrumentation but will not have a direct impact on the overall E&L strategy. There is a need for advances in efficiency for acquiring and interpreting appropriate data to meet today’s quality expectations; perhaps novel approaches to proven models will be explored in the future.
In my opinion, upcoming advances should be a combination of improving technologies for identifying/qualifying leachables along with development of new materials that are engineered to fit a purpose in a quality-by-design (QbD) paradigm. Accurate and precise analytical measurements will be the means to enabling future applications of the right knowledge at the right time to materials used in the manufacture, containment, and delivery of high-quality pharmaceutical products.
1. PQRI,Safety Thresholds and Best Practice for Extractables and Leachables on OINDP, (September 2006), accessed Mar. 26, 2014.
2. C.T. Houston, “Extractables and Leachables in Parenteral and Ophthalmic Drug Products: An Evolving Strategy,” presentation at the Extractables & Leachables Conference (Vienna, December 2012).
3. ICH, M7, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 2 version (February 2013).
4. ICH, Q2(R1), Validation of Analytical Procedures: Text and Methodology, Step 4 version (November 2005).
5. ICH, Q3C(R5), Impurities: Guideline for Residual Solvents, Step 5 version (Feb. 2011).
6. EMA, Guideline on the Limits of Genotoxic Impurities (London, June 2006).
7. ICH, Q6A, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances, Step 4 version (1999).
8. ICH, Q6B, Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, Step 4 version (1999).
9. ICH, Q8, Pharmaceutical Development, Step 4 version (August 2009).
10. ICH, Q9 Quality Risk Management, Step 4 version (Nov. 2005).
11. ICH, Q10, Pharmaceutical Quality System, Step 4 version (June 2008).
12. USP, United States Pharmacopeia, General Chapter <1663> Assessment of Extractables Associated with Pharmaceutical Packaging and Delivery Systems.
13. USP, United States Pharmacopeia, General Chapter <1664> Assessment of Leachables Associated with Pharmaceutical Packaging and Delivery Systems.
About the Author
Adeline Siew is the scientific editor for Pharmaceutical Technology.