Tino Otte is senior consultant at Intertek, tino.otte@intertek.com, Tel: +41 (61) 686 48 56.

Tino Otte

Orally inhaled and nasal drug product (OINDP) formulations, which are primarily a propellant including an organic solvent, have a high potential for the leaching of substances from the delivery device components. In this context, a device such as a dry powder inhaler (DPI) or pressurized metered dose inhaler (pMDI) is considered a primary packaging material or a container closure system (CCS). An extractables and leachables (E&L) investigation should be conducted to guarantee that the pharmaceutical packaging system is safe and does not negatively influence the drug product.

	Extractables are compounds that are released from a CCS into an extraction solution, which is typically a simulation solvent that mimics the drug formulation, during forced extraction experiments. Leachables are compounds that leach from a CCS into the drug formulation under normal storage conditions, such as those applied during a formal stability study.

	Extractables are common, but not always the worst-case leachables; new reaction products formed from extractables and drug formulation components can also be considered as extractables. Leachables are drug product impurities that have the potential to affect patient safety.

	For example, in a pMDI, precipitates were identified that were found to be polyaromatic hydrocarbons (PAHs), mercapto-benzothiazol, and N-nitrosamines originating from the rubber materials used for construction of the inhaler devices (1, 2). Other examples of potential leachables are isopropylthioxanthones, which are used as photoinitiation agents in inks, and N-nitrosamines, which originate from printing compounds. Both have also been found as contaminants in packaged food (2).

	In general, additives and process chemicals that are present in packaging material are small molecules, and the propellants used in pMDIs are quite effective solvents for such molecules.  In addition, there are many non-intentionally added substances, such as those derived from process chemicals and degradation products present in packaging materials, all of which may occur as later drug impurities. For this reason, a well-designed E&L study will help to avoid analytical surprises, mitigate risks associated with impurities, and help minimize costs if problems are identified late in the product development process.

	Guidelines describe the proper design of E&L studies for container closure systems, metered dose inhalers, nasal spray/spray drug products, and all types of plastic packaging. The most common guidelines and internationally recognized testing approaches from regulatory authorities and organizations such as the 

Guidance for Industry: Container Closure Systems for Packing Human Drugs and Biologics 

Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products

Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products

for Guidance for Metered Dose Inhalation Products Packing Materials

		Product Quality Research Institute (PQRI), 

Safety thresholds and best practices for extractables and leachables in orally inhaled and nasal drug products

, submitted by the PQRI Leachables and Extractables Working Group (9).

 <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems (10)

 <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging Delivery Systems (11)

 <1664.1> Orally inhaled and nasal drug products (12)

 <1664.1>)  generically describe how to carry out E&L studies.

	In all guidelines, an initial risk estimation is performed with consideration of data obtained from solvent extraction E&L screening. For toxicological risk evaluation of inhalation product extractables data, PQRI recommendations can be applied (9). These PQRI documents focus on orally-inhaled and nasal products, as well as parenteral and ophthalmic drug products. The recommendations were developed in collaboration with FDA, and they provide clear direction and technical considerations for carrying out E&L studies with guidance on how to evaluate data, as well as how to use toxicological relevant limits in E&L data.

	Strategies for an extractables and leachables study

	An E&L study should be able to provide a complete overview about potentially harmful substances that could leach from the packaging. Several steps must be considered to ensure that the study is in alignment with the current guidelines and tailored to the specific drug products and packaging properties. A well-designed E&L study can be divided into the following major steps:

		Critical assessment: a critical evaluation of the packaging system and the properties of the pharmaceutical formulation, as well as an evaluation of the guidelines

		Extractables study: a set of forced laboratory experiments to extract as much as possible out of the packaging material (under “realistic worst-case conditions” [15])

		Migration or leachables check experiment: includes the use of a drug formulation or placebo in original packaging under worst-case conditions and long-term storage at accelerated temperatures

		Data evaluation: evaluation of the extractable study data, including a toxicological assessment, for the selection of critical leachables

		GMP-leachables study: the final stage, performed as part of the stability study for the drug product after appropriate method optimization and validation for the selected leachables.

 In the first step, the different materials of construction of the packaging must be evaluated.  Each type of polymer matrix (e.g., polypropylene, polyethylene, cyclic olefin copolymer, Teflon, elastomer) contains small molecules that are used as additives (e.g., antioxidants, light stabilizers, modifiers); process chemicals, printing inks, or adhesives may also be present. A typical pMDI, for example, is made of several types of polymers, rubbers, and metals, as described in 

. Similarly, several materials are used in a nasal spray device (see 

	For a critical assessment of the formulation properties, the interaction potential has to be considered in relation to the administration route for the drug. In the PQRI (9) and FDA/EMA guidelines (3–8), tables and flow schemes are given to guide this step. Depending on the final risk, an E&L study is required. The highest risk is typically considered for inhalation or injectable products because they are directly delivered into a target organ (e.g., lung, blood) without any dilution; ophthalmic and nasal solutions are considered as medium risk.

	The interaction potential for the formulation depends on the physical properties. Liquid samples with solvents are related to a high risk of interaction, but solid dosage forms are supposed to have lower risk.

	Analytical screening methods that are capable of finding low concentrations of unknown extractables should be used. In the guidelines, thresholds such as the safety concern threshold (SCT) are detailed (9, 16, 17). The SCT varies depending on the route of administration of the drug and the related risk for the patient. Inhaled products are known to be more critical than other delivery routes because they typically exhibit SCTs of 150 ng/day (9). Below this threshold, the intake of an extractable compound can be considered as less risky for the patient independent from its chemical structure.  

	For extractables with a concentration above the SCT, a full characterization and quantification must be performed. Since the SCT is given in ng per day, the analytical evaluation threshold (AET) has to be calculated with consideration of the volume of the packaging and the maximum daily dose of the drug product. The extraction experiment should be designed in a way that unknown compounds, with a concentration in the range less than the AET, are still detectable; the analytical screening method applied to the extract should be sensitive enough to cover the calculated AET.

	The following examples illustrate that the AET calculation is essential for proper design of subsequent extraction studies, because the analytical detection limit varies depending on application scenario and size of the packaging system.

		Lowest acceptable daily dose for an E&L compound (SCT) = 150 ng/day (based on PQRI [9])

		The application scenario is 0.1 mL in 3 doses per day = 0.3 mL/day

		150 ng/day / 0.3 mL/day = 500 ng/mL (i.e., concentration of extractables)

		500 ng/mL x 15 mL = 7500 ng = 7.5 mg (i.e., total released amount of an extractable)

		Assuming a part has a weight of 1 g, 7.5 mg/g (ppm) of an extractable must be analyzable with the applied method.

		Quantitation limit for extractables must be better than 7.5 ppm (i.e., typical value in extractable studies).

Example 2: impact of route of administration on AET. 

Compare a 2.0 mL unit dose vial used for two different applications: an ophthalmic drug product and an inhalation drug product in a nebulizer.

		Lowest acceptable daily dose for an extractable (SCT) is:					

				150 ng/day for OINDPs (based on PQRI)

				1.5µg/day for parenteral and ophthalmic drug products.

				0.5 mL for the ophthalmic application

				Two ampules/day for the inhalation drug product

				For the ophthalmic solution: 1.5 µg/day/0.5mL/day = 3µg/mL

				For the inhalation product: 0.15µg/day/ 4 mL/day = 375 ng/mL.

 The extraction conditions and solvents have to be adapted to realistic conditions that may occur during the storage of the drug product. In general, the extraction experiments should reflect the worst-case scenario. The extraction conditions should include thermal stress without deteriorating the polymeric matrices, and the chosen solvents should mimic the drug formulation and have similar properties (e.g., with respect to solvent properties, polarity, pH) while slightly exaggerating its extraction strength. Typically, pure organic solvents or mixtures of water and organic solvents are used for this purpose; the content of organic solvent in such mixtures should slightly exceed the content of organic components in the drug formulation to ensure worst-case conditions. It must be ensured, however, that the chosen solvents do not degrade the drug formulation or dissolve the polymer matrix of the packaging.

 lists typical simulation solvents and extraction set-ups for typical drug products and application cases.  Inhaler devices or containers for nasal applications consist of many different assembled parts, which are sometimes only partially in contact with the drug formulation or not accessible for the simulation solvent due to the specific construction. In this case, it makes sense to perform the extractables study with the dissembled parts of the device. The different rubber and plastic materials are extracted and analyzed individually or the individual extracts are pooled and analyzed once. For the pooling approach, the mass or surface contribution of each individual part defines its percentage in the final extract sample. The individual screening of each part has the advantage that identified extractables may be assigned to a specific part of the inhaler. If the pooling of the extracts is performed, it could be helpful to carry out an additional analysis using thermodesorption coupled to gas-chromatography-mass spectrometry (TDS–GC/MS) on the single parts to get a qualitative comprehensive overview of most of the contained, generally volatile and semi-volatile, extractables that will simplify the later assignment of specific extractables to specific parts.

	In some cases, the devices can be incubated with the simulation solvent as assembled devices. For spray products, for example, the assembled device can be filled with the extraction solvent and  the pump released a few times to bring all internal parts in contact with the solvent, which would simulate the application.

	For a dry powder inhaler, instead of organic extraction, a solid adsorbent (e.g., TENAX organic sorbent) can be used  for simulation of the solid drug product. In the case of a solid drug product, most of the extractables will be volatiles, which may be adsorbed on the solid surface of the powder. The solid adsorbent is then extracted with organic solvents, which are analyzed with comprehensive techniques or TDS–GC/MS.

	After extraction of the device or container closure system with different solvents, the screening analysis is conducted and different analytical techniques can be applied. Sometimes it will be possible to directly inject the extract solution into the analytical instrument. In most cases, however, a back extraction with solvents suitable for specific analytical techniques is required. Typical screening techniques are GC/MS with and without derivatization, headspace GC/MS, high-performance liquid chromatography (HPLC)-MS and inductively coupled plasma (ICP)-MS or optical emission spectroscopy (OES) for elemental impurities coming from catalyst residues or filling material.

 migration or leachables check experiment. In addition to the extractions with simulation solvents, a leachables check experiment should be performed in which the sample is incubated with the pure drug formulation or placebo to capture potential reaction products formed from extractables and formulation components. Moreover, volatile compounds tend to migrate through polymeric layers or seals if the barrier properties are not good enough. Well-known sources for migrating substances include labels, adhesives, inks, or even secondary packaging components, such as cardboard boxes, often made from recycled paper, which potentially contain inks or volatile photoinitiator residues. Those compounds are only detectable if the sample is incubated for a longer period at accelerated thermal conditions or if aged samples are analyzed. 

 evaluation and assessment of the E&L data. After the analytical work of the E&L study is finalized, all the results obtained must be evaluated. A list of all relevant extractables and potential leachables is generated. All components above the AET limit have to be identified, and these compounds must be checked frequently as potential drug impurities during a GMP leachables monitoring study, such as a formal stability study. Sometimes, a toxicological assessment may be performed for dedicated extractables to replace the AET and monitoring specifications with a new limit that is based on existing or derived toxicity data.

GMP leachables study. The leachable study is performed as part of the stability study for the drug product and conducted after appropriate method development and validation is complete for the selected leachables. The monitoring is compound-specific and fully quantitative. Moreover, the validation has to be performed according to International Council for Harmonization (ICH) Q2A/Q2B, which includes experiments to ensure sufficient linearity, specificity, accuracy, precision, reproducibility, limit of detection, and limit of quantification. From this stage, the monitored leachables are considered as potential drug impurities. The monitoring study has to be carried out under full quality control. In contrast to the extractables screening, after finalization of the validation, there is no experimental freedom for adaption of the methods as was the case during the initial screening steps.

	Choosing the correct solvent strength is crucial. In 

, a typical GC/MS-chromatogram obtained after organic extraction of polyethylene (PE) is shown. Clearly visible is a series of PE homologues that are dissolved by the organic solvent. In this case, the solvent may be too strong, because more critical extractables, such as stabilizer additives and their degradation products, are hidden in the baseline noise. If the concentration of these extractables exceeds the AET level, they must be considered in subsequent leachables monitoring.

Articles

Follow guidelines for E&L studies of an orally inhaled and nasal drug product formulation in its delivery device.
