Abstract

Leachables from sample container closure systems (CCS) from primary and secondary packaging component that migrate into a drug products have a potentially negative impact on safety.  Analytical methods are needed to detect leachable in the drug product. The first step toward developing analytical methods for leachables is to identify the extractables that could become leachables by doing extraction studies. Extraction studies are designed to simulate both intended use and “worst case scenario” models to identify as extractables the leachables that could migrate into the drug product.  Analytical methods are then developed with sensitivity to detect the leachables in the drug product at the threshold determined by the toxicity of the leachable.  Analytical methods for leachables are validated similarly as methods intended to evaluate the stability of the drug product.  Leachable analysis can then be used in the long term stability studies or in migration studies designed to specifically evaluate leachables.

Introduction

Leachables are compounds that migrate into a drug product from the sample container closure system (CCS) under normal storage condition.  Both the primary CCS in direct contact with the drug product (metered dose inhaler, prefilled syringe, eye dropper, IV bag, HDPE bottle, LDPE ampoule, etc.) and the secondary CCS which does not contact the drug product (printed label, cardboard box, foil pouch, environmental exposure, etc.) can be sources of leachables. Leachables present a potential risk to the patient both from the toxicity of the leachable and from the possible negative impact upon stability and efficacy of the drug product.  Examples of common leachables can be seen in Table 1.

Although many types of materials can be used in a primary CCS system, the three most common are glass, polymers and elastomers.  One may expect that the manufacturer of the component of the CCS to be able to provide a complete list of the formulation and process used to manufacture the component, however this may not always be the case. The two main reasons for manufacturers not providing this information are that the manufacturer may consider the information to be proprietary or the manufacturer may not have the information. The second reason is particularly common for polymers. The main reason for this among the manufactures of polymer CCSs is that their upstream suppliers do not need to place strict control over their processes.  For example, a resin manufacturer will set specification for their product on its physical characteristics only and then sell the same resin to a manufacturer of a CCS and a manufacturer of lawn furniture. This example resin manufacturer may not have needed to keep accurate records on the amounts and type of antioxidants used as long as the resin met the manufacturer’s specifications, but these antioxidants do have the potential to leach into a drug product.

Leachables can enter any type of drug product including solid dosage forms. Generally, orally inhaled and nasal drug products (OINDP) and parenteral and ophthalmic drug products (PODP) are the most common drug products at high risk of leachables. Table 2 summarizes the risk for most common drug products. Low risk is not the same as no risk as evident in several high profile of recalls of solid dosage forms due to leachables. An assessment of the risk of leachables into a given drug product needs to be done when considering a testing strategy for leachables.

The toxicity of a leachable is dependent upon the route of entry into the body.  Levels of a compound that can be safely ingested can have a toxic effect when the same level is inhaled. As a result the potential route of administration of a leachable must be considered when assessing the risk of a leachable.

Leachables present unique analytical challenges. Since leachables are not related to the drug product, the analytical methods used to detect impurities in the drug product may not be able to detect the leachables.  Even when leachables could be detected by drug product impurities methods, the leachables are often at levels orders of magnitude lower than drug degradation products or related substances, thus below the sensitivity of the method. Thus separate analytical methods are usually needed for the analysis of leachables in the drug product.

Before an analytical method for leachables can be developed, first potential leachables need to be identified. This is done by performing an extraction study on the CCS under exaggerated conditions with the goal of identifying the observed extractables.  Extractables are the compounds that can be extracted from the CCS that might become leachables.  Figure 1

illustrates the ideal relationship between extractables and leachables.

The conditions of the extraction study are selected based upon the drug product and are designed to mimic a “worst case” scenario for the intended drug product. Care must be taken in the selection process so that conditions are aggressive enough to ensure that the extractables include all leachables while not being too aggressive thus generating an impractically large number of extractables that are not leachables. The extraction study should not lead to a complete deformulation of the material.

Study Design

Sample Selection

All components of the CCS that directly contact the drug product either during storage or during the administration of the drug product are considered to be primary components of the CCS.

All components of the CCS that do not contact the drug but do have the potential to interact with the primary CCS are considered to be secondary components of the CCS.  A secondary CCS component will either contract the primary CCS or contact another secondary CCS component that does directly contact the primary CCS.  Table 3 shows some common examples of primary and secondary components of CCSs.

All primary CCS components should be included in the extraction.  If in the final CCS the

components are to be pre-treated in any way (e.g. sterilized) before being filled with the drug product, the samples to be used in the extraction study should be pretreated in a similar manner to ensure that the extraction profile correctly models the CCS exposed to the drug product.

Selection of secondary CCS components for inclusion in the extraction study is based upon a risk assessment. In this risk assessment the likelihood of the secondary CCS component giving rise to leachables and the likelihood of these leachables being able to contact and penetrate the primary CCSC are considered. One secondary CCS component that will usually need to be included in the extraction study is a printed label if it is to directly contact a part of the primary CCS.

Extraction Studies

The first step toward evaluating leachables is to perform extractions studies. There are two types of extraction studies; Controlled Extractions and Simulated use extraction. These two extractions can be done in series or in parallel.  In some cases, just one of the extraction studies may be sufficient.

A Controlled Extraction study (also called materials characterization study) involves extracting the CCS in 2-3 solvents of varying polarities. A CE study using 3 solvents is required for drug products at the highest risk based upon the route of administration in Table 2.  A CE study using 2 solvent is recommended for drug products in the other two risk categories for route of administration if the risk of packaging component-dosage form interaction is high in Table 2.

The solvents are selected based upon the drug product with at least one of the solvents representing a “worst case scenario”. The extraction conditions used are aggressive, typically reflux or oven incubation. The combination of the “worst case scenario” solvent with the aggressive extraction conditions is intended to yield a high number of extractables. The end result of this approach is that all potential leachables (except those that react or have a unique affinity with the drug product) will be identified.  Table 4 shows example extraction solvents for an aqueous drug product.

A simulated use extraction study (also called a simulation study) involves extracting the CCS in solvents that closely mimic the drug product. The extraction conditions are usually static storage of the CCS in the solvent at a temperature above the intended storage condition of the packaged final drug product. The end result of this approach is that the observed extractables are likely to be leachables.

A simulated use extraction is designed to be less aggressive than a controlled extraction study, thus less extractables are expected to be identified in a simulated use extraction compared to a controlled extraction. The simulated use study is more likely to identify only the extractables that will become leachables compared to the controlled extraction study which will potentially identify many extractables that will not become leachables. However, a simulated use study is more likely to “miss” a potential leachable than a controlled extraction study. Both studies reveal useful information on the potential leachables from a given material but the project team must be aware of the strengths and weaknesses of each study.

Regardless of type of extraction study performed, once completed, the sample extracts are analyzed by at least GC-MS, LC-MS and ICP-MS.  The goal of these analysis is to identify as many extractables as possible and to semi-quantitatively determine the level of each extractable.  Based on the material, additional analysis may be required for specific leachables known to be highly toxic.  Since the methods are designed to detect unknowns, these methods cannot be validated. Results from these analyses are reported as the amount of the extractable (usually in µg) per weight (usually in g) or surface area (usually in cm2) of the CCS component.

Analytical Evaluation Threshold

At the completion of the extraction studies, a list of extractables is generated.  The challenge at this point is to select which extractables present a toxicological risk and thus should be monitored as leachable.

To evaluate the toxicity of each observed extractable, the safety concern threshold (SCT) is used. The SCT is the absolute highest acceptable exposure of a patient to a leachable in drug product and is usually expressed in terms of µg of leachable per day.   If an SCT is not known, the recommended SCT by the PQRI should be used.  The PQRI selected the recommended SCT as representing a threshold below which leachables would have negligible safety concerns from carcinogenic and non-carcinogenic toxic effects.  For orally inhaled and nasal drug products (OINDP), the PQRI recommended SCT is 0.15 µg of each individual leachable per day.   For parenteral and ophthalmic drug products (PODP), the PQRI recommended SCT

is 1.5 µg of each individual leachable per day.

To apply the SCT to a given drug product, an analytical evaluation threshold (AET) is calculated based on the SCT of an individual leachable, the number of doses of the drug product administered per day, the number of doses contained in the container closure system (CCS), and the weight of the CCS (can also use volume of drug product in the CCS.

The AET will have units of µg/g unless other units were used in the calculation. Surface area of the CCS or volume of drug product in CCS instead of the weight may be applicable in some situations. The uncertainty factor is an adjustment for the confidence in the identification and quantitation of the extractables needed for OINDP.  For all other types of drug products, the uncertainty factor is not needed.

Selecting Leachables

All extractables above the AET should either be selected to be monitored as a potential leachable or submitted for a toxicological assement to determine a compound specific SCT.

An example set of extractable results are shown Table 5 for a fictional CCS with an AET of 10.0 ppm for each extractable. The results listed in italics are well below the AET and would not be selected as target leachables. The results that have been bolded are significantly above the AET and would definitely need to be selected as target leachables. The results that are underlined represent results that would require additional consideration since the results are close to the AET. The SCT and the uncertainty factor should be reevaluated before selecting or dismissing these extractables as leachables. A conservative selection of including an extractable that is just below the AET as a target leachable is an acceptable and common practice.

Development and Validation of Analytical Methods for Leachables

The goal of the analytical methods is to have sufficient sensitivity so that the LOQ is at or below the AET. Extensive sample preparation may be necessary to ensure sufficient sensitivity.

The analytical methods are then validated with the goal to meet the ICH acceptance criteria. However, since the challenge of these methods is to be able to detect very low levels of leachables in often complex drug product matrices, some allowances may need to be made in other aspects of method performance to allow sufficient sensitivity. These allowances may be seen in higher acceptance criteria than in drug product impurity methods.

Analysis of Leachables in Drug Products

The analytical methods are then used to analyze drug product stored in the CCS under the intended storage conditions. Ideally this testing can be done as part of the stability study but it can also be done in a separate migration study. Results from the analysis are reported as concentration of the leachable in the drug product.  If a leachable is observed above the AET, additional experimentation may be necessary to confirm the identification of the leachable. Additional toxicological evaluation may also be needed to assess the risk of the leachable.

Control and Placebo Samples

Inclusion of control samples can greatly simplify the analysis of the leachables results. One recommended control is to store the drug product in a different CCS under the same storage conditions for the same length of time.  Ideally the different CCS would be expected to yield significantly less and different leachables (e.g. a glass vial with a Teflon coated lid).  This control is used to distinguish degradation products of the matrix from leachables.

Including placebo samples stored in the CCS in the leachable study is strongly recommended. These samples can help to confirm the presence of leachables observed in the active and leachables might be observed in the placebo that might have been missed in the active. One cannot assume, however, that if a peak is observed in the active that is not in the placebo that the peak is not a leachable. The active drug may facilitate the migration of the leachable or the active drug could react with the leachable.

Impact of Leachables and in the Drug Product Above the AET

If a leachable is observed in the drug product above the AET calculated for that specific leachable, the project team must take actions to prevent patients from being exposed to this level of the leachable. The options are the shelf like must be shortened to a time before the leachable exceeds the AET or a different CCS must be selected. If a different CCS is selected, the entire extractables and leachables testing must be repeated on the new CCS.

If no leachables are observed in the drug product above the AET the project team can set the shelf life and storage conditions of the drug product in the CCS based solely on drug product stability. Thankfully this is commonly the case.

Conclusion

Leachables present a unique challenge in assuring drug product safety and efficacy. The    experimental approach discussed in this chapter represents a rational experimental approach to evaluate this risk. When a project team designs experiments based on this approach, the more information the team gathers on the material composing the CCS and on the drug product, the more effective and efficient the experimental strategy will be.

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