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GET A QUOTESAMPLE TRANSMITTAL FORMI. Abstract
Leachables from single use systems (SUS)and multi-use manufacturing equipment (MUE) that migrate into drug or biological products have a potentially negative impact on safety. To evaluate this risk, extraction studies are performed under conditions designed to simulate the use of the equipment. The goal of these extraction studies is to identify as extractables the leachables that could migrate into the product. The extractables profile can then be used to set operational limits on the SUS or MUE as needed. Further toxicological assessment may be required based upon the observed levels of leachables.
II. Introduction
Leachables are compounds that migrate into drug or biological products from materials encountered in the manufacturing process. Plastics and elastomers components are the most common sources of organic leachables and metal components are the most common sources of inorganic leachables. Examples of common organic leachables can be seen in Table 1. Any component of the manufacturing equipment with direct contact with a liquid that eventually becomes part of the final product is a potential source of leachables. Examples of SUS and MUE components that can give rise to extractables include filters, hoses, bioreactor bags, connectors and filling needles. Manufacturing equipment that is not directly in contact with a liquid that enters the final product is unlikely to be a source 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 final product.
The manufacturers of drugs, biologics and biotherapeutics are required to evaluate the risk of leachables from SUS and MUE used in the manufacturing process. Many equipment vendors will provide extractables results for their components generated in many different model solvent systems that bracket the pH, polarity, and ionic strength of most aqueous based drug products. The vendor extractables testing is typically performed according to the “white papers” issued by the Bioprocess Systems Alliance (BPSA) and the BioPhorum Operations Group (BPOG). A scientific based assessment comparing the extractive power of the drug product that will be manufactured using the equipment to the vendors conditions of contact in the extractables testing has to be performed to demonstrate that the vendor extractables profiles were generated under “worst case” conditions. Any “gaps” identified in the correlation of the vendor extractables data to the conditions used in manufacturing can bead dressed utilizing a simulated-use extraction study. As part of the assessment, a justification can be made to exclude components of the manufacturing train from the simulated-use extraction study if there will be significant dilution of leachables or potential removal of the leachables during purification techniques (such asrecrystallization and diafiltration).
In a simulated-use extraction study, the components of the SUS or MUE are extracted with a model solvent or placebo under representative conditions of contact encountered during manufacturing. The sample extracts are analyzed by GC-MS, LC-MS and ICP-MS to identify all of the organic and inorganic. Any pre-treatment of the components that would be done during manufacturing (e.g. pro-active flushing of filters and tubing) should be done on the sample before the start of the simulated-use extraction study.
I. Simulated Use Extraction
A. Sample Extraction
In a simulated use extraction study, the extraction solvent is selected to closely mimic the drug product. The extraction conditions are usually static storage at the temperature intended for temperature for a minimum of two time points. The first time point is the intended routine time the individual component would be in contact with the product and the final time point would represent the longest allowable time the product would be in contact with the product.
B. Extractable Analysis
The sample extracts are analyzed by 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. 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 component.
C. Analytical Evaluation Threshold
At the completion of the extractables analysis, a list of extractables is generated. The challenge at this point is to only report extractables that present a toxicological risk. 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 Product Quality Research Institute (PQRI) for a parenteral drug is 1.5 µg of each individual leachable per day (1). The PQRI selected this SCT as representing a threshold below which leachables would have negligible safety concerns from carcinogenic and non-carcinogenic toxic effects.
To apply the SCT to a given product, an analytical evaluation threshold (AET) is calculated based on the SCT of an individual leachable (usually in µg) per day, the number of doses of the drug product administered per day, the number of doses contained in the container closure system, and the volume of product in the container closure system . The AET is defined as follows:
The AET will have units of µg/mL of the product and can be converted to the sample extracts based upon the extraction conditions.
D. Interpretation of Results
If quality manufacturing equipment has been selected and the extraction conditions were appropriately selected, the number of extractables observed will usually be small. From the generated extractables profile,only the extractables above the AET present a risk to patient safety.
As is commonly observed, in some cases the levels of extractables will increase over time until it rises above the AET. If a time can be identified where the extractables levels are below the AET, the manufacturing process should be modified to limit the exposure time thus ensuring the extractable levels will stay below the AET in the final product. This is commonly sufficient to eliminate the risk from leachables from manufacturing components.
In rare cases, changes to the manufacturing process are not sufficient to reduce the risk from a specific extractable. In this case a toxicological assessment to determine a compound specific SC is recommended to fully evaluate the risk from the specific extractable.
I. Conclusion
Leachables present a unique challenge in assuring drug product safety and efficacy. The experimental approach presented represents a rational experimental approach to evaluate this risk. When properly executed and interpreted, a simulated use extraction can be used to evaluate and minimize the risk of leachable from manufacturing equipment.
II. Acknowledgements
The authors would like to thank Michael Ruberto of Material Needs Consulting for his contributions to this white paper.
VI. References
1. “TheProduct Quality Research Institute (PQRI) Leachables and Extractables Working Group Initiatives for Parenteral and Ophthalmic Drug Product (PODP)”, PDA JPharm Sci and Tech 2013, 67 430-447
Leachables from the backing, release liner and storage pouch of transdermal patches present a potential risk to patient safety if these leachables enter the patient during the administration of the transdermal patch. Since these leachables have the potential to be a threat to patient health, evaluation of leachables from transdermal patches is likely to be requested from the FDA.
The first step toward evaluating the risk of leachables is to identify the potential leachables from the components of the transdermal patch and its pouch. This is done by performing an extraction study under exaggerated conditions with the goal of identifying the observed extractables. Extractables are the compounds that can be extracted from the patch and pouch that might become leachables. For transdermal patches and pouches, an extraction study will typically be done by extracting the components in two solvents for a predetermined time and temperature. The solvents should be selected based upon the drug product but will usually be water and 50% isopropanol in water. The extractables in the sample extracts are identified by GC-MS, LC-MS and ICP-MS.
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 leachables. 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 (which is typically the case), the recommended SCT for a transdermal patch is 1.5 µg of each individual leachable per day.
The analytical evaluation threshold (AET) is calculated from the safety concern threshold (SCT) of 1.5 µg/day, the number of doses per day, the number of doses contained in the patch (typically 1 dose/patch), and the weight of the transdermal system.
The AET will have units of µg/g (surface area instead of the weight may be applicable in some situations resulting in units of µg/cm2).
From the observed extractables, target leachables are selected from the extractables above the AET and analytical methods are developed for these compounds in the extraction solvent to be used during the leachables evaluation. In most cases, the solvent for the leachables evaluation will be an aqueous buffer intended to mimic human perspiration and the analytical methods will be GC-MS, LC-MS and ICP-MS. Patches that had been aged in pouches for various times including the target shelf life are extracted with the leachables solvent and then analyzed using the developed analytical methods.
The observed levels of leachables are evaluated against the analytical evaluation threshold. If all leachables remain below the AET for the entire shelf life, there is no risk to patient safety. If an individual leachable is observed above the AET, a toxicological assessment is required on the specific leachable to determine the risk to patient safety.
If good materials were selected for the container closure system (CCS) for a parenteral drug product, it is not uncommon for the results of the forced extraction study to be that no extractables were detected above the analytical evaluation threshold (AET). While the PRQI guidances does allow for the conclusion to drawn from these results that the CCS presents no risk to patient safety, many drug development teams are hesitant to make this conclusion due to the legitimate concern that regulatory reviewers may still request leachables results. However, the same drug development team may be hesitant to commit the time and money for unneeded leachables testing. An alternative study proposed by Pine Lake Laboratories is a simulated use extraction to further support the conclusion of no risk from leachables without the expense and time of full leachables testing.
In a simulated use extraction study, the extraction solvent is selected to closely mimic the pH and solvating strength of the drug product. For simple drug products, the placebo may be a good choice if it does not present significant interferences to the analytical methods used to detect the leachables. The extraction solvent should be selected to ensure it is compatible with the analytical methods.
The extraction conditions are selected based upon the intended shelf life of the drug product so that the “real time” storage equivalent can be determined. According to USP <1663>, the relationship between the diffusion rate and temperature can be expressed empirically by the Arrhenius equation and has been established in ASTM F1980-07 (2011) “Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices”. Therefore, the following equation can be used to determine the “real time” storage equivalent for a drug product intended to be stored at 5 C from the results of a simulated use extraction where the CCS is extracted for 60 days at 40 C :
AAR (Accelerated Aging Rate) = Q10 ((Te – Ta)/10)
Where Ta = Normal Storage Temperature = 5 C
Te = Elevated Temperature = 40 C
Q10 = Reaction Rate = 2
= 2 ((40 –5)/10)
= 11.31
AATD (Accelerated Aging Time Duration) x AAR = Desired Real Time
60 Days x 11.31 = 679 days or 22.6 Months at 5oC
As can be seen, a simulated use study done at 40 C for 60 days for a drug product intended to be stored at 5 C would give the same results 22.6 months at the target storage condition. The time and temperature of the simulated use extraction can be altered as need based upon the targeted shelf life and storage conditions.
At the end of the simulated use extraction study, the extractables profile generated will be for an extraction solvent that closely mimicked the drug product under extraction conditions that are equivalent to the intended shelf life and storage conditions. This extractables profile provides valuable additional information that can be used to ensure patient safety without the need for full leachables testing.
Pine Lake Laboratories is the scientific leader in extractables and leachables (E&L) studies. We have extensive experience with pharmaceutical container closures, single use system components, and combination devices.
Our experienced scientific staff utilizes the following analytical methods for expert identification of extractables observed in a forced extraction study:
Our team has experience developing and validating leachables methods based upon the observed extractables in a wide variety of dosage forms:
Protocols are designed to be study specific and follow PQRI, BPOG or client specific. Pine Lake Laboratories can also perform USP <661.1> and <661.2>.
A toxicological risk evaluation for E&L results can be performed by our staff toxicologists.
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.
ABSTRACT
Recent changes in the FDA’s 510(k) requirements for medical device applications have spawned many inquiries from clients on how to address the request for extractables, leachables and drug compatibility data. Meeting the expectations of the CDRH can be challenging in that any given study design is not universally applicable to all devices. A good study design requires elements of the best practices documented in ISO-
10993-12, the PQRI guidance for E&L testing of OINDP as well as any specific requests for drug compatibility data from CDRH.
A hybridized study design, incorporating the essential regulatory elements, has been developed and successfully implemented for a variety of medical device applications. The rationale behind selection of the elements, overall experimental design strategy and interpretation of the resulting data will be presented.
INTRODUCTION
Extractables and leachable testing is required by the CDRH in the FDA for many medical devices. Experimental design for evaluation of extractable and leachables from medical devices can be done based on the most likely route for a leachable to enter the body. One route of entry is for leachables from a medical device to enter a drug product that carries the leachable into a patient. Examples of medical devices were
this is the leachable route of entry include infusion pumps, syringes, and syringe filters. For leachables in this category, both the toxicity of the leachable and the potential impact of the leachable on the drug product
need to be considered. The second route of entry is direct migration of the leachable from the medical device into the patient from direct tissue contact. Examples of medical devices where this is the leachable route of entry include dental implants, artificial joints, stents, bandages, and contact lens. For some medical devices, both routes of entry for leachables are possible. Examples of medical devices where both routes of
entry are possible include drug releasing implants and catheters. If both routes of entry are possible, follow
the second experimental design for direct migration route of entry. If leachables from a medical device are unlikely to enter the body from one of these two routes, an evaluation of extractables and leachables is probably not necessary.
Until recently, only medical devices where the leachable route of entry was from direct tissue contact were required to perform extractable and leachable testing. This requirement has changed as evidenced in the below example of a recent response from the FDA to a 510 (k) for an infusion pump:
“For each route of administration identified in your statement of intended use, you should identify an FDA approved drug or biologic to demonstrate that at least one such product is approved for infusion through the proposed route of administration and at the proposed dosage.
If your infusion pump includes a reservoir, we recommend that you provide stability and compatibility data for each drug or biologic that you have identified above, which assesses the stability and compatibility for the recommended use period and conditions included in your labeling.
In addition to demonstrating that the drug or biologic retains its specifications, we recommend that you include a safety evaluation of any leachables, extractables, impurities and degradants. Analytical methods should be used to identify and quantify impurities, degradants, leachables and foreign particulates in the effluent.”
There are two important requests in this FDA response to the 510 (k). The first request is to assess the stability and compatibility of each drug or biologic intended to be used with the medical device. The second is a safety evaluation of any leachables, extractables, impurities and degradants from the medical device into the drug product.
To address extractables testing for medical devices, in the FDA Modernization Act of 1997, the FDA recognized ISO 10993-12 Titled “Sample Preparation and Reference Materials”. In this document are clearly defined extraction experiments for extractable and leachable evaluations. Some of the definitions and experiments in ISO 10993-12 are similar to the definition of an extractable and the forced extraction studies described in the PQRI guidance for E&L testing of OINDP. Acceptance criteria for extractables and leachables are not defined in ISO 10993-12.
Based upon the similarities between ISO 10993-12 and the PQRI guidance for E&L testing of OINDP, a study design for medical devices where the route of entry for leachables is in a drug product will be presented that includes elements of both documents. The study design to be presented for medical devices where the leachable route of entry was from direct tissue contact will be based only on ISO 10993-12.
STUDY DESIGN
Extractables and leachables study design for medical devices where the route of entry for leachables is in a drug product
Before starting to evaluate drug compatibility and leachables from the medical device, an FDA approved drug(s) intended for use with the medical device must be selected. If the device is intended for just one drug, like an insulin pump, the selection of the drug is obvious. If the device can be used with multiple drugs and multiple routes of administration, select a total of three drugs that are commonly used from the three most common routes of administration. For example, if evaluating an infusion pump that is intended to deliver drugs intravenously and as an epidural, pick two common drugs for intravenous infusion and one for epidural infusion. Once the drug(s) has been selected, pick the simplest formulation of the drug to evaluate drug compatibility and leachables.
To address drug compatibility and leachables from the medical device, the experimental approach is divided into two steps. The first step is the determination of extractables from the medical device in controlled extraction studies. Based upon these results, analytical methods are then developed to be used to evaluate leachables in the second step. The second step is the evaluation of leachables from the medical device into the drug product, and the evaluation of drug stability in the medical device.
Only the components of the medical device that directly contact the drug product need to be included in the controlled extraction study although other components can be included if deemed to present a significant risk. Separating components of the medical device for extractions will facilitate the identification of extractables, but the medical device can be extracted intact if separation is not practical.
An overview of the controlled extraction study can be found in Table 1 and is similar to what is done for a sample container closure system following the PQRI guidance for E&L testing of OINDP. The medical device is extracted in a polar solvent and a non-polar solvent with the solvents selected based on the representative drug products. The extraction type is based on the solvent type and the analytical methods for analysis of extractables are the same for all extractions. Extractables are identified by MS and quantitated against structurally similar standards.
Table 1. Overview of Controlled Extraction Study
Solvent Extraction Type Analytical Methods 1. Polar – buffer(s) that match (or bracket) the pH and ionic strength of the drug product vehicle(s), water
2. Non-polar – 50/50
Ethanol/water if drug product contains surfactants, IPA if drug product contains no surfactants
1. Neat solvents : Soxhlett
2. Mixed solvents and buffers: Batch extraction with agitation or reflux
1. Volatile organic extractables by GC-MS
2. Non-volatile organic extractables by LC-MS
3. Inorganic extractables by
ICP-MS (aqueous extract only)
Once the extractable profile of the medical device has been determined, analytical methods are then developed that can analyze for the extractables present as leachables in the representative drug products. Hopefully GC-FID and HPLC-UV methods can be developed for the organic leachables, but detection by MS may still be needed based upon the extractables identified and the number of unknowns. For both methodologies the drug may present significant interference for detection of potential leachables and extensive sample preparations, like liquid-liquid extractions, may be required. For inorganic leachables, ICP- MS is commonly used. All of these methods should be validated for accuracy, precision, specificity, LOD/LOQ and linearity. Acceptance criteria for validation should be set based upon the demonstrated performance of the method and the intended use of the method.
Analytical assay methods are also needed to demonstrate the stability and compatibility of each drug with the medical device. If available, the USP method for the drug product should be used. If a USP method is not available for the drug product, an analytical assay method will need to be developed and validated.
Once all methods are in place, the experimental steps shown in Table 2 are followed.
Table 2. Steps in Study To Determine Drug Compatibility and Leachables from Medical Device
Acceptance criteria are not universally defined. For assay we recommend setting the difference between the control and the sample to be the same as the USP acceptance criteria for assay. For example, if the USP method has the assay value for a drug product to be +/- 10.0 % of label claim, the acceptance criteria for compatibility should be that the assay value for the sample be within +/- 10.0% of the assay value of the control. For leachables and medical device impurities we recommend using the same acceptance criteria as process impurities of 0.05% of the drug product label claim.
Extractables and leachables study design for medical devices where the leachable route of entry is from direct tissue contact
To address extractables and leachables, two different extraction studies are done. The first experiment is an exaggerated extraction study which is defined in ISO 10993-12 as “any extraction that is intended to result in
a greater amount of a chemical constituent being released as compared to the amount generated under the simulated conditions of use”. An exaggerated extraction study is a forced extraction study to generate a complete extractable profile for hazard identification and is required by ISO 10993-12 to be exhaustive. The second experiment is a simulated use experiment which is defined in ISO 10993-12 as “evaluating leachable material levels available to the patient or user from devices during the routine use of a device using an extraction method that simulates product use.” The experimental conditions in a simulated use experiment are modeled after the intended tissue environment for the device with the goal of determining leachable exposure to the patient.
An overview of the exaggerated extraction study can be found in Table 3. The key decision in study design is solvent selection. For an exaggerated extraction study, the extraction solvents are selected based upon the anticipated tissues the device will encounter. The extraction type is based on the solvent type and the analytical methods for analysis of extractables are the same for all extractions. For exaggerated extractions, the extraction must be proven to be exhaustive, therefore extraction time is established experimentally. Extractables are identified by MS and quantitated against structurally similar standards.
Table 3. Overview of Exaggerated Extraction Study
Solvent Extraction Type Analytical Methods1. Polar – water, phosphate buffered saline, culture media without serum
2. Non-polar – vegetable oil, ethanol/water, ethanol/saline, polyethylene glycol 400, dimethyl-sulfoxide, culture media with serum.
1. Low boiling neat solvents : Soxhlett
2. Mixed solvents, buffers and high boiling neat solvents: Batch extraction with agitation or circulation
1. Volatile organic extractables by GC-MS
2. Non-volatile organic extractables by LC-MS
3. Inorganic extractables by
ICP-MS (aqueous extract only)
An overview of the simulated use extraction study can be found in Table 4. Again the key decision in study design is solvent selection. Like the exaggerated extraction study, the extraction solvents are selected based upon the anticipated tissues the device will encounter and the results of the exaggerated extraction study. The extraction type is batch extraction with agitation and the analytical methods for analysis of leachables are the same for all solvents. The extraction conditions should be the highest temperature listed that does not exceed the glass transition temperature of the material. Leachables are identified by MS and quantitated against structurally similar standards.
Table 4. Overview of Simulated Use Extraction Study
Solvent Extraction
Type
Extraction
Conditions (select one)
Analytical Methods 1. Polar – water, physiological saline, culture media without serum
2. Non-polar – vegetable oil, ethanol/water, ethanol/saline, polyethylene glycol 400, dimethyl- sulfoxide, culture media with serum.
Batch extraction with agitationa) 37°C for 72 hours b) 50°C for 72 hours c) 70°C for 24 hours d) 121°C for 1 hour1. Volatile organic extractables by GC- MS
2. Non-volatile organic extractables by LC-MS
3. Inorganic extractables by ICP- MS (aqueous extract only)
Acceptance criteria for the levels of extractables and leachables in a medical device are not included in ISO
10993-12. A risk based approach method to set acceptance criteria that includes a toxicological evaluation of each extractable and leachable is presented in ISO 10993-17 but this approach may not be recognized by the FDA. A second option would be to use a predefined default level appropriate for the device and its intended use.
If the medical device contains a drug (e.g. a drug releasing implant), sample selection needs to be
considered and can be different for the above two extraction studies. Depending upon the amount of drug in or on the device, a “placebo” device without drug may be considered for the exaggerated extraction study to avoid excessive interferences from the drug in the identification of extractables. However, the final medical device including the drug should be used in the simulated use experiment since the presence of the drug could effect the migration of the leachables from the device.
CONCLUSION
Extractables and leachables testing are required by the CDRH in the FDA for many medical devices. A
study design was presented that was based on both ISO 10993-12 and the PQRI guidance for E&L testing of
OINDP for medical devices in where the route of entry for leachables is in a drug product, and a second study design was presented based only on ISO 10993-12 for use on medical devices where the leachable route of entry is from direct tissue contact. Both study designs have been used to support successful 510(k) submissions.
REFERENCES
At the end of the stability study, results from the leachables analyses will be reported. There are two basic outcomes to a leachables study:
Leachables are compounds that migrate into a drug product from the sample container closure system (CCS) under normal storage condition. 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.
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 the table below.
An exaggerated extraction study on a medical device is a forced extraction study to generate a complete extractable profile for hazard identification and is required by ISO 10993-12 to be exhaustive. An overview of the exaggerated extraction study can be found below. The key decision in study design is solvent selection. For an exaggerated extraction study, the extraction solvents are selected based upon the anticipated tissues the device will encounter. The extraction type is based on the solvent type and the analytical methods for analysis of extractables are the same for all extractions. For exaggerated extractions, the extraction must be proven to be exhaustive, therefore extraction time is established experimentally. Extractables are identified by MS and quantitated against structurally similar standards.
Overview of Exaggerated Extraction Study for Medical Devices
Solvent Extraction Type Analytical Methods 1. Polar – water, phosphate buffered saline, culture media without serum
2. Non-polar – ethanol/water, ethanol/saline, dimethyl-sulfoxide.
1. Low boiling neat solvents : Soxhlett
2. Mixed solvents, buffers and high boiling neat solvents: Batch extraction with agitation or circulation
1. Volatile organic extractables by GC-MS
2. Non-volatile organic extractables by LC-MS
3. Inorganic extractables by ICP-MS (aqueous extract only)
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 this 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 is defined as follows:
AET = (SCT/number of doses per day) x (doses per CCS/weight of CCS) x uncertainty factor
The AET will have units of µg/g unless other units were used in the calculation. Surface area of the component of the CCS or volume of drug product in the 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.
All extractables above the AET should either be selected to be monitored as a potential leachable or submitted for a toxicological assessment to determine a compound specific SCT
Leachables from container closure systems (both primary and secondary packaging component) that migrate into injectable vaccines and related biological products can have a potentially negative impact on safety and efficacy. To assess the risk from leachables, extraction studies are designed to simulate both intended use and “worst case scenario” models to identify as extractables the leachables that could migrate. At the end of the extraction study, an assessment of the observed extractables is done to determine if the risk justifies the need for additional leachables studies.
At Pine Lake Laboratories, we have extensive experience performing extraction studies on container closure systems commonly used for injectable vaccines and related biological products. The extraction study design followed at Pine Lake Laboratories for injectable vaccines and related biological products is based upon the PQRI guidance for Parenteral and Ophthalmic Drug Products.
Pine Lake Laboratories is a GLP/GMP compliant analytical and bioanalytical contract testing laboratory. Our lab, located in Bristol, CT, is FDA registered and inspected and DEA licensed for Schedules 1 through V.
