Abstract
During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. In order to properly assess the risk and manage the hazard posed by migratory substances, it is necessary to establish the identities of the migratory substances and the levels to which they will accumulate in the finished drug product, as these two pieces of information establish the hazard posed by an individual substance and the magnitude of the patient exposure (dose). The process by which migrating compounds are discovered and identified, and by which their accumulation levels in a finished drug product are established, is termed chemical assessment. Because the development of a finished drug product is a long and complicated process, chemical assessment is most typically not a single action but rather a series of actions that together establish a process of risk management. It is the purpose of this manuscript to establish a high-level strategy, illustrated in the chemical assessment triad, which can be applied to such a risk management process.
LAY ABSTRACT: During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug product, which is of concern due to the potential toxicity of the migrating substances. It is the purpose of this manuscript to outline a high-level strategy, illustrated in the chemical assessment triad, to chemically establish the safety risk related to the migrating substances.
Introduction
During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components and systems. During contact, the drug product and these entities can chemically interact, potentially modifying either the drug product or the packaging system. Although it is the case that these manufacturing, packaging, and delivery systems are constructed with materials and by processes that seek to minimize the extent to which interactions can occur during contact, it is unfortunately the case that neither truly inert materials and systems nor truly benign contact conditions exist and that interactions with potential product quality impact are the rule rather than the exception.
One type of interaction that can occur between a pharmaceutical drug product and an entity that it contacts is the migration of chemical substances out of that entity and into the pharmaceutical drug product. The accumulation of such migratory substances in the finished drug product is of concern due to the impact that such substances could have on the finished drug product's suitability for use. Clearly, such migratory substances could adversely affect the safety and efficacy of the finished drug product, both by direct and indirect means. Thus it is both necessary and mandatory that the finished drug product's vendor ascertain the extent of such an interaction and establish that the impact of the interaction is within acceptable limits.
This paper focuses on one specific aspect of the suitability for use issue, direct impact on patient safety. Clearly a migrating substance can directly affect patient safety if the substance itself has some biological impact (for example, if it is a carcinogen). In order to properly assess the risk and manage the hazard posed by migratory substances, it is necessary to know the identities of the migratory substances and the levels to which they will accumulate in the finished drug product, as these two pieces of information establish the hazard posed by an individual substance and the magnitude of the patient exposure (dose). The process by which migrating compounds are discovered and identified, and by which their accumulation in a finished drug product is established, is termed chemical assessment.
Because the development of a finished drug product is a long and complicated process, chemical assessment most typically is not a single action but rather a series of actions that together establish a process of risk management. It is the purpose of this article to develop and discuss a high-level strategy, illustrated in the chemical assessment triad, that can be applied to such a risk management process.
Key Definitions
The terms extractables and leachables are used to describe migratory substances. Although the two terms are closely related, they are neither equivalent nor interchangeable. In fact, the distinction between extractables and leachables is a key aspect of the systematic chemical assessment approach that is the subject of this manuscript. More universally, the distinction between these two terms is a cornerstone of regulatory expectations and best demonstrated practice recommendations that address the issue of material-product interactions (1⇓⇓⇓–5).
To clarify the distinction between an extractable and a leachable, let us first restate the situation at hand. This situation is defined by two phases, a donor phase (specifcially the material that is contacted by the finished drug product) and a receiving phase (specifcially the finished drug product itself). A migrant is a substance that migrates from the donor phase to the receiving phase as a result of the two phases contacting one another. This definition is useful because it captures interactions that are “active” (that is, interactions in which the receiving phase exerts a chemical or physical influence on the donor phase, such as solvation), and those that are “passive” (that is, interaction in which the receiving phase exerts no influence on the donor phase and merely serves as a “sink” for substances that leave the donor phase, such as sorption). For example, the process of extraction is an active process, as it implies that the receiving phase exerts a physiochemical influence on the donor phase. Alternatively, the process of thermal desorption/sorption is a passive process, as the receiving phase absorbs substances that leave the donor phase due to an externally applied thermal stress.
The distinction between an extractable and a leachable can be established in the context of the identities of the donor and receiving phases and in terms of the conditions of contact, as shown in Table I.
Definitions of Extractable and Leachables
Genesis of the Triad
It is both intuitively obvious and well documented in regulatory guidelines and best demonstrated practice recommendations that the definitive assessment of the potential impact of contact between a material (or a system) and a final drug product involves testing the final drug product for leachables. Thus, in its most essential form, chemical assessment involves performing a migration study whose purpose is to discover, identify, and quantitate leachables that have migrated from the contact material (or system) and accumulated in the finished pharmaceutical product (Figure 1). It is a point of practical reality that such a study is performed in the later stages of product development, typically after the product's composition, the product's manufacturing process, and the material's characteristics (from both compositional and processing perspectives) have been established and “locked down.” This being the case, it is clear that the potential safety risk associated with leachables is not managed, in any meaningful way, until the late-stage migration study has been completed. From the perspective of risk management, this is an untenable situation, as the identification of a potentially product development–ending issue (the catastrophic outcome that one or more leachables are present in the product at potentially unsafe levels) does not occur until considerable value has been added to the nearly market-ready product. Additionally, such an approach is not consistent with quality by design (QbD) concepts and practices that are being adopted throughout the pharmaceutical industry.
Simplified chemical sssessment. In its simplest form, chemical assessment involves characterizing the final drug product for leached substances. The characterization process involves discovering, identifying, and quantifying the leachables.
Although there may be circumstances that reduce the risk of such a catastrophic outcome (for example, a new drug formulation is being packaged in a system that has been previously well-characterized with other similar drug products), it is generally the case that a chemical assessment strategy based only on late development leachables testing (migration study) is recognized as being both ineffective risk and quality management. Such a one-step chemical assessment process is rarely applied with pharmaceutical products.
Recognizing the issues of risk and quality management, it is clear that the one-step chemical assessment process shown in Figure 1 must be modified. This modification must allow risks to be managed much earlier in the development process and must allow quality to be built into the final product. One place where such a modification can be made is at the material screening/selection phase of early product development. Specifically, a requirement that can be loosely stated as “the material shall not contain potentially unsafe ingredients, additives or processing aids” can be added to a material's requirements definition. During the selection process, candidate materials are screened for their compliance versus this requirement.
In this circumstance, the chemical assessment process includes two steps: screening and selection of materials based on the chemical characterization of candidate materials, and the finished product assessment (migration study); see Figure 2. The intent of the screening and selection phase is clear; materials are characterized and either rejected or approved for use depending on the outcome of the characterization and the specified quality requirements. Inappropriate materials (so-called “bad actors”) are eliminated from further consideration, increasing the likelihood that those materials that are ultimately used in the finalized packaging system will not contribute to an undesirable safety outcome. Thus the screening and selection process reduces the risk that an unfortunate outcome will occur in the finished product assessment, achieving the dual objectives of proper risk management and appropriate quality design. This is especially true because the screening and selection processes occur in the very early stage of product development, before much value has been added to the product concept.
Modified chemical assessment. Recognizing that finished product assessment involves carrying significant risk into the late stages of product development, the simplified assessment is modified to include a material screening and selection phase. This phase, which occurs very early in the product development cycle, allows for candidate materials to be screened for worthiness and leads to the rejection of inappropriate materials (“bad actors”). In so doing, risk of an adverse outcome (leachables at undesirable levels in the finished drug product) is reduced and the proactive aspects of QbD are exercised.
Considering the chemical assessment process further, one focuses on the finished product assessment, specifically considering the practical aspects of performing the required actions of leachables discovery, identification, and quantitation in the actual drug product. While it is the case that the material characterization performed in the screening and selection phase may produce information relevant to the identity of leachables, it is most likely the case that even the most rigorous characterization will reveal only ingredients and/or extractables that could tentatively be leachables because (a) the characterization is performed on materials, as opposed to finished systems, and (b) the characterization is performed during the concept phase of early stage development, as opposed to the defined system phase of late stage development. Additionally, while one might be able to augment the characterization data with information provided by the material's supplier, it is still generally the case that such information provides insight into, at best, compounds that could tentatively be leachables. Thus it is generally the case that a migration study must accomplish the processes of discovery and identification with limited foreknowledge about the entities (leachables) that will need to be discovered and identified.
It is a general rule in analytical chemistry that it is much easier to answer the question “does the sample contain compound X above a certain concentration y?” than it is to answer the question “what are all the entities that are present in a sample above concentration y?” It is this second question that represents the most significant analytical challenge related to performing a migration study. It is the unfortunate circumstance that pharmaceutical products further complicate this already complex issue. To understand this situation, it is reasonable and logical to note three practical realities of analytical chemistry:
The higher the concentration of an entity in a sample, the easier it is to discover and identify that entity,
The less chemically complex a sample is, the easier it is to discover and identify trace level entities in that sample, and
The higher the concentration of an entity in a sample, the more likely the entity can be readily quantitated with a high degree of accuracy and precision.
It is the unfortunate circumstance that leachables assessment in pharmaceutical products falls on the wrong side of these realities. That is to say that (a) leachables are typically present in pharmaceutical products at ultra-trace levels (what is good news for safety assessors is bad news for analytical chemists) and (b) pharmaceutical products are typically chemically complex mixtures, consisting of multiple components [active pharmaceutical ingredient (API), stabilizers, buffers, isotonic agents, solubilizers, etc.] which are themselves impure and/or degraded to some extent. The juxtaposition of these two circumstances complicates the task of the analytical chemist greatly, in some cases to the point that achieving the necessary outcome of discovering, identifying and quantifying leachables in the drug product pushes modern analytical science past its technical and/or practical limits.
If the activities of discovery, identification, and quantitation cannot readily be achieved in a migration study, then a strategy must be adopted which produces this information by another means. One such means is to divorce the processes of leachables discovery and identification from the processes of leachables quantitation and product safety assessment. That is to say that a step is added to the assessment process to allow the discovery and identification of probable leachables to occur by a means other than testing the final pharmaceutical product.
Furthermore, while the issue of timely risk management was addressed by adding material screening and selection to the chemical assessment process, the issue was not fully resolved by this action. It may still be the case that the amount of product development time between the screening/selection and product assessment phases is so great that the hazard of financial loss due to an unfavorable leachables assessment is beyond a company's tolerance for risk. In this circumstance, there is ample justification that there be an intermediate step between screening and selection and the product assessment migration study.
Lastly, it is noted that a migration study can be a drawn-out affair, as the finished drug product must be tested for leachables up to and including the end of product shelf-life, which in some cases can be several years. A means of obtaining information similar to that produced by the migration study but in a shorter period of time would greatly facilitate the risk management and product approval process.
Considering all three points, an intermediate activity is added to the chemical assessment process (Figure 3). The primary objective of this intermediate step is to produce the data necessary to convert the final product assessment from a “find and identity all leachables” activity to a “quantitate known and specifically targeted leachables” activity. A secondary objective of this intermediate step is to produce “leachables-like” information in a much shorter time period than is required for a complete and rigorous migration study. To accomplish these objectives, this intermediate activity must perform two functions: find and identify extractables as probable leachables and establish which extractables must be targeted as leachables in a migration study. Accomplishing the objective of discovering and identifying extractables as target leachables requires a study that produces a test article (the extract) that is more analytically expedient than the drug product and which mimics the final product from the perspective of the accumulation of probable leachables but does so in less time than it takes to perform a migration study. Such a study mimics, or simulates, the circumstances experienced by the final drug product, because it is this ability to mimic these circumstances that allows one to extrapolate the results of this intermediate study to the migration study. Thus the term simulation study is used to describe such an activity.
Generalized chemical assessment, the chemical assessment triad. A simulation study may be an appropriate and effective bridge between the material characterization process, which establishes ingredients as probable extractables and tentative leachables, and product assessment, which measures confirmed leachables. As the name suggests, a simulation study seeks to mimic the product assessment by using simulating solvents to facilitate the analytical tasks and using extraction conditions that accelerate the product contact conditions. The simulation study may be the basis of a preliminary toxicological assessment and can be used to establish target leachables to measure during product assessment.
Accomplishing the objective of establishing which extractables are to be targeted as leachables in a migration study requires a means by which the potential product impact of the extractables is determined. This is the case because it is logical that targeted leachables are those leachables that could have an undesirable product impact. There is little value, other than perhaps scientific curiosity, to target leachables for assessment that have no potential to adversely affect product safety and/or efficacy. As the focus of this paper is product safety, one understands that a safety or toxicological risk assessment is the primary means by which a population of extractables, representing potential leachables, is condensed into a smaller population of target leachables.
It is beyond the scope of this paper to provide insights or comments on the many factors that dictate how a simulation study is properly designed, executed, and interpreted. Nevertheless, it is important to note that a properly designed simulation study not only specifies extraction conditions that accelerate, but do not excessively exaggerate, the actual conditions of contact, but provides a detailed, science-based justification of how closely the simulated conditions mimic the actual conditions of contact. Additionally, it is important to note that the extract analysis process must include techniques and methods whose abilities to accomplish the processes of discovery, identification, and quantitation are well-established and are well-suited to perform what is essentially a screening process. The analytical strategy employed for extract characterization must include a means of establishing whether the process has properly discovered, identified, and quantified all the relevant extractables, as an analytical strategy that “misses” extractables can only lead to a flawed safety assessment. Finally, the analytical strategy employed must be capable of performing the functions of discovery, identification, and quantitation for all extractables that are present in the extracts in potentially impactful amounts.
A chemical assessment process that involves three distinct actions and phases is consistent with regulatory expectations and best demonstrated practice recommendations (Table II). For example, the Food and Drug Administration (FDA) 1999 Container Closure Guidance requires that the chemical composition of all materials of construction (plastics, elastomers, adhesive, etc.) be revealed. Extraction studies are specifically called out in numerous places in this guidance. Product assessment (leachables) testing is captured in the FDA guidance under the classification of other studies as appropriate. The three-phase nature of safety assessment is more clearly reflected in the European Medicines Agency (EMEA) 2005 Guidelines for Plastic Immediate Packaging Materials, which are based on general information (complete qualitative composition of the plastic material), extraction studies, and migration studies (corresponding to the material characterization, simulation study, and product assessment portions of the triad). The concepts of compositional information, (controlled) extraction studies, and leachables (migrants) studies are central to the best demonstrated practice recommendations proposed for orally inhaled and nasal drug products (OINDP) and for single-use manufacturing systems. Finally, the three triad steps are consistent with the material characterization, system qualification, and system validation activities that have been previously proposed by this author.
Examples of Three Phase Approaches to Chemical Assessment
Further Development of the Triad
The existence of the chemical assessment triad can be interpreted as suggesting that there is one “standard” approach to the chemical safety assessment process that fits all situations. This is not the case for two reasons. Firstly, the means of accomplishing the various tasks indicated in the triad may differ depending on the circumstances relevant for a given product. For example, it may be the case that material screening can be accomplished in two ways: by complete compositional characterization of the material or by testing of the material by standardized methodologies than are known to be “predictors” of potential safety impacts. Similarly, it may be the case that for certain chemically simple drug products, it is possible to accomplish the primarily simulation tasks of discovery, identification, and quantitation in the drug product itself (previous discussion notwithstanding). In such a case, these activities are incorporated into the migration study and the purpose of the simulation study becomes bridging the information gap between material selection/screening and leachables assessment.
Thus one can envision a detailed triad, such as that shown in Figure 4, which illustrates all three steps in the triad as well as the various means by which the steps in the triad can be accomplished. This detailed triad is simplified for each specific situation to contain no more than three components, representing the specific tasks that must be performed and the relative importance of those tasks.
Complete chemical assessment. It is recognized that the processes of material screening and selection and product assessment can be performed in multiple ways. Thus the complete chemical assessment process establishes that screening may be accomplished via either compositional characterization of the candidate material (controlled extraction study) or by testing the candidates by methods that are considered to be diagnostic of the material's suitability for use (e.g., compendia testing).
As plastic systems can be used in a number of pharmaceutical applications (e.g., packaging, devices, manufacturing), it is reasonable to expect that their safety assessments may require different strategies, as was noted previously. In such situations, the triad can represent the necessary strategy by the contents of its individual regions and the relative size of those regions. This property of the triad can be illustrated by contrasting a packaging system with a manufacturing system. The generic situation for a packaging system is shown in Figure 5. In this case, the material screening and selection process is accomplished by compositionally characterizing the candidate materials and performing a very preliminary toxicological assessment on the compositional results. Depending on the nature of the packaged drug product, appropriately designed simulation and migration studies are performed, as is necessary and appropriate, and their results are safety assessed.
Chemical assessment for a generic packaging system. For a packaging system, the material screening and selection process is properly performed by compositionally characterizing the candidates via a controlled extraction study. The product assessment process is properly performed by measuring targeted leachables in the finished drug product.
A somewhat different triad, Figure 6, can be designed to reflect a somewhat different process for a manufacturing system. In this case, rigorous and complete material characterization may not be an appropriate screening method. Rather, it may be more relevant to subject the manufacturing system's materials of construction or components to testing whose outcome is taken to be diagnostic of potential safety issues. For example, compendial tests methods such as those which appear in the USP (e.g., USP 〈381〉, 〈661〉, 〈87〉, and 〈88〉) may be useful means of screening materials and components for use in manufacturing applications. In such a situation, the ability to obtain favorable test results would provide the necessary assurance required to approve a material or component for potential use in the system. Such a preliminary screening exercise would be followed by a rigorous and extensive simulation study that establishes the component's or system's extractables profile. It is anticipated that in many cases, such a rigorous simulation study would be followed by limited, if any, migration testing. This is the probable and desired case for several reasons. It is the probable case because it is typically (but not always) the case that contact between a product stream solution and a manufacturing component occurs in the early (downstream) parts of the manufacturing process. It may be the case that extractables that are released into the product stream due to this contact are either removed from the process stream by upstream processes (such as chromatographic separation, diafiltration, etc.) or significantly diluted during these upstream processes. In either event, the effect of upstream processing is that the amount of an extractable that exits in the finished product as a leachable could be so small that the outcome of a migration study can confidently to be predicted to reflect no significant safety concern. This is a desired outcome as testing of actual manufactured product may be difficult and time-consuming (due to a complex drug product matrix) and expensive (due to the intrinsic cost of the drug product and or handling issues).
Chemical assessment for materials used in finished drug product manufacturing. In the case of manufacturing materials, material screening may not require that the candidates be fully characterized in terms of their composition. Rather, it may be appropriate that screening and selection is accomplished by performing tests that are considered to be diagnostic of the material's tendency to have an undesirable product impact. For example, compendial tests such as those that appear in the USP (e.g., USP 〈381〉, 〈661〉, 〈87〉, 〈88〉) may be useful means of screening candidates for their potential to adversely affect safety. Additionally, it is observed that the simulation study has an increased importance in the qualification of materials for manufacturing systems due to the practical issues of testing manufactured products (especially biopharmaceuticals) for leachables.
Considering another example, it is reasonable to anticipate that the relative importance of material selection/screening, simulation study, and migration study may vary from circumstance to circumstance. As was noted previously, the simpler the drug product, the more likely that the discovery, identification, and quantitation activities can all be accomplished in the migration study. In such a circumstance the purpose of the simulation study is merely to produce actionable information early enough in the product development cycle so that risks can effectively be managed. Alternatively, it may be the case that a chemically complex drug product requires an extensive simulation study whose outcome is such that only limited (if any) migration testing is necessary. That is to say that the results of the simulation study may provide an essentially complete set of information from which the probable safety impact can be reliably inferred. Such diverse situations can be illustrated in the triad by adjusting the relative sizes of the areas representing the individual task (larger size = more significant task), for example, Figures 7 and 8.
Chemical assessment for a packaging system used for chemically complex drug products. The aqueous nature of certain parenteral products suggests that there will be significant differences between the tentative leachables identified during material screening and confirmed leachables that accumulate in the finished drug product. In such a circumstance, a simulation study is vital to efficient and effective product development, providing the source information for a preliminary toxicological assessment and establishing the target leachables to be monitored during product assessment. The relative importance of the simulation study to this class of pharmaceutical products is reflected in the expanded size of the simulation study portion of the triad.
Chemical assessment for a packaging system used for chemically simple drug. In such a circumstance, a simulation study is may be of limited, but still measurable, value to the product development process. In this circumstance, the product assessment becomes the primary step that establishes the suitability of the finished drug product. The relative importance of the simulation study to this class of pharmaceutical products is reflected in the diminished size of the simulation study portion of the triad.
Tentative, Probable, and Confirmed Leachables
Inherent in the chemical assessment triad concept is the notion of tentative, probable, and confirmed leachables. This notion is significant in the sense that it establishes a relationship between ingredients, extractables and leachables and in the sense that it dictates how such information is utilized to establish probable safety impacts.
The concept surrounding these terms is straightforward; the greater the difference between the conditions under which ingredients or extractables are experimentally generated and the actual product contact conditions, the weaker is the link between the discovered ingredients, extractables and actual leachables. The weaker the link between the discovered ingredients, extractables and actual leachables, the less accurate are safety assessments that consist of toxicological evaluations performed on extractables data or inferred from ingredients data. This circumstance is illustrated in Figure 9. As the first step in the triad, material screening can be accomplished by extracting the test material and characterizing the extracts for “extracted” substances (i.e., the material's ingredients). Thus the information generated is “extractables” information, although the design of the materials screening study is such that the process of extraction is used to reveal ingredients. Therefore, the extraction performed in material screening is not designed to simulate the conditions of contact between the final drug product and the system of interest (which is to be composed of the material being screened) but rather is designed to liberate the major compositional components of the material in an analytically expedient matrix. In such a situation, it is logical to expect that the resultant ingredients information would only be remotely relevant to the product contact situation (i.e., leachables), both in terms of the identities of the ingredients and their concentration in the extracts. In such a situation, it is reasonable to expect that there would be a limited degree of overlap between the population of ingredients and the population of leachables. In such a circumstance, the link between the ingredients revealed during material screening and the leachables present in the finished drug product would be tentative and any toxicological assessment of such ingredients would be considered to be, at best, an inexact estimation of potential product impact. This is why the material screening stage is considered to be a filtering step (filter out the bad materials, allow the potentially good materials to continue on the process) and not a safety assessment step.
Correlation between extractables and leachables in the three stages of chemical assessment. As the extractions performed in material screening are not designed to mimic the commercial conditions of contact between the finished drug product and material of interest, it is reasonable to suspect that the ingredients (red region, horizontal pattern) identified in material screening (probable extractables and tentative leachables) and the confirmed leachables (blue region, vertical pattern) that accumulate in the finished drug product may be different populations with limited overlap (purple region, box pattern). However, it is the nature of the simulation study that the gap between tentative extractables and confirmed leachables is lessened, as the simulation study is specifically designed to mimic the commercial conditions of contact. The closer the simulation, the greater the overlap between probable leachables (derived from extractables) revealed in a simulation study and confirmed leachables measured in a product assessment. In product assessment, target leachables (derived from extractables) are confirmed leachables and the overlap is complete.
Because by its very definition a simulation study is an acceleration and modest (if any) exaggeration of the actual product conditions of contact, it is inevitably the case that the link between extractables discovered in the simulation study and leachables in the finished drug product is a close one and that such extractables are, in fact, probable leachables. To wit, it is the objective of the simulation study to reveal all potential leachables and to provide the greatest possible concentration that a leachable could accumulate to in the drug product. As such, the extractables from a simulation study are the worst-case leachables. In this context, a toxicological assessment performed on the extractables data would establish the worst-case safety impact. If, based on extractables data, it can be established that the worst-case dose has little if any associated safety risk, then it is clear that the finished drug product will have little associated safety risk from leachables because it is the case that the leachables dose from the drug product will be no more than the calculated dose of the extractable. Alternatively, if it is established that an entity as a extractable might have a dose that represents a safety risk, it would be proper to perform a migration study targeting that extractable as a leachable in anticipation that the actual concentration of the entity as a leachable would be less than the maximum concentration predicted by extractables data.
It almost goes without saying that once an extractable is chosen as a target leachable and is found to be present in the drug product at a measurable level, then that extractable is, by common definition, a confirmed leachable.
This concept of ingredients and extractables as tentative, probable, and confirmed leachables is directly linked to a fundamental question in chemical assessment: how low in concentration must one go in order to fulfill the objectives of the chemical assessment? As was noted earlier, this question is of primary importance due to the practical issues associated with discovering, identifying, and quantifying trace level leachables in analytically complex drug products. The chemical assessment triad, and the concepts of tentative, probable, and confirmed leachables, provides actionable answers to this question. As the intent of the material screening stage of the chemical assessment is material characterization (finding ingredients as probable extractables and tentative leachables), the level to which entities are discovered, identified, and quantified at this stage is not dictated by safety concerns but rather by the objective of the stage, which is to reveal the major compositional components (ingredients) of the material. In this case, the issue of “how low do you go” translates to “to what degree must the materials be characterized to reveal its major compositional components?” As ingredients are typically present in materials at levels of 100 μg/g (ppm on a weight basis) or higher, such a level provides the answer to the “how low” question.
Alternatively, the extractables (as probable leachables) revealed in the simulation study are to be safety assessed. As such extractables are of unknown identity at the start of the simulation study, the question of “how low do you go” becomes one of “at what level can an unidentified compound produce an undesirable safety effect?” This question has been addressed in various settings by concepts such as the threshold of toxicological concern (TTC) or the safety concern threshold (SCT). Thus the analytical methods utilized to characterize simulation study extracts must be such that they can perform the functions of discovery, identification, and quantitation at levels equal to an analytical evaluation threshold (AET) that is tied to either the TTC or SCT.
Because of the design of the simulation study (use of analytically viable simulating solvents and modest product exaggeration), it is possible to obtain acceptable analytical performance at AET levels that are unobtainable in the finished drug product. Furthermore, it may be the case that as a simulation study develops, the answer of “how low do we go” evolves. That is to say that the use of the TTC or SCT is predicated on the worst-case situation that the unidentified extractable is carcinogenic. If it can be established that the unidentified extractable is not a carcinogen, then a higher threshold, such as the qualification threshold, is relevant and applicable. Thus an initial objective of the simulation study could be to establish that none of the extractables are carcinogenic. Clearly this can be established by identifying all the extractables. However, it is also the case that this can be established by potentially simpler means. On the chemical side, it may be easier to establish the chemical nature (probable structural characteristics) of an extractable versus its specific identity. Such structural characteristics can be interpreted in terms of their carcinogenic potential (e.g, structure-activity relationship, SAR, analysis). On the biological side there may be either in vivo or in vitro test procedures that can establish the carcinogenic potential of a mixture of compounds (such as an extract).
Once the chemical assessment moves to the migration study stage, the focus of the investigation is targeted extractables, which, by definition, are identified compounds. In such a circumstance concepts such as SCT and TTC are generally irrelevant, as one can calculate a permissible daily exposure for an identified compound assuming relevant toxicological data exists for that compound. Only in the case where there is insufficient relevant toxicological data would a targeted leachable need to be quantified at levels dictated by an SCT or TTC.
A High-Level Process Flow Diagram
While the chemical assessment triad depicts the chemical assessment process, it does not illustrate the sequence of actions taken to perform the process. Such a process flow diagram is illustrated in Figure 10. This diagram identifies and links essential process steps, including the production of candidate materials from their ingredients, the characterization of the candidate materials for their intentional and accidental components (ingredients), the use of the characterization information to screen materials for suitability for use, the construction of packaging systems from acceptable materials, the testing of such systems for extractables under simulated use conditions, the interpretation of the extractables information with respect to probable safety risk, the generation of the finished product (reflecting the combination of the packaging and the packaged drug product), the testing of the contents of the finished product under actual conditions of use for leachables, and, finally, the interpretation of the leachables data with respect to actual safety risk. In addition to establishing process flow, the diagram highlights the responsibility that product developers, analytical scientists, and toxicological experts share in terms of ensuring that marketed products are suitable for their intended use (including safety) and indicates key places in the product development process where collaboration between these stakeholders are essential for achieving this objective in an effective and efficient manner.
The flow of activities associated with implementing the triad. Materials that are candidates for use in a packaging system are constructed from their base polymer and ingredients (this process is shown in brown). The materials are then characterized to establish their intended and unintentional composition. These characterizations are used to screen the materials for their suitability for use; acceptable materials continue as candidates while unacceptable materials are rejected (this process is shown in green). Eventually, the packaging system, constructed from acceptable materials, will be established and can be tested via a simulation study to establish the system's extractables. These extractables can be safety assessed; if the safety assessment concludes that the safety risk is acceptable, the packaging system moves further through development. If the safety assessment concludes that the safety risk is unacceptable, then the system is either revised or rejected (this process is shown in blue). When necessary and appropriate, an acceptable packaging system will be tested as a finished pharmaceutical product (package + drug product) via a migration study that establishes the levels of leachables in the contained drug product. These leachables are safety assessed; if the safety assessment concludes that the safety risk is acceptable, the finished pharmaceutical product becomes marketable. If the safety assessment concludes that the safety risk is unacceptable, then the finished pharmaceutical product is either revised or rejected (this process is shown in red).
Conflict of Interest Declaration
The author declares that he has no financial or non-financial competing interests related to this manuscript and the contents thereof.
Acknowledgments
The concepts reflected in this manuscript were developed during the author's participation in the PQRI-sponsored effort to establish best demonstrated practice recommendations for the safety assessment of packaging used with Parenteral and Ophthalmic Drugs Products (PODP). The author thanks the other members of this effort's Chemistry Working Group, including Diane Paskiet, James Castner, Thomas Egert, Thomas Feinberg, Christopher Houston, Desmond Hunt, Michael Lynch, Kumudini Nicholas, Mike Ruberto, Daniel Norwood, and Edward Smith, for the discussions that lead to the development and clarification of the triad concept.
- © PDA, Inc. 2012
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