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Pharmaceutical Manufacturing and Packing Sourcer

Container Closure Systems

Diane Paskiet of West Pharmaceutical Services puts forward strategies for assessment of leachables in parenteral drug products

The quality by design (QbD) approach for pharmaceutical development is intended to build quality into drug products based on characteristics that define safety and efficacy. Specific physical, chemical, biological or other properties that may have an impact on product quality are critical quality attributes (CQA) that can be identified using risk management tools, and subsequently critical process parameters (CPP). This type of development model is based on a multidimensional space employing input variables that will determine the ranges in which a consistent quality product can be achieved. The quality, safety and efficacy of a drug product can be linked to the suitability of a container closure system (CCS), and recent regulatory expectations are to obtain knowledge of the CCS early in the drug development process so as to contribute to the building of quality drug products.

The selection and control of CCS used in drug product administration, and those used in the manufacturing process and storage, are important parameters in pharmaceutical development and throughout the drug product lifecycle. A greater understanding of the product and its manufacturing process can create a basis for more flexible regulatory approaches. The degree of regulatory flexibility is predicated on the level of scientific knowledge provided (1). The pharmaceutical development process can be enhanced by creating a design space for one or more unit operations that result in product quality. The design space defines the boundaries established by linking input variables and process parameters with CQAs. An input variable or process parameter that has an effect on quality over the full range of operation should be included in the overall design space.

The CCS design space can be considered as an independent unit but integral to CQAs of the drug product. The design space for producing a CCS is in the domain of the component manufacturer, and the protection, performance or delivery, compatibility and safety are the major indicators of suitability for the intended use and are the ultimate responsibility of the sponsor. Thresholds for CCS parameters can be identified by the common regions of successful operating ranges for multiple CQAs with respect to drug product quality. Critical CCS parameters for compatibility should be identified so that there are no unacceptable changes in the quality of dosage form or interactions, such as loss of potency, degradation, changes in pH, absorption/adsorption, precipitation, discolouration and leaching.

 Packaging safety is linked to the overall compatibility based on the chemical characterisation of the materials used in the CCS construction. The chemical nature of the CCS will greatly influence the potential leachables in drug products. The identification and evaluation of critical potential leachable substances is a major consideration in CCS material selection, but it is the likelihood of CCS-dosage form interaction that will define the CQA. Drug product contamination occuring from CCS interaction is dependent on transport properties of the migrating substance in relation to the package, product and environment. The prediction of migration and drug product contamination of a given substance is complex due to polymer chemical characteristics and properties, and the influences of diffusion, permeation, solubility, equilibrium, as well as mechanical factors.

PACKAGING MATERIALS ASSOCIATED WITH PARENTERAL PRODUCTS

Components that are in contact with drug products, and suitable for the pharmaceutical and medical device industries, have a wide variety of applications and diverse functions. Plastic, elastomers, glass, metals, inks/coatings, adhesives and paper are the principal classes of materials used in CCS. Whether an individual component or combination of components is used in single-use devices, intermediate- or long-term storage applications, the science of the material must be understood to make informed decisions. The route of administration is a significant factor in determining the components to be evaluated and the amount of information needed to ensure patient safety and satisfy regulatory requirements. Inhalation, injectable, transdermal and ophthalmic dosage forms all have a high degree of concern for package-product interaction and it is the regulatory expectation to assess leachables (2). Common CCS components used in different dosage forms are listed in Table 1, along with typical materials of construction.

The list of components and materials serves as an example and is not intended to be inclusive of all possibilities. Other sources of potential leachables to be considered are drug product storage, process and filling equipment such as tanks, filters, reactors and disposable systems.

Contamination from the CCS and equipment used in the manufacturing process for biologic protein products is of particular concern for contamination as leachables can have a negative affect for the patient as well as the protein products, as expressed by Markovic (3). A multicomponent and multi-material CCS poses greater potential for package-dosage form interaction in conjunction with the affinity of migrants to the dosage form. The propensity for package interaction is related to the chemical constituents and nature of drug product matrices – solutions, emulsions, suspensions, creams, solids, gels, aerosols and ointments. Leachables are a function of potential migrants (extractables) and their transport properties. There are scores of potential leachables to be considered as a result of migration, degradation and/or interaction.

QUALITY BY DESIGN STRATEGIES FOR LEACHABLE & EXTRACTABLE STUDIES

A contaminated drug product can affect the patient’s well-being as a result of toxicity, and undesirable changes to the drug product can result in impaired therapeutic effects. The CCS chemical characterisation in relation to the administration, dose, duration and population will need to be evaluated to ensure that a patient will not be exposed to undesirable amounts of potential leachable substances. The desired CCS is one that would not have migrating species. This is not, however, practical for many materials, since the material formulations consist of a mixture of different chemical constituents to achieve the required CCS suitability. The challenge here is to identify and predict worst-case migrating species (extractables) and correlate to leachables, so as to determine negative effects during drug product development, enabling an informed CCS decision to be made. Packaging components that are compatible with a dosage form will not interact to cause unacceptable changes in the quality of either the dosage form or the packaging component (2). The CCS materials can be evaluated for quality attributes, taking into consideration the interaction between the critical component extractables and drug product leachables. A risk management organisation tool such as an Ishikawa diagram (see Figure 1) illustrates the potential variables that could impact the safety and efficacy in relation to CCS compatibility.

The likelihood of CCS interaction with a drug product can have an impact on the product’s safety and efficacy throughout its lifecycle, and the variables for leachables and extractables should be factored into the experimental design to indicate compatibility. The compatibility and control of critical components can be established from data acquired in controlled extraction studies, which can then support drug product quality once a correlation to leachables is shown.

Extractables

An understanding of the chemical makeup and behaviour of a CCS will provide parameters for correlation to endof- shelf-life leachables. Once critical components are identified, an initial extractable profile can be performed. An extractable study typically begins with gathering information on the chemistry of the CCS. Assessment of the CCS system for the most current information is accomplished by performing a qualitative extraction study using multiple solvents and analytical techniques. Conditions for CCS extraction and analysis should achieve detection limits consistent with a value that could be associated with the risk for leachables. The experimental design should lead to an understanding of the variability for potential leachables to be linked to a CQA. Lack of information will inhibit development of proven acceptable ranges for extractables, which could result in a compromised drug product. To minimise the chance of unexpected leachables, solvents should be representative of the drug product, worst case and exaggerated conditions to obtain comprehensive extractable information for an initial toxicological review. Organic solvents and aqueous extractions of CCS may be an important consideration for parenteral products as liquid formulations contain surfactants, salts and chelating agents, as noted by Fliszar (4).

The results of a qualitative extraction profile can be examined for substances that may seriously compromise quality, or should be targeted for measurement and further assessment. Toxicology support can provide initial information on safety concern compounds and those sanctioned by regulatory agencies that may have applicable specifications (5,6). If the outcome of the study is favourable, a quantitative extractable study can be performed to indicate worst-case extractables that can be correlated to end-of-shelf-life leachables. The extractables that can be linked to a CQA on the basis of safety or performance are determined prior to optimisation of the quantitative methods. The qualitative analysis conditions may need to be modified, depending on amounts/types of extractable species. The nature of migration can be determined through achieving the asymptotic level of each extractable. The quantitative extraction study should also consider analyte solubility, sensitivity, profile repeatability, interferences, reactivity, hydrolysis and by-products.

If a correlation can be established between extractables and drug product leachables and the sources of CCS variability understood, upstream controls can be put in place to ensure drug product quality. Because of the decisive nature of extractable information, the method used to measure extractables species should be validated within acceptable standards to ensure accurate measurements.

Leachables

The intent of a leachables study is to link drug product quality with patient safety based on the identity and amount of any given extractable species that contaminates or interacts with the drug product. Since the end result is to ensure patient safety, the selection of the appropriate analytes to conduct a leachables study is paramount. Ascertaining the suitable analytes is a complex process in which comprehensive extractable data is assimilated to potential leachables. The likelihood of contaminated drug products can be predicted based on recognition of the critical CCS materials with an understanding of the CCS configuration/ function, environment, drug product matrix and extractable migrating characteristics.

The occurrence of deleterious effects from contaminated drug product is dependent on the level of contamination, patient population, dose and leachable toxicological characteristics. The drug product can be exposed to various CCS components during manufacture, storage, filling, final packaging (primary and secondary) and administration devices; each has the potential to contribute leachables. Those leachables that can cause harm to a patient and/or affect the efficacy of the drug product is needed to be qualified and controlled within specified limits. A major aspect of CCS compatibility is the leachable qualification, and the mechanism for qualification relies on knowledge of the chemical characterisation of all critical CCS components, the probability of migration and the impact on patient safety. Once the appropriate leachable analytes have been justified, methods can be developed to measure those analytes in the drug product. A control drug product that has not been in contact with the CCS can be evaluated relative to the methods used in the extractables studies to indicate possible interferences and conditions for optimisation. Detection and quantitation limits correlating to a safety concern level and relative to the amount available in the component will indicate the basis for drug product sampling. Spiking and recovery studies may be carried out in control and degraded drug product to ensure detection of leachables at trace levels. The detection and measurement of leachables will require validation of the methods prior to evaluation of samples representative of initial, accelerated and long-term stability, as this data will be used to develop specifications and acceptance criteria.

Results from accelerated stability studies can be used to predict end-ofshelf- life leachables in support of early toxicological evaluation. Correlation of extractables data to that of leachables will indicate the safety of the CCS and convey the critical extractables to be monitored. A comprehensive real-time stability study will be the final proof of the suitability of a CCS, as there may not be a direct correlation of accelerated to real-time results for leachables testing (2). The proven compatibility of the CCS will provide the basis for process validation, process improvement and continuous process verification. Statistical analysis of results from routine CCS testing will enable specifications to be determined and acceptance to be based on the impact to the drug product. It is conceivable that, with a greater understanding of downstream CCS processes, drug product leachables can be controlled using upstream quality controls. The regulatory expectation for the amount and type of extractable and leachable data required is complex and can vary based on the dosage form, route of administration and possibility of interaction. The relationship of the CCS design space to the drug product quality can be related using risk assessment tools, and proper control strategies can be implemented. As additional process information is gained, expansion or reduction of the design space may be made.

CONCLUSION

The design space for a container closure system encompasses protection, performance/delivery, compatibility and safety. Consideration of chemistry along with toxicology of the materials will, in part, establish CCS safety and justify selection of materials. The relationship between the amount of migrating substance in the CCS material and potential leachables can be anticipated based on the principles of mass transfer. Relevant knowledge gained from initial qualitative extraction experiments will enable comprehensive characterisation of the CCS and provided data to identify and evaluate risk; quantitative extractable studies will provide the basis for the final selection of materials, leachable studies and critical quality attributes for ongoing monitoring and control. A scientific understanding of the CCS compatibility will support specifications for validation and establishment of acceptance criteria for CCS and enable a shift to upstream process controls. This assessment paradigm for CCS suitability can be used to ascertain leachables and ensure safety for drug products that have a high concern level for CCS drug product interactions. This process holds true for innovator or generic products and can be used as a means of comparison for post-approval changes.

References

  1. Q8 (R2) Pharmaceutical Development, CDER/CBER ICH Guidance for Industry, November 2009
  2. Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry Manufacturing and Controls Documentation, CDER/CBER/FDA Guidance for Industry, 1999
  3. Markovic I, Challenges Associated with Extractables and/or Leachable Substances in Therapeutic Biologic Protein Products, American Pharmaceutical Review: pp20-27
  4. Fliszar K, Walker D and Allan L, Profile of Metal Ions Leached from Pharmaceutical Packaging Materials, PDA Journal of Pharmaceutical Science and Technology 60(6): pp337-342, 2007
  5. Official Journal of the European Union, Commission Directive 2007/19/EC April 2007
  6. Inventory of Effective Food Contact Substances (FCS) Notifications, CFSAN/Office of Food Additive Safety USFDA

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Diane Paskiet is the Associate Director of Scientific Affairs at West Pharmaceutical Services. Her background includes management of laboratory operations and project advisor for method development and method validation studies in support of IND and NDA filings. Diane holds a BSc in Chemistry from the University of Toledo and a QA/RA Graduate Certificate from Temple University School of Pharmacy. She has authored many papers on the subject of leachables and extractables and is an active member of the Parenteral Drug Association’s (PDA) Packaging Science Interest Group, the Product Quality Research Institute (PQRI) Leachables and Extractables Working Group, and the Society of Plastics Engineers.
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