QbD and Parenterals

Strategies for assessment of leachables in parenteral drugs

By Diane M. Paskiet

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 and/or other properties that may impact 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 in the drug development process are for early knowledge of the CCS, to contribute to the process of building quality drug products.

Photo courtesy and copyright of West Pharmaceutical Services, Inc.

The selection and control of CCS used in drug product administration, as well as those used in the manufacturing process and storage, are important parameters in pharmaceutical development and throughout the drug product lifecycle. While the delivery of the product is a CQA, it is also essential that the CCS is compatible with the drug product and safe, so contamination or interaction from substances with potential to leach will not impact the effectiveness of the drug product. Those substances, more commonly referred to as leachables, are expected to be identified and evaluated for possible toxicological or immunological impacts. Our focus for this article is to describe a process for identification, management and control of drug product leachables incorporating principles based on QbD.

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, cited by Nasr in Q8R1.¹ The pharmaceutical development process can be enhanced by creating a design space (or spaces) 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/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, discoloration and leaching.

The packaging safety is linked to the overall compatibility based on the chemical characterization 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. Contamination of the drug product is dependent on the 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.

The Nature of Migrating Substances

Several different types of components that can comprise a CCS may be in contact with the drug product during various time intervals. The CCS components may be of a primary or secondary nature, and each component can be made of different polymers with a range of formulation ingredients. The release of these ingredients, when in direct contact with the drug product, can be the result of diffusion through the thickness of the package, at the package/drug product interface, and through the product. In the case of secondary components, a drug product can be contaminated by the transmission of molecules through the polymer. Permeation rate depends upon the amount of permeant and thickness of the wall in relation to the time of exposure, area and pressure drop across the wall. The magnitude of permeation is related to the free volume between the molecules of the polymer structure and the type of permeant along with other chemical and physical factors.² The impact on the drug product from a substance permeating through or from a polymer is related to the solubility or reaction of the substance and diffusion in the drug product.

The concentration of migrant in the polymer, along with the volume of drug product, contact area and time all influence the capacity for leachables, as does the polymer density, thickness and ratio of migrant to polymer at equilibrium. The change of concentration of a particular migrant within a diffusion volume follows Fick’s second law:


where c = concentration, t = time, x = distance and D = diffusion coefficient. Theoretical diffusion can be estimated based on the material’s specific constants, diffusion coefficients and relative molar mass of each migrant. Mathematical migration modeling can be accomplished by assuming that there is homogeneity in the CCS and a lack of resistance from boundaries, and that the total amount of migrant in the CCS relative to the drug product remains constant.³ The time predicted for drug product contamination is variable but it can be useful to provide estimates of certain leachables, to aid in the selection of materials early in the drug development stage or to indicate parameters that can be used as a basis for experimental conditions.

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. The principle classes of materials used in CCS are plastic, elastomers, glass, metals, inks/coatings, adhesives and paper. Whether an individual component or a combination of components are employed in single-use devices, intermediate- or long-term storage applications, the material science must be understood in order to make informed decisions. The route of administration is a significant factor to determine the components to be evaluated, the amount of information needed to ensure patient safety and satisfy regulatory requirements. Inhalation, injectable, transdermal and ophthalmic dosage forms have a high degree of concern for package-product interaction and it is the regulatory expectation to assess leachables.⁴ Common CCS components used in different dosage forms are listed in Table 1 along with typical materials of construction.

Table 1: CCS Components & Materials
Dosage Form	Components	Example Material
Inhalation	MDI/DPI components, canisters, valves, gaskets, blister packs, bottles, actuators, mouthpiece, pumps, closures, liners, label/inks	polyolefins, styrene butadiene rubber, ethylene propylene diene monomer, rubber, thermoplastic elastomers, polyacetal, polyesters, polyamides, acrylics, epoxies, paper / paperboard, metals, glass
Injectable	SVP 100ml cartridge, syringe, vial, amp-oules, flexible bag, closures / plungers, injection ports, needles, adhesives, inks, overwraps	polyolefins, butyl rubber, ethylene propylene diene monomer rubber, polyvinyl chloride, polyurethanes, polycarbonate, acrylics, poly-amides, polystyrene, thermoplastic elastomers, silicones, polyesters, epoxides, cellophane, fluoropolymers, styrenics, paper / paperboard, metals, glass
Ophthalmic	bottles, droppers, screw caps, liners, tips, tubes/liners, labels/ink	polyolefins, acrylics, vinyls, epoxies, polyamides, thermoplastic elastomers, polyesters, cellophane, glass, paper / paperboard, metals
Transdermal	adhesives, membranes, barrier films, reservoir, coatings, blister packs, preformed trays, overwraps, substrates, topical aerosol components	polyolefins, acrylics, vinyls, polyamides, polyesters, styrenics, rubber material thermoplastics, metal
Associated Components	nebulizers, dosing spoons, dropper, dosing cups	polyolefins, glass, rubber, thermoplastics, polyesters

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 include 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 are of particular concern for contamination, since leachables can have a negative impact on the patient as well as the protein products, as expressed by Markovic.⁵ A multi-component 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, i.e. solutions, emulsions, suspensions creams, solids, gels, aerosols, 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. Plastics components will have many low molecular weight compounds that are not part of the polymer backbone which originate from polymer residuals, processing aids or performance additives. These are considered suspect leachables. Examples of the different classes of plastic additives are found in Table 2.

Further information on specific chemical entities related to polymer materials and allowable migration and formulation limits, as sanctioned for foodstuffs, can be found in the Official Journal of the European Union, Commission Directive 2007/19/EC⁶ and USFDA CFSAN Inventory of Effective Food Contact Substance (FCS) Notifications.⁷

Table 2: Typical Plastic Additives

• Lubricants
• Antistatic Agents
• Initiators
• Stabilizers
• Impact Modifiers
• Antioxidants
• Bactericides
• Catalysts
• Blowing Agents
• Processing Aids
• Plasticizers
• Colorants
• Brighteners
• Release Agents
• Vulcanizing Agents

Regulatory Guidelines

The responsibility of providing the appropriate CCS information to regulatory authorities is that of the sponsor. The ultimate goal is to manufacture a safe drug product, hence satisfying regulatory requirements. The regulatory environment is continually evolving based on regulatory concerns, industry experience and best practices. There is new GMP guidance advocating the QbD process outlined in Quality Systems Approach to Pharmaceutical CGMP Regulation⁸ in accordance with ICH Q8 Pharmaceutical Development and ICH Q9 Quality Risk Management. The main USFDA guidelines governing CCS suitability include: (i) Container Closure Systems for Packaging Human Drugs and Biologics, (ii) draft Metered Dose Inhaler (MDI) and Dry Powder Inhaler and (iii) Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products.^{4, 9, 10}

The European Medicines Agency (EMEA) and Health Canada have also published guidelines encompassing the same scope.^{11, 12, 13} Globally, the recommendations are similar with respect to conducting extraction, interaction/leachable, migration, compatibility and toxicology studies on CCS. There is an allowance for the use of plastics meeting EP criteria that is specific to the EMEA guideline. Compendia tests are required for CCS according to both EMEA and USFDA, but results are limited to the information that can be used to conduct a comprehensive leachable study. There is also some discrepancy between EMEA and the U.S. regarding extractable testing for DPI dosage forms.^{12, 13} Overall the guidelines require thoughtful interpretation. Working within a QbD framework will reduce the uncertainty associated with the amount and type of data needed to scientifically justify CCS suitability.

The highest level of concern in relation to drug product / CCS interaction is that of the inhalation route of administration. In August 2006, the Product Quality Research Institute (PQRI) approved Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products as an industry accepted standard.¹⁴ This document proposes the use of threshold values, and details best practices for leachables and extractables studies within the spirit of the QbD principles. The basic premise of the PQRI document is to obtain CCS information early in the development phase to enable selection of appropriate components that have been scientifically justified, based on desired performance in relation to safety.

QbD Strategies for Leachable and Extractable Studies

The strategy for selecting and qualifying a CCS used for parenteral products can incorporate QbD principles to establish boundaries for producing a suitable system. Compatibility is a dimension in the design space for CCS suitability, in addition to the safety, performance/delivery, function and protection needed to achieve a quality product. The safety and efficacy of a drug product can be linked to the combination of these four major CCS parameters, and safety is a principle driver for the overall compatibility. Safety can be viewed as a subset in a design space for compatibility. The CCS chemical characterization 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.

A contaminated drug product can impact the patient’s well-being as a result of toxicity or undesirable changes to the drug product, resulting in an impaired therapeutic affect. The challenge here is to identify and predict worst case migrating species (extractables) and correlate these to leachables to determine negative effects during drug product development, so an informed CCS decision can 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.⁴ 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 organization tool such as an Ishikawa diagram (Figure 1) illustrates the potential variables that could impact the safety and efficacy in relation to CCS compatibility.

Figure 1:Ishikawa diagram

The likelihood of CCS interaction with a drug product can impact the product’s safety and efficacy throughout the drug product 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 behavior of a CCS will provide parameters for correlation to end of 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. This can be obtained from the supplier, literature and previous experience. 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 minimize the chance of unexpected leachables, solvents should be representative of the drug product, and worst-case and exaggerated conditions be used 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.¹⁵

Applicable analytical techniques for identification and quantitation of organic leachables and extractables typically involve the combination of gas and liquid chromatography with compound-specific detection. Every possible leachable may not be detected using a particular method or combination of analytical methods or techniques; the methods and conditions are designed to target unique classes of compounds related to specific components, defined by Norwood.¹⁶ Analytical techniques, such as inductively coupled plasma (ICP), may need to be included in the methodology for evaluation of inorganic extractables for parenteral products. In certain cases when volatile species are suspected, headspace gas chromatography may provide key data. Comprehensive knowledge of CCS materials and processing along with drug product formulation will enhance the scientific rationale for selection of appropriate analytical methodologies. The desired CCS would have the least amount of extractables; however, that does not guarantee the best performance. Typically worst-case and exaggerated extraction profiles will generate many chemical entities, but these entities will not necessarily become leachables. Data acquired from worst-case or exaggerated conditions will need to be representative of potential leachables, yet ensure that the results are not anomalous, so that a comprehensive extractables list can guard against unexpected leachables and provide for material control criterion.

The results of a qualitative extraction profile can be examined for substances that may seriously compromise quality or should be targeted for measurement and/or further assessment. Toxicology support can provide initial information on safety concern compounds and those sanctioned by regulatory agencies that may have applicable specifications.^{6, 7} If the outcome of the study is favorable, 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 optimization 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 factor in the analyte solubility, sensitivity, profile repeatability, interferences, reactivity, hydrolysis and/or byproducts.

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

Leachables

The intent of a leachable study is to link drug product quality with patient safety based on the identity and amount of any given extractable species that contaminates and/or interacts with the drug product. Since the end result is to ensure patient safety, the selection of the appropriate analytes to conduct a leachable 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 product can be predicted based on recognition of the critical CCS materials with an understanding 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 step has the potential to contribute leachables. Those leachables that can cause harm to a patient and/or impact the efficacy of the drug product need to be qualified and controlled within specified limits. The CCS compatibility is defined by the leachable qualification, and the mechanism for qualification relies on knowledge of the chemical characterization of all critical CCS components, the probability of migration and impact to 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 optimization. Detection and quantitation limits correlating to a safety concern level (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. Detection and/or measurement of leachables require validation of the methods prior to evaluation of samples representative of the initial, accelerated and long-term stability, as this data will be used to develop specifications and acceptance criterion.

Results from accelerated stability studies can be used to predict end-of-shelf-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 realtime 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.⁴ 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(s) may be made.

The selection and control of container closure systems are important parameters in pharmaceutical development and throughout the drug product life cycle. Photo courtesy and copyright of West Pharmaceutical Services, Inc.

PQRI Leachables and Extractables Working Group

A PQRI Working Group was formed in early 2000 to address concerns related to the FDA guidance documents on Orally Inhaled and Nasal Drug Products (OINDP). Specifically, there was concern over the recommendation for a toxicological assessment of all leachables and extractables. In order to propose some boundaries for analysis, control and toxicological evaluation of OINDP, the Working Group developed a safety threshold for OINDP, corresponding to a leachable threshold below which would not harm a patient. The group also developed best practices for analysis and identification of leachables. This threshold concept and best practices are consistent with current regulatory thinking, and now other drug products with high likelihood of drug product-dosage form interaction are the focus of the Parenteral and Ophthalmic Drug Product (PODP) Working Group. The goal of the Working Group is to establish a uniform, consistent, quantitative and science-based approach to evaluate and qualify leachables in PODP. This approach will extrapolate the SCT, QT and AET principles previously developed by PQRI for OINDP to PODP, and will include best demonstrated practice recommendations for conducting chemical assessments for the discovery, identification and quantification of CCS-derived leachables and extractables in PODP. An anticipated result may include a matrix to help establish a uniform and risk-based approach that can lead to an efficient product development process.¹⁷ The Thresholds and Best Practices document and the activities of the PODP working group are posted at www.pqri.org.

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 establish CCS safety and justify compatibility for appropriate 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 characterization of the CCS and provide data to identify and evaluate risk; quantitative extractable studies will provide the basis for 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 (R1) Pharmaceutical Development Revision 1, CDER/CBER Draft Guidance 1/10/2008
2. Brandrup J., Immergut E.H., Polymer Handbook Third Edition, 1989, Wiley
3. Rosca I.D., Vergnaud J.M. Problems of Food Protection by Polymer Packages, Journal of Chemical Health and Safety. March/April 2007 (14-20)
4. Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry Manufacturing and Controls Documentation, CDER/CBER/FDA Guidance for Industry, 1999
5. Markovic I. Challenges Associated with Extractables and/or Leachable Substances in Therapeutic Biologic Protein Products, American Pharmaceutical Review. (20-27)
6. Official Journal of the European Union, Commission Directive 2007/19/EC April 2007
7. Inventory of Effective Food Contact Substances (FCS) Notifications. CFSAN/Office of Food Additive Safety USFDA
8. Quality Systems Approach to Pharmaceutical CGMP Regulations, CDER/CBER/CVM/ORA, Guidance for Industry, 2006
9. Draft Metered Dose Inhaler (MDI) and Dry Powder Inhaler, Chemistry Manufacturing and Controls Documentation, CDER Guidance for Industry, 1998
10. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Product, Chemistry Manufacturing and Controls Documentation, CDER, Guidance for Industry, 2002
11. Guideline on Plastic Immediate Packaging Materials. European Medicines Agency, EMEA/CVMP, 5/19/05
12. Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products, European Medicines Agency, EMEA/CVMP, 10/06
13. Guidance for Industry Pharmaceutical Quality of Inhalation and Nasal Products, Bureau of Pharmaceutical Sciences, Health Canada, October 2006
14. Safety Thresholds and Best Practices for Extractables and Leachables in Orally In and Nasal Drug Products. OINDP Leachables and Extractables Working Group, August 2006, Product Quality Research Institute (PQRI)
15. Fliszar K., Walker D., Allain L., Profile of Metal Ions Leached from Pharmaceutical Packaging Materials. PDA Journal of Pharmaceutical Science and Technology 2007, 60, (6), 337-342
16. Norwood D., Granger A., Paskiet D. Extractables and Leachables in Drugs and Packaging. Encyclopedia of Pharmaceutical Technology, Third Edition, 2007, Informa Healthcare
17. Proposal for Reporting and Qualification Thresholds for Leachables in Parenteral and Ophthalmic Drug Products. PODP Leachables and Extractables Working Group, March 2007, Product Quality Research Institute (PQRI)

Diane M. Paskiet is Associate Director of West Analytical Services.