The FDA Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, addresses the review and evaluation of packaging requirements. According to this document, each New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) should contain enough information to demonstrate that a proposed container closure system and its components are suitable for its intended use.

The type and extent of information required will depend on the dosage form and route of administration. Qualification and quality review is applied to packaging materials and to the actual dosage form. Packaging suitability is based on four attributes: protection, safety, compatibility and performance (function and/or drug delivery). For injectable dosage forms, the document outlines the tests required to show that interaction is not a problem. Associated components, such as those used only at the time a dosage is administered, self-adhesive labels and secondary packaging materials are also included in the review process.

Inhalation and injection drug products have the highest requirements. There are product-specific draft guidelines for Metered Dose Inhalers (MDI), Dry Powder Inhalers (DPI), nasal sprays and inhalation solutions, suspensions and spray drug products. The identity and concentration of leachables in inhalation and nasal drug products must be monitored throughout the dosage form’s shelf life, since the product consists of the dosage form and container closure system.

Extractable and Leachables in Primary Container/Closures Systems
Primary container/closure systems, as well as other packaging components, have the potential to interact with the dosage form. Factors that must be considered in evaluating container closure systems are: materials of construction of the container/closure system, surface treatments and/or processing aids, dosage form active ingredient and excipients, sterilization and/ or other related processing and storage conditions.

The presence of extractables is determined through artificial means. An extractable is a chemical species that can be released from a container or closure material of construction that has the potential for contaminating the dosage form. Under certain exaggerated solvent, temperature and time conditions, an extractable may be generated through an interaction with the closure system.

Extractable testing studies are recommended even if containers or closures meet compendial suitability tests. Extensive testing for extractables should be performed as part of the qualification of the container/closure components. Testing under stressed conditions should demonstrate that the extractable profile is acceptable for the specific dosage form and that levels observed will not be approached or exceeded during the shelf life of the drug product.

A leachable is a chemical species that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies. Leachables are substances identified in a defined laboratory regimen by simulating use conditions. The industry is focused on potential problems associated with extraction of chemicals from packaging materials into drug product. Leachables are a subset of extractables.

Industry Response
Numerous guidances (see Table A below) mention the appropriate evaluation of packaging components. These guidances recommend that the safety and compatibility of the dosage form with the primary container closure system be established early in the development process. Specific focus is on the potential for drug/biologic interaction with the container or closure because of leaching or absorption.

Table A: Guidances for Packaging Components CPMP: Note for Guidance on Development Pharmaceutics (1998) CPMP: Development Pharmaceutics for Biotechnological and Biological Products, Annex to Note for Guidance on Development Pharmaceutics (1999) ICH Q6A: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (2000) ICH: The Common Technical Document for the Registration of Pharmaceuticals for Human Use, Quality (Draft, 2000)

Industry-based working groups have been established to assess extractable concerns and other scientific issues. The Product Quality Research Institute (PQRI) was established to conduct research that generates scientific information to support the development of regulatory policy. PQRI is driven by its member organizations which include (but are not limited to) the American Association of Pharmaceutical Scientists (AAPS), the Pharmaceutical Research and Manufacturers Association (PhRMA), the Generic Pharmaceutical Association (GPhA), the Parenteral Drug Association (PDA) and the U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER). PQRI is a nonprofit foundation that serves as a vehicle for FDA, industry and academia to collaborate on key issues in pharmaceutical product quality through research and expert analysis. Currently, PQRI’s working group for leachables and extractables is attempting to better define and clarify analytical and toxicological issues relating to these key areas.

Another industry group, the International Pharmaceutical Aerosol Consortium on Regulation and Science and the Inhalation Technology Focus Group of AAPS developed a Points-to-Consider document in reference to leachables and extractable testing as defined in the MDI/DPI draft guidance and the Nasal Spray/Inhalation Solution draft guidance. The concept recommends establishment of identification and qualification thresholds for extractables and leachables along with other suggested points clarification.

Testing Criteria
Testing criteria include:

• That the materials of construction of the container/closure components are safe for their intended use. This is usually done via chemical analysis for extractables and, if necessary, toxicological evaluation of the extractable substances.
• That the container/closure components are compatible with the dosage form by demonstrating that the dosage form does not interact sufficiently with the container/closure components to cause unacceptable changes in the quality of either the dosage form or the packaging components. Such reactions might include degradation of the active ingredient induced by a chemical leached from the packaging component or a reduction in the concentration of an excipient due to absorption, adsorption or leachable-induced degradation.
• That the container/closure system provides the dosage form with adequate protection from factors that can cause a degradation in the quality of the dosage form over its shelf life; these factors include seal integrity and the ability to reseal when applicable.
• That the container/closure system functions in the manner for which it was designed.

Leachables have the potential to interfere with drug product assays. For instance, leachables might have the same retention time as a drug in an HPLC assay. Leachables also may interfere with medical diagnostic tests, increase the impurity level of a drug product to an unacceptable range or increasing the toxicity of a drug product. If leachables react with one or more drug product components, they could cause a precipitate or pH change.

Testing Processes
Extractable screening during safety studies is an important part in choosing the appropriate container or closure for a dosage form. It can minimize the time and money needed for future suitability studies. Because test methods must be specific to the extractable, the laboratory performing the testing must use the correct techniques. Test methods must be specific to the drug product and placebo in order to evaluate interferences, linearity and other critical factors. In addition, evaluators must test the final packaging/drug combination for leachables during stability studies.

Prescreening procedures should begin with a basic evaluation of container/closure options. The protocol can involve multiple temperatures and conditions for acceleration. It should be designed to identify the appropriate container/closure candidate for inclusion in stability programs. Identifica-tion of extractables can be achieved through analytical testing, such as Liquid Chromatography/Mass Spectrophotometry (LC/MS), Gas Chromatography/Mass Spectrophotometry (GC/MS), Inductively Coupled Plasma (ICP) and Infra Red (IR). Suppliers of these systems may be able to provide some information on testing procedures. The testing laboratory can then develop methods and complete validation of them.

Using rubber closures as an example, the laboratory would identify a potential extractables list for the rubber formulation. This list would include chemicals that can leach into the product from the base closure formulation. These extractables have a direct relationship to the ingredients of the rubber closure. If the laboratory has prior experience with certain potential extractables, previously used methods are chosen for the study. Otherwise, the laboratory will engage in methods development and conduct an assessment to determine the potential for analytical interference, the limits of quantification (LOQ) and typical percentage of recovery of spiked extractables in non-degraded and degraded product and placebo.

If there is significant interference during method feasibility testing, such as HPLC column deterioration evidenced by peak fronting, peak splitting, retention time shortening and poor recovery after multiple injections for extractables, the laboratory determines that these extractables cannot be detected by that particular method. If issues with column performance are noted, dilution of drug product with an organic solvent and cleanup injections between sample injections may be investigated, and analysis of these extractables by other methods with a new sample preparation technique may be attempted.

Typically, methods development would be required to address leachables. Sometimes methods development studies are expanded to improve sample preparation before analysis with a particular instrument. In one case of certain extractables analyzed by HPLC, it has been determined through several organic solvent investigations that client samples require dilution with an equal volume of tetrahydrofuran (THF) to enhance the solubility of the extractables. Samples must then be centrifuged at a preset time and speed to allow presence of a clear THF top layer. The laboratory then analyzes this layer and allows for proper detection of compounds at required concentrations. It has also been determined that the cleanup step in-between sample injections must be made with acetonitrile in order to maintain column performance. For some extractables, new sample preparation techniques are investigated.

Once appropriate methods are developed and verified through multiple sample preparation repetitions and varying factors, formal procedural methods are written in detail for method validation.

Methods validation for detection of leachables in placebo and dosage form are based and recommended on industry practice and International Conference for Harmonization (ICH) Guidelines. A validation plan for each identified test method is developed and approved by the client. Each plan includes detailed standards and sample preparation techniques, system suitability, validation criteria and pass/fail specifications.

Once the appropriate test methods are validated, samples are analyzed for leachables. Then testing of development and stability lots is performed under accelerated and long-term conditions. If leachables are found, toxicological evaluation should be conducted and routine testing or testing of the annual stability lot may be necessary. Typically, three lots of each dosage strength will be tested at predetermined conditions. The extractables testing may be incorporated into the master stability study protocol. This “next phase” testing allows for monitoring of leachables during long-term storage conditions and will assess any negative or positive impacts that may occur with the primary packaging components.

The FDA’s June 1999 Container Closure Guidance has accelerated the requirements for extractable and leachable testing of container/closure packaging components.

Obtaining this information may require testing methods not previously completed within the manufacturers environment. Further, additional testing will require time and money that must be built into the qualification and stability studies of the container/closure system early in the product development cycle.

Container/closure prescreening assures suitability for use with the dosage form and establishes appropriate methodology to test leachables using validated methods. These tests minimize risk and allow for a successful product launch in a timely manner.