2.3.P.7 Container Closure System

With respect to the container and closure system (CCS), there are related questions in 2.3.P.2.4 and 2.3.P.7 of the QbR–QOS. Often information in one or both sections are missing or inadequate. There are assumptions made, based on previously approved ANDAs, which lead to ANDA applicants not providing necessary information in their submissions. While it is generally appropriate to reference approved CCS from other ANDA, it may not always be appropriate if specific drug substance or drug product characteristics need to be mitigated by the use of a specific CCS (e.g. moisture protection, light protection, droplet size, use of an inert system, etc.). If a statement is provided referencing products that have been approved using the same packaging system, then a copy of the test results for the components should be provided in the body of data, and in some cases, justification that this previously approved system is appropriate to the specific product based on the existence of similar drug substance or product characteristics.

In the development section (2.3.P.2.4) of the QbR–QOS, the following question is linked to the rationale for choice of the container closure system:

Whereas in 2.3.P.7, specific details on the chosen system should be provided to answer this QbR question:

• What container closure system(s) is proposed for packaging and storage of the drug product? Has the container closure system been qualified as safe for use with this dosage form?

In the development section, the rationale for choosing a CCS should be provided. This is an opportunity for the sponsor to discuss any studies conducted to identify any critical attributes including suitability (protection, compatibility, and performance) and safety of the CCS. It is recommended to take into consideration the recommendations and information found in current FDA guidance (8) to decide critically of attributes based on the dosage form.

Suitability for use. Suitability for use includes multiple characteristics of the CCS with respect to performance, functionality, and safety. In too many cases, testing that will be used to ensure CCS performance and safety is not provided or is poorly documented. Relevant compendial test results and controls (e.g., USP <381>, <87>, <88>, <660>, <661>, and <671>) should be also provided, as appropriate (5). These tests are intended to demonstrate CCS identity, performance, suitability, compatibility and safety. If this information is lacking deficiencies will be cited.

Any other testing or certification, such as Code of Federal Regulations (CFR) references to demonstrate suitability of use for pharmaceutical products, should be also provided. (e.g., 21 CFR sections 174–186 provide a list of materials that are safe for use in direct or indirect food contact) (9).

In many cases, for solid oral products, the most crucial container closure development studies are related to drug product chemical stability. Although tablet integrity (physical stability) may need to be studied for low hardness or highly friable tablets such as orally disintegrating tablets (ODTs) or chewable tablets. Further discussion on this topic can be found later in the article.

For any drug products that incorporate delivery devices (e.g. nasal sprays, inhalation products, oral solutions, ophthalmics, etc.), pharmaceutical development studies conducted with respect to demonstration of performance should be discussed. Performance testing of the CCS might include dropper consistency, calibration of delivery device, droplet size, etc. It may also be necessary to compare the ANDA product performance with the reference listed drug (RLD) to demonstrate similar dosing will occur.

Specific cases. In the case of parenteral products, and other drug products that are solutions or suspensions, compatibility testing should be provided (e.g., extractables and leachables for the stoppers or the CCS materials, as applicable, dye or adhesive migration from labeling, etc.). If this information is not provided, deficiencies have and will continue to be cited. Also, the analytical method used for the analysis should be appropriate for the detection of the extractables and leachables from the CCS. While proposing quality or safety limits for the extractables and leachables, it should be remembered that these are not covered by the International Conference on Harmonization (ICH) Q3B (R2) guideline or the related ANDA impurity guidance (10, 11). Thus, the acceptance criteria proposed should be supported by sound rationale, based on available toxicological information in the public domain, or information provided in the applicable CFR sections (9).

In USP <1>, closures for multiple-dose containers permit the withdrawal of the contents without removal or destruction of the closure (5). The closure permits penetration by a needle and, upon withdrawal of the needle, closes at once, protecting the container against contamination. Suitable controls (e.g., coring, seal-sealing, fragmentation, etc.) should be in place to demonstrate that the stopper is adequate if it is intended to be used in a multiple use product.

With respect to blister packages, an often cited deficiency is a lack of data to demonstrate that the blister components protect the product from moisture. We recommend that data be provided for moisture permeation of the proposed blister pack. Additionally, as an in-process, and in some cases for release and stability analysis, a leak test may be necessary.

Occasionally inquiries are made regarding integrity of tablets during transportation and storage. This is common when the dosage form is an ODT or some other low hardness tablet (e.g., chewable tablet), which are packaged in bottles having large headspace. It is well known that tablets are constantly subjected to mechanical shocks and abrasion during the transportation and storage. Such stresses can lead to chipping, abrasion or even breakage of orally disintegrating tablets, which are known to have low friability. It is therefore important for the ANDA applicant to demonstrate that the tablets are able to withstand such stress without damage and provide information to assure the integrity of the tablets during transportation and storage. In use and "shipping" studies should be taken into consideration when designing low hardness products, as well as, other dosage forms that may be affected by transportation.