USP <661.1> and <661.2> – A History of Challenges

When after years in the pharmacopeial forum, the proposed final drafts of USP <661.1> and <661.2> were published to USP39 NF34 in May, 2016, there were still many challenges to practical implementation faced by industry. Partially for this reason, but more largely due to the expanded scope of testing relative to the old <661> chapters they were replacing, an original effective date of May 1st, 2020 was proposed for <661.1> and <661.2>. At the time of this writing, however, USP <661.1> and <661.2> are scheduled to be effective December 1st, 2025. Throughout the history of these chapters, early adoption has been encouraged by USP, regulatory bodies, and contract laboratories alike, including CS Analytical.

Although the general strategy and differences between the chapters is defined in more detail here and here, it is most straightforward to define <661.2> as being performed on the final package system – its method requiring that the final package be filled to its nominal volume for extraction. In comparison, <661.1> is intended to focus on materials of construction – this is done without respect to the volume of the final intended container. A known amount (mass) of plastic material is extracted in a constant volume of extraction media, most commonly water, with some variations on mass to volume ratios depending on the polymer. USP <661.1> also includes some more rigorous tests not found in <661.2>, such as extractable metals and plastic additive testing.

A practical example of how this may present in the real world is testing a final HDPE resin blend by <661.1>. This <661.1> data may be used in support of all package systems including a component manufactured from this resin, HDPE bottles of different sizes, for example. However, each of those different sized HDPE bottles, along with their corresponding closures, would be subject to USP <661.2>.

USP <661.1> and <661.2> Testing of Blister Cards – A Practical Challenge

Amongst the challenges for practically implementing the new USP <661.1> and <661.2> was a defined approach for testing blister cards and their materials. This was a concept discussed in a June, 2016 conference session at EastPack Pharmaceutical and Medical Packaging 2016 in NYC . CS Analytical’s CSO Brandon Zurawlow participated on the panel with USP representatives and industry stakeholders, much of which became a Q&A for those in the audiences.

The primary issue regarding blister cards was filling sufficient cavities with water in order to yield enough solution for <661.2> testing. In order to perform the prescribed tests, at least 40mL of extraction solution is required. In the case of blisters, this could mean dozens or even hundreds of water-filled cavities would need to be prepared by the manufacturer for analysis.

Outside of the large number of samples required, logistically, preparing these samples have their own challenges. Due to the specialized, often custom process of forming and filling, and sealing blisters, this meant that many manufacturers would be required to shut down their line (or at least schedule time outside of production), manually fill sufficient cavities with water after forming, and send them for sealing. Many companies found this hard to get done from a production and quality perspective, while more still faced challenges with consistent filling using USP-grade water, or sealing due to water on critical surfaces.

While the option to create a “representative sample” with the same materials surface-area-to-volume ratio as the final blister design was and is allowed by <661.2>, designing tooling for a larger cavity that maintained these dimensional attributes remains both challenging and cost-ineffective.

The challenges in testing the final package system above ultimately led many companies to explore testing the forming material and lidding material separately by <661.1>. This too led to issues.

For one, <661.1> was written for individual materials of construction: HDPE, PP, PVC, etc., for example. While some blister forming materials are solely PVC, for example, many blister card materials are multi-layer. Establishing meaningful tests and specifications for multilayer materials, while possible and permitted, was a similar challenge to those looking to implement the revised test regime, as was obtaining each material, possibly from different suppliers, in its single-layer form.

Regardless, this did not circumvent one glaring issue, that <661.1> alone was not intended to demonstrate the suitability of the final packaging system, which was to be established by <661.2>.

USP Revisions Attempt to Provide a Solution

When the to-be-official chapters were pulled back into PF in 2019, in addition to extending the implementation period to December 1st, 2025 and other revisions, the USP critically changed the scope of USP <661.2> from “this chapter applies specifically to plastic packaging systems. . .” to “this chapter applies specifically to plastic packaging components and systems. . . “.

While this may be a small verbal change, the implications were wide. With the new proposed language, individual components could be tested directly to USP <661.2> specifications and demonstrated as “chemically suitable for its intended use”. However, this change actually muddied the waters.

To test individual plastic components, say, a plastic cap that would be affixed to a 100mL Type 3 glass bottle, the entire component “is placed in an inert extraction vessel and put into contact with an amount of purified water that is equal to the packaging system’s nominal capacity”, in this case 100mL.

What’s interesting here is that under this proposed change, the material-to-solvent ratio is often less than would be if the individual plastic materials of the cap were isolated and tested to the physicochemical tests of USP <661.1>, which despite their different sample solution (extract) preparation, are largely identical to the physicochemical tests of USP <661.2>.

Additionally, non-plastic materials such as paper-backed liners in the caps that would otherwise not be submerged in an assembled package system, are put into the extraction, which can impact results.

Despite Updates, Challenges for Testing Blister Cards Persist

In the case of blisters, these challenges present in different ways. Cutting up an entire blister card, placing it into an extraction vessel, and filling it to the “nominal volume” of the package system is not practically feasible when the combined volume of the cavities is only a few mL, not sufficient to extract material. Furthermore, many blister cards have printed, paper-backed foil lidding. Paper materials have been known to impact TOC results, and inks an impact to absorbance. Under actual conditions of use, although migration is always a concern, these materials would never be in direct contact with the product-holding portion of the container, separated by the polymer-coated foil barrier.

In summation, despite efforts to revise the USP <661.1> and <661.2> chapters to ease implementation by further considering the many use cases for plastic packaging materials, components, and systems, a practical solution to testing blister card configurations has largely evaded industry.

CS Analytical’s Solution

In that 2016 EastPack panel discussion, on the topic of testing filled and sealed blisters, USP Scientific Liaison Desmond Hunt at the time stated “We’ll have dialogue – if Brandon has a robust method, we could include it”, adding that approaches are “evolving”.

In 2022, it is the opinion of CS Analytical that the solution for testing blister cards is already present, but it is a matter of an experienced laboratory understanding the challenges, regulatory expectations, and the risk-based approach to container qualification testing that has been a dominant theme in USP chapter revisions over the last decade. With this, a solution can be developed and implemented.

As of October, 2022, CS Analytical offers the ability to seal formed blisters in-house. Through collaboration with the client, custom tooling is acquired to seal blisters at lab-scale in our analytical laboratory, taking the burden off the client to acquire line time, expertly fill with USP-grade water, and introduce water to their filling and sealing operation. This is often more efficient from a time, cost, and regulatory perspective than designing tooling for a larger cavity that maintains the critical surface-area-to-volume ratio of the final configuration or justifying alternate approaches previously discussed.

With CSA’s solution to this challenge, a client sends us their blister cavity technical drawings, often required as part of the process for determining desiccant to be used for USP <671> testing, a related, but separate test set that evaluates permeation and light resistance of blister cards. CSA will determine, and the client will provide, a sufficient formed blisters and lidding material to yield the total solution volume required for testing. At CSA, formed blister cavities are filled with USP-grade water using a micropipette, sealed, and placed into the extraction condition before being removed, cooled, and the resultant extract removed from each cavity and combined to perform all USP <661.2> tests.

For clients looking to take a conservative approach to USP <661> testing, USP <661.1> testing of individual plastic materials of construction used in the blister system remains available, including specialized tests for PVC impurities and extractable metals. These data can be used to further support the qualified status of the system tested by <661.2>.

CSA, with supporting comments from our clients, believes that this proposed approach provides a direct solution to the business, technical, and regulatory challenges companies can face when updating existing packaging data to USP <661.1> and <661.2>, or ensuring the success of new product-packaging coming to the market.