Shipper & Payload Bracketing: How to Implement ISTA’s PCG-03 Recommendations

Shipper & Payload Bracketing: How to Implement ISTA’s PCG-03 Recommendations

On July 22nd, 2022, ISTA released PCG-03: Performance Qualification (PQ) and Performance Verification (PV) Best Practice Guideline. PCG-03 takes the first steps toward standardizing best practices for PQ strategy and execution for the biopharmaceutical industry, as it is the first document to compile strategies from thought leaders in the industry and provide a path forward for transport validation work.

We applaud ISTA for this useful and comprehensive list of considerations for determining your PQ strategy. However, there remains a clear gap on how to manage and implement their recommendations. The items listed within the document require further context to enable the industry to form a cohesive approach to PQ strategy.

This article series will seek to dive deep into the considerations listed by ISTA and discuss the implications and risks of each topic. Each article will contain a recommended tactical approach to each of these considerations:

1. Scope and Timing
2. Lane Bracketing
3. Shipper and Payload Bracketing
4. Monitoring
5. Acceptance Criteria
6. Management

As each article is released, we will link it in the Table of Contents above so you can navigate to each topic. In this article, the experts at Modality Solutions are diving into the Shipper & Payload Bracketing recommendations found in PCG-03.

Shipper Bracketing

The second installment of this series was focused on how to reduce the number of shipments in your PQs by bracketing your shipping lanes. This third installment keys in on how bracketing of thermal shippers can help to further condense the number of shipments required.

Similar to a traditional lane qualification strategy, the historical approach has been to use three separate shipments per unique thermal shipper. A PQ is meant to study the shipping process rather than the shipping equipment. Therefore, the number of separate PQ protocols and shipments can be reduced by keeping the focus on the overall goal by analyzing the comparability of the processes across different lanes and thermal packaging.

There are three main components that factor into a bracketing approach:

1. Determining Equivalency
2. Assessing Comparability for Bracketing Purposes
3. Determining the Bracketing Strategy

Equivalent Shippers

The first step in designing a shipper bracketing strategy is to determine if the shippers are equivalent, comparable, or non-comparable. Equivalent shippers should be identical in all construction and materials that will affect thermal performance. These factors include size, insulation type and thickness, and phase change material type and amount.

If shippers are equivalent, no bracketing is needed as they can be used interchangeably. A memo or other short-form report is recommended to document equivalency between multiple named shippers. However, no further consideration is needed between these equivalent shippers in a PQ study.

The most likely scenario for equivalent shippers occurs when using multiple couriers. Couriers will often purchase a thermal shipper from a vendor but replace the generic outer layer with a self-branded layer. In these cases, the shippers may have different model names but their only difference is the outer shell which does not impact thermal performance. Therefore, there is no difference in thermal performance, rendering them equivalent and interchangeable.

Assessing Comparability

Comparable shippers are unique shippers that are comparable in their usage. As discussed in the first post in this series, PQs are intended to verify the process. Therefore, if the process of using certain shippers is comparable, they can be bracketed together to test under a single protocol.

Thermal shippers that use different types/conditions for PCM and/or are different in their preparation and use in the field should be considered non-comparable. Non-comparable shippers should not be bracketed in a PQ.

The most straightforward comparability determination is when using multiple sizes of the same line of shippers. For example, a thermal shipper vendor will often have the same model available in 4 L, 8 L, 12 L, etc. designs. Typically, the only difference in use between these multiple sizes is amount of phase change material – either in number of PCM packs/panels or in their size. In this scenario, the process for packing out each shipper is very similar; often times the vendor will even have a single universal packout instructions form. Therefore, a single PQ can adequately verify the performance of this suite of shippers.

Bracketing can also be a valid strategy for unique shippers if the usage process is similar enough. This is mostly dictated by use-cases and responsibilities such as the type of PCM: do the shippers use PCM that must be conditioned at a set temperature and/or in multiple stages, or is it a set quantity of material such as dry ice or liquid nitrogen? If it is the latter, the instructions for preparing a shipment can be very similar regardless of the type of thermal shipper being used.

Additionally, often the sending site does not prepare the shipment directly for a dry ice or liquid nitrogen shipper; the courier will bring a fully prepared thermal shipper to the site where it is loaded with product. Therefore, if you are using three different types of LN2 dewars, for example, a single PQ can verify that the shipping process is valid for all three dewars.

Bracketing Strategy

For an example of applying a bracketing strategy, we will consider three thermal shippers: Alpha, Bravo, and Charlie. All three are LN2 dewars that come to the site prepared by the courier and are loaded with product by the site staff. For this example, we will assume that:

• Shipper Alpha is qualified to maintain temperatures ≤ -135 °C for 144 hours
• Shipper Bravo is qualified to maintain temperatures ≤ -135 °C for 120 hours
• Shipper Charlie is qualified to maintain temperatures ≤ -135 °C for 144 hours

We want to create a bracketing strategy that will reduce our overall number of shipments while still verifying that the process is both consistent and is comparable between the shippers. There are four unique strategies that can be applied (also shown in the table below):

• Three shipments for each unique thermal shipper type
• Three shipments in the worst-performing shipper (Bravo) and one shipment each in the others
• Three shipments in the worst-performing shipper (Bravo)
• One shipment in every unique thermal shipper for a minimum total of three shipments

Strategy	Alpha Shipments	Bravo Shipments	Charlie Shipments	Total Shipments
1	3	3	3	9
2	1	3	1	5
3	0	3	0	3
4	1	1	1	3

 

Strategy 1 does not apply any bracketing; three shipments are sent in each of the three unique shippers for a total of nine shipments. This is included in the table as a reference to the most conservative approach. Strategies 2 and 3 take into account worst-case performance. Shipper Bravo has been qualified for a full day less than Alpha and Charlie and is therefore highlighted in these strategies. Strategy 4 does not take into account worst-case performance but ensures that all shippers are tested under the PQ.

All bracketing strategies should be used with a risk-based approach that determines the appropriate reductions to be made to the PQ process, if any. We recommend following Strategy 2 when employing a bracketing strategy for multiple thermal shippers, unless the conditions stated below require following Strategies 3 or 4.

Strategy 2 reduces the total number of required shipments while still using enough shipments to prove both repeatability and comparability. The Bravo shipper is tested in triplicate to demonstrate that it will consistently perform as intended with the shipping process while Alpha and Charlie are used once each to demonstrate comparability to the Bravo shipper process.

Strategy 3 and 4 lack the demonstration of comparability and repeatability, respectively. These strategies are best used when there are infrequent shipments or other issues limiting the number of PQ shipments that can be completed. For example, Strategy 3 can be used when there is a single ‘preferred’ shipper type but others are desired to be available for use when need arises (such as inventory issues). Strategy 4 is best used when there are infrequent shipments but all shipper types are desired to be included.

The total number of shipments in your PQs should now be fully determined through lane and shipper bracketing. You can now begin to dive into the specifics of investigating the shipments: what data needs to be collected, how to collect it, and what analyses need to be done. The next installment in this series will focus on best practices for monitoring during PQ shipments followed by creating and assessing Acceptance Criteria for the shipping studies. Catch up on the first two articles in the series below:

1. Scope and Timing
2. Lane Bracketing

Modality Solutions is a leading provider of innovative and comprehensive solutions for the biopharmaceutical industry. Our team of experts has extensive experience in the industry and works closely with national and international regulators to ensure that our clients stay ahead of the latest industry developments and best practices. We pride ourselves in providing tailored solutions to meet the unique needs of our clients, and we are committed to helping organizations achieve their PQ goals. Contact us for more information on how we can help your organization navigate the complex world of biopharmaceutical transportation. And don’t forget to follow us on LinkedIn to stay updated on our latest developments.