Advanced therapy medicinal products (ATMPs) offer ground-breaking opportunities for treatment of injury and disease, in particular cases of severe, untreatable or chronic diseases that do not respond adequately to more conventional treatments. This therefore creates more possibilities to improve the quality of life in particular population cohorts.

As a result, ATMPs such as cell and gene therapies (CGT), typically have very rigid temperature requirements that pose unique challenges throughout the supply chain. These products often must be held at ultra-low temperatures (ULT) between minus 20 and 80 degrees Celsius, with very little scope or time for deviations away from these target temperatures.

Much attention has been paid to the risk of temperature excursions during shipping, and those risks have been minimized successfully with special packaging and temperature tracking. However, the industry is perhaps less familiar with the steps that need to be taken during labeling and packaging to ensure that these products stay well within their acceptable temperature ranges. Appropriate processing requires careful planning, experimentation and validation, tight controls and extreme caution.

While the onus is on contract development and manufacturing organizations (CDMOs) to handle these products properly, drug manufacturers should be aware of the risks and complications involved in every step in the supply chain. They must ensure that their CDMO has the expertise to control for, and mitigate against the risks.

High stakes, narrow margins of error

ATMPs are delivering on the promise of personalized medicine. In many cases, these treatments are curative, making them life altering and even lifesaving. The production, delivery and administration of these therapies is complex and time-sensitive, with patients’ health at stake. Often, patients require treatment within days of diagnosis and therefore any delay or product degradation during any stage of processing or delivery could have devastating consequences for their health.

Also, these medications are extremely costly. Personalized medicines can run into millions of dollars per individual pack, and the risks associated with handling them are magnified when several hundred packs are packaged as a batch. It is not unheard of for the retail value of a batch to approach $200 million, so the financial consequences of ruining a pack or batch range from severe to catastrophic.

Therefore, there are ample health and financial reasons to ensure that ATMPs are never out of their acceptable, ultra-low temperature range during labeling, packaging and shipping. Doing so, though, takes extraordinary planning and care, as handling these products, even for a few seconds can alter their temperature. A product can become unusable within a short time period of being out of frozen conditions.

Additionally, many of the materials commonly used for labeling and packing—even the simplest steps of the process, such as label ink types and carton adhesives are not suitable for use under ULT conditions. As a result, all the primary and secondary packaging components are challenged rigorously to ensure that are fit for purpose when exposed to the temperature extremes of materials such as dry ice. This includes, for example, assessment of batch specific variable information that has been overprinted onto packaging to ensure that the printed information is not impacted during both production processing, low temperature production storage and supply chain activities, ensuring that the information is still legible for the end user as per regulatory requirements for individual markets. Assessments will also be performed on the adhesive properties of labels applied to items in the packaging process including product labels and tamper evident labels, ensuring that their performance is not compromised by the temperatures these items are exposed to across the various activities within the supply chain.

Every step involved in labeling and packaging must be performed in a consistent manner, and under specific conditions, requiring that team members be trained and experienced in following special procedures. All aspects of the production process need to be robustly challenged with worst case scenarios being identified in each process step. An example of this is the re-labeling of vials. The robust challenges on the process are performed prior to validation by formal risk assessment during the process design. All processing activities are simulated during process validation batches to provide clear, precise evidence and data to support each work activity. These simulations and the corresponding temperature mapping of work activities provide evidence that the processes can be controlled without temperature excursions beyond defined temperature limits thus maintaining product quality.

All aspects of the process need to be tested and perfected to ensure results are repeatable based on clear, and usually customized operating procedures.

Working in a partnership

Pharmaceutical companies that engage CDMOs should understand the proposed packaging process and have a clear idea of what information their partner will need in order to work most efficiently and effectively. Our experience is that every ATMP comes with its own set of requirements, therefore it will be necessary to develop a bespoke distinct process and a unique set of controls for each operation. This is, necessarily, a collaborative effort between the CDMO and the drug manufacturer. Consequently, manufacturers should be prepared to share all available information with the CDMO from the outset on what is known about the product’s temperature parameters and handling requirements as well as what materials are preferred.

In addition, manufacturers should also be prepared to contract with the CDMO to conduct proof-of-concept work, if the product’s temperature profile has not been assessed for labeling and packing activities. This work will assess any changes to the product’s temperature over the course of various handling steps. The goal should be to ensure repeatability of those results and to prepare a detailed report on what will be required. The defined packaging process will be intricately detailed, down to how each vial can be handled, when a supervisor must be called, etc.

Key considerations in defining the best packaging process include:

1. The allowable time out of condition
2. Conditioning time requirements when taken from one environment to another
3. Material specifications for labels and cartons
4. Label design
5. The need to pre-print batch numbers and expiration dates on labels and cartons to minimize time of controlled environment
6. The final pack-out configuration with any ancillary components (such as patient information leaflets)
7. The level of serialization aggregation required (from carton to shipper to pallet, for example)
8. Temperature controlled distribution and global supply chain

Sufficient time for process validation must be allowed and, where applicable, equipment qualification depending on the requirements of the client and the product. Once the product’s temperature parameters are established, the next stage will be advanced through the validation cycle, a many-phased exercise that includes:

A Validation Plan. The objective of the Validation Plan (VP) is to outline the validation approach that will be taken by the CDMO to demonstrate and provide documented evidence that the packaging process is capable of consistently producing product that meets the required specification. 

Engineering Studies. The objective of the Engineering Study (ES) is to provide documented evidence that the packaging materials and the equipment being used are capable of producing product that meet the Critical Quality Attributes (CQAs) for this product type. These studies enable us to for example determine the risk to the product’s temperature profile during various scenarios including application of labels to product and all ancillary secondary packing activities.

Performance Qualification. Performance Qualification is needed to demonstrate that acceptable product can be produced using a draft master batch record that mimics the intended commercial packing process while utilizing the parameters established during engineering study while ensuring that the product temperature is maintained within the required temperature ranges throughout all process steps (including reprocessing steps) when running the operation at worst case conditions. 

Process Validation. Generally, Process Validation is performed on three pack batches. The number of packs associated with each batch should reflect the intended commercial batch sizes for the product. Each batch will be packed using a fully approved master batch record and will utilize packaging components that are either commercial components or commercially representative components. The batch processing will again challenge worst case scenarios and will be performed in a time period that includes production breaks and shift handover. During the packaging operation In Process Checks and Critical Device challenges will be performed as directed by the Master Batch Record and Process Validation documentation ensuring that each operation produces product of consistent and acceptable quality.

Conducting all of these activities, and reporting the results takes time, therefore manufacturers should be prepared for a three- to four-month window across the various validation steps.

Strategies for success

Due to the requirements for labeling and packaging of ATMPs being different from those of products that don’t need to be held at low temperatures, it is critical to work with a vendor who has experience in this area. The risks are too great to entrust the work to inexperienced partners. While no two products and situations are exactly alike, lessons learned from one situation can often be applied to another, and a body of knowledge can gradually be amassed that can circumvent much trial and error in developing the packaging process. This prior knowledge also helps to ensure that teams are trained properly and know how to work with precision in critical steps of the operation.

The best solutions will emerge when the manufacturer and CDMO are open to out-of-the-box thinking. Processes or materials that work for products kept minus 20 degrees Celsius, does not mean they will work for ULT products, often they don’t. Plus, situations/conditions will arise that even an experienced CDMO will not have faced, requiring new, creative ideas and methodologies.

Just-in-time processing is one technique that if used when appropriate can improve the CDMO’s responsiveness and expedite the delivery of orders. This approach allows the product to be labeled and packed upon receipt of an order, in line with the particular patient’s dosing requirements.

Manufacturers should strive to stay closely involved as the packaging processes are being defined. They should be given access to the findings of all the process qualification and validation studies and should even be able to watch the studies being performed. Almac, for instance, welcomes clients on site to see the operations first-hand.

It is also incredibly important to ensure temperature stability throughout the entire supply chain, from the initial shipment of the product to the CDMO, to its receipt at a clinic. There must, for example, be specific processes for receiving products on site, transferring product from shippers to freezers, dispatching product to clinics and getting through customs, etc. The packaging process is a just a small part of the whole process, but it takes just a few moments of inattention or one poorly conceived procedure to permit product degradation.

A case in point

For one gene therapy product that Almac packages, the treatment dose and the number of vials that need to be packed are based on the patient’s weight. The product is for the EU market, so the product needs to be placed in country-specific packaging with the patient’s information on the pack. Between the varying weights and the country information, Almac had over 420 SKUs for this one product.

To accommodate this client’s needs, Almac has dedicated a GMP footprint within its facility for packing this product. When an order is received, which could be as small as one vial per batch, the specialist team picks the product from the client-dedicated freezers, labels and packs it over dry ice. The product is then released by a Qualified Person in real time, and it is ready for direct distribution to the patient for receipt within 24-48 hours.

In order to ensure the patient receives the product in prime condition, Almac combines its temperature controlled logistic expertise with the use of reputable, experienced and trusted supply chain providers. This unique solution offers a comprehensive end-to-end service which guarantees expedited delivery of products direct to the patient. Using innovative shippers, temperature monitors and digital platforms which enables real-time visibility into product and shipper conditions, as well as location of the shipment, ensures that valuable gene therapy will not be compromised during transit.

Collaboration with our clients is the most vital aspect of our approach. Almac’s experienced team of technical experts works intensively with each client to gain a deep understanding of both their product and patients, before mutually agreeing a customized approach to manage and deliver treatment exactly when required.