Developing a Cell and Gene Therapy Packaging Strategy
Scott Sznyter, Associate Director, Head of Drug Product Manufacturing and Cell Banking, The Center for Breakthrough Medicines
Optimal packaging and labeling solutions help ensure the delivery of safe, effective viral vector products
Demand for viral vectors used for cell and gene therapies (CGT) is increasing dramatically as hundreds of these novel treatments advance through the clinic towards commercialization. Many challenges must be overcome to ensure the cost-effective manufacturing of these complex biomolecules, including selecting the right solutions for packaging, storage and transport of these expensive and potentially lifesaving products.
Viral vectors have poor stability at room temperature so out-of-freezer time must be limited and fill-finish and packaging activities must be performed in minimal time. The oftentimes small batch sizes typically preclude the use of automated solutions, which currently are designed to support the processing of larger volumes leading to manual packaging and labeling operations. Solutions must also meet good manufacturing practices (GMP) and country-specific requirements and withstand extremely low temperatures. Additionally, multiple packaging and shipping configurations are needed to cover a broad range of vial sizes and storage temperatures.
The key to overcoming these challenges is to take steps at the start of product development to identify optimal packaging and labeling solutions with commercial considerations in mind. Time-out-of-refrigeration/freezer and various stability studies should be performed as soon as representative material is available. Sacrificing a few extra vials of vector product upfront to establish critical data can help prevent large product losses later on. This approach can also ensure the selection of packaging and labeling solutions that can withstand the stressors from freeze to ship to a clinic, and maintain integrity and compatibility with automated tracking, reconciliation and segregation.
Time and batch size
Processing volumes for viral vectors are quite small, with the number of vials filled per batch at typically 500 to 1500. A few outlier batches may comprise less than 100 or greater than 1500 vials. In all cases, vectors are stable for a much shorter timeframe (e.g., between 8-15 hours for lentiviral vectors) than traditional vaccines or monoclonal antibodies requiring faster processing times.
Fill-finish and packaging operations must be completed quickly while still assuring product quality. The timer starts as soon as the bag of bulk drug substance (BDS) is thawed prior to filling. The product must be inspected, labeled and packaged right after filling. In most cases, it cannot be frozen and thawed again. Consequently, the overall time for all operations from filling to packaging must be considered when planning the process.
Primary packaging (filling) is commonly performed in a different location than secondary or tertiary packaging. Most secondary/tertiary packaging consists of cardboard and other materials that are non-sterile and may create particulates in the grade A spaces product is usually filled.
Once vials are filled, they are visually inspected. Samples for batch-release testing are pulled and segregated from the final product vials. The sample vials and vials going to clinics are labeled as appropriate, with the former then sent to quality control.
Labeled vials for clinical trials are placed in boxes with dividers that hold multiple vials per box. In some cases, it may be necessary to place each vial in an individual carton to meet the requirements of the country receiving the vials. After the boxes are filled with vials, additional labels must be placed on the outside of the boxes, with one label on each part of the box in case the pieces get separated at any point.
Tamper-evident tape should also be placed over any edges between sections within the boxes. Depending on site procedures, quarantine labels may be appropriate to ensure the product is not shipped prior to testing or release. The boxes of packed vials are placed in freezers for storage prior to release, with the most common storage temperature being -80° C. Once the batch is released, the boxes are placed in temperature-controlled shippers with dry ice in a validated configuration. Temperature monitors are placed in the shippers to ensure the temperature is maintained throughout the shipping process.
Mostly manual operations
Currently, most viral vector packaging and labeling operations are manual due to small batch sizes. Current automated solutions, particularly commercial-grade equipment, are designed to process large volumes and are not suitable even for commercial CGT manufacturing, which typically involves small volumes.
For manual operations, it is important to prove processes can be performed aseptically through operator qualifications and aseptic process simulations (media fills). Thorough risk assessments should evaluate possible issues and identify control measures to avoid them.
Whenever appropriate, the use of automated solutions should be considered to minimize risk, increase speed, and assure greater sterility. There are a few solutions on the market for primary packaging, and some companies are willing to create custom solutions for small CGT manufacturers. The development of automated inspection, secondary packaging, and labeling solutions appears further behind. Most currently available equipment is either slower than manual labeling and packaging or has a large footprint and prohibitive cost, especially for smaller companies getting into the viral vector space.
Coordination and communication are essential
One factor often overlooked by smaller CGT manufacturers when considering packaging and labeling operations is the amount of coordination required between all groups onsite in both the planning and execution stages. It is imperative that groups communicate during packaging and labeling operations to ensure completion within a set time.
The quality assurance group must be on constant alert to respond to questions, deviations and any needs for split-second decisions during processing. Quality control personnel, meanwhile, must be ready to receive and test samples as soon as they are pulled. Engineering and automation must be ready to respond quickly if any equipment issues arise. In addition, because products, labels, and packaging must all be reconciled, periodic communication between groups is key to ensuring no documentation errors occur during concurrent operations.
Considerations when selecting CGT packaging
Packaging systems for viral vectors include primary (vials), secondary (typically cardboard boxes) and tertiary (temperature-controlled shippers) components. They must meet GMP requirements and ensure the quality and integrity of the viral vector are maintained during storage and shipment, while also providing easy access to the product.
Vials as primary packaging for viral vectors must be durable under freezing conditions (-80° C). Unfortunately, at this point, there is limited data regarding which vials are best for use with different types of viral vectors, but the stability of the product in different types of vials should be considered. Top-of-the-line vials with low particulates and excellent quality control should always be selected. Given the high value of viral-vector products, it is not worth saving a small amount of money using an inferior vial.
Cardboard boxes used for secondary packaging must withstand thermal and mechanical stresses, including freezing conditions and exposure to dry ice and condensation (if warming occurs). Packaging design should take into consideration regulatory compliance requirements, such as separation of leakproof vials, and the needs of clinics, particularly the optimum quantity of vials that will avoid the necessity for further repackaging and easy access.
Tertiary packaging must be durable and provide robust temperature control. Here again, the use of the highest-quality packaging solutions is recommended, as it is not worth taking any risk of product loss. Time must also be invested in conducting thorough shipping validation studies, if not with actual viral vector product, at least with a representative buffer solution.
The right labeling solutions are crucial
Labeling may seem like a simple task, but for viral vector products that must be immediately placed in low-temperature freezers before typical labels have sufficient time to properly adhere to vials, proper label selection is essential. Similarly, the printing ink used for labels must stand up to freezing conditions and be legible even if vials are covered in frost.
The factors that can impact the specific text that must be included on labels placed on primary, secondary, and tertiary packaging for viral vectors should not be overlooked either. The best approach is to establish a procedure for text generation and approval that clearly outlines approval responsibilities.
The text must comply with regulatory requirements for each country to which the viral vector product will be shipped.
Planning for all scenarios
Whether viral vectors are produced by a CGT company or a contract development and manufacturing organization (CDMO) like Center for Breakthrough Medicines, planning for possible disruptions to packaging, labeling and shipping operations should be a key focus when establishing a packaging strategy. Being prepared for any scenario that can compromise a lot can be the difference between a viral-vector product getting to the clinic or expiring before it ever reaches patients.
The first step is conducting a robust risk assessment to identify possible undesirable scenarios. Most important are those that lead to the product being exposed to non-freezing temperatures. For instance, freezers may fail, or a CGT company could be acquired while viral vector product is in the freezer, making it necessary to re-label vials. Delays during shipment or the failure of temperature-controlled packaging are other possible concerns.
The performance of comprehensive stability studies allows the determination of time-out-of-temperature limits, which will then dictate the speed at which packaging and labeling operations must be performed and the time available for resolving temperature-control failures if they do occur. Shipping validation studies using a representative surrogate provide confirmation that the chosen packaging and shipment solutions provide adequate temperature control and that appropriate procedures are in place to manage unexpected situations.
The selection of multiple packaging and shipping configurations is also recommended. CDMOs will need to meet the varying requirements of clients shipping viral vector products to many different countries.
CGT companies pursuing in-house viral vector production can also benefit from having multiple options available during early development phases. With this approach, different vials and dosages can be sent to clinics as needed, and no additional work will be required once the final configuration is selected.
Indeed, some packaging can have very long lead times of a year or more depending on the specific configuration. Switching to new configurations and/or adding new suppliers involves significant time and cost later in development. Time spent upfront to plan in multiple scenarios avoids such costly delays.
Testing is fundamental
It is also important for CGT manufacturers to confirm that the properties of the cardboard and the adhesion of glues are sufficient in secondary packaging after exposure to freezing temperatures and during transport.
Labels on primary and secondary containers should be tested as well to ensure they remain adhered at frozen temperatures and that printed text and graphics remain legible even if the package is bent or dented and the labels become scratched, abraded or otherwise affected during shipment.
In general, specific protocols for comprehensive testing of packaging and labeling solutions should be established that accommodate all possible temperature requirements, packaging configurations and transportation arrangements.
Start early with commercial needs in mind
Many CGT candidates receive accelerated development designations from regulatory authorities, leading to dramatically reduced development timelines for these complex products. For this reason, it is imperative that the evaluation of packaging and labeling solutions be initiated at early development stages — and with commercialization in mind, rather than when viral vector products reach phase 3 clinical trials. The earlier future scale-up of the batch size is considered when selecting filling, inspection, labeling and packaging equipment, the greater the likelihood a program will meet the aggressive timelines.
Selecting primary, secondary and tertiary packaging designs; choosing appropriate labels, adhesives, and inks; putting quality agreements with packaging and transport suppliers and qualification protocols in place; and establishing qualification protocols should be initiated in phase 1.
Thought should also be directed toward the possible storage solutions that may be applicable at different development phases. Storage at -80° C is commonplace for preclinical and phase 1/2 clinical materials because at this stage using a conservative approach is best, and most vectors are expected to be stable at this low temperature. As products advance to later clinical stages, however, having data that demonstrates stability at -30° C or even warmer temperatures can have a significant impact on storage, transportation, and general logistics costs and be a game-changer for the transition to commercialization.
Rapid advances anticipated
Packaging and labeling of viral vector products for gene and cell therapy applications currently present some significant challenges. The industry is moving forward at lightning speed, recognizing the many issues faced by CGT companies and responding appropriately. Effective solutions for faster, more automated viral vector packaging and labeling processes, even for small batches, are already anticipated. Each year, growing numbers of vendors are bringing measurable improvements to the packaging and labeling space.
As CGTs continue to increase in importance from a market perspective, further developments are expected at an even more accelerated pace. Viral vector batch sizes will also likely increase as advances in gene and gene-modified cell therapy manufacturing are achieved and more candidates targeting diseases that affect larger patient populations move closer to commercialization. Regulations will simultaneously evolve and drive further solutions for inspection, packaging, labeling, serialization and more.
Throughout all of these changes, the focus will always remain on ensuring that the quality and integrity of viral vector products are maintained during packaging, labeling, storage and transport — ensuring the delivery of safe and highly efficacious medicines to patients.