Cell and Gene Therapy Regulatory

Introduction

The journey that a cell or gene therapy takes as it goes from development, to manufacturing, to patient bedside requires intricate logistics to maintain product integrity at ultracold or cryogenic temperatures. This takes on an additional level of complexity when it comes to cell therapies. Logistical strategy requirements can vary according to the specific type of cell therapy and requires a deep understanding of the complete cell therapy production workflow. This multistep manufacturing process broadly involves:

  1. Cell collection from a patient or donor
  2. Transportation to a manufacturing facility for manipulation
  3. Processing into the drug product
  4. Return of the final product to a clinical environment where it is administered to a patient 

As a patient’s cells are transformed into a living drug product, they move through a range of storage conditions varying from refrigeration (2°C to 8°C) to cryo-storage (–150°C to –196°C) (Figure 1). This chapter will outline some of the broad topics to consider when developing a cell therapy supply chain or distribution strategy, and highlight nuances that may apply differently when considering autologous cell therapies versus allogenic cell therapies.

 

Diagram of logistical path a cell therapy takes from patient collection through manufacturing

Figure 1. Overview of cell therapy logistics.

Autologous versus allogeneic cell therapy logistics

Autologous cell therapy is a vein-to-vein supply chain process where the starting point is material collection directly from a specific patient. This specimen serves as the raw material input for the manufacturing process. Vein-to-vein supply chains begin with the collection and transportation of patient starting material to the cell manufacturing site, and ends with the distribution of a final drug product from the manufacturing site to the hospital. Because of the critical temperature requirements at each step of the manufacturing process, and the fact that the therapy is personalized to a single patient, it is of utmost importance to mitigate risk within the supply chain as much as possible to ensure final product quality and chain of identity. Critical drivers for maintaining this supply chain include: 

  1. Dose availability—there may only be one dose available for a particular patient.
  2. Patient condition—the receiving patient may be very sick, which means that any delay in the supply chain could put the receiving patient at risk. 
  3. Therapy identification—ensuring chain of identity and chain of custody throughout the logistics process is essential to delivering the right drug to the right patient.

The logistical strategy begins with leukapheresis (collection of the patient’s blood) or other patient specific samples. To maintain consistency and ensure high cell quality, standardized apheresis (or sample) collection kits can be used to ensure conformance and adherence to standard operating procedures (SOPs), and promotes a method for standardized collection of the raw material input. Kit usage ensures consistent starting material quality for the manufacturing process and can minimize operator-induced effects on efficacy. Coordination of kit assembly; shipper preparation and arrival at the collection site; and apheresis collection need to occur simultaneously. Following harvest from the patient, cells can either be shipped fresh (2–8°C) or cryopreserved and stored for later use. While cryopreservation allows for more flexibility in the manufacturing timeline, most manufacturing protocols still require fresh cells.

Allogeneic therapy logistics have similar requirements to autologous therapy, but the overall workflow allows for some flexibility of supply. An immediately apparent difference in the supply chain is the sourcing of donor material. Once the HLA type or other cell characteristics have been identified, a donor must be identified to provide the starting material. While autologous therapies rely on cell harvest from individual patients, repeating the supply chain per each individual treatment, allogeneic products make use of pooled healthy donor cells as the input starting material. Cells must be sourced according to GMP guidelines, and must also adhere to strict chain of custody and identity requirements. Until truly allogeneic products are developed, the characteristics of the starting material will determine whether a patient is a good match for the final drug product.

Regardless of the treatment type, once any cells enter into the manufacturing process, they are packaged and labeled in adherence to strict considerations and guidelines. Following completion of the manufacturing process, the drug product is cryopreserved, placed inside a dry vapor shipper, and shipped via next-flight out specialty courier services to the clinical site for patient dosing.
 

Storage

Storage conditions of the cells throughout the entire process are critical to ensure the integrity of the drug is not compromised during any stage. Gene therapies require a minimum storage temperature of –80°C, and cell therapies are primarily stored at –196°C or below. These ultra-cold temperatures make it essential to consider some key factors when selecting a storage facility to ensure proper ultra-cold or cryogenic storage conditions.
 

Ultra-cold and cryogenic storage

Whether you are selecting a cold storage service provider or establishing an internal storage facility, there are several important considerations to note, as described in Table 1.

Table 1. Considerations for cold storage in cell therapy logistics.

Redundancy
  • Is there a more than one storage system in place to protect your specific material?
  • Are there redundancy within the systems in case one path fails to ensure continuous protection of your materials?
Risk mitigation
  • What is the backup capacity to transfer materials in case of storage failure?
  • Are there backup generators to maintain storage conditions in the event of power failure?
  • How secure is the facility? Is it access controlled? Monitored 24/7?
GMP compliance
  • Does the facility have the appropriate licensing and permits needed to meet regional/state/national requirements?
  • Are regular audits performed by regulatory organizations to ensure the facility’s compliance?
Scale-up ability
  • Can the provider accommodate a future transition from clinical to commercial-scale material volumes? Considering this particular feature will allow the early establishment of more universally applicable SOPs and facilitate a future transition from clinical to commercial processes seamlessly.
Cell and gene therapy experience
  • This factor is very important due to the small volume packaging nature of many final drug products.
  • Storage considerations and SOPs require cognizance of minimizing the time spent “out of temperature” whenever a sample is removed from storage.
Storage model
  • Is the site a centralized single site model or a decentralized (multi-site) model? It may be important to have storage facilities across different geographies and various regions.

 

vials stored in LN2 being lifted from the storage tank by a gloved hand

One important way to mitigate risk is by utilizing decentralized storage facilities and storing samples at multiple sites. This is particularly important for master cell banks (MCBs) and drug products. Utilizing an organization that has multiple sites can also influence the ability to perform and accommodate just-in-time (JIT) deliveries for patient procedures. 
 

Packaging/Labeling considerations for cryogenic drug products

For both allogeneic and autologous therapies, many of the considerations for packaging and labeling of the products are similar. In either case, the final drug product is typically stored and transferred under cryogenic storage conditions. This requires specific considerations when deciding on the packaging and labeling of these products. An important difference arises in handling autologous therapies, because these therapies require an ability to trace the treatment products through the entire process—from start (patient cell or tissue harvest) to finish (therapy administration to the patient). Unlike allogenic therapies, autologous therapies will require an additional Chain of Identity (COI) tracing capability to ensure that the right therapy is administered to the right patient, and the therapy has not been compromised during any stage in the development process. 

The first consideration is the type of container to use. Both the choice of whether to use a cryovial or cryobag and the volume of the storage container are important. These initial selections will impact your options for the label type, which then affects the kind of information that can be included on the primary label. Once the type and size of your packaging is determined, the process by which the label is applied to the container must be addressed. Options include application of the labels manually or mechanically by a machine. This has further implications for the type of environment where the labeling activities will take place—specifically the temperature conditions (ambient, cold, dry ice, or cryocart). Machine labeling often leads to more consistent labeling results, but may not be part of the process when manufacturing a single dose. Importantly, how application of a label at ambient temperatures relates to the temperature of the product itself are important to understand for quality and consistency of label adherence. It is critical to choose labels that are appropriate for the final storage temperature conditions, ensuring that the label will maintain adherence throughout the lifetime of the product.

Finally, choosing the type of label can also affect several downstream decisions. A label can be a single-panel label or a booklet label. While booklet labels allow more information to be included, several components are involved in manufacturing a booklet label, and not every component is optimized to handle cryogenic conditions (e.g., the type of paper used and the hot melt used to bind pages together). Cell and gene therapy products are generally stored and shipped in cartons, and it is important to anticipate whether the label connections and the final labeled material can fit inside the chosen storage boxes. 

The actual content printed on the label can vary depending on different country regulatory requirements. While these requirements can vary from region to region, basic required information typically includes:

  • Dosing instructions
  • Translations into local languages
  • Final storage temperatures 
  • Details related to the sponsor and manufacturer

For autologous therapies, because of the highly individualized nature of the therapy, there may be additional requirements for label information. This can include the listing of unique tracing information such as the chain of identity and the use of specific barcodes or identification tags to minimize the risk of an incorrect treatment delivery to a patient. 
 

Transportation considerations for high-value materials

The top priority for cell and gene therapy transportation is maintaining the integrity of the drug while ensuring it arrives on time. With autologous therapies, there is a high value placed on individual components of the supply chain given the highly personalized nature of the drug product itself. The impact of failure during any part of the supply chain, whether it affects the initial patient harvested sample or the final drug product, has significant impact on the final patient outcome. It is essential to move materials quickly and safely to meet the needs of often extremely ill patient populations. This includes ensuring sufficient supply and storage conditions for raw materials; collection and transportation of apheresis or other patient derived starting material; and final distribution back to the patient. To achieve flawless operation, qualified shipping technologies and data loggers can be employed to monitor and track temperature fluctuations and maintenance of cold chain. The task of maintaining speed, temperature, and integrity becomes complicated with these drugs because many gene therapies are transported at a minimum of –65°C, while many cell therapies are moved at cryogenic temperatures, which can be as low as –150°C. Important characteristics to look for when evaluating qualification protocols include but are not limited to:

  • Ambient profile—custom or industry standard
  • Seasonality—e.g., summer and winter
  • Payload used (minimum and maximum)
  • Repeatability—triplicate tests
  • International Safe Transit Association (ISTA)-certified packaging testing lab
  • Industry standard-calibrated equipment 
  • Design qualification (DQ), operational qualification (OQ), and performance qualification (PQ)

Equally important when making decisions and establishing SOPs is the shipping lane validation. This is a complex process that requires consideration of many different attributes that could affect product integrity in transit. The origin, destination, and transport route can all impact the stress temperatures that a product passes through. Seasonality can also add an additional dimension in establishing protocols. Placement of temperature monitoring devices within the container is important to ensure an accurate representation of actual product temperature maintenance is recorded rather than fluctuations in the outside environment. All shipping protocols should be validated using a minimum of triplicate shipments and importantly, should undergo periodic re-evaluation to ensure that any subtle changes in any part of the supply chain are constantly monitored and quality controlled. An often underestimated aspect to logistics and supply chain is the level of regulatory compliance needed for the final step of the supply chain, the actual delivery of the drug product. Maintaining 21 CFR part 11 compliance in the ever-evolving regulatory landscape requires constant evaluation of product integrity over the course of the product’s shelf life. This is often addressed by choosing trusted service providers. These partnerships typically provide a range of services, including offering validated SOPs and different levels of service such as just in time (JIT) service (e.g., Patheon logistics next-flight out).

Using an experienced and trusted partner that has the ability to navigate trade compliance, regulatory compliance, and risk management is critical. Processes need to take into consideration potential issues arising from customs holds or delays that could affect product integrity. When shipments are made at –65°C conditions, re-icing can be performed to maintain temperature continuity. However, for liquid nitrogen (LN2) shipments, recharging is not possible with current packaging technology, which limits the maximum hold time to 8–14 days depending on shipper type. To minimize this limitation, multiple layers of risk mitigation can be employed: 

  • Prepare appropriate documents ahead of time to avoid possible delays (e.g., custom holds)
  • Partner with experienced custom brokerage services 
  • Consider free-trade zone options
  • Develop decentralized supply networks to reduce the risk

In order to orchestrate a flawless operation, many clients or service providers have found utilization of a control tower approach to be an effective way to manage cell and gene therapy transportation and logistics. The control tower is a centralized hub that consolidates all of the monitoring systems and data gathering tools that are employed across all stages of the supply chain. This gives the user complete visibility over the entire process. The control tower can either be developed by a client to encompass their chosen tools and components, or can be developed by the logistics service providers.

A major advantage of using a control tower approach is the ability to identify points of failure and strengths of the supply chain, enabling implementation of predictive analytics to maximize efficiency and improve processes. Additionally, full visibility allows for real time monitoring to ensure execution of specific instructions to individual logistics service providers. Ultimately the data feeds into effective management of incidents or exceptions, allows the customer to generate pre-developed escalation plans and contingency procedures, and drives effective customer service. 
 

Chain of custody and identity

As mentioned, the supply chain for cell therapies, especially for patient-specific autologous therapies, requires a strict level of compliance and chain-of-custody establishment. Complete end-to-end visibility and documentation is required and includes location monitoring, temperature tracking, and documentation of all handoffs between providers (i.e., ground transportation to air transportation to customs inspections, etc.). During transit, individual tracking from the point of pickup through final delivery requires identifying authorized individuals (shipper/consignee) and associated chain-of-custody documents including initials, dates, and times. Additionally, real-time temperature and GPS location monitoring and confirmation of location throughout transit allows for the ability to alert customers of potential delays.

In the case of cell and gene therapies, information must be maintained at a per-dose level, and this documentation must be readily available in case of a temperature excursion or other issue. Allogeneic therapies can use bulk storage solutions and be stored in vapor phase LN2. Because not all companies are able to support vapor phase LN2 transportation, partnering with companies (e.g., Thermo Fisher Scientific) that do have an ability to support this type of supply chain can help ensure quality of the final drug product.

For autologous therapies, chain of identity becomes a critical driver of logistics to ensure that the correct drug product makes it to the right patient on time. When establishing a chain of identity process, it is important to consider the following: 

  1. List patient unique identification number and lot information on product primary and secondary packaging
  2. Routinely evaluate chain of identity (COI) controls in a risk management cycle: define plan and stakeholders; draft and approve process maps for applicable areas; draft failure-mode exception analysis (FMEA); develop deviation and risk assessment; review and approve in document control; training and implementation
  3. Ensure SOPs are in place and regularly reviewed
  4. Minimize risks of mix-ups with appropriate segregation, line clearance, and changeover within the plant 
  5. Implement verification steps (manual or electronic) throughout the process to ensure the appropriate link is maintained from cell collection to drug product infusion at the treatment site
  6. Balance COI with Health Insurance Portability and Accountability Act (HIPPA) and other privacy laws

 

Distribution—pick/pack/ship

The next phase is selecting a partner to distribute the product. When selecting a service provider, some questions to ask are: 

  1. Does this service provider have appropriate proper licenses to operate both for clinical samples and for commercial products?
  2. What are the lead-time requirements for the service? Do you need to request shipping materials in advance? Can they distribute next-day or same-day? Make sure to establish service-level agreements so that you understand the logistics, including what information your provider needs in order to get the shipment out on time. 
  3. Is the partner able to accommodate JIT requests? (Note that JIT scheduling needs to account for the health of the patient receiving treatment). 
  4. Does the provider have serialization capabilities to support my future commercial launch?

 

Transitioning from clinical to commercial supply volumes

Initially, most decisions about supply chain and logistics will be made when working at a clinical level, where the sample size and volume may be smaller and less likely to be in bulk. However, whether the current supply chain will be able to transition and accommodate commercial supply requirements is critical to success. While clinical supply chains may operate on a regional or domestic level, commercial supply chains often require transportation across borders and involve multiple points of contact between the initial pickup and final point of delivery. As the manufacturing process becomes more global, additional compliance, transportation, and supply issues need to be addressed (see Table 2 for summary).
 

Table 2. Questions to consider in transition towards a commercial-scale operation.

IssueQuestions
Scalability of supply chain
  • Can the current supply chain handle a scale up and scale-out to accommodate commercial level needs?
  • Are the partners you selected for the different phases of storage, transportation, and distribution able to accommodate a higher volume as therapy requirements increase?
Global trade compliance and value-added tax (VAT)
  • Are there any adjustments or modifications required to your current processes to ensure global trade compliance?
  • What are the tax requirements of each region?
Regulatory
  • Are there providers with ATMP QPs on staff that can issue a QP declaration for my product?
  • What documentation does the QP require to issue a QP declaration?
  • What is the lead time for QP batch or product release?
  • How far in advance do I need to engage with a QP prior to applying for EMA approval?
Serialization
  • How will my product be required to comply with the Drug Supply Chain Security Act?
  • What EPCIS system should we select to integrate with our commercial packaging and distribution partner?
Label and artwork design
  • Does the final commercial product label comply with the appropriate region’s requirements?
  • What labels or components do I select in order to withstand storage and distribution at cryogenic temperatures?
European Union “Blue Box”
  • Does the label comply with guidelines issued by European Medicines Agency (EMA) authorization? 

 

With commercialization, these highly sensitive materials may need to travel greater distances and encounter a greater number of transitions based on different world destinations. Different countries have different regulations and what may comply with one country’s requirements may not work for another. Processes may need to change to ensure global trade compliance. Additionally, different countries may have tax requirements that add tax at different points in the manufacturing-distribution-sales process. This could affect the ability to operate in or provide a product to certain countries such as countries within the European Union.
 

Map of the world showing connections between continents

Within the United States, there are important FDA compliance considerations as a product transitions from clinical use to commercial use. Compliance with the Drug Supply Chain Security Act allows the ability to trace prescription drugs as they are distributed around the country. In particular, the ability to implement an electronic interoperable system is critical to comply with Title II of the Drug Quality and Security Act.

When a product transitions from a clinical trial setting into the commercial realm, many strict guidelines covering final product label artwork and information have an impact. These requirements are governed by the FDA in the United States, and by equivalent agencies in other countries around the world. Every country has their own requirements, so approval from the United States or the European Medicines Agency does not mean the label will comply with other countries’ standards, leading to a label re-design to comply with each individual target market. For the European Union, label guidelines are issued by the European Medicines Agency (EMA). Their authorization for a single drug application outlines guidelines dictating what information must appear on a label; the languages in which the text must appear depending upon the country where the product will be marketed; additional text requirements that may be member-country specific; colors, logos, color schemes, and other features of the label; and the inclusion of a marketing authorization number on the label, among other specifics.
 

Summary

Although the specific details for each supply chain and logistics plan will differ depending on the specific clinical and commercial needs of the product, key areas exist where forethought and planning can decrease risk and decrease the potential loss of materials and expensive solutions. For cell therapies, these special considerations include storage temperatures, transportation modes, chain of custody and identity, and labeling, and the regional regulations and differences that impact them. Choosing a trusted materials and service suppliers experienced in working with cell therapies can alleviate some of these challenges, helping cell therapy manufacturers deliver their precious drug in a timely and safe manner to extremely ill patients.