Introduction
The risk of compromising biopharmaceutical materials in internal shipping and external distribution is relatively high, as these materials are particularly vulnerable to degradation when exposed to various environmental and handling conditions. The risks can be managed effectively through qualification of transport packing systems, handling, and transport procedures. This guidance summarizes suggested considerations in the cold chain management (CCM) of biopharmaceuticals
Recommendations & Rationale
- Biopharmaceuticals Background
- Regulatory Expectations
- Cold Chain Basics
- Cold Chain Management (CCM) Considerations for Biopharmaceuticals
- Recommendations for CCM of Biopharmaceuticals
Definitions:
| Shipping: | Transit of materials from one site location (including contract organizations) to another site location (i.e. from a manufacturing site to a distribution center) |
| Distribution: | Delivery of materials (usually finished product from a distribution center) to a first paying customer external to Site |
| Packaging: | The GMP activity at the packaging site. Typically include components such as primary, secondary and tertiary containers |
| Packing: | The process of preparing and protecting the material for transit usually conducted at a warehouse or distribution center. Packing components include but are not limited to bubble wrap, paper dunnage, Expanded Polystyrene containers, temperature monitoring/temperature indicating devices, etc. |
| Production materials: | All APIs, drug substances, work in process materials, bulk materials, finished products, etc |
Biopharmaceuticals Background
Biopharmaceuticals, like other drugs, are used for the treatment, prevention or cure of disease in humans. Biopharmaceuticals are of large molecular size and structural complexity and may include proteins, monoclonal antibodies, glycosaminoglycans, hormones, vaccines, oligonucleotides and PEGylated molecules. Biopharmaceuticals products are generally derived from living material: human, animal, or microorganisms, are complex in structure, and are usually not fully characterized. Many forms of the same molecule collectively define the drug “heterogeneity profile”. Unlike small molecular weight drugs, which have a well-defined structure and consistent purity, biopharmaceuticals are of large molecular size and structural complexity, and display consistent heterogeneity. Traditional small molecule drug products usually consist of pure chemical substances that are easily analysed after manufacture. Biopharmaceutical products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes to the biological product itself and potentially require additional clinical studies to demonstrate the product’s safety, identity, purity and potency. Biopharmaceuticals are further characterized by their high susceptibility to irreversible degradation and exceptionally high financial value per unit. Temperature, agitation and exposure to light are among the conditions known to degrade protein and oligonucleotide based materials. A risk assessment should be conducted that examine potential conditions under which the integrity of each biopharmaceutical materials is known to be compromised. Among the points to consider:
Temperature: The severity and duration of the temperature excursion beyond the labeled storage conditions and the amount of stability data available may dictate the final disposition of the material.
Exposure to CO2: Dry ice is widely used to maintain the temperature for frozen shipments of biopharmaceuticals. Exposure to dry ice and the resulting CO2 gas may pose a number of consequences for biopharmaceuticals, which should be considered when establishing shipping/distribution protocols.
Agitation/Vibration: Proteins may be susceptible to shear or formation of aggregate caused by shaking or rough handling. Vibration may cause foaming and turbidity of liquid solutions transported under refrigerated conditions. While motion in transportation is obviously inevitable, the packing configuration should be designed so that the primary containers are secured and cannot move in the container interior. Securing primary containers also minimizes the risk of damage to the primary or transport containers.
Pressure Cycles: During transport by air, each take-off and landing may result in pressure changes that could potentially impact container integrity through expansion and contraction, as well as accelerated coolant loss due to increased pressure. To a lesser degree, pressure changes must also be considered for ground transportation in specific geographical locations. Light: Photo stability studies conducted on some biopharmaceutical products have shown that aggregate formation is possible on exposure to light. Transparent packaging, especially for refrigerated materials, should be avoided due to potential light exposure in walk-in cold rooms.
Regulatory Expectations
Cold chain management of biopharmaceuticals is regulated by cGMPs and GDPs, which require that the storage and transportation of materials shall be conducted in a manner that prevents alterations to the safety, identity, potency, purity and quality and physical properties of any product. Storage and transportation procedures for products requiring special conditions should be based on local GMP/GDP regulations; regulations in the markets where the product may be sold, the product’s labeled storage conditions, allowances made in product filings, and relevant product stability data. In addition, numerous industry organizations provide guidance on maintaining the quality of temperature sensitive products through the transportation environment. There is a continuum of expectations for clinical supplies to commercial supplies. For clinical materials, a ‘generic’ qualification of the shipping process/container is often sufficient.
However, if there is a unique or known issue with the product, then additional qualification may be required beyond the generic qualification to ensure the integrity of the material. For commercial materials, qualification of the transport process/containers with actual data from the product is required. Additionally, there is a need to consider data that may be required to meet this requirement for older/existing products. The shipping and distribution processes for drug substances and drug products should be qualified for commercial products, a summary of which is required for regulatory marketing applications of biopharmaceuticals. It should be noted that transport temperature ranges may be wider than the labeled storage temperature range for any given product, however, data to cover the anticipated transport process (mode, duration, container) and qualification testing of the product after transport is expected.
How to meet this requirement should be evaluated on case-by-case basis, utilizing stability data. There is no need to temperature monitor every transport if there is sound qualification data including lane characterization information, pack out qualification, thermal mapping, etc. The decision for inclusion of temperature loggers should be based on an assessment of the product value, criticality of the shipment and chance of excursions versus the qualification data.
Basics of Cold Chain Management
Temperature: Temperature excursions can occasionally occur as a result of inadequate thermal protection under unexpected or unusual circumstances in routine transits. Temperatures outside of the allowable shipping range can often be attributed to shipment delays, unanticipated ambient temperature extremes during transit, or incorrect shipping methods. In addition, the position of primary containers within the transport container should be carefully considered to prevent unintended warming or freezing as a result of proximity to external conditions or cooling source. These factors are typically considered in transport container selection and designing the qualification study. Even with careful planning and rigorous qualification testing, excursions may occur from time to time under extreme and unanticipated ambient conditions. Properly placed temperature monitoring devices included in transits record the severity and the duration of excursions, and set the foundation for investigating the root cause and product impact evaluation. The severity and duration of the excursion and the amount of stability data available may dictate the final disposition of the batch.
Packaging:
- Primary package – The container which is in direct contact with manufactured material; e.g., the
vial which contains the drug product - Secondary package – Contains the primary package; e.g., the box which contains a vial of drug product (shelf packs, unit cartons, etc)
- Tertiary package – Contains secondary package(s), often used to provide protection against mechanical impact. Example: shipper carton, case, etc.
- Ancillary packing system or equipment – Used to maintain temperature and/or integrity of shipment. Examples: shipper, pallets, etc.
- Active Transport System – System that utilizes a thermostatically-controlled container (or vehicle) that usually employs fans, a refrigerant, and is designed/engineered to maintain a desired temperature range for as long as the unit is on and will function as intended against all ambient conditions (i.e. Enviro Tainers, etc).
- Passive Transport System – Typically consist of a box with gel-packs, freezer packs or dry ice within an insulated box. These systems are designed/engineered to passively cool for a period of time against specified ambient conditions.
NOTE: the primary package, the secondary package, and the tertiary package are the GMP components that are typically applied to the product during the packaging operation at a manufacturing/packaging facility. The manufacturing facility will probably also utilize ancillary packing equipment (i.e. pallets) to assist with the movement and storage of the product. However, it is typically the warehouse or distribution center that utilizes the (active or passive) transport systems to assist with the shipping /distribution of the products.
Active and passive systems are often sold as pre-qualified stock items by commercial vendors to maintain a specified temperature range against moderate, predefined ambient temperatures for a minimum duration of time. Such systems are routinely and successfully employed, however, it is important to understand the conditions under which the system was qualified. For instance, a passive shipping solution which has been qualified to maintain 2-80C for 48-hour may satisfactorily perform well in shipments during summer temperatures, but may fail to provide protection from freezing the product when the exterior temperature falls below -100C. Thermostatically controlled active systems are typically more capable to hold the desired interior temperatures against a wider range of ambient exterior temperatures and may function for a longer duration of time, but are more expensive.
Temperature Controlled Trucks, Trailers and Ocean Containers: Transport vehicles themselves may function as an active system (i.e. temperature controlled trailers). Proper setting of the temperature set point and loading of materials in a container or trailer is required to ensure that the temperature is properly controlled. Unless otherwise qualified, loads should not be placed against the walls of the transport vehicle to allow for proper air circulation within the cargo area and to ensure ambient outside temperature does not transfer directly to the load. Temperature is typically controlled by air circulation; as such air vents must not be blocked by the shipment materials.
Most temperature controlled trucks, trailers ands containers are not intended to meet GMP requirements, with the exception of certain specialty carriers. Temperature mapping is not valid without GMP controls. The requirements to maintain GMPs include written procedures for operation, maintenance, change control, and deviation handling, which are rarely maintained by most commercial carriers. From a Quality perspective, there should not be a reliance on the temperature of the transportation environment. The use of “controlled” temperature environments should only be used to supplement qualified transport solutions.
Pressure Cycles: It is important to understand the transit route prior to qualification in order to understand the impact on container integrity. Examples of pressure effects on product include loss of product container integrity through expansion and contraction, accelerated coolant loss due to pressure changes, primary container leakage, microbial contamination due loss of container cap torque, syringe barrel movement and/or vial stopper movement due to pressurization, and gas ingress or egress (loss of gas overlay).
Mechanical Stresses: Mechanical stresses can impact both product and transport container integrity. Mechanical stresses to be considered include vibration, both long duration /low impact (such as ground/sea transportation), and short duration / high impact (such as bumps on ground/sea, air take-off and landings, loading/unloading). Crushing and impact damage can also occur. One of the greatest effects of mechanical stress is agitation of the product and the air/liquid interface, resulting in oxidation and/or aggregation.
External Delivery and Handling Targets: All cold chain transports must take into account the length of transit time, physical security/integrity, and delivery days of the week. The considerations for qualification of the cold chain transport system must plan for the temperature conditions at the origin, destination points and throughout the complete route. The decision for inclusion of data/temperature loggers should be based on the product value, ambient temperatures expected to be encountered while in route, criticality of the transport, expectations of the local regulations or customer expectations, and chance of excursions versus the system qualification.
Considerations for Biopharmaceutical Cold Chain Management The focus of cold chain management for biopharmaceuticals is on prevention of product degradation, maintenance of activity or efficacy, and maintenance of the physical purity and characteristics of the material. Biopharmaceuticals transported under temperature controlled conditions include cell banks (live cells), intermediates, bulk drug substances, bulk drug products, samples, and finished packaged/labeled drug product. Storage and shipping temperatures typically range from -1960C (liquid nitrogen, liquid phase) to +150C. Among the points to consider for cold chain management of biopharmaceuticals are:
Clinical / Commercial Stage: The focus of the cold chain management approach for the clinical supply chain is on maintaining temperature. Temperature should be maintained within the demonstrated stable range of the material, with temperature excursions allowable as supported by data. Temperature should be monitored as necessary within the assurance limits provided by the qualification of the transport and storage units. As such, platform technologies are generally employed for the storage of clinical stage biopharmaceuticals while stability data is generated.
The focus of the cold chain management approach for the commercial supply chain is on the entire cold chain process and compliance with regulatory expectations and product filings. At the commercial stage there should be an established understanding of product attributes and verification of planned commercial transport supports. The product temperature stability profile should be well established, including storage temperature, allowable excursions, and the effects of freeze/thaw. There should also be available data on the physical restrictions such as limitations for CO2 exposure (pH) and vibration effects.
Exposure to CO2: Dry ice is widely used to maintain the temperature for frozen shipments of biopharmaceuticals. Exposure to dry ice may pose a number of consequences for biopharmaceuticals, which should be considered when establishing shipping protocols.
Sublimation rate: The rate of dry ice sublimation is dependent on the transit container and the method of transport. It is important to account for the maximum percentage of dry ice expected to be lost during transit. For long duration transits, dry ice may have to be added to the transport container by the carrier in order to maintain appropriate temperature conditions.
C02 Generation: Carbon dioxide gas generated from dry ice sublimation may alter the pH of protein based material if the shipping container does not allow venting and / or the primary packaging does not adequately protect the material. When using dry ice, the integrity and impermeability of the primary container should be established. It may be necessary to increase protection from C02 by using additional protective intermediate packaging/packing.
Thermal Expansion/Contraction: Physical changes to the primary packaging on exposure to temperature extremes should be considered. Expansion or contraction due to temperature cannot be prevented, but efforts should be made to ensure the integrity of the seal.
Liquid Biopharmaceuticals. Liquid biopharmaceuticals are typical stored at refrigeration temperature (20– 80C), whereas the transport of liquid biopharmaceuticals is often carried out at either 2° to 8°C, With excursions allowed down to 0°C and up to 15°C during storage, internal shipping and external distribution, as long as the Mean Kinetic Temperature [MKT] does not exceed 8°C, or are carried out at 0°-15°C (depending on the availability of supporting stability data).
There is a need to understand the allowable excursions and transit temperature ranges for the particular biopharmaceutical formulation. In some cases shipping at 2-300C may be acceptable, whereas in other cases the MKT must be maintained at or below 80C. Liquid biopharmaceuticals are often transported in containers typically from <0.3mL to 200L, with containers ranging from pre-filled syringes and vials to flexible bags and stainless steel tanks. It is relatively easy to maintain 2° to 8°C with active thermostatically controlled transit systems , but typically harder to control the same temperature range with passive transit systems , thus the weight and cost of the passively temperature controlled transports may be of concern with larger volumes of liquid biopharmaceuticals. Frozen biopharmaceuticals are typical stored below -300C, as the Tg’ (Glass Transition Temperature) for many formulations of biopharmaceuticals is near -300C.
Frozen biopharmaceuticals are often transported in containers typically ranging in size from 10mL to 500L, with container types varying from vials to flexible bags and stainless steel tanks. It is relatively easy to maintain frozen temperatures with passive transport systems at small volumes, but often active temperature maintenance is required or used to supplement larger volumes of materials. The weight and cost of transits is typically larger for frozen versus liquid materials Passive transport systems are usually controlled by wet ice (<-150C), dry ice (<-600C), or liquid nitrogen in a dry shipper (<-900C). Among the points to consider during the transit of frozen biopharmaceuticals are:
Temperature: The temperature of biopharmaceuticals must be maintained below a specified maximum temperature. Cooling too low generally is not a technical concern. The Tg’ must be determined for the specific formulation, as it may be well below the visual appearance of being a solid. The provided temperature should be below <Tg’ of the formulation. The Freeze/thaw impact on product integrity must also be understood in order to evaluate the effects of multiple freeze/thaw cycles which may occur during material handling.
C02 Generation: As noted above, exposure to C02 may pose a number of consequences for biopharmaceuticals, which should be considered when establishing shipping protocols.
Container Characteristics: The characteristics of the product container will undoubtedly have an impact on the cold chain transit requirements.
Plastics: The container integrity of plastics is greatly affected by temperature. Physical changes to the primary packaging on exposure to temperature extremes should be considered. Loss of closure torque on bottle freezing expansion or contraction due to temperature cannot be prevented, but efforts should be made to ensure the integrity of the seal. For example, bulk shipments made in polymer bottles must be properly sealed. Typically, the bottle manufacturer will provide technical information regarding recommended torque to be applied to screw cap type closures. A torque wrench should be used to accurately achieve the recommended torque. Prior to shipment of polymer bottles on dry ice, the bulk bottles should be frozen and then “torqued” to the recommended specification. Meeting the torque requirements in the frozen state will help maintain closure integrity. If the bottles are only “torqued” under warm conditions, expansion/contraction of the bottle may cause the cap to become loose and jeopardize the integrity of the seal. Similarly, multi-layer flexible bags incur different temperature effects per layer. For instance, Stedim Flexboy bag layers include Ethylene vinyl acetate (EVA) as the main bag structure along with EVOH, Ethyl Vinyl Alcohol (EVOH) as the main gas barrier, a Tie which bonds outer film layer and Ethylene Vinyl Acetate Mono-material (EVAM®) as the fluid contact layer. Freezing of bags requires custom equipment and bag sizes are limited to the equipment. The bags may also become brittle or crack at variable freezing temperatures depending on the materials.
Stainless Steel: Stainless steel containers offer the advantage of robust integrity at the expense of high container costs and high transit costs, thus the use of stainless steel is generally limited to storage and transit of bulk drug substances. The impact of freeze/thaw characteristics of tanks must be carefully evaluated with respect to product impact and thermal changes during transportation. At this time there is no current technology available for controlled rate freeze/thaw of tanks below -400C.
Glass Bottles and Vials: As with plastics, the container integrity of glass is greatly affected by temperature. Physical changes to the primary packaging on exposure to temperature extremes should be considered. Loss of vial stopper sealing and/or cap closure torque on freezing expansion or contraction due to temperature cannot be prevented, but efforts should be made to ensure the integrity of the seal.
Recommendations for Biopharmaceutical CCM
he foundation for many decisions in qualification and validation of transit systems is the distance that the material is transported, the method(s) of transport, the duration of time in route, the expected ambient temperatures to be encountered while in route, and route to be taken. The fastest possible route should be the default requested of the carrier(s) to minimize risk to the material. Carriers should be selected based on their ability to minimize risk in transport. In general, planning for handling and transport of biopharmaceuticals has the following elements:
- Selection and qualification of the transit container system
- Qualification of the transit procedures and route
- Assessment of impact on the product
Selection and Qualification of the Transport Container System: Transport containers are tested for their ability to withstand and protect the product/material from ambient environmental conditions and rough handling. The International Safe Transport Association (ISTA) Guidances and the American Society for Testing and Materials (ASTM D 4169-98 and ASTM D3103-92) provides standard test methods for qualification testing of transit containers. Standard tests for compression, shock, vibration, atmospheric conditions, and thermal insulation quality are generally conducted. Contract packaging laboratories can assist in selecting the test methods required to verify the container’s suitability for the application. Many suppliers maintain a set of qualified shipping containers. Suitable transit containers can be selected based on the size and temperature requirements and expected transportation route from the set of pre-qualified containers, requesting specific additional qualifications, and then proceeding with transit studies.
The selection of a transit solution and should include consideration of:
- Route duration
- Ambient temperature profiles of the route
- Variability of transit time,
- Mechanical stress effects on material being transported (vibration, air pressure cycles, etc),
physical stresses (crushing, handling, dropping, leakage from/onto, package orientation, package placement) and security (inspection, tampering, radiation exposure)
The initial selection of the packing system is based on:
- Quantity to be shipped
- Temperature requirements
- Degree of thermal insulation and damage protection required
- Maximum possible duration of transport
- Material sensitivity
Qualification of the transport container system requires an operational qualification (OQ) to establish that the system will consistently maintain the established temperature range under defined conditions. OQ testing of the transit system is performed under a pre-approved protocol or procedure using temperature controlled rooms and/or laboratory controlled temperature, such as a Heat/Summer simulation and a Cold/Winter simulation or combination profile. OQ testing is performed for durations and temperatures beyond what is expected for typical transits in order to provide assurance that the system will provide controlled temperatures during atypical transport events. Calibrated temperature data loggers are used during qualification, in direct contact with simulated product at representative positions. The OQ protocol for a transit container system includes:
Description of Transport Containers – The primary, intermediate packaging, and outside transit container should be described in sufficient detail, including supplier, and technical features applicable to the study (physical and thermal protection capability). A description or drawing of the packing configuration for securing the primary or intermediate containers and preventing movement. Procedures for opening and repacking during transport should be provided. Coolant addition, customs inspection, or other issues may necessitate accessing the inside of the shipping container.
Coolant Required for Maintaining Temperature – If dry ice or liquid nitrogen is used for international transit, the amount used must comply with International Law. National or local transit regulations should apply. The carrier can provide specific information.
Batch size – Maximum and minimum batch sizes are represented among the packaging configurations. Where batch sizes or conditions are expected to vary, extremes should be represented using a bracketing approach in the design of the study. Worst-case conditions should be carefully considered, and rationale should be provided in the study protocol. For example, in frozen shipments, minimum batch sizes provide less thermal mass and are often considered worst case; however, in refrigerated shipment, the opposite may be true. The worst-case condition may be represented twice in the study.
Transit container interior temperature – The acceptable temperature range (supported by stability data) is defined. This temperature range is often wider than the recommended labeled storage temperature under normal conditions, but the range specified must be supported by stability data (including expiry considerations). A description of the calibrated monitoring device that will log interior temperatures during temperature and transport should be included.
Transit container exterior temperature – The acceptable temperature range within a transport container is a function of the exterior temperature surrounding the container. Transits that are subject to a number of transfers between carriers, or material sent via ground transportation could be exposed to extreme seasonal temperatures. Laboratory testing of temperature extremes conducted during container selection will demonstrate the minimum time that the shipping container will maintain the specified temperature, such as a Heat/Summer simulation, a Cold/Winter simulation, and/or a combination profile (i.e. thermal profile of the route) Test plan, including the temperature profile study duration which should exceed the expected actual transportation duration. Unexpected delays or other events that prolong transport must be considered in the transit study. Two to four times the expected transit duration should be represented, and the route and expected duration in transport will dictate the best strategy for including reasonable allowances in the study.
Qualification of the Transit Procedure and Route (Performance Qualification): Once the transport container has been identified and laboratory test results or data support the suitability of the container, the transit procedure and route should be qualified. Actual transits are conducted to substantiate the results of laboratory testing. Several transits over the actual planned route are conducted to demonstrate that the transport container provides thermal and physical protection under actual conditions and that the transport and handling procedures are adequate. Note that seasonal differences in temperatures and routes should be accounted for in either the laboratory or actual transit studies. Concurrent studies may be conducted with transits of actual material if sufficient experience with similar containers, materials, batch sizes and shipments justifies the risk. Where the benefit of experience does not justify the risks of concurrent studies, trial transits or prospective analysis using buffer placebo or water should be considered. The qualification of the transport procedure and route is a performance qualification (PQ) of the transit system, which establishes that during the transit of materials in the system are maintained within predefined ranges. The PQ testing of the transit system consists of:
- Replicate field transportation tests
- Actual, rather than simulated, temperature variations
- May use both primary and alternate routes
- May use actual product in one or more of the replicate tests In considering study design for worst case transit conditions, two to four times the amount of time
expected for normal transport should be factored into the test plan, as appropriate. - A test plan for international transits may include transport to the final destination, where the material is unopened, and returned through customs to the origin. This plan allows for twice the amount of time expected in routine transits.
- An approach for domestic or sample transits may involve a triple shipment (manufacturer to test laboratory, return to manufacturer, return to the laboratory) before opening to examine temperature monitoring data and testing of material. Lesser transit times may be qualified, although additional risk to material integrity is taken.
A complete study design in the shipping qualification test plan should include destination, duration and explanation of bracketing strategy. International transport should be considered and described as appropriate. The test plan should include:
- Pre-Shipment sampling and testing requirements (as required)
- Packing instructions
- Diagram outlining placement of temperature monitoring probes / devices
- Name and qualifications of carrier(s)
- Transit instructions: Specify transits for the maximum allowable duration OR provide instructions for qualified carrier to recharge container with coolant.
- Preferred route(s)
- A plan for unexpected conditions encountered during the test
- Pre-established transit temperature range specifications
- Damage assessment criteria for transport system and primary containers
- Dates of transport
- Post-transit sampling and testing requirements (as required) and criteria for determining
material impact when compared with the test results from pre-transit samples. Calibrated temperature monitoring devices are included in the transports to measure the degree to which ideal conditions were maintained inside the container during transport. Carriers must be notified of and understand specific requirements for replenishment of dry ice or cold packs, as well as the procedures for restoring the original placement / orientation of materials (containers and monitoring device) after replenishing coolant. Instructions for resealing the containers must also be provided to the carriers. The carrier is responsible for completing the appropriate documentation pertaining to addition of coolant, manipulation of contents and chain of custody.
Concurrent shipping studies using actual material can be designed so that pre-transit and post transit material sampling is conducted such that analytical comparison testing may be performed to demonstrate that no material changes have occurred during transport. Pre- and post- shipment sampling and testing is not always necessary, and an assessment should be performed to determine whether analytical testing adds value to the study.
A visual inspection of the transport containers is performed at the final destination to verify the absence of damage, demonstrating the transit system container’s ability to protect the material from damage that could be sustained in normal handling and transport. Material should be unpacked, inspected, and moved into designated storage environments within a reasonable time (specified by the protocol) of receipt. Three successful shipments representing worst case conditions are typically adequate for performance qualification of the transport system, unless compelling rationale based on experience with similar shipments justifies a different study design.
Assessment of Impact on the Product: Actual shipments of product are needed to provide assurance that the qualified transit system does not adversely affect the material shipped. Design Qualification, Operational Qualification and Performance Qualification and procedures are often required for market applications. The stability data needed to support a market application is used to determine transit temperature range and allowable excursions. If concurrent performance qualification studies were conducted with shipments of actual material, than there may be limited need for additional testing as the performance qualification data may be available to support regulatory submissions and responses to regulatory queries.
The purpose of testing actual shipments of product is to test for product sensitivity to transit conditions. The test is of the product, and is not a test of the qualified transit procedure or a duplication of stability data. Multiple product lots should be considered. While OQ, PQ and stability testing addresses the expected variations in temperature and handling, biopharmaceuticals may be susceptible to unanticipated variations encountered during transport.
For instance, USP guidance allows use of MKT when evaluating temperature excursions; however, the USP mean kinetic temperature (MKT) may adversely affect biopharmaceuticals if temperature excursions limits exceed the thermal denaturation limit of the protein Similarly, proteins may be susceptible to oxidation, shear or formation of aggregate caused by shaking or rough handling. Vibration may cause foaming and turbidity of liquid solutions shipped under refrigerated conditions. While motion in shipment is obviously inevitable, the packing configuration should be designed so that the primary containers are secured and cannot move in the container interior. Additionally, proteins may be exposed to magnetic fields, X-rays (radiation), ingress (CO2, microbial), leakage (liquid, gas overlay, sublimation), and physical inspection. Testing of samples is generally performed using stability indicated assays
Summary of Recommendations for Shipment of Clinical Stage Biopharmaceuticals
The focus of the cold chain management approach for the clinical supply chain is on maintaining temperature. Operational qualification of the transit container is recommended. Often the OQ is commercially available from the vendor or for transit of other products. Temperature should be monitored as necessary within the assurance limits provided by the qualification of the shipping and storage units. As such, platform technologies are generally employed for the storage of clinical stage biopharmaceuticals while stability data is generated. Performance qualification of the transport procedure and route is not required, but should be conducted during the progression from clinical to commercial stages, or if special known product consideration.
Stability data should be used to determine transit temperature range and allowable excursions. If the biopharmaceutical material is frozen, knowledge of the Tg’ and the impact of freeze/thaw on the product, and knowledge of the temperature effect on the product container is required prior to shipment. The use of different transit temperature ranges versus storage temperature may be acceptable if supporting data is available. The use of temperature data loggers is recommended for all transports of bulk drug substance and bulk drug product due to the high value of the material.
The use of temperature data loggers is also recommended for transits critical for the market or clinical trial and transits via shipping lanes where the delays are not uncommon. The use of temperature data loggers may not be necessary for routine low-value shipments when a qualified transit container is used.
Summary of Recommendations for Shipment of Commercial Stage Biopharmaceuticals
The focus of the cold chain management approach for the commercial supply chain is on the entire cold chain process and compliance with regulatory filings. At the commercial stage there should be an established understanding of product attributes and verification of planned commercial transport supports. The product temperature stability profile should be well established, including storage temperature, allowable excursions, and the effects of freeze/thaw.
There should also be available data on the physical restrictions such as limitations for CO2 exposure (pH) and vibration effects. Transit qualification and procedures are often required for market applications. The stability data needed to support a market application is used to determine transit temperature range and allowable excursions. Different transit temperature ranges versus labeled storage temperature ranges is acceptable if properly supported by qualification data and if filed with the regulatory authorities The use of a qualified (OQ and PQ) transit system is required, with data available for the transport of actual material. The product quality attributes must be measured based on stability profile and knowledge of the specific protein.
The use of temperature data loggers is recommended for all shipments of bulk drug substance and bulk drug product due to the high value of the material. The use of temperature data loggers may not be necessary for routine low-value shipments using a qualified shipping container.