Introduction
The risk of compromising biopharmaceutical materials in shipping 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 packaging, handling, and transport procedures.
This guidance describes the qualification studies required to validate product specific shipping procedures for biopharmaceutical materials derived from biotechnological processes, including:
- Bulk Intermediates
- Bulk Drug Substance
- Drug Product bulk vials
- Fully packaged sample kits in commercial packaging.
- Samples for analytical testing
The quality of biopharmaceutical materials can be protected during shipping through well-considered planning, selection of appropriate protective packaging, and qualification testing conducted at worst case conditions.
This guidance provides strategies and recommendations for designing studies that
cover a broad range of conditions. Planning for worst-case environmental conditions and unexpected shipment delays when designing qualification studies can prevent loss of valuable biopharmaceutical materials. The following topics are covered in this document:
- Conditions known to degrade biopharmaceutical materials, and considerations for preserving quality in shipment;
- Planning for handling and transport;
- Selecting the appropriate shipping container;
- Qualifying transport and handling procedures;
- Protocol and report content recommendations;
- Evaluating the degree of shipping validation for analytical test samples.
Preserving Quality During Shipment of Biopharmaceuticals: Points to Consider
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 accounts for ways the integrity of biopharmaceutical materials are compromised. Among the points to consider:
Temperature: Temperature excursions can occasionally occur as a result of inadequate thermal protection under unexpected or unusual circumstances in routine shipments. Temperatures outside of the allowable shipping range can often be attributed to shipment delays, unanticipated temperature extremes during shipment, or incorrect shipping methods. In addition, the position
of primary containers within the shipping 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 shipping 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 conditions. Properly placed temperature monitoring devices included in shipments 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.
Exposure to Dry Ice: Dry ice is widely used for frozen shipments, where temperatures of –70° C must be maintained. 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 shipping container and the method of transport. It is important to account for the maximum percentage of dry ice expected to be lost during shipment.
For long duration shipments, dry ice may have to be added to the shipping 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.
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. 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.
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 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. Securing primary containers also minimizes the risk of damage to the primary or shipping containers.
Pressure Cycles: During transport by air, each take-off and landing results in pressure cycles that may impact container integrity through expansion and contraction, as well as accelerated coolant loss due to increased pressure. To a lesser degree, pressure cycles must also be considered for ground transportation in specific geographical locations.
Light: Photo stability studies conducted on biopharmaceutical products have shown that aggregate formation is possible on exposure to light. Transparent packaging, especially in refrigerated materials should be avoided due to potential light exposure in walk-in cold rooms.
Shipping Validation for Bulk Intermediates, Drug Substance and Bulk Drug Product (For Further Processing)
The foundation for many decisions in qualification and validation of shipping is the distance that the material is transported, the method of transport, and route to be taken. The fastest possible route should always be requested of the carrier(s) to minimize risk to the material. Carriers are selected based on their ability to minimize risk in transport.
In general, planning for handling and transport of biopharmaceuticals has three elements:
- Selection and qualification of the shipping container system
- Qualification of the shipping procedures
- Proper packaging and handling before and after shipment.
Selection and Qualification of the Shipping Container System
Outer shipping containers are selected and tested prior to executing a shipping study. Initial selection is based on:
- Quantity to be shipped
- Temperature requirements
- Degree of thermal insulation and damage protection required
- Maximum possible duration of shipment
- Material sensitivity
Shipping containers are tested for their ability to withstand and protect the product from rigorous environmental conditions or rough handling damage. The International Safe Transport Association (ISTA) Guidance and the American Society for Testing and Materials (ASTM D 4169-98 and ASTM D3103-92) provides standard test methods for qualification testing of shipping 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 (for example, ISC has such containers and data available). Suitable shipping containers can be selected based on the size and temperature requirements and expected transport from the set of pre-qualified containers, requesting specific additional qualifications, then proceeding with shipping studies.
Once the shipping container has been identified and laboratory test results or data support the suitability of the container, actual shipments are conducted to substantiate the results of laboratory testing. Three shipments over the actual planned route are conducted to demonstrate that the shipping container provides thermal and physical protection under actual shipping conditions, and that the transport and handling procedures are adequate. Note that seasonal differences in temperatures and shipping routes should be accounted for in either the laboratory or actual shipping studies.
Shipments for Qualification of Transport and Handling Procedures
Concurrent studies may be conducted with shipments 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 shipments or prospective analysis using buffer placebo or water should be considered.
In considering study design for worst case shipping 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 shipments may include transport to the final destination, where the material is unopened, and returned through customs to the shipping origin. This plan allows for twice the amount of time expected in shipping.
An approach for domestic or sample shipments could involve a triple shipment (manufacturer to test laboratory, return to manufacturer, return to laboratory) before opening to examine temperature monitoring data and testing of material. Lesser shipping times may be qualified, although additional risk to material integrity is taken.
Calibrated temperature monitoring devices are included in the shipment 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-shipment and post shipment 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 shipment containers is performed at the final destination to verify the absence of damage, demonstrating the shipping 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 shipping validation, unless compelling rationale based on experience with similar shipments justifies a different study design.
Shipping Study Protocol
A complete study design in the shipping qualification protocol includes:
Batch size – Maximum and minimum batch sizes are represented among the shipments. 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.
Shipping container interior temperature –The acceptable temperature range (supported by stability data) is defined. This temperature range is often wider than the recommended storage temperature under normal conditions, but the range specified must be supported by data. A description of the calibrated monitoring device that will log interior temperatures during temperature and transport should be included.
Shipping container exterior temperature –The acceptable temperature range within a shipping container is a function of the exterior temperature surrounding the container. Shipments 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.
Expected duration in transport –Unexpected delays or other events that prolong transport must be considered in the shipping study. Two to four times the expected shipping duration should be represented, and the shipping route and expected duration in transport will dictate the best strategy for including reasonable allowances in the study.
Description of shipping containers –The primary, intermediate packaging, and outside shipping container should be described in sufficient detail.
Primary drug container
Exact description of primary container including materials of construction, volume, supplier, and technical features applicable to the study. (Thermal threshold)
Torque or special requirements to assure integrity of the primary container under recommended storage conditions and during transport.
Intermediate packaging (corrugated container and partitions, for example)
Intermediate packaging description should include the ability (or lack thereof) of the intermediate packaging to protect the primary containers from damage during shipment.
Intermediate packaging should be tested for the ability to securely maintain the position and placement of primary containers.
Shipper / protective packing material
Exact description of shipping container including materials of construction, volume, 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.
The initial testing of the shipping container performed by outside packaging laboratories should be referenced to support the selection of the shipping container.
Coolant required for maintaining temperature -If dry ice or liquid nitrogen is used for international shipping, the amount used must comply with International Law. National or local shipping regulations should apply. The carrier can provide specific information.
Test Plan – Destination, duration and explanation of bracketing strategy. International transport will be considered and described as appropriate. The test plan will 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)
- Shipment instructions: Specify shipment for the maximum allowable duration OR provide instructions for qualified carrier to recharge container with coolant.
- Fastest possible route
- A plan for unexpected conditions during the ship test
- Pre-established temperature range specifications
- Damage assessment criteria for shipper and primary containers
- Date of shipment
Post Shipment sampling and testing requirements (as required) and criteria for determining material impact when compared with the test results from pre-shipment samples.
Shipping Study Report
Following execution of the protocol, a summary report will document the study. The following information will be included in the report:
- Number of primary containers (or saleable units) shipped
- Date received
- Actual shipping route
- Inspection of shipper and accounting of damage noted
- Amount of coolant remaining at end of shipping
- Duration of shipment
- Temperature data from all probes
- Full primary container inspection and accounting of damage noted
- Exceptional conditions
- Comparison data from analytical evaluation
- Conclusions
Guidelines for Shipment of Samples for Analytical Testing
The degree to which shipping validation is conducted for analytical test sample transport should be evaluated. The investment in full shipping validation should be made where necessary, but risk may not warrant full validation in all cases.
Samples that must be shipped routinely for release testing or stability testing should undergo comprehensive shipping validation.
For infrequent or one-time shipments, qualified shipping containers with calibrated temperature monitoring devices may be adequate for protecting sample integrity.