Biotechnology industries have adopted single-use systems in their manufacturing processes. The adoption started with applications managing peripheral fluids and is now moving towards the main drug manufacturing process. This transition is leading to more challenging safety and quality requirements especially in very demanding or high stress applications such as transportation of bulk drug substances (BDS). There is an increasing need to define safe, stable and integral systems for shipping biopharmaceutical solutions around the world. A new approach for qualifying this process step has been established based on well-known international standards: ASTM D4169. The test protocol has been developed and is justified according to both real shipping data and system characterization under laboratory conditions. The qualification testing programs have been performed at two different temperatures (4°C and 40°C), thus providing the safety margin needed for qualifying the systems and bracketing the liquid shipping from cold to ambient temperatures. These data can be leveraged by end-users to support the qualification of this liquid transportation process.
Transportation is an integral part of the drug manufacturing process. It is considered a critical process step requiring robust and documented process validation. To ensure safe and reliable fluid transportation, there is a need for closed system processing, packaging integrity, container closure and simplified and robust logistics.
Regulatory Guidance
Current regulatory guidelines provide clear insights about the end-user responsibility for validating the shipping of liquids in single-use systems, however, there is no specific expectation or dedicated regulatory guidance on the subject. As a basis, the regulatory bodies (FDA1 or EMA2) require qualified processes and proof that the process will meet the quality standards of the final drug product. Validation is “Establishing documented evidence that provides a high degree of assurance that a specific process” including shipping “will consistently produce a product meeting its predetermined specifications and quality attributes” (FDA). According to the PDA technical report TR663, “Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer”. International standards such as ASTM D4169 or ISTA 3 series are available, but leave many choices for shipping validation depending on the system used and the type of distribution cycle.
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Well-Known International Standards ASTM D4169 or ISTA 3 Series
ASTM D41694 and ISTA3 series5 both provide standardized validation methods using a variety of simulated shipping hazards. They aim to compare or evaluate the effectiveness of protective packaging and/or a packaged-product’s ability to withstand the hazards of distribution.
The level of severity for testing must be defined according to real shipment condition in addition to the desired safety margin. It is essential to know the intended distribution cycle, schedule, duration, severity level, and acceptance criteria to establish the rationale for the validation tests performed. The suitability for the intended use can only be qualified by end-users since these conditions are likely to differ from one site to another or from one product to another.
With the complexity of these norms, the knowledge of a packaging engineer is critical for accurately defining the system to be tested and the definition of a meaningful testing program. The choice of the testing program needs to be carefully assessed and justified. The test parameters and test sample configuration can only be selected through knowledge of the transportation cycles and the type of impact received by the load during transportation. This requires preliminary testing and analysis.
Defining the Adequate Testing Program
The test protocol needs to simulate the life cycle phases of the shipped unit. Knowledge of the shipped product and the type of transportation (means and sequences) is key to understanding the shipping cycle and providing an adequate safety margin during the qualification testing program. Some typical distribution sequences between two plants in the biotech industry can be represented by the following schematic:
For example, distribution cycle 12 (DC12) of ASTM D4169 is representative of the typical shipment shown in figure 1 for loads >68.1 kg (150 lb) or unitized shipment. DC12 includes six modular test programs adapted to simulate each segment of the projected distribution (Figure 2) with impact (horizontal impact, rotational flat drop and edge drop), low pressure (representative of shipment by plane or high altitude) and vibration tests.
Complete Logistic Solution Qualified with an Extensive Four-Step Testing Approach
This approach provides a clear understanding, based on testing, of the behavior of the shipping system under real and normalized conditions. This approach for liquid shipping validation has been performed on Flexsafe® 3D shipping systems (Figure 3)
This four-step qualifi cation approach is based on the necessity to understand the impact of transportation under real world shipping conditions and to characterize the shipping system behavior when submitted to extreme forces such as shocks, shakes or vibrations according to their shipping conditions (plane and/or truck; palletized or non-palletized shipments).
STEP 1: Real Shipping tests are performed to understand the impact of usual distribution cycles on the liquid shipping systems. Accelerometers are placed on the filled Flexsafe® shipping system during a variety of long distance, real transportation cycles (including handling, truck and airplane shipment) to provide full data records of each shipment for later analysis.
STEP 2: Normalized laboratory testing is performed to characterize the shipping system according to norms. This step is required to characterize the filled Flexsafe® shipping systems and provides the analysis of acceleration measured on the systems during their test in laboratory conditions according to ASTM D4169 (at all severity levels) and ISTA 3E series.
STEP 3: This is the core analysis step. Data gathered from the real shipping data and laboratory normalized characterization is compared and provided the rationale for the choice of the parameter setting that will be used for the ultimate qualification protocol of the shipping system along with the definition of the worst case conditions.
STEP 4: The ultimate step where the system (a filled Flexsafe® 3D bags in their shipping Palletank®) was qualified. Under the defined worst-case conditions the system undergoes the complete testing program that was defined previously (STEP 3). Filled Flexsafe® 3D bags from 100L to 500L were tested according to ASTM D4169 level II, cycles 12 and 14 at 4°C (39°F) and 40°C (104°F).
Based on a risk assessment and on knowledge of usual distribution cycles, this comprehensive qualification method has been established to ensure that appropriate safety margins are applied during qualification tests. This ensures a variety of real conditions are covered and allows safe and reliable shipping processes.
Case Study for Four-Step Approach
Our four-step approach was assessed as a qualification process for the Flexsafe® 3D shipping system. This system is intended for shipping of high value biopharmaceutical fluids. Distribution cycles #12 and #14 are relevant for this testing as they can be linked to the most common distribution cycle used by biopharmaceutical industries (Figure 5)
For each test sequence, the method and severity level have been specified for the ASTM D4169-14 DC12 and 14. Several options are available and depend on knowledge of real transport conditions, the type of system to be transported and the level of severity.
After the ASTM test cycles, the system is inspected for the absence of damage and the bags are inspected for the absence of leakage by visual inspection and dye penetration testing.6
The following acceptance criteria are used for the tests:
- Visual inspection during test – no leak, no damage to the system
- Visual inspection of the emptied bag – no leak
- Dye penetration test on emptied bag – no leak
Shipping of liquid filled bags – ASTM D4169 cycle 12 and 14, level II after storage during 72 hours at 4°C (39.2°F) and at 40°C (104°F):
Flexsafe® 3D bags in the shipping Palletank® were tested according to the protocol described in this article and met the acceptance criteria for liquid shipping qualified according to ASTM D4169 cycles 12 & 14 at the assurance level II for a temperature range of 4°C (39.2°F) to 40°C (104°F).
Conclusion
Shipping is a complex and challenging bioprocess application and the end user should not simply rely on vendors’ claims about regulations (i.e., claims of being “ISTA certified” or “ASTM compliant”). It is important to understand what is behind each claim and verify that it is applicable for the intended use of the product. The end-user should understand the trial conditions used in the vendor tests and compare them to their specific application. The acceptance criteria (for bag and shipper), the protocol, and trial conditions should also be considered.
Shipping validation needs to be carefully defined in close collaboration between end-user and vendor, with parameter setting linked to actual use. Collecting vibration data on real shipments helps the end user and the vendor to understand the physical constraints of the shipping mode and select the best protocol to replicate them in laboratory testing. The robustness of the system is defined using knowledge of the safety margin compared to the tests under real transport conditions.
The selection of proven and robust single-use solutions provides end users with safe and easy-to-use handling systems that minimize risk of product loss. Long-term product integrity and stability is maintained and safe international shipments are ensured. The selection of the ASTM D4169 qualification method as being a stringent supplier qualification and the results of this testing methods contribute to demonstrating the robustness of the shipping solution in Flexsafe® bags. These Standard shipping tests data can be leveraged by end-users to support their own qualification for liquid shipping in single-use systems. ASTM D4169 provides the highest safety factor and end-users can leverage the data for their own process validation. Flexsafe® single-use bags qualified under ASTM D4169 method provide a safe and reliable method for shipping high value drug substances
Author Biographies
Elisabeth Vachette is the Flexel® & Flexsafe® Product Manager at Sartorius Stedim Biotech France.
Frédéric Bazin is the R&D Program Manager at Sartorius Stedim Biotech France.
Jean-Marc Cappia, is the Vice-President for FMT Marketing at Sartorius Stedim Biotech France.
References
- FDA, Guidance for Industry Process Validation: General Principles and Practices, January, 2011
- EMA, Guideline on Process Validation for the Manufacture of Biotechnology derived Active Substances and Data to be provided in the Regulatory Submission, London, April, 2014
- PDA, Technical Report N°66, Application of Single-Use Systems to Pharmaceutical Manufacturing, 2014
- ASTM D4169: Standard Practice for Performance testing of Shipping Containers and Systems, 2014
- ISTA: General Simulation Performance tests
- Technical Report of Flexsafe® 3D Bags Qualification for Liquid Shipping according to ASTM D4169 – Sartorius Stedim Biotech, Publication N°: SPT1105-e161201, Order N°: 85037-557-48, Ver.: 12|2016