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Magali Barbaroux is R&D vice-president at Sartorius Stedim Biotech FMT, Aubagne, France.
Jean-Marc Cappia is vice-president of marketing for fluid management technology at Sartorius Stedim Biotech FMT, Aubagne, France.
Increased use of single-use systems has led to a need to redefine safe, stable and integral systems for shipping biopharmaceuticals around the world. This article provides qualification data under international ASTM D4169 norms.
This article was published in Pharmaceutical Technology Europe, Volume 30, Issue 5, May 2018.
Current regulatory guidelines provide clear insights into end-user responsibility for validating the shipping of liquids in single-use systems. At this point, however, there is no specific expectation or dedicated regulatory guidance on the subject.
The US Food and Drug Administration (FDA), the European Medicines Agency (EMA) (1,2), and other regulatory bodies require that companies have qualified processes and can prove that the process will meet the quality standards of the final drug product. Guidance like the Parenteral Drug Association (PDA) technical report TR66 (3) provides following recommendation: “Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer.”
Drug manufacturing processes include more frequently international shipment which have to be defined. A risk assessment of the potential impacts of vibration, handling, delays, and seasonal variation on product should be established.
Shipment tests can be based on international standards such as the American Society for Testing and Materials’ (ASTM) D4169 or the International Safe Transit Association (ISTA) 3 series. Shipping and packaging expertise is necessary to define the appropriate validation level depending on the system used and the types of distribution cycles.
ASTM D4169 (4) and ISTA 3 series (5) are both well-known standards for shipping systems. They provide standardized validation methods using a variety of simulated shipping hazards and aim to compare or evaluate the effectiveness of protective packaging and/or a packaged-product’s ability to withstand the hazards of distribution. Table I compares the main differences between ASTM and ISTA standards for pharmaceuticals.
The level of severity for test conditions must be based on real-world shipment conditions and the desired safety margin. To optimize system validation tests, end users must know the distribution cycle, schedule, duration, severity level, and acceptance criteria, each of which may differ between sites or from one product to another.
Packaging engineers can be instrumental in defining the system to be tested, as well as in developing the most meaningful testing programme. Testing parameters and sample configurations can only be selected once the transportation cycles and the type of impact received by the load during transportation are well understood. Developing this understanding, however, requires preliminary testing and analysis.
The test protocol must simulate the lifecycle phases of the shipped product. Knowledge of the product and the type of transportation used (both the means of transportation used and the sequences involved) are crucial to understanding the shipping cycle and to providing adequate safety margin during the qualification testing programme.
For example, ASTM D4169’s distribution cycle DC12 is representative of the typical shipment shown in Table II for loads >68.1 kg (150 lb.) or unitized shipments. DC12 includes six modular test programmes adapted to simulate each segment of the projected distribution with impact (horizontal impact, rotational flat drop, and edge drop), low pressure (representative of shipment by plane or high altitude), and vibration tests.
An integrated, four-step approach (Figure 1) has been developed to clearly understand, based on testing, the behaviour of the given shipping system under real and normalized testing conditions. This approach provides data that allow a final qualification protocol to be chosen that will guarantee the system’s safety with a measurable safety margin (6). This approach for liquid shipping validation has been taken with Flexsafe3D shipping systems, shown in Figure 2.
Step 1: Real shipping conditions. Recorded data provide snapshots of what can happen during the chosen real transportation cycles, including a variety of conditions that would be found in truck or airplane transport, or in cases that involve long-distance travel, and severe road conditions.
Each of the filled 100-, 200-, and 500-L Flexsafe 3D Bags in its shipping Palletank was equipped with a data logger and shipped under two real transportation cycles, as shown in Figure 3. Under the supervision of a trained packaging engineer, the resulting data can be visualized with an event chronogram (Figure 4).
For example, the recorded vibration levels provide complex and chaotic acceleration measurements over time. The vibration levels must be mathematically transferred from a time axis to a frequency axis using Fast Fourier Transform, in order to obtain the vibration level reading in a power spectral density (PSD) curve, as shown in Figure 5. In this example, the number of vibratory events per hour varies greatly during the distribution cycle. This is due to the fact that events are especially intense during truck transport in India and the final phases of transport on the airport tarmac.
Step 2: Testing under lab conditions, following ASTM D4169 and ISTA 3E. One each of a 100-, 200-, and 500-L Flexsafe 3D Bags was filled with water in its shipping palletank and equipped with a data logger. Each bag was then tested according to ASTM D4169 Levels I, II, and III and ISTA 3E requirements. Transportation configurations (with and without a pallet between the vibratory table and the palletank) were tested to define the worst-case scenario for qualification testing.
Analysis of the results provides complete knowledge about the shipping system behaviour when submitted to severe physical conditions (Figure 6).
Characterization tests allow the definition of which norm should be used for the final qualification by assessing the most stringent testing programme possible. Qualification tests should be established in order to provide adequate safety margins, thus guaranteeing the reliability of the shipping system when product is shipped in real conditions.
Secondly, characterization tests provide the worst-case shipping conditions: depending on the configurations (e.g., with or without pallet, or using one or two systems per pallet). Results of the tests can differ significantly, especially in terms of condition severity.
Finally, the tests allow for a compartison of the levels of intensity between ASTM and ISTA testing. In the example (Figure 7), Physical shakes have been chosen to demonstrate the level of severity for ASTM D4169 level II and ISTA 3E for each volume (100-, 200-, and 500-L). The acceleration seen by the shipping system when submitted to these normalized tests shows clearly that ASTM D4169 level II is more stringent than ISTA 3E.
Step 3: Determination of the final qualification testing programme by comparing real shipping data with laboratory characterization data for the shipping systems.Comparison of real transportation measurements and data obtained during ASTM D4169 and ISTA3E, in addition to typical transportation cycle analysis, allows the definition of an adequate testing protocol. This comparison is performed on all physical entities. The comparison is illustrated in Figure 8, in terms of PSD, the root mean square or Grms value, and shakes for horizontal and vertical shocks.
Step 4: Final qualification testing programme performed on filled Flexsafe 3D bags in their shipping Palletank according to ASTM D4169, assurance level II at 4 °C (39 °F) and 40 °C (104 °F).In this stage, 100-, 200-, and 500-L Flexsafe 3D bags that had been gamma irradiated at 50 kilogray (kGy), were set as the worst-case level. The bags were filled with water and installed in their shipping palletank, each with a shipping kit. Four bags per volume taken from two different batches were tested under the testing protocol defined previously. Qualification tests were performed at 4 °C (39.2 °F) and 40°C (104 °F) with previously defined worst-case configurations.
The same bags were tested after one and three years of accelerated ageing. The validation protocol was based on ASTM D4169-14. Distribution cycles numbers 12 and 14 were selected as the closest to the normal transportation conditions in the biotech industry, as shown in Table III.
For each test sequence, the test method and severity level must be specified for the ASTM D4169-14 distribution cycles. Qualification protocol choices are shown in Table IV. Several options are available. The best choice depends on knowledge of real transport conditions, the type of system being transported, and the severity of conditions in that mode of transport.
After ASTM tests cycles, visual inspection and dye penetration tests were used to inspect the bags for damage or leakage, and to find any system damage. The following criteria were used:
Results of shipping liquid-filled bags using ASTM D4169 cycle 12 & 14, level II after storage during 72 hours at 4 °C (39.2 °F) and at 40 °C (104°F) are shown in Table V.
Shipping is a complex and challenging function. The end-user should not simply rely on system or material vendors’ claims (e.g., of their products being “ISTA certified” or “ASTM compliant”). It is important to understand what is behind each vendor’s claim for its products. In addition, each claim should be verified to ensure that it is applicable to the intended use of the biopharmaceutical product.
Finally, the end-user should understand the trial conditions used in the vendor tests and compare them closely to conditions for their specific application. The acceptance criteria (for both bag and shipper), the test protocol, and trial conditions must also be closely considered.
Shipping validation must be carefully defined. This requires close collaboration between the end-user and vendor, with parameter setting linked to actual use.
Collecting vibration data on real shipments will help the end user and vendor to understand the physical constraints of the shipping mode and select the best protocol to replicate them in laboratory testing. The limits of the system should be defined using knowledge of the safety margin and be tested under real packaging and real transport conditions.
1. FDA,Guidance for Industry Process Validation: General Principles and Practices (January 2011), fda.gov
2. 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), ema.europa.eu
3. Parenteral Drug Association (PDA)“Technical Report Number 66, Application of Single-Use Systems to Pharmaceutical Manufacturing,” store.pda.org, 2014.
4. ASTM D4169: Standard Practice for Performance testing of Shipping Containers and Systems, 2014, astm.org
5. ISTA: Guidelines for Selecting and Using ISTA Test Procedures and Guidelines, General Simulation Performance Tests, ista.org
6. 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
Pharmaceutical Technology Europe
Vol. 30, No. 5
When referring to this article, please cite it as E. Vachette, F. Bazin, M. Barbaroux, and J. Cappia, "An Integrated Approach to Shipping Liquid in Single-Use Systems," Pharmaceutical Technology Europe 30 (5) 2018.
Elisabeth Vachette, Elisabeth.Vachette@Sartorius-Stedim.com, is senior product manager; Frederic Bazin is R&D programme manager; Magali Barbaroux is R&D vice-president; and Jean-Marc Cappia is vice-president of marketing for fluid management technology, all at Sartorius Stedim Biotech FMT, Aubagne, France.