Qualification and Validation of Single-Use Shipping Systems

As the biotech industry evolves, there are mounting concerns about the transportation, security, and robustness of cell-culture media, intermediate, or bulk drug substance (BDS). Safe, stable, and closed systems are needed when sterile products are shipped in single-use bags (1). In this article, the authors look at the limitations of the validation for a single-use shipping system and provide a perspective on what shipping validation means.

The increasing need for shipping product in the biotech single-use market
The complexity of biopharmaceutical manufacturing processes requires continuous improvement. The expansion of manufacturing capacity worldwide has resulted in the multiplication of links between production facilities as well as the increasing need for storage or transportation of media, intermediate, BDS, and drug products.

Outsourcing to contract manufacturing organizations (CMOs) offers a solution to the capacity constraint. CMOs bring to the biopharma industry valuable technical expertise and flexible capacity and reduce the total risks associated with building internal capacity; however, a robust and validated manufacturing process (2), including product transportation between facilities, is required.

Single-use technology (SUT) continues to expand because of its potential for reducing both capital and operating expenses (3). The growing adoption of single-use, especially in critical process steps, has increased the need for product quality, robustness, and integrity. The biotechnology industry is now expanding its implementation of single-use bags into all bioprocess steps for applications including cell-culture preparation (4), filtration (5), purification (6), storage (7), mixing (8), freeze-thaw operations (9), and fill-finish (10).

Depending on the manufacturing process organization and the level of outsourcing, the challenge of safe and robust BDS transportation becomes a crucial step from a risk analysis point of view (11, 12).

Achieving safe shipmentRequirements of suppliers and end-users
To comply with modern manufacturing requirements, SUT must offer similar levels of security and robustness as multi-use technology (MUT). A MUT shipping container is designed to withstand the different static and dynamic forces to which it is subjected during transportation, handling, and storage operations. The shipped product must also be protected from climatic conditions, such as temperature and humidity (13). Reusable products must:

• Be robust in terms of providing protection to the shipped product against rigorous environmental and handling conditions

• Maintain product sterility

• Maintain product stability

• Ensure operator safety

• Align with current logistic operation

• Be compatible with variable volumes.

Stainless-steel tanks for bulk freezing and distribution between drug substance sites and drug product sites were the processing units of choice until recently, when the technology was challenged by SUT (9, 14, 15). It is important to note that there is a simpler supply chain with SUT shippers because there is no need to manage the return of empty tanks or to clean and verify them.

In addition to the aforementioned standard requirements, shipping with SUT requires the following additional needs:

• Maintenance of the structural integrity of the single-use bag (i.e., no leaks)

• Qualification of product in contact with the single-use material (i.e., extractable and leachable testing).

While SUT shipping can offer substantial advantages compared to MUT shipping, there are challenges with SUT shipping as summarized Table I. Several considerations are related to the material of construction of SUT. Moreover, the end-users’ requirements for shipping depend largely on the application as shown in Table II.

Regulatory aspect
As indicated in the Parenteral Drug Association’s (PDA) Technical Report (TR) N°66 (16), the supply of process solutions in large-volume bags, from point of manufacture to point of use is a well-established practice that involves the following elements:

• A bag designed to fit a rigid wall outer container

• A rigid wall outer container such as a plastic drum or tote or a stainless-steel bin

• Secondary packaging materials (e.g., dunnage) and lids or other mechanical devices to suppress the fluid wave action in the bioprocess bag.

Transportation of process solution in small-volume bags (nominal volume lower than 20 L) is also a common process that requires less complex packaging solution (16). The exception is the transportation of frozen materials that necessitates temperature-resistant materials and cold-chain logistics (17).

Shipping systems must be qualified for their intended use through proper design and testing in consultation with a packaging engineer. The International Safe Transit Organization (ISTA) (18) and the American Society for Testing and Material (ASTM) D4169 (19) are good references for testing standard. These standards are complex with many different protocols, and the selection of a relevant protocol linked to an application is not trivial. It must be analyzed with a packaging and transport expert. The following are some key considerations for end-users:

• What is the shipping unit (size, weight, and form of construction)?

• What are the shipping routes: intercontinental (truck/air/boat), national (long-distance truck), or continental (short-distance truck)?

• What is the assurance level that should be established? Level I > level II > level III

• Define the lifecycle phases of the shipped unit (storage, transport, handling, transport, use)

• What are the associated environmental conditions for each phase of the lifecycle (temperature, humidity, compression, vibration, shock, free fall, bump, and pressure)?

• What are the handling conditions (forklift, tarmac, roads)?

• What are the type of shock, shake, and vibrations associated with the shipping routes?

• Can the shipping unit be stacked?

• What is the appropriate number of samples for validation?

• What is the adequate severity of the simulated shipping test?

• What are the acceptable safety margins?

• What are the acceptance criteria: product is damage-free, package is intact, or both?

Based on the projected distribution, the end-user should define a test plan using the distribution cycle (DC) defined in Table I of the ASTM D 4169 (19). The DC chosen should correlate with the projected lifecycle phases of the shipped unit (20).

In addition, many pharmaceutical or biotechnological products are temperature sensitive and require specific precaution during storage and transportation (21). Transport and storage conditions have to be determined considering the risks of product degradation (22, 23).

PDA TR N°66 has highlighted specific factors of importance for transportation that must be considered by end-user (16). These factors are:

• Dimensional factor (i.e., volume to be shipped and dimensions of the shipper)

• Mode of transportation, whether it’s ground, air, rail, boat, or combination of more than one mode of transportation. Metrics must include hold time on tarmac.

• The associated environmental conditions (temperature, humidity, pressure, and variation)

• Functionality (i.e., forklift access, stack ability of outer container, access to fill and drain port, secondary container to collect leak)

• Room classification such as fill and drain procedure to maintain sterility

• Logistics (e.g., external shipper, cold-chain logistics).

In addition to PDA TR66, the analysis of the regulatory requirements and relevant references can be summarized as follows:

• The transportation routes must be defined for international shipment. A risk assessment for vibration, handling, delays, and seasonal variation should be established (11).

• The suitability of the containers (compatibility, safety, robustness) and of the container-closure system (material of construction, integrity, interaction) must be defined as well as a rational for the choices of the material, the barrier properties, the compatibility, and the safety (13).

• Recommendations are given to define storage and shipping conditions, to assess risk of the environmental parameter variation, to define labeling, and to assess short-term excursion outside storage conditions according to the International Council on Harmonization (ICH) accelerated testing (24).

• Qualification and validation of the shipped product can be performed in real shipment with monitoring (25-27) or in simulated shipment according to ASTM D4169 (19) or ISTA (18).

• In addition, precautions for transport of hazardous materials and dangerous goods are also described in additional regulations. The Economic Commission for Europe has defined regulations applicable to road transportation of chemical dangerous goods (28). Part 3 of the documents lists the chemical entities considered as dangerous goods for which special precautions are required.

• The United Nations has established regulations for any type of transports (air, road) of biological and infectious substances (29).

• The International Air Transport Association has established regulations applicable to safe air transportation of dangerous goods (30).

Shipping is indeed complex and users should verify the vendor’s claims about some regulations. It is important for the end-user to understand what is behind the claim and the relevance to its application. As discussed in this article, shipping validation protocol for mechanical constraints needs to be carefully defined with parameters setting linked to the application in close collaboration between end-users and suppliers.

It is a requirement of the US Food and Drug Administration (FDA) (12, 31), EMA (32), the European Union (11) and other drug regulatory agencies that the process produces consistently similar and reproducible results that meet the quality standard of the product. According to FDA, 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 pre-determined specifications and quality attributes” (33). A properly designed system will provide a high degree of assurance that every process step, including shipping, has been properly evaluated before its implementation.

In the biopharmaceutical industry, qualification and validation are intended to demonstrate that the manufacturing process provides the desired level of product quality and specifically its activity, sterility, and potency. Qualification of a shipping system and shipping equipment is part of the validation.

Mechanical robustness and integrity

A SUT shipping system composed of a bag and a stainless-steel bin should ensure safe shipment (i.e., no loss of integrity and no loss of product sterility). It can be granted by the mechanical robustness of the shipper. The objective is to verify that no leaks occur during transportation. According to Tull, “Product quality can be defined in terms of the ability of a product to perform its desired function despite the stresses to which it has been exposed before and during its intended use” (23).

Bag leakage can be analyzed following methods described in the PDA TR N°27 (34). This document, however, describes high-sensitivity methods adapted for final packaging and not necessarily for intermediate or BDS. More global test methods such as diffusion of a dye, detection of a liquid leak, or damage of the bag (films and seals) may be more relevant (35).

Ensuring a safe shipment means preventing leakage and loss of integrity when the SUT shipping system undergoes the mechanical stresses generated during shipment. It is difficult to define these stresses and to determine the adequate safety margin.

ASTM and ISTA Standards

As already mentioned, a well-known and common practice is to apply the ASTM or ISTA standard protocol on shipping system and check its performance according to these agency guidelines. Table III briefly describes the main features of the ASTM and ISTA standards. It is, therefore, difficult to select the right parameters to grant a safe validation.

Selecting a Protocol
It is important to choose a protocol that correlates to the projected lifecycle phase of the shipped unit. Knowledge of shipped product and the type of transportation (mean and sequences) is important. A typical distribution sequence between two plants is depicted in Figure 1.

ASTM (19) proposes 18 DC for modeling any type of transport by carrying out accelerated and stringent testing. For example, DC 12 of ASTM is representative of the typical shipment shown in Figure 1. DC 12 includes five test programs adapted to simulate each segment of the projected distribution (see Table IV) with impact (horizontal impact, rotational flat drop, and edge drop), low pressure (representative of shipment by plane or high altitude), and vibration tests.

A second step is to define the severity of testing (level and duration). Some differences between the three assurance levels are shown in Table V, which is not exhaustive. Duration is always a decision to be taken by the end-user even though standards may make recommendation, unless conditions dictate otherwise. ASTM also recommends level 2 in that case. The level of severity must be defined according to real shipment condition in addition of desired safety margin.

There is no official ASTM claim; suppliers can only claim that they pass ASTM selected tests described by the standard. Therefore, knowing the distribution cycle, schedule, duration, severity level, and acceptance criteria are mandatory to understand the validation performed on the system. Moreover, the suitability with the intended use can only be proven by end-users; these conditions might differ from one site to another or from one product to another. Transport simulation test results performed according to DC12 of ASTM D4169 as well as test results obtained in real shipping conditions will be described in a forthcoming paper. The paper will present mechanical robustness and vibration data test results in a simulated and real-life scenario to define and validate the conditions for safe transportation, the safety margin, and the limits of the each system.

Conclusion
Shipping is indeed complex and the user should not be assuaged simply by vendors’ claims about regulations (i.e., claims of being “ISTA certified” or “ASTM compliant”). It is important to also understand what is behind each claim and verify that it is applicable to the product’s intended use. The end-user should understand the trial conditions used in the vendor tests and compare them to its application. The acceptance criteria (bag and shipper), the protocol, and trial conditions shall be discussed. 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 the real use will help 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 limits of the system should be defined with knowledge of the safety margin and be tested under real packaging and real transport conditions.

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Article DetailsPharmaceutical Technology European Outsourcing Outlook
Vol. 28, No. 13
Pages: 14–18

Citation:
When referring to this article, please cite it as N. Voute et al., “Qualification and Validation of Single-Use Shipping Systems," Pharmaceutical Technology European Outsourcing Outlook 28 (13) 2016.