Direct Dispense Packaging Innovation for Biopharmaceutical Manufacturing

Biopharmaceutical manufacturing is a complex process involving precise amounts of materials and numerous variables that can affect drug product quality and yield. While a strong focus on quality, safety and drug efficacy is essential, biopharmaceutical manufacturers are also committed to reducing costs and improving manufacturing efficiencies. One area involving significant costs (and potential risk to quality) is the buffer and cell culture materials preparation process. This production step is labour-intensive, requires investment in storage and environmental resources, and involves repeated quality assurance (QA) testing as bulk materials are subdivided for individual process runs. However, new innovations in raw materials packaging can help biopharmaceutical manufacturers streamline operations, mitigate risks and improve efforts toward operational excellence (OpEx).

Traditional raw material delivery methods

Upstream biopharmaceutical processes consume various raw materials, including cell culture media, carbohydrates, amino acids and buffers, which are typically supplied in powder form. The bioreactors and medium preparation tanks that use these materials often operate around the clock. This includes both large-scale reactors with 10,000 L capacity, to newer generation single-use technologies, with multiple 2,000 L bioreactors.

In general, two kinds of packaging systems are used today to supply bulk dry materials: traditional 100 kg drums with one or two plastic liners; or smaller cardboard boxes with plastic liners holding 50 kg. Both bulk packaging systems are part of standard practices that most raw materials suppliers have established for their supply chain systems.

The end user (ie. the biopharmaceutical producer) typically orders, receives and stores enough salts, buffers and other cell culture powdered materials to last several weeks or months. These materials are then subdivided by the biopharmaceutical producer and used in smaller amounts depending on the processes they are running. This bulk material packaging and delivery methodology satisfies the raw material supplier’s operational requirements, but without full consideration of how that material is used by the end biopharmaceutical producer.

Traditional operational inefficiencies and risks

The biopharmaceutical manufacturer must then follow multiple processing steps with this method to properly manage and utilize these bulk raw materials. Bulk materials are received and inventoried in storage areas under the appropriate temperature and humidity controls to maintain product integrity. The container’s outer packaging is cleaned and sanitized and brought into a clean room suite, where a sample is taken to independently confirm via lab analysis that the product’s quality, purity and characterization match what was ordered. After confirmation, the bulk material is cleared for use in the producer’s dispensing operation.

Once cleared, the package is once again brought into a clean room packaging suite where the contents of the drum are subdivided by hand according to manufacturing requirements – for example, if 45 kg are initially required, that quantity is removed and packaged into temporary transit packaging while the remainder of the drum is put back into storage.

This subdivision step is time-consuming and risks cross-contaminating the remaining bulk material.

Complications due to material caking/clumping

Various raw materials such as salts, buffers, amino acids and carbohydrates tend to form clumps or cake due to their crystal structure and surface moisture content. This caking, or clumping is a common problem with packaging, storing and sub-dividing powdered materials in bulk containers. Severe cases of caking can result in complete solidification of the entire package. Caked materials must be completely broken up, in order to measure out the precise amounts needed for bioreactor processes. This can be time-consuming and involves an open container which is at risk for cross-contamination and absorption of additional moisture, potentially extending the problem. This practice also creates a potential safety risk, as operators work with mallets or hammers and manually break up clumps while the container is open, and can lead to injury and material loss.

New packaging innovation for pre-weighed, free-flowing materials

Most recently, innovative chemicals suppliers have begun offering single-use, pre-weighed product bags that provide biopharmaceutical producers with an easy-to-use method for dispensing salts, buffers and other cell culture materials directly into their media or buffer preparation tanks, in the exact amounts they specify for a given process.

This innovative packaging option essentially completes the evolution from one-size-fits-all 50 kg and 100 kg bulk product drums, to individual direct dispense bags. The bags are constructed using the same type of polymers already used to line the traditional bulk drums, so there generally is no need for biopharmaceutical manufacturers to re-validate the packaging material.

In addition, the size, shape, sealing and seams of these bags are designed so that when they are inverted, they dispense virtually all the pre-weighed material into the bioreactor. An important consideration here is that pre-weighed and dispensing amounts are within a one-percent tolerance of the amount of material required.

To help ensure a free-flowing dispensing system, the bags also incorporate design features to reduce clumping, including outer and inner layers with special desiccant materials installed between the two layers. The inner layer uses a vapor permeable material so that any moisture that develops within the bag passes through this material and is controlled by the desiccant to maintain the correct moisture levels and reduce clumping to an absolute minimum.

Direct dispense bags simplify sampling and testing

Traditional large-volume bulk container packaging also requires time-consuming sampling and testing to verify the material properties of a newly delivered drum of product. New direct dispense bag systems are compatible with non-destructive identity-testing tools, such as contact-free Raman spectroscopy. With Raman testing, there is no need to open the bag and take a physical sample to verify the product; the closed bag can be scanned and verified upon delivery, saving multiple testing steps. The packaging is also tamper-evident, to ensure validity and supply chain security.

In addition to near Raman testing, a “tailgate” or side sample can be provided with the bags, so any biopharmaceutical producer that is required to conduct full analyses of all materials used in their processes doesn’t need to open the bag to obtain a product sample. The tailgate is fully traceable ensuring its equivalency to the materials packed in the bag.

Direct dispense system saves time and money

Expanding the use of these direct dispense systems can help advance OpEx initiatives and reduce costs within the biopharmaceutical industry’s supply chain. There are multiple savings associated with the use of these systems:

Labour: Eliminates the time and cost of personnel who need to weigh, subdivide and dispense materials from bulk containers. Facilities: Use of direct dispense systems can eliminate the need for dedicated raw material clean room preparation areas, drum storage and handling equipment, and environmental (temperature and humidity) controls for those areas. Testing/validating: Use of Raman testing and tailgate samples greatly simplifies the testing identification step. Quality: Pre-weighed direct dispense systems eliminate the need to clean the weighing and dispensing area for another operation saving time and reducing cross-contamination risks. Material stability and efficient use:  Reduced-clumping packaging design improves raw material yields by avoiding material non-conformities and inaccurate ingredient measurements from severely clumped materials. Safety: Reduced-clumping packaging leads to better environmental, health and safety practices, as employees no longer need to engage in the potentially unsafe practice of breaking up clumps that can form in traditional drums. Raw materials savings: Pre-weighed amounts in direct dispense bags that match specific biopharmaceutical process requirements eliminates the need to buy and store material in bulk, reducing overages, out-of-date materials and disposal costs.

By developing raw material packaging and delivery options to align more closely withthe operational requirements of biopharmaceutical producers, innovative raw materials suppliers are helping to eliminate inefficiencies and drive down costs within the overall supply chain and production environment.