Raw Materials Packaging Innovations for Biopharmaceutical Manufacturing

While a strong focus on quality, safety, and drug efficacy is absolutely essential, biopharmaceutical manufacturers are also committed to finding ways to reduce costs and improve manufacturing efficiencies. One production step with significant costs (and potential risk to quality) is the buffer and cell-culture materials preparation process: it is labor-intensive, requires investment in storage and environmental resources, and involves repeated quality assurance (QA) testing as bulk materials are subdivided for individual process runs.

New innovations in raw materials packaging technologies can directly impact this process--streamlining operations, mitigating risks, and contributing to operational excellence (OpEx). In this article, the author examines new methods of raw materials packaging and how they may lead to manufacturing efficiencies, elimination of raw material yield losses, reduction in QA testing time and costs, and lower costs in weigh and dispense production.

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 operation includes both large-scale reactors with 10,000 L capacity that run continuously for anywhere from 15-35 days, to newer generation single-use technologies, with multiple 2000-L bioreactors operating in overlapping sequences to achieve similar or greater productivity.

In general, two kinds of packaging systems are in use today: Traditional steel 100 kg drums with one or two plastic liners, and 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 (i.e., the biopharmaceutical producer) typically orders, receives, and stores enough salts, buffers, and other cell-culture powdered materials to last several weeks or months. The material consumption rates can be substantial: a typical buffer media preparation/usage cycle may consume between 150 and 400 kg of dry products per run, and uses multiple raw materials per cycle. These materials are then subdivided by the biopharmaceutical producer and used in smaller amounts depending on the processes they are running. In essence, this bulk material packaging and delivery methodology satisfies the raw material supplier’s operational requirements, without full consideration of how that material is used by the biopharmaceutical producer.

Operational inefficiencies and risks
Following the more traditional method described above, the biopharmaceutical manufacturer must follow multiple processing steps to properly manage and use these bulk raw materials.

• Bulk materials are received and inventoried in storage areas that must have the appropriate temperature and humidity controls to maintain the material’s integrity.

• The container’s outer packaging is cleaned and sanitized. A sample is taken to independently confirm via lab analysis that the product’s quality, purity, and characterization match what was ordered. Once this is confirmed (and analysis can take multiple days), the bulk material is cleared for use in the producer’s dispensing operation.

• Once cleared, 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 the remainder is put back into storage. For a 2000-L bioreactor, a manufacturer may need to subdivide a 100 kg drum of material between two and five times.

• This subdivision step is time-consuming and risks cross-contaminating the remaining bulk material. Some biopharmaceutical producers conduct multiple lab analyses of these drums, each time a new quantity of material is removed, to confirm that no issues have occurred.

Much of this activity precedes, and is not directly related to, the value-added process of protein manufacturing. It is time and effort spent on materials management and warehousing activities, particularly the sub-dividing step, to supply the bioreactors with the precise amount of material needed for production.

Complications due to material caking/clumping

Various raw materials, such as salts, buffers, amino acids, and carbohydrates, have an intrinsic propensity to form clumps or cake due to their crystal structure and surface moisture content. The presence of available surface moisture catalyzes the process of caking when free moisture migrates onto the surface of the crystals and dissolves a small portion, forming a salt bridge. This caking, or clumping (Figure 1), is a common problem with packaging, storing, and sub-dividing powdered materials in bulk containers.

Changes in ambient temperature or humidity are the principal factors driving this process; the number of temperature-change cycles will increase the strength of the cake. 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 is a time-consuming manual activity with 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 to manually break up clumps while the container is open, and can lead to material loss.

Matching packaging size to process needs
Over the past few years, pharmaceutical and biopharmaceutical manufacturers have worked with bulk material suppliers to modify packaging approaches. The goal was to enhance operational excellence and reduce wasted time and impact on process and product quality. The initial focus was on bulk material container sizes, which typically held many more materials than were needed, and forced on-site storage and subdividing steps. While continuing to offer the standard 50 kg and 
100 kg containers, suppliers began to provide smaller, more manageable container sizes, such as 12 kg and 25 kg.

This approach reduced the length of time containers were kept in storage and the number of times a container was subdivided. Subdividing was still required, however, because the exact amounts of sugars, buffers, salts, and other powdered bulk materials varied greatly by manufacturer, based on the specific process, protein, and bioreactor equipment being used. Subdividing also adds a measure of uncertainty to the amount of raw materials dispensed in a particular process step. Biopharmaceutical production uses extremely tight control on process parameters to protect the final drug’s safety and quality, and finding ways to strictly control the amount of raw material that goes into bioreactors can enhance operational excellence and process yield.

Figure 2: To help ensure a free-flowing dispensing system and eliminate clumping, some bags have outer and inner layers with special desiccant materials installed between the two layers. The inner layer uses a vapor permeable material; any moisture that develops within the bag passes through this material and is controlled by the desiccant, to maintain the correct moisture levels.

New packaging for pre-weighed, free-flowing materials
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. The packaging options that are now used essentially complete the evolution from 50 kg and 100 kg bulk product drums, to individual direct dispense bags. The packaging is constructed of transparent polymers, the same materials that have already been used to line the traditional bulk drums; therefore, biopharmaceutical manufacturers do not have to re-validate the material as safe for use.

The packaging’s design offers biopharmaceutical manufacturers more choices with regard to packaging size. Manufacturers can order the materials in a wide range of smaller, precise quantities (e.g., from 250 g to 100 kg). 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 amounts should be within a 1% tolerance of the amount of material required. This is crucial, especially when the direct dispense bags are used in single-use bioreactors. If a biopharmaceutical manufacturer has determined that an exact amount of glucose or sodium citrate is needed to achieve maximum yield on a process, the ability of the packaging to freely deliver that amount to very tight tolerances must be assured.
To help ensure a free-flowing dispensing system, the bags also incorporate design features to eliminate clumping, including outer and inner layers with special desiccant materials installed between the two layers (Figure 2). The inner layer uses a vapor permeable material already in use in other container-lining applications. 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 (Figure 3).

Direct dispense bags simplify sampling and testing
Traditional large-volume bulk container packaging also necessitates the time-consuming process of sampling and testing to verify the material properties of a newly delivered drum of product. Direct dispense bag systems use transparent polymers that 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, some suppliers also will provide a tailgate sample along with the bags. Biopharmaceutical producers that are required to conduct full analyses of all materials used in their processes don’t need to open the bag to obtain a product sample. The tailgate sample process must be validated to ensure that the material in the tailgate sample is equivalent to the materials packed in the bag.

Direct dispense systems: Time and cost savings
Expanding the use of these direct dispense systems can help advance operational excellence initiatives and reduce costs within the biopharmaceutical industry’s supply chain. By adopting flexible manufacturing technology, such as the direct dispense systems, biopharmaceutical manufacturers may be able to reduce their operating costs in certain areas by up to 40%. There are multiple savings associated with the use of these systems:

• Labor: Eliminates the time and cost of personnel who need to weigh, subdivide, and dispense materials from bulk containers. The savings can be significant. Depending on the process, each 1000 L run of a cell-culture reactor may require approximately 1000 to 2000 kg of more than 50 raw materials for the production process. The media/buffer preparation activities could require 30-50 labor hours for dispensing and adding the materials to the reactors.

• Facilities: Use of direct dispense systems can eliminate the need for dedicated raw material preparation areas, drum storage and handling equipment, and environmental (temperature and humidity) control equipment. In some cases, these systems can reduce floor space needs by 40-70%.

• Testing/validating: Use of Raman testing and tailgate samples greatly simplifies the testing/validating step. Products do not have to be re-validated each time material is sub-divided from a bulk container. In addition, the primary packaging material typically used for these bags is the same as standard drum liners, so contact material does not have to be re-validated.

• Quality: Pre-weighed direct dispense systems eliminate the need to clean the weighing and dispensing area for another operation, saving time and eliminating risk of cross-contamination and employee exposure.

• Material stability and efficient use: Anti-clumping packaging design improves raw material yields by avoiding material non-conformities and inaccurate ingredient measurements from clumped materials.

• Safety: Anti-clumping packaging leads to sound 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 large drums.

• Raw materials savings: Pre-weighed amounts in direct dispense bags that match specific biopharmaceutical process requirements eliminate the need to buy and store material in bulk, reducing overages, out-of-date materials, and disposal costs.

Advances in bulk material packaging focus on improving overall OpEx
By evolving raw material packaging and delivery options to align more closely with the operational requirements of biopharmaceutical producers, raw materials suppliers are helping to eliminate inefficiencies and drive down costs within the overall supply chain and production environment. The success of these bag-based, pre-weighed, free-flowing direct dispense systems is also encouraging the development of streamlined systems for other types of materials beyond bulk powders. Some raw-materials suppliers are investigating new packaging methods to deliver ready-made liquid solutions to customers, which would eliminate the biopharmaceutical manufacturing step of taking solid materials and creating solutions. While the transportation and storage considerations for liquid solutions are more complex than solids, there are opportunities to apply innovations to raw-materials packaging designs to improve the efficiency, productivity, safety, and quality of biopharmaceutical manufacturing.

Article DetailsBioPharm International
Vol. 29, No. 7
Pages: 40–43

Citation:
When referring to this article, please cite it as N. Deorkar, "Raw Materials Packaging Innovations for Biopharmaceutical Manufacturing," BioPharm International 29 (7) 2016.