Liquid or Powdered Media?

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For decades, innovations in research and production techniques have been driving forces in the biopharmaceutical industry. But market conditions fueled by the economic downturn over the past five years have increased regulatory burdens in the United States and Europe. Rising costs and risks associated with new drug development now require that biopharmaceutical companies manufacture their products more quickly and cost-effectively than ever before. To this end, companies are looking for new ways to reduce expenditures, increase profitability, speed research, enhance their portfolios of pipeline products, reduce pharmaceutical product development timelines, and move products from laboratory to market in record time.

Trends from mega-mergers to a tendency among regulators and payers to deny or only cautiously accept me-too products — have resulted in a shift toward higher-value and higher-risk products. Pressured by regulators and payers, biopharmaceutical companies are now increasingly looking toward unmet needs and considering development of more novel drugs and drug candidates. That approach has led to higher overall costs for the industry and increased risks of failure.

In 2012, consultants experienced in biopharmaceutical benchmarking in research and development (R&D) at the KMR Group (Chicago, IL) published a report showing that the success rates of drug candidates in pharmaceutical drug pipelines is rapidly declining (1). Another study shows that the number of new drugs approved per billion US dollars spent on R&D has roughly halved every nine years since 1950, falling around 80-fold in inflation-adjusted terms (2).

Efficiency, Risk, and Cost

In most industries, the discussion to pursue or terminate a specific R&D project is based solely on economics and/or financial considerations. The pharmaceutical industry, however, generally makes such decisions on the basis of science, especially (lack of) efficacy or safety. But such characteristics might become apparent only in late-stage clinical trials, increasing the potential financial and economic risks.

Steadily increasing demands requiring flexibility, responsiveness, increased efficiency, consistency, and the elimination of risk and economic pressure are key reasons for pharmaceutical executives and their development teams to search for innovative ways to better control their supply chains.

Successful biopharmaceutical development and manufacturing strategies depend on a number of key factors, including the selection of appropriate cell culture medium. So executives are intently looking at the total cost of ownership of each individual process to identify valid opportunities for cost savings. That involves evaluating bioproduction processes and process development strategies to determine which steps can reduce costs, eliminate risks, and increase efficiency and regulatory compliance of the entire process. In the development chain, the right choice of cell culture media, reagents, supplements, cell culture media formulations, endothelial cell culture, and cell culture techniques has become essential in lowering costs and improving productivity.

Changing Processes

Complicating that decision-making process, production of biologics and specialized therapeutics has changed dramatically. For large-scale production, process development engineers may prefer scalable dry-format or powdered media. But the demand for large manufacturing facilities with tens of thousands of liters of bioreactor capacity is losing ground. The emergence of personalized biotherapeutics — which require smaller production systems— has had a major impact on the industry.

To accommodate various needs, liquid culture media (raw materials essential to the bioproduction process) have become more important over the past decade. Coupled with the advantages of flexible single-use systems — which allow for use of smaller equipment at commercial scale — high product titers, and improved downstream purification methods, liquid media use can provide several benefits. Using liquids can reduce manufacturing costs and shorten production turnaround timelines while maintaining a consistent product throughout development and manufacturing.

Introduction of single-use systems has also increased the need for liquid media. Single-use systems such as storage bags and disposable bioreactors are validated for sterility, thereby removing the need for time-consuming cleaning and validation. Safe, sterile, and accurately formulated liquid media are formulated to be stable during transportation and storage. They are delivered in single-use bags that can be directly attached to a disposable bioreactor, which also helps reduce time, cost, and the risk of contamination during development and manufacturing.

From Powder to Liquid

An increasing number of biologics manufacturers, both upstream and downstream, are switching from ball-milled (see “Milling” in sidebox) premixed powders — which need to be reconstituted with water and quantitatively evaluated for their capacity to support proliferation of cell strains in the absence of serum, protein, or protein hydrolysates — to liquid media of the same formulations. By making that change, companies are preventing the need and liabilities associated with hydrating powder and filtering and testing a solution.

Historically, pharmaceutical companies transitioned from using liquid media to powder formats when moving beyond phase 2 or 3 clinical trials. Such a transition was generally part of an accelerated scale-up from laboratory- and pilot-scale processes toward a robust commercial biopharmaceutical production process. Successfully switching from liquid to powdered media typically required new process parameters and demanded reengineering an entire production process. Companies primarily switched from liquid culture media to powdered preparations because of perceived benefits. Additional costs associated with this transition were generally viewed as acceptable because of the potential costs savings elsewhere in development or manufacturing.

For example, if a water-for-injection (WFI) loop was available in a production facility, it allowed manufacturers to store and more easily reconstitute culture media as needed. Typically, bigger manufacturing facilities needing larger amounts of media found the logistics of powdered media easier to accommodate than those of liquid variants.

But trends specific to media show an identifiable shift over the past few years. Single-use technologies and improved process efficiencies allow companies to use smaller equipment in commercial biopharmaceutical processes. Subsequently, that decreases the actual amount of media needed — resulting in a tendency to continue using liquids throughout a clinical process and keeping certain solutions such as feeds, additives, and supplements in a liquid format through commercialization.

More About Powder Media

Milling: SAFC uses proprietary pin-milling technology. In comparison with other milling technology platforms, pin milling allows greater process control, including temperature, feed rates, and milling speed to pr
ovide powder media with increased consistency and performance.

Contamination: Powder that is not captured during the production process has the potential to cross-contaminate subsequent production cycles. This is one of the continuing problems for producers of powdered media.

Raw Materials: Most raw materials components in powdered media are hygroscopic, which means that they tend to become damp and “cake” when exposed to moist air. To avoid the undesirable effect clogging and weight gain during a production process, a relatively low humidity is required. Many traditional production facilities have limited ability to control humidity. As a result, the final product needs to be dried before it can be packaged. Heat associated with this drying process may result in a degradation and possible unwanted bacterial growth of the final product.

To improve their operations and reduce costs, some manufacturers with years of experience in reconstituting powdered media have switched or are considering a switch from using powdered formulations to liquid media as long as the integrity of their supply chains can be guaranteed. That requires working with a trusted, specialized vendor and experts who have a keen understanding of the entire development and biomanufacturing process.

Costs Benefits

The transition from liquid to powder media requires a solid analytical approach to determine all requirements involved in development and manufacturing. Liquid media may not always be the best choice. In many production processes, however, they may indeed be the best option. In such cases, the use of liquid media eliminates a number of process steps, reduces the potential for hazardous exposure, and makes development and manufacturing simpler and more flexible than they would be using powdered media.

Although the use of preformulated and premixed liquid media may be more expensive, the actual cost increase is generally limited to 3–5% of total biopharmaceutical production costs, and the overall benefits may surpass the expense. Optimally formulated liquid media may increase the efficiency of an entire production process. In addition, ready-to-use liquid media may eliminate the need for balances, mixing containers, and installation of a WFI loop needed for mixing powder media.

Pros and Cons

Proponents of dry-powder media use advocate that it saves precious energy that otherwise may be wasted by shipping large volumes of liquids. They argue that a powdered medium allows the flexibility to make as little or as much liquid as needed, claiming that storing powder media is simple because of its compact size. They explain that the longer shelf life offered can greatly improve efficiency of a company’s research effort. Although valid, such benefits can be negated if media are not precisely blended, are contaminated with inert materials or dust from previous production processes, or inadequately protected against atmospheric moisture (see “More About Powdered Media”).

The significant heat built up during production of powdered media with traditional ball-milling can potentially damage key media components. It also may adversely affect the quality of culture media, thereby reducing cellular growth and protein production capability.

Furthermore, heat introduced by the use of WFI (generally at 80 °C) in which powdered media is mixed and solubilized can potentially alter media components.

In-Line Dilution

In-line dilution (when process operators dilute a concentrated buffer premix for which the complex mixing of all components has already been completed) can affect the choice between powdered media and liquid formulations. The process has several applications in biopharmaceutical manufacturing, including purification, chromatography, solvent for pH adjustment, and cleaning. In-line dilution also can solve some capacity, financial, and quality concerns relating to process-solution preparation and delivery. Efficiency and consistency are especially important in large-scale commercial operations for which manufacturing 10,000-L batches of process solutions in large tanks is inherently difficult.

Producing small, 1-L solutions in a laboratory setting is relatively easy and precise and can be validated using analytical instruments that are calibrated at milligram sensitivity. But manufacturing 10,000-L solutions is more difficult and less precise, thus requiring specialized personnel. To achieve guaranteed consistency and highly accurate media for mixing large-scale solutions, companies must conduct ongoing mixing studies and process validation to ensure that the mixing process is reliable and repeatable.

Benefits of Outsourcing

Producing cultured media from powdered resources is labor intensive, so outsourcing preparation of liquid media has advantages. In addition to cost benefits, use of liquid media also increases the speed and ease for operators. However, media are complex mixtures of different components.

Many traditional fed-batch processes call for a base medium and a number of different supplement additions intended to provide extra nutrients and trace elements designed to enhance process efficiency and yield. One challenge of formulating multiple components in a bioreactor is that each step increases the risk of a breach in sterility. Compounding a number of additives may reduce the risks involved. However, that process requires development of a compounded solution such that its various components remain in a solubilized, liquid format. In turn, that requires a full understanding and experience in concentrate development. Outsourcing this formulation process — while relying on the expertise of a trusted partner to prepare and mix all components of a medium, feed, supplement or buffer — enables manufacturers to focus on their own core competencies and primary objectives.

Such outsourcing provides a number of additional benefits. Making a liquid media formulation from scratch or reconstituting a ready-to-use powdered formulation both require use of difficult-to-handle chemicals such as sodium hydroxide (lye or caustic soda) for cleaning applications. Ready-to-use liquid media eliminate the need to use such chemicals, thereby reducing health hazards and safety concerns for operators involved in development and manufacturing.

A Balanced Approach

Experts agree that liquid media offer many advantages. Even in large-scale manufacturing processes, companies can benefit from the overall increase of efficiency by using liquid media.

However, there will always be a place for dry-powder formulations. Finding the right, balanced approach is key. Experienced vendors who understand the specific needs in each process of development and manufacturing are instrumental in delivering the right solution. Although it may not be economically advantageous to use liquid media in very high volumes, smaller volumes may create a definite cost advantage.

Enhanced Supply Chain Integrity

Trusted vendors such as SAFC understand the regulatory requirements involved in biopharmaceutical development and production.

Experienced vendors with confirmed supply chains are familiar with the documentation needed. They understand the processes involved in continual monitoring, documenting, and updating data. Because culture media are complex mixtures involving many different ingredients, guaranteeing proper traceability requires a large amount of work.

Such services and ongoing efforts of culture media vendors in developing innovations in research and production techniques have indeed been driving forces in the biopharmaceutical industry. Those efforts help reduce total development and manufacturing costs while maintaining the industry’s ability to move products to market quickly.

About the Author

Author Details
Joanna Hudson is the EU business development manager, sterile liquids, at SAFC;


1.) Silverman, E. 2012.Are Drug Pipelines Really Getting Better? Pharmalot.

2.) Scannell, JW. 2012. Diagnosing the Decline in Pharmaceutical R&D Efficiency. Nat. Rev. Drug Discov. 11:191-200.