Saturday, October 24, 2009

Cost-Effective Tools for Acetonitrile Shortage

Situation is an opportunity for optimization and innovation


With no end in sight to the worldwide shortage of acetonitrile, the popular high-performance liquid chromatography (HPLC) solvent, laboratories are in search of cost-effective solutions to manage the impact on their research and business time line. The emerging innovations represent yet another example of how “greener” and more cost-effective laboratory practices are advancing the field of analytical chemistry, especially in HPLC analysis.

The pharmaceutical industry consumes approximately 70% of the world’s acetonitrile supply, using the solvent in a range of applications in both manufacturing and analytical settings. Acetonitrile is commonly used in gas chromatography (GC) analysis, ultraviolet (UV) analysis, thin-layer chromatography (TLC), and HPLC applications, as well as other wet chemistry test methods in the laboratory. Acetonitrile is the chosen solvent for today’s HPLC analyses, largely due to its miscibility with water and most organic solvents as well as its low toxicity, viscosity, and chemical reactivity. Acetonitrile is also used in the synthesis and manufacturing of drug substances and products.

The Great Acetonitrile Shortage, as it has come to be known by suppliers, arose due to a series of events that occurred in 2008. First, Chinese production of acetonitrile dropped significantly as the country prepared to host the 2008 Summer Olympics in Beijing. Chinese factories in the vicinity, including China’s largest acetonitrile producer, were shut down to minimize air pollution. After the Olympics, newly implemented import bans significantly limited acetonitrile export from China. At the same time, active hurricanes in the Gulf of Mexico interrupted acetonitrile manufacturing in Texas. Possibly the most substantial and long-lasting impact on the acetonitrile supply was triggered by the worldwide economic slowdown that started in 2008.

Acetonitrile is a by-product of the synthesis of acrylonitrile. In this process, manufacturers use acrylic fibers and acrylonitrile-butadiene-styrene resins to produce plastics for automobiles, carpeting, luggage, telephones, computer housings, and other products. Due to the economic downturn, consumer purchasing and manufacturing production of these items has slowed. This shrinking demand prompted the world’s acrylonitrile producers to slow production; now, fewer resources are being invested in collecting and purifying acetonitrile to the high purity grades the pharmaceutical industry requires.

Impact in the Lab

Consequently, the prices for high quality and HPLC-grade acetonitrile skyrocketed in 2009, with acetonitrile prices increasing from $30/liter to $100/liter between July and September. As the major acetonitrile producers ration their supplies, they have started advising customers to develop alternative methods in order to eliminate or reduce acetonitrile use. Although the long-term forecast of cost and availability is still uncertain, the general feeling is that acetonitrile prices will continue to rise. Many labs will find it difficult to acquire needed quantities in a cost-effective way.

Because the pharmaceutical industry relies on acetonitrile for a wide range of applications, including many that must be conducted under current good manufacturing practices (cGMP), the scarcity of this single industrial chemical has the potential to delay progress. From a drug development standpoint, the shortage can affect the timeline for application approvals and delay market launches. For agency-approved products, it will become the norm for companies to manufacture fewer batches to reduce the amount of testing.

The U.S. Food and Drug Administration (FDA) has received numerous inquiries related to the acetonitrile shortage, primarily with regard to the solutions that companies may apply to already validated methods requiring acetonitrile. FDA response has been cautious: “Regardless of the changes a firm makes to address the shortage, appropriate method validation and compliance with relevant current good manufacturing practices (CGMPs) are necessary.”1

Changes made to existing validated test methods within an approved application—New Drug Application (NDA) or Abbreviated New Drug Application (ANDA)—to accommodate the use of less acetonitrile or an alternative solvent may be as simple as a minor change in the annual report for the given drug application, as long as the change meets the criteria stated in the FDA Guidance for Industry: Changes to an Approved NDA or ANDA and in the Code of Federal Register title 21 CFR 314.70(d)(2)(vii). The guidance and CFR allow “A change in an analytical procedure used for testing … that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical procedure described in the approved application…” If the same or increased is not achieved, prior approval supplement will be required.1

As the acetonitrile shortage continues, the pharmaceutical industry is motivated to locate both short- and long-term solutions that will minimize reliance on acetonitrile.

Recommended Solutions

The prices for high quality and HPLC-grade acetonitrile skyrocketed in 2009, with acetonitrile prices increasing from $30/liter to $100/liter between July and September. As the major acetonitrile producers ration their supplies, they have started advising customers to develop alternative methods in order to eliminate or reduce acetonitrile use.

One possible solution is outsourcing. Companies using acetonitrile with cGMP-validated HPLC methods that have already been submitted in application have two options. These companies can continue to pay the current high—and escalating—prices to secure a continued acetonitrile supply, or they can modify their methods to eliminate or reduce their acetonitrile use based on a risk-benefit analysis.

In the latter instance, companies without extensive understanding of the regulatory guidelines and HPLC technology may strategically opt to partner with an analytically focused contract laboratory facility that is versed in up-to-the-minute regulatory guidelines and HPLC method optimizations. By outsourcing to a contract laboratory, cGMP HPLC projects can minimize the delays that many small and large pharmaceutical companies are experiencing because of the shortage.

For companies committed to finding a long-term, cost-effective solution that minimizes their use of acetonitrile as an HPLC solvent, a contract laboratory can explore replacing acetonitrile with a more widely available solvent or identifying a method optimization to reduce overall solvent consumption significantly.

Another potential solution is solvent replacement, but three fundamental factors must be considered: the chemical properties of the solvent, the physical properties of the solvent, and the effects these properties have on the chromatographic process (e.g., separation, detection limits, and analytical reproducibility). Unfortunately, acetonitrile has no equivalent substitute in the reverse-phase (RP) HPLC ultraviolet (UV) application, where it is employed the most. The superior UV absorbance characteristics and solubilizing properties of acetonitrile are unmatched.

Depending upon the chromatography type and the detection wavelengths used, it may be possible to replace acetonitrile with methanol or with a longer chain alcohol; however, because of methanol’s significant absorbance, up to 215 nm, its substitution for acetonitrile is restricted either to working at > 235 nm or limiting the methanol level in the mobile phase to less than 15% at = 215 nm. Tetrahydrofuran (THF) is also a viable substitute, although drawbacks associated with unpreserved or UV-grade THF make it significantly less suitable than methanol.

Solvent Reduction

Because solvent replacement can substantially affect method performance and specificity/robustness, it is not technically feasible in many situations. It is often less complicated to optimize a method that will lower solvent consumption. Reduced consumption patterns are further supported by many pharmaceutical companies’ commitments to greener strategies in an effort to minimize pollution and waste. There are three approaches to reducing acetonitrile use: simple changes to what occurs pre- and post-separation, method changes that reduce the overall amount of the mobile phase required, and a reduction of the percent of acetonitrile required for effective separation.

First, an analysis of what occurs pre- and post-separation can lead to significant reductions in acetonitrile use. For RP column equilibration, for example, most modern columns can be equilibrated using only 10 column volumes. Methods should also be evaluated to minimize run times after final peak elution, possibly using more needle wash capabilities prior to the next injection. Finally, for optimal solvent conservation, solvent recycling technologies that collect acetonitrile are an option as long as the components of the mobile phase remain separate.

Method changes that can reduce acetonitrile usage can be grouped into those that may and those that may not affect specificity/robustness. One of the most common changes that reduces the amount of mobile phase appreciably without significantly affecting specificity/robustness is to reduce the column’s internal diameter (ID). For example, a 2.1 mm ID column consumes nearly five-fold less mobile phase than the more commonly used 4.6 mm column; this represents an 80% reduction in acetonitrile usage.

This approach, however, requires instrument parameter adjustments in the method (i.e., flow rate) as well as to the analytical system (i.e., smaller diameter tubing, connectors, and microflow detector cells) to achieve the separation and pressure criteria required by the method. When gradient programs are required, the dwell volume should also be scaled down using smaller-volume mixing chambers.

Alternate HPLC Applications

Although lowering the column ID is the easiest approach, it does present limitations. An alternative is ultra HPLC (UHPLC). UHPLC involves smaller particle sizes and smaller columns. The UHPLC approach minimizes solvent usage while optimizing peak separation ability. Combining UHPLC with new column technologies means that HPLC separations are far more efficient. Separations that were not possible in the past are now achievable—with less solvent use.

In addition to UHPLC, technological advances in HPLC packing materials, such as fused-core particle technologies, have been specially developed for hyper fast chromatographic separations and universal detection. While UV detection is the most widely used HPLC application, it has significant limitations because molecular structure dictates the absorbance of UV light. By using universal detector technologies such as evaporative light scattering detectors and chemiluminescent nitrogen detectors, scientists can measure the electrical charge associated with analyte particles. The charge is in direct proportion to the amount of the analyte in the sample and remains consistent regardless of the compound. The result is that universal detection can “see” any non-volatile analyte, including those without chromophores, thus reducing dependence on highly polarized solvents like acetonitrile and offering a wider range of usable solvents.

The pharmaceutical industry is under pressure to find cost-effective solutions for the acetonitrile shortage. Aligning with a reputable and knowledgeable contract laboratory can enhance your ability to select the best strategy to meet their unique product goals and testing timeline. With appropriate guidance, a successful acetonitrile reduction or replacement program can become a competitive advantage. Moreover, reducing acetonitrile use is consistent with a broader move towards green industry practices by significantly reducing waste and inefficiency. In short, the global acetonitrile challenge is an opportunity for optimization and innovation.

1 comment:

Steve W said...

The Great Acetonitrile Shortage is over!
INEOS, the Worlds largest manufacturers of acetonitrile have announced new technology that allows greatly increased production of acetonitrile. The new process is currently being operated at their plants in the US and Europe. Supply has stabilised, and is guaranteed for the future. Good news indeed.