The market for generic drugs is growing rapidly and the prospect for continued expansion remains high as more blockbuster drugs like Lipitor, Viagra, and Plavix come off patent in the next few years. Recently there has been substantial activity among generic drug manufacturers and major pharmaceutical companies seeking to enhance or establish their positions in this growing business. Data from IMS Health, Norwalk, Conn., a clearinghouse for drug sales information, indicates that $24 billion worth of branded drugs will have generic alternatives this year. This figure is up significantly from $18 billion only a year ago and is predicted to reach $30 billion by 2012.1 As the generic drug market grows, manufacturers will naturally face more fierce competition. While this is good for consumers, the challenges to manufacturing and QA/QC laboratories are significant.
Substantial costs are associated with laboratory QA/QC testing of generic drug products in the form of qualified employees, lab equipment, lab space, and chemicals. Lab managers in these environments are now seeking ways to reduce costs and improve productivity to help their organizations maintain or create a competitive advantage.
An important area in the QA/QC stages is drug impurity testing. Because many drug stability and impurity assays employ high-pressure liquid chromatography (HPLC), there is more interest than ever before in newer, more efficient HPLC/UHPLC column technologies and equipment. Five years ago, HPLC columns employing sub-2 µm chromatographic particles were introduced that offered substantial productivity improvements over existing 3 µm and 5 µm particles. There was much discussion and debate over the practical utility and cost of implementing the sub-2 µm technology in a routine QA/QC testing environment because it required the purchase of specialized high-pressure-capable HPLC instrumentation, retraining, and the development and validation of new analytical methods. Additional challenges are encountered when methods developed on sub-2 µm columns with specialized instrumentation are transferred to conventional LC systems. This poses a particular problem for multinational manufacturers with a large number of conventional LC instruments. These factors coupled with tight capital budgets have significantly slowed the widespread adoption of sub-2 µm particle technology despite its potential advantages.
|Method Parameter||Acceptable Modification||Monograph 0703 Atenolol||Kinetex 2.6 µm Fast Method||Modification|
|Mobile phase pH||±0.2 units||3||No change||—|
|Concentration of salts in buffer||±10%||As specified||No change||—|
|Ratio of components in mobile phase||±30% of the minor component(s), or 2% absolute of that component, whichever is greater, but a change in any component can not exceed ±10% absolute||As specified||No change||—|
|Wavelength of UV detector||no deviations permitted||226 nm||No change||—|
|Injection volume||Increased to as much as twice the volume specified, provided no adverse effects—must be within stated linearity range of the method||10 µL||No change||—|
|Column temperature||±10°||Ambient||No change||—|
|Column length||±70%||125 mm||100 mm||-20%|
|Column inner diameter||±25%||4.0 mm||4.6 mm||+15%|
|Particle size||-50%||5 µm||2.6 µm||-48%|
|Flow rate||±50%||0.6 mL/min||0.9 mL/min||+50%|
Table 1: Acceptable modifications for meeting system suitability (Source: European Pharmacopoeia guidelines)
Most sub-2 µm LC columns in use today are based on fully porous silica particle technology. Recently, an alternative LC particle technology—based on core-shell silica—has shown promise as an alternative solution for improved performance. Phenomenex, Inc. (Torrance, Calif.) offers a core-shell particle technology that delivers performance comparable to fully porous sub-2 µm particles but at significantly lower operating pressures. This allows them to be used on existing conventional LC instrumentation.
The Phenomenex Kinetex 2.6 µm core-shell particles are comprised of a nearly monodispersed 1.9 µm solid silica core and a 0.35 µm porous silica shell. This particle design results in a stable and homogeneous packed column bed that significantly reduces peak dispersion due to eddy diffusion. Additionally, the short diffusion path of the 0.35 µm porous silica shell allows faster kinetics of diffusion, minimizing peak dispersion due to resistance to mass transfer. Figure 1 shows the Kinetex 2.6 µm core-shell particles.
|Fully porous 5 µm||Kinetex 2.6 µm C18 0.9 mL/min||Kinetex 2.6 µm C18 1.3 mL/min|
|Column dimensions||125 × 4.0 mm||100 × 4.6 mm||100 × 4.6 mm|
|Particle size||5 µm fully porous||2.6 µm core shell||2.6 µm core shell|
|Flow rate||0.6 mL/min||0.9 mL/min||1.3 mL/min|
|Backpressure||168 bar||270 bar||380 bar|
|Resolution of impurities J & I||1.95||3.72||3.65|
|S/N ratio for Impurity J||40||78.1||78.7|
|S/N ratio for Impurity I||12.3||30.2||28.7|
|S/N ratio for Impurity G||3.31||9.38||9.33|
|N of Impurity J||8,206||21,118||19,473|
|Elution time of last peak||33.3 min||11.9 min||8.0 min|
Table 2: Improvements to EP Monograph 0703 for Atenolol and related substances using core-shell particle technology results in a three- to four-fold reduction in analysis time and organic solvent usage. (Source: Phenomenex)
Generic drug QA/QC labs performing routine HPLC assays with traditional 3 µm or 5 µm fully porous LC columns can significantly reduce operating costs by taking advantage of the increased analysis speed and reduced solvent consumption that core-shell technology provides. These costs savings can be achieved without replacing existing HPLC instrumentation and with minimal changes to validated methods by employing shorter length columns and/or higher mobile phase flow rates when using core-shell columns.
To demonstrate the performance of this core-shell technology in a generic drug QA/QC laboratory environment, a Phenomenex Kinetex 2.6 µm core-shell C18 column was compared with a traditional fully porous 5 µm C18 column referenced in European Pharmacopoeia (EP) Monograph 0703 for the determination of Atenolol and related substances on a conventional HPLC system (Agilent 1100 LC System, Agilent Technologies Inc., Palo Alto, Calif.).2
Table 1 summarizes the various parameters of a chromatographic test that may be adjusted to satisfy system suitability (when replacing one column with another of the same type, for example) according to European Pharmacopoeia guidelines. Within these guidelines for allowable changes, the Kinetex 2.6 µm core-shell C18 column was used according to the conditions specified in the monograph.
Using the core-shell column, the flow rate was increased by 50 percent and the column length was reduced by 20 percent. This adjustment to the method was performed on a conventional HPLC and resulted in the reduction of total analysis time from more than 33 minutes to just under 12 minutes—nearly a three-fold increase in productivity (Figure 2).
To determine the capability of the Kinetex core-shell particle technology outside of the allowable changes, the flow rate of the EP 0703 method was further increased and the analysis time was further reduced to eight minutes—a four-fold increase in productivity—on the same conventional HPLC instrument (Table 2, page 26).
In addition to achieving faster analysis times, the new core-shell technology provides generally improved chromatographic performance. As noted in Table 2, Kinetex core-shell columns outperformed the traditional technology in important chromatographic parameters such as resolution (the degree of separation between sample analytes) and sensitivity (for easier detection and quantification of low-level sample analytes such as impurities or degradants). This translates to better quality data and more reproducible results in routine QA/QC operation.
Drug developers also can reduce organic solvent usage. Solvents are not only expensive to purchase, but also to dispose of after use. Many companies have implemented green chemistry initiatives that call for a general reduction of chemical use and waste. An HPLC impurity assay completed four times faster reduces organic solvent consumption by 75 percent.
As the generic drug market grows and becomes more competitive, manufacturers must cut costs and time while maintaining or improving quality. Ideally the best solutions will be fast and easy to implement, require little or no capital expenditure, have a low cost of ownership, and a big impact on the bottom line. Migrating a lab from an existing HPLC system platform to a new one can cost millions and take months or years to integrate in to an organization. Replacing traditional HPLC columns in validated methods with advanced core-shell column technology is perhaps the least expensive and quickest path to lower operating costs and significant productivity gains a generic drug manufacturer can take.
About the Authors
Elli Abbasi is an Application Chemist in the Phenomenex Applied Technology Group. Her work focuses on developing new HPLC and SPE methods using Phenomenex separation technology. Jeff Layne is a Senior Manager in same group, providing support for current Phenomenex products and developing new technologies. He holds a Ph.D. in pharmacology from the University of Vermont. Heiko Behr is Technical Manager for Phenomenex in Europe, working with customers to implement HPLC technology. He holds a Ph.D. from the Technical University of Munich. Sky Countryman is a Product Manager and heads up the Applied Technology Group. In addition to giving talks worldwide and authoring many technical papers, he is currently under contract with the US Pharmacopeia to help educate labs on USP changes. Jason Campbell is Senior Marketing Manager at Phenomenex. He is involved with product development and quality management and applied technology services.
1. Feldman C. CNN.com. Generic Drug Superstars. Posted August 5, 2009. Accessed on September 9, 2009. Available at https://money.cnn.com/2009/08/05/news/companies/top_generic_drugs.fortune/.
2. Abbasi E, Layne J, Behr H, Countryman S. Increased Sensitivity, Improved Resolution and Faster Analysis Times for Compendial Methods. 8th Balaton Symposium on High-Performance Separation Methods, Technical Program, Poster MP1, September 4, 2009.
This article was published in Drug Discovery & Development magazine: Vol. 12, No. 9, October, 2009, pp. 24-26.
Filed Under: Drug Discovery