Biocatalysis for Efficient Ultrasonic Manufacturing Rheometer Possible PAT Candidate SM Pharma Chemicals (DPC, Sit- and biotransformations at DPC. As an tard, the Netherlands) and Diversa example, Wubbolts explains how An innovative viscosity measurement DCorporation (San Diego, CA) have enzymes can be used to selectively mod- technology developed at Pacific North- signed an agreement for the discovery ify a macrolide, a complex antibiotic west National Laboratory (PNNL, Rich- and development of biocatalysts, with that may contain various similar func- land, WA) could potentially help the aim of simplifying and lowering the tional groups. “If you want to modify advance the pharmaceutical industry’s cost of chemical transformations. Under one specific alcohol functionality PAT-driven push toward real-time the agreement, DPC, a division of DSM among five others to get a new product, process monitoring and control systems. Pharmaceutical Products, will identify you can do that with an appropriate the targeted chemical conversions and enzyme, because of its selectivity. With Diversa will develop the appropriate bio- organic chemistry, you would have to catalysts. DSM will then scale up the re-synthesize the whole molecule.” process to manufacture pharmaceutical Enzymes can have three types of selec- intermediates and active ingredients. tivity—chemoselectivity, regioselectivity, Biocatalysis, in which enzymes are and stereoselectivity. Chemoselectivity used to drive chemical reactions, can be means that enzymes, unlike some chemi- used in pharmaceutical manufacturing cal catalysts, are capable of distinguishing as an alternative to standard organic between chemical structures such as an chemistry. The key advantage of biocat- amino group and hydroxyl group. Regio- PNNL’s prototype ultrasonic rheometer. alysts is that their use can often simplify selectivity, seen in the macrolide exam- the synthesis of complex molecules, ple, means that enzymes can distinguish The “ultrasonic rheometer” combines reducing the number of steps required between identical groups in different ultrasonic and pressure-sensor data and the related costs, particularly when locations. For example, if a ring structure using sophisticated signal processing chiral molecules are involved. The selec- contains two hydroxyl groups, an enzyme algorithms to determine the viscosity of tivity of enzymes in particular can make can selectively modify one of them, based material flowing in a pipeline in real certain chemical conversions more com- on its position, whereas a chemical cata- time. Since viscosity is often a quality- mercially attractive. lyst would modify both, because they are control parameter in blending opera- “The selectivity of enzymes is phe- chemically equivalent. The third type of tions, the ability to collect measurement nomenal,”says Marcel Wubbolts, PhD, selectivity is stereoselectivity, which data without interrupting production competence manager for biocatalysis BIOCATALYSIS continued on page 20 processes for off-line batch testing could provide pharmaceutical producers sig- nificant cost and time savings. As noted by David Pfund, PNNL senior research engineer, the need for off-line viscosity measurements to either confirm specifications or ensure quality control inevitably increases production schedules as well as the amount of stor- age capacity required. “And, if it turns out that the product is off-specification, it will have to either be re-blended or scrapped, increasing waste.” PNNL first began work on the tech- nology in the late 90s with funding from the Department of Energy, which was Figure 1: DPC uses an R-hydroxynitrile lyase (R-HNL) to produce an R-mandelic acid derivative for a pharmaceutical intermediate. RHEOMETER continued on page 22 Pharmaceutical Technology MARCH 2004 17 In the Field NIR Spectroscopy Bioerodable Eye Brings PAT into Focus Implant May Help When FDA set forth its process analyti- Treat Macular Edema cal technologies (PAT) initiative, there was little doubt that it would foster new A bioerodable sustained-release eye collaborations among the agency, the implant shows promise as an effective pharmaceutical industry, and equip- method for treating eye diseases such as ment manufacturers. And, the industry’s macular edema (swelling of the retina first innovations specifically targeted at that causes decreased vision). Data from meeting PAT objectives are indeed now a six-month Phase II clinical trials study making their debut on the marketplace. revealed that patients with macular Especially notable are those incorporat- edema experienced a significant increase ing near infrared (NIR) spectroscopy. in vision after being surgically implanted Already a familiar laboratory tech- Figure 1: L.B. Bohle’s integrated NIR system with the investigational technology. nique for raw material identification for real-time monitoring of blend homogeneity. and quantitative assessment, NIR tech- nology is expected to move on to the venting “pockets” where raw material next logical step of being implemented may be trapped; a flush interior that on the manufacturing process line. won’t restrict powder flow; and, most For example, late last year, L.B. Bohle important, the ability to maintain con- (Bristol, PA)unveiled its integrated NIR ditions inside the blender that will allow system for monitoring blend homogene- stable readings with the NIR probe. ity in real time (Figure 1). Designed for Although operating and maintaining laboratory- and full-scale production, the the “correct” conditions is essential for instrument combines the company’s project management, understanding the The Posurdex eye implant is bioerodable and blending technology with NIR spec- process is equally, if not more, important. provides sustained drug release. troscopy and 21 CFR Part 11–compliant Says Sievert, “We have customers ask us software. Data are obtained by shooting How do you scale up? How do you scale NIR light through a window mounted on down? With what speed should we The "Posurdex" implant from Aller- the bin blender and results are sent to an blend? If we transfer from a V-blender to gan, Inc. (Irvine, CA), delivers dexam- on-line or remote-access computer. a bin blender, how fast do we have to ethasone (a corticosteroid) in small Because sampling doesn’t involve rotate the bin? How about filling levels? amounts over an extended period of physically opening the bin, the material But what’s really important here is not time, which allows the drug to reduce is always in containment, which is espe- establishing these individual parameters, the swelling of the retina while curtail- cially beneficial to manufacturers of but rather achieving blend homogeneity ing possible side effects. Recent data potent materials. Also, bringing the and then understanding how these indi- from other studies has provided evi- analysis on-line saves time because test vidual factors impact that homogeneity.” dence that corticosteroids can be useful results are immediate. As Reinhard Siev- Establishing such correlations among for treating several retinal diseases, ert, general manager at L.B. Bohle ob- manufacturing processes and how they specifically macular edema. However, serves, “It’s much faster than the tradi- affect product quality is a goal of the the main side effects of steroid use in tional method of taking a sample out of PAT initiative. As observed by Robbe the eye are glaucoma (increased pres- the blender, going to the lab, and analyz- Lyon, deputy director of FDA’s Division sure in the eye) or cataracts. ing the result to find out, only then, if of Product Quality Research, PAT According to Scott Whitcup, MD, you have blend homogeneity.” “requires a level of scientific under- vice-president and head of the ophthal- Integrating an analytical system with standing of how formulation and man- mology therapeutic area at Allergan, the a complex manufacturing process was ufacturing process factors affect product sustained-release aspect of Posurdex was not an easy task. “You can’t just take quality and performance.” one of the main factors of its success in NIR technology, install it onto a blend- Although PAT can essentially incor- the Phase II clinical trials. "The thought ing system, and expect it to work,”says porate several technologies, NIR is prov- is that if a patient receives smaller Sievert. “It’s a combination of the hard- ing to be a preferred method among amounts of steroid over time, as ware, the optics, the electronics, and the analysts. In part, this is because during opposed to big boluses of steroids, then software with the blending system that the past 10–15 years, the implementa- maybe you can minimize the complica- makes it perform well.”Sievert notes at tion of infrared cameras, array detec- tions but maximize the treatment least three major attributes that had to tors, digitally tunable infrared optical effects," he says. be incorporated into the design: pre- NIR continued on page 224 IMPLANT continued on page 223 18 Pharmaceutical Technology MARCH 2004 www.pharmtech.com In the Field BIOCATALYSIS continued from page 17 In many cases, the use of biocatalysts biocatalyst toolbox more quickly. means that enzymes can be used to pro- makes the process more cost effective. In “What DPC is looking for from us are duce different stereoisomers of chiral one application, DPC uses an R-hydroxy- unique activities where the known molecules. nitrile lyase (R-HNL) to produce an R- enzymes just don’t perform well,”says “Enzymes are really one of the