Retention parameters determined by each method correlated well with shake-flask log P values. Combining the data from both techniques provides a better predictive model than does either method alone. Camilleri and co-workers demon­strated the method by analyzing 106 struc­turally diverse compounds (acids, bases, and neutrals) with a wide range of log P values (-0.52 to 7.63). Indeed, the system is so efficient that, rather than serving solely to characterize potential new drugs, the authors anticipate that it may also con­tribute to the design and selection of candi­date drug substances.

Shake-flask technology still has its place in drug registration, where accurate values are required, but even here "it may eventu­ally be superseded," says Camilleri.

What's next? Efforts to modify the hy­drophobic phase to even more closely mimic biomembranes are ongoing. Camil­leri believes the next major advance will involve the incorporation of liposomes, con­taining varying amounts of different natu­rally occurring membrane lipids. Other potential uses can be envisaged in the field of agrochemicals and the screening of envi­ronmental pollutants.

Raewyn Town

NEWS FROM THE ACS NATIONAL MEETING

Britt Erickson reports from Dallas.

Improved control methods lead to faster drug approval "Therapeutic monoclonal antibodies initially got off to a slow start," says Robert Garnick, vice president of regulatory affairs for Ge-nentech, "due to production, control, and immunogenicity problems." However, tilings have changed, and, according to Garnick, it is thought that approximately 80% of the new biologies waiting to be approved by the FDA are monoclonal antibodies.

Part of the problem is that high doses (0.5-4 g) of monoclonal antibodies are of­ten required to achieve the desired thera­peutic effect for cancer treatment. Those high-dose requirements put a tremendous strain on drug manufacturers who typically have to produce 50-200 kg of drug per year to meet these needs. More importantly, because such large amounts of the drugs are required, they must be of the highest purity. Historically, analytical methods for the characterization of therapeutic mono­clonal antibodies have focused on purity and impurity determinations, but that is all changing, says Garnick. Today quality con­trol efforts are focusing on biological activ­ity and its relationship to carbohydrate dis­tribution As a result of improved charac­terization and control methods the FDA approval of monoclonal antibodies has been greatly facilitated and accelerated

For example, the rapid FDA approval of the drug Rituximab, sold under the trade­mark Rituxan, is a prime example of how attitudes at FDA are changing, says Gar­nick. Based on a 166-patient open-labeled

phase-Ill clinical trial, which showed re­sponse rates equivalent to chemotherapy but without the severe side effects, FDA approved Rituxan for the treatment of non-Hodgkin's lymphoma in less than six months. A lot can be learned by looking at the analytical methods that were used to characterize Rituxan, says Garnick.

Rituxan, which is a "humanized" chi­meric monoclonal antibody, is an excellent example of a molecule that could be con­sidered well-characterized. Multiple struc­tural methods were used to confirm the identity of the compound, including Edman sequencing and peptide mapping by MS. The secondary structure was investigated using circular dichroism. The purity of the compound was determined based on charge heterogeneity (ion-exchange CE with isoelectric focusing), size-exclusion chromatography, and sodium dodecyl sul­fate polyacrylamide gel electrophoresis. Potency testing was performed using a highly biomimetic bioassay that mimics the function of the drug in humans.

Unexpectedly, the molecule was found to contain three forms of biantennary oligo­saccharides, which all differed in their bio­logical activity. Glycosylation adds tremen­dous complexity to a molecule, says Gar­nick. The three forms could be separated by CE, and the bioactivity of the molecule was found to be a function of galactose con­tent. Garnick believes that CE is an invalu­able tool for routine quality control of bio­technology products. The recent advances in CE and MS have significantly improved the control and characterization of thera­peutic monoclonal antibodies, he says.

GOVERNMENT AND SOCIETY

NACLA launches membership drive An open workshop was held on April 16 at NIST to discuss the status of the National Cooperation for Laboratory Accreditation (NACLA), a program aimed at reducing the number of accreditations for testing and calibration laboratories in the United States (Anal. Chem. 1197,69,161 A). Or­ganizers of NACLA believe that if all ac­creditors are recognized by the same pro­cedure, then accreditors and their accred­ited laboratories will all meet the same minimum level of performance. Since its establishment in May 1997, NACLA's in­terim board of directors has been develop­ing procedures and criteria for accredita­tion and reciprocal recognition. Their ongo­ing efforts have resulted in the approval of NACLA documents the bylaws, recogni­tion document, and quality manuall A mem­bership drive is now underway to solicit interest in NACIA, with expectations that it will be operational by September 1998

Laboratory accreditation in the United States has evolved into a complicated mix­ture of more than 150 different programs. With so many programs, it becomes a time-consuming, costly, and at times confusing task for laboratories to become recognized as competent, say NACLA organizers. Moreover, there is no guarantee that a lab­oratory will also be recognized internation­ally. According to Belinda Collins, director of NIST's Office of Standards Services and chair of NACLA's interim board accredita­tion typically costs a laboratory operating in the United States from $10 000 to $50,000 per year.

NACLA organizers say that they do not intend to become another accredita­tion body but rather a coordinating body. As a cooperative partnership between the private and public sectors, NACLA could lead to fewer accreditors and more world­wide acceptance of credible data. As the program devel­ops, it is expected to broaden its mem­bership to include accreditation bodies in Mexico and Can­ada the NA in NACLA will eventu­ally stand for North

Belinda Collins solicits interest in NACLA

Analytical Chemistry News & Features, June 1, 1998 373 A