December 2006

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-12-02-2006, Volume 30, Issue 12

Proof of concept is a new development paradigm.


Poor OOS Review Leads Causes of FDA Citations

Philadelphia, PA (Oct. 24)—Failures to review batch failures and unexplained discrepancies are the leading causes of US Food and Drug Administration Form 483 observations and Warning Letter citations issued to pharmaceutical companies. Violations of the review requirement (21 CFR 211.192) accounted for 16.3% of 818 observations in the 2006 fiscal year, pushing the category into first place from eighth on last year's list.

Figure 1

Kristen D. Evans, a senior regulatory operations officer in the Office of Compliance at FDA's Center for Drug Evaluation and Research, offered a summary of the 2006 compliance statistics during his keynote address at the Institute of Validation Technology's Validation Week.

Warning Letters and GMP citations

In Evans's analysis of Warning Letters and GMP citations (see Table I and Figure 1), 21 CFR 211.192 failures were followed by 2005's leading citation: shortcomings in the performance of the quality-control unit (21 CFR 211.22[d]). Poor in-process sampling and testing (21 CFR 2110[a]) followed. These categories accounted for 44% of the citations analyzed.

Table I: Causes of Form 483 and Warning Letter citations based on 818 FY 2006 citations.

Failures to follow sampling procedures (21 CFR 211.100[a]), validate production procedures (21 CFR 211.100[b]), or establish proper laboratory controls (21 CFR 211.160[b]) followed on this year's list, each accounting for ~10% of citations.

Figure 2

Rounding out the top ten were lapses in testing and release (21 CFR 211.165[a]), batch- record review (21 CFR 211.188), personnel qualifications (21 CFR 211.25[a]), and equipment cleaning and maintenance (21 CFR 211.67[a])


Evans summarized the causes of 215 of the year's 361 product recalls (240 of prescription products and 121 of over-the-counter medications; see Table II and Figure 2). Subpotency was the most common reason (prompting 16% of recalls), followed by container defects, impurities and degradation products, and poor assurance of sterility (each of which caused about 12% of the recalls). Other causes included CGMP deviations, labeling errors, microbial contamination of nonsterile products, nonsterility, dissolution-test failure, and failure of stability data to support the stated expiration date.

Table II: Causes of recalls based on 215 FY 2006 recalls.

–Douglas McCormick


Pharma Majors and CMOs Build Capabilities Through Acquisitions

Abbott Labs, Eli Lilly, Genentech, Lonza, and AAIPharma were among the companies building through acquisitions. On the restructuring front, 3M divested its branded-pharmaceutical business to focus on drug delivery, and Bayer AG unveiled plans for integrating Schering AG into the newly formed Bayer Schering Pharma.

Abbott to buy Kos for $3.7 billion

Abbott Park, IL (Nov. 6)—Abbott Laboratories ( agreed to acquire specialty pharmaceutical company Kos Pharmaceuticals, Inc. (Cranbury, NJ, for $3.7 billion. The move expands Abbott's position in the lipid-management market. Kos Pharmaceuticals's two lead products are "Niaspan" (niacin extended-release tablets) and "Advicor" (niacin extended-release and lovastatin tablets). A new Niaspan caplet formulation with a range of dosages is under review by FDA. Kos also is in late-stage development for "Simcor," a fixed-dose combination of Niaspan and simvastatin.

Eli Lilly to acquire ICOS for $2.1 billion

Indianapolis, IN (Oct. 17)—Eli Lilly and Company ( agreed to acquire ICOS Corporation (Bothell, WA, for $2.1 billion. The deal is expected to close in late 2006 or early 2007. The companies have partnered since 1998 in Lilly ICOS LLC, a joint venture that manufactures, markets, and sells "Cialis" (tadalafil), an oral PDE-5 inhibitor.


Genentech to buy Tanox for $919 million

South San Francisco, CA (Nov. 9)—Genentech, Inc. (South San Francisco, CA, agreed to acquire Tanox, Inc. (Houston, for $919 million. Tanox is a biotechnology company specializing in the discovery and development of biotherapeutics based on monoclonal antibody technology.

3M sells branded-drug arm for $2.1 billion

St. Paul, MN (Nov. 9)—3M Co. ( will carve up and sell its global branded pharmaceuticals businesses for a total of $2.1 billion. Graceway Pharmaceuticals (Bristol, TN) will pay $875 million for operations in the US, Canada, and South America. Meda AB (Solna, Sweden, will buy 3M's European drug subsidiaries for $857 million, and private equity firms Ironbridge Capital (Sydney, Australia, and Archer Capital (Dawes Point, NSW, Australia, partnered to pay $349 million for 3M's Asia-Pacific pharmaceutical properties.

The agreements cover regional marketing and intellectual-property rights for 3M's current drug portfolio, which includes "Difflam," "Duromine," "Tambocor," "Maxair," "Metrogel-Vaginal," and "Minitran." 3M will retain its Drug Delivery Systems Division.

Bayer begins integration of Schering AG

Leverkusen, Germany (Nov. 9)—Bayer AG ( outlined its initial strategy for integrating Schering AG (Berlin, Germany) into the newly formed Bayer Schering Pharma. Bayer AG's board of management agreed on a "concept" for the future of some 70 Bayer Schering Pharma sites. Bayer will consolidate its R&D operations into three major sites in Berkeley, California and in Berlin and Wuppertal, Germany. Bayer HealthCare's research sites in West Haven, Connecticut, and that of Berlex, Inc., a US subsidiary of Schering AG based in Richmond, California, will be closed.

Bayer Pharma will relocate remaining departments and functions based in West Haven into headquarter locations in New Jersey. Wayne and Montville, New Jersey will be headquarters for the company's US pharmaceutical commercial operations, global oncology, and specialized therapeutics business units; US-based global drug development groups; and other business support functions. Bayer's Berkeley site will continue to house a biologics manufacturing facility for "Kogenate," and a site in the Puget Sound region of Washington will continue to make "Leukine."

Bayer expects that roughly 600 US positions will be eliminated, primarily in research, and expects to eliminate 200 more US-based positions over time.

Lonza builds biologics capabilities

Basel, Switzerland (Nov. 8)—Lonza Group (Basel, Switzerland, agreed to buy Genentech's mid-scale mammalian biopharmaceutical manufacturing facility in Porriño Spain for $150 million. The facility has 40,000 L of biologics manufacturing capacity and produces Genentech's "Avastin" (bevacizumab), which Lonza will continue to supply.

Lonza also will build an 80,000-L large-scale mammalian biopharmaceutical production facility in Singapore. The facility is expected to be licensed by FDA in 2010. Genentech will have the exclusive option to acquire the Singapore facility from Lonza between 2007 and 2012 for $290 million plus $70 million in milestone payments if certain goals are met. The facility will be Lonza's second manufacturing site in Singapore, where the company is building another 80,000-L plant that is expected to come on stream in 2011.

The deal follows Lonza's decision to buy the bioproducts and biopharmaceutical segments of Cambrex Corporation (East Rutherford, NJ, for $460 million.

AAIPharma completes purchase of CRO

Wilmington, NC (Oct. 26)—AAIPharma Inc. ( completed its acquisition of the contract research organization Cvitkovic & Associés Consultants S.A. (CAC, Le Kremlin Bicetre, France). CAC, which specializes in oncology drug development and medical consulting, and will form the foundation of AAIOncology.

–Erik Greb, Brianne Harrison, Douglas McCormick, Patricia Van Arnum


Contract Services Growth Strong,but Slowing

AAPS, San Antonio, TX (Oct. 30)—Market growth in the outsourcing industry is strong, but slowing, said Jim Miller, president of PharmSource Information Services (Springfield, VA, and publisher of Bio/Pharmaceutical Outsourcing Report, in a presentation entitled, "Surveying the Contract Services Industry: The Outlook for 2007 and Beyond," given at the 2006 AAPS meeting.

Spending on services

The annual Pharmaceutical Technology–PharmSource outsourcing survey indicates that spending on contract services may decrease in 2007, said Miller. Only 10% of respondents said in the 2006 survey that spending would grow at least 20% in 2007. Said Miller, "There are still opportunities for contracts, but you may need to work a little harder for them."

New paradigms

According to data from IMS (Fairfield, CT, on the global drug pipe-line, spending on Phase I/II candidates grew steadily over the past four years. But, Miller said, the Phase I pipeline is flattening, which could reflect a slowdown in candidates entering later-phase studies or less funding. At the same time, industry has seen little growth in products going to registration because many products are killed before late-stage development.

"It's interesting what we are seeing in the market," said Miller of the challenge to get candidates into late-stage development. "Contractors are starting to respond." Miller stressed that "proof of concept" (POC) is a new development paradigm and contractors are closely watching the critical period between when a compound is deemed safe and when companies decide how to proceed with it. New concepts are designed around getting APIs through POC and into Phase II more quickly.


Most offshore outsourcing activities are non-GMP intermediates, clinical research, and discovery chemistry. Part of the reason, said Miller, is that it is easier to find clinical trials subjects in China or India than in the US, for example. And, databasing is less expensive overseas. Miller speculated it will be 3–5 years before US-based companies have overseas competition for GMP custom-manufacturing services. "You'll see more companies jump into the generics market than GMP services."

Lessons to learn

To deal with the slowing market and the threat of overseas competition, companies should examine unused capacity. "Capacity can't be inventory," Miller said, and recommended that companies find ways to sell excess capacity. Companies should keep in mind that customers are looking for more than just basic commodities and are willing to pay for them.

–Kaylynn Chiarello-Ebner


Challenges in Analytical Method Transfer

AAPS, San Antonio, TX (Oct. 31)—Concerns over process variability have prompted industry to take a closer look at analytical method transfer processes. During the presentation, "Challenges in Analytical Method Transfer," at the AAPS Annual Meeting, Horacio Pappa, PhD, scientist and Latin American liaison, Standards Development, US Pharmacopeia (USP, Rockville, MD, discussed why USP is interested in working with analytical method transfers (AMTs).

Pappa presented the three stages of method life cycle: R&D method development, quality control (QC) methods used in QC labs, and QC USP methods used in generics. He explained that USP is introducing Chapter ‹1226›, "Verification of Compendial Procedures," that would apply between the last two stages for how to verify suitability for "intended use." USP has started initial discussions of a proposed chapter applicable between the first two stages for the transfer of analytical procedures and invited attendees to submit their thoughts on the proposed chapter.

AMTs explained

Saji K. Thomas, associate director of quality operations at Par Pharmaceuticals (Spring Valley, NY), reemphasized the importance of timing and the preparedness of the sending and receiving companies. Defining method transfer as "the process that qualifies a lab to use an analytical test," Thomas outlined the main reasons why an analytical method may be transferred: it is part of the natural progression of the product's life cycle; to provide additional capacity; the business has relocated; or as a result of merger and consolidation.

Thomas reviewed "criteria for success," including the skills of the individual assigned to the project, defining the roles and responsibilities between the sending and receiving units, and the receiving units' ability to manage expectations and handle deviations during implementation. "The most important part of the process is the transfer of knowledge gained during the life cycle of the method, and the key is that the sending unit and receiving unit agree on the acceptance criteria," he said.

One trend is the "covalidation approach," which involves the receiving lab in the validation process and in identifying the validation parameters that must be challenged. Another approach is for the receiving lab to file a method transfer waiver, which may be applicable when the lab is already familiar with the procedure, when the process is a line extension, when its analytical methods are the same or very similar to those in use, when the person who developed and validated the method moves to the receiving lab, and when the new method doesn't cause major changes.

To facilitate documentation, templates should be used and all chromatograms should be attached. "Make sure the receiving lab can meet all limit-of-quantitation criteria and can obtain a similar impurity profile. Spiked samples could be used if impurities are not detected above the reporting threshold," said Thomas. For dissolution methods, he suggested using Level 2 testing (12 units) instead of the 6 units typically used for method transfer. In addition, bracketing may be appropriate for multiple strengths.

Over the life cycle of the product, the method may have to be revalidated, especially when the sponsor makes changes to the analytical procedure. "The need to transfer a revalidated method depends on the severity of the change," said Thomas.

Nonchromatographic methods

Dana C. Vaughn, principal researcher at Procter & Gamble Pharmaceuticals (Norwich, NY), presented common pitfalls companies encounter when transferring nonchromatographic methods. Particle-size distribution (PSD) presents unique challenges because there is little guidance on PSD methods. Problems also stem from sampling procedures as well as from the instrument response functions that highlight variation in detector geometry and scattered light intensities. PSD methods also may involve proprietary algorithms, and setting particle size specifications is not easy because it may have stability, processing, and content-uniformity issues.

Vaughn presented several real-world case studies demonstrating the challenges of PSD method transfer. As an example of instrument variation, he presented the particle-size distribution of an API on two instruments, one which gave a D[v, 0.5] of 3.39 μm and the other which gave a D[v, 0.5] value of 3.62 μm. He also provided an example in differences between reporting mean, median, and mode averages and an example in which the same instrument from two different manufacturers resulted in a similar D[v, 0.5] values, but differed significantly in their relative standard deviations (1.3% versus 9.7%).

Manufacturers also must know the difference between transfer and site validation. "Although site validation offers added confidence, knowledge, and ownership, and potentially stronger specifications, it also may lead to problems with local SOP issues because the CMO may have its own set of SOPs. On the other hand, method transfer is cheaper and faster and 'relationship-friendly,' but there is less knowledge and ownership," said Vaughn.

–Maribel Rios


Antimicrobial Preservatives in Protein Drugs

AAPS, San Antonio, TX (Oct. 31)—As biologic-based drugs become a larger part of product portfolios, optimizing their formulations is increasingly important. "The Impact of Preservatives on Physicochemical Properties of Therapeutic Proteins" session at the 2006 AAPS meeting addressed a key step in this process: selecting an antimicrobial preservative.

About 25% of protein products on the market contain antimicrobial agents, said Michael Akers, senior director, pharmaceutical research and development at Baxter Pharmaceutical Solutions (Bloomington, IN, and editorial advisory board member of Pharmaceutical Technology. M-cresol, phenol, and benzyl alcohol are the most widely used agents in protein multidose products.

Several issues must be considered when selecting an antimicrobial agent, explained Akers. "First is understanding that there are potential incompatibilities with the protein itself, as well as potential incompatibilities with processing materials (tubing and filters), other formulation ingredients (polysorbate 80 and other polymers), and packaging materials (rubber)."

Another challenge is to find a globally acceptable agent, particularly given the differences in acceptance-test criteria in preservative-efficacy testing (PET) in the US Pharmacopeia (USP) and the European Pharmacopoeia (EP). PET evaluates the effectiveness of preservative systems in the final product when microbial agents are inoculated in the product. It demonstrates the the preservative's effectiveness throughout the shelf life and product use.

"EP test acceptance criteria are much more stringent than USP criteria," explained Akers, with the EP requiring bacteriocidal formulations and the USP requires bacteriostatic. In Europe, benzyl alcohol is the preferred antimicrobial preservative, but 0.9% concentrations will not meet EP's criteria, whereas 1.2–1.5% concentrations will. Phenol (0.5%), m-cresol (0.3%), or chlorocresol (0.25%) are acceptable. Parabens are not preferred because of potential anaphylactic shock.

Detection of protein aggregation

The choice of analytical method to detect protein aggregation is another key consideration. For protein therapeutics, the presence of aggregates is undesirable because they may lead to immunogenic or adverse reactions upon administration.

"Preservatives frequently cause aggregation in formulations, and several methods exist to detect aggregation, each offering advantages and disadvantages," said Mary Cromwell, scientist and senior group leader of Genentech, Inc. (South San Francisco, CA, and committee chair of the AAPS Focus Group on Protein Aggregation and Immunogenicity.

Size-exclusion chromatography, which separates particles based on hydrodynamic volume, is the industry workhorse for detecting aggregation, but dilution onto the column may cause dissociation, and large aggregates may not enter the matrix. Sodium dodecyl sulfate-based techniques such as capillary electrophoresis or polyacrylamide gel electrophoresis also may be used and offer versatility because they are not protein-specific and are sensitive to trace quantities. Analytical ultracentrifugation, fluid-flow fractionation, light-scattering techniques, light obscuration, and the Coulter counter are also good for particle detection, said Cromwell.

Evaluating benzyl alcohol-induced aggregation

Eva Y. Chi, postdoctoral research fellow at The University of Chicago (, discussed a way to evaluate the mechanism and kinetics of benzyl alcohol-induced aggregation of rhIL1-ra, a recombinant human interleukin-1 receptor antagonist.

Chi said that benzyl alcohol accelerates the non-native aggregation and precipitation of rhIL-1ra by increasing the population of aggregation-prone, prenucleating species, which react to form insoluble precipitates. Kinetically, nucleation rates increased by four orders of magnitude in the presence of 0.9% benzyl alcohol. Once insoluble aggregate nuclei are formed, the nuclei growth rate into larger aggregates was not significantly affected by benzyl alcohol. Sucrose blocked rhIL1-ra aggregation by favoring compact native state structures that were not aggregation-prone. The addition of sucrose sharply decreased aggregate nucleation rates and had little effect on the aggregate growth rate.

–Patricia Van Arnum