Wrap Up: AAPS National Biotech Conference

"It's an exciting time to be in a biotechnology field--we are on thethreshold of amazing possibilities," said Robert G. Bell, PhD,president of Drug and Biotechnology Development LLC (Clearwater, FL) duringthe opening remarks at this week's AAPS National BiotechnologyConference in Boston, Massachusetts. More than 1100 attendees from 19countries participated in the event.

Approximately 40% of drugs now being tested are derived frombiotechnology, said Bell, and the widespread impact of these productswill be extensive. "There will not be an area not affected bybiotechnology. Make no mistake, everyone will be affected."

Topics covered at the event included

drug development opportunities

,

setting specifications

, and

vaccine technologies and industry events

.

Drugdevelopment opportunities
Kevin Eggan, PhD, assistant professor of molecular and cell biology atHarvard Stem Cell Institute (Cambridge, MA,

www.stemcell.harvard.edu

),spoke about the implications of stem cell research in the discovery ofnew drugs. "Stem cells can lead to new assays, which can lead to thediscovery of new drugs," he said in his opening address. Scientistsface several challenges in disease research studies, however, includingdifficulties in obtaining patient material samples, obtaining samplesthat are not representative of the endpoint of the disease, and dealingwith the complex genetic nature of diseases. Challenges to biologists,material scientists, engineers, and nanotechnologists include:

• finding several appropriate affected cells for study;
  
  

• maintaining these cells in culture long enough to manifestdisease;

• creating "environments" for these cells that will best representthose in which they reside and function;

• designing assays for assessing the functionality of these cellsand their progression toward a disease phenotype.

Eggan concluded his presentation with preliminary results of his workin using parabiosis to find a treatment for the inherited form(familial) of amyotrophic lateral sclerosis (ALS, or "Lou Gehrig'sDisease"), including the generation of ALS-specific human embryonicstem cells for somatic cell nuclear transplantation.

The low productivity of the biotechnology industry to bring new drugsto market did not go unnoticed, however. In his presentation, "WhereHave All the Products Gone?" Burt Adelman, MD, executivevice-president of development at Biogen Idec, Inc. (Cambridge, MA,

www.biogenidec.com

)noted that the industry faces several challenges, includingless-than-popular opinions from constituents and a regulatoryenvironment that "has not necessarily built the systems for theaccurate, rapid, and complete collection of data." Nonetheless, "newdrugs, as well as old, must be defined by clear evidence of clinicalvalue, and I continue to believe that drugs with important clinicalvalue will be recognized," he said. Adelman said the industry needs tounderstand human pathology in order to understand pathogens andchallenged the industry to aim research efforts toward "breakthroughs"rather than incremental achievements, which will involve embracingrisk. Scientists should develop a "safety database" during research andpreclinical development. "We need fundamental change in mindset," hesaid, "so that safety is reconfirmed every day." Product safety shouldbe "prospectively planned during clinical development and proactivelymanaged during commercial distribution."

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Settingspecifications
"Specifications are part of a total control strategy," said PatrickSwann, PhD, acting deputy director of the Division of MonoclonalAntibodies at FDA's Center for Drug Evaluation and Research (Rockville,MD,

www.fda.gov/cder

),referring to specifications defined in the Q6B guidance from theInternational Conference on Harmonization (ICHm Geneva, Switzerland). Selecting quality parametersfor setting specifications for biotechnology products is a complextask, because biotechnology has been "poorly understood" in terms ofthe relationship between structure and function. In addition, there isoften a "weak link" in how attributes are assessed and how thisassessment relates to product performance.

Acceptance criteria and action limits should be based on relevantpreclinical development data, lots used in clinical studies (what Swannreferred to as "the gold standard"), manufacturing history, stabilitystudies, and analytical method validation data. In addition to Q6B,which requires that "appropriate statistical analysis should be appliedwhen necessary to quantitative data reported," Swann suggested anapproach in which "values are specified to ranges observed from eitherentirely of clinical experience or pivotal trials." Biologicalcharacterization is also important to setting specifications, anddevelopers should use the knowledge of the "mechanism of action" to setthese specifications. Regarding FDA's regulatory initiatives, includingits CGMPs for the 21st century initiative, process analytical technology (PAT), and ICH's Q6B, Q8, andQ9 guides as well as the Quality by Design approach, Swann observedwhat he termed an "evolving paradigm" in the industry, in which"quality is confirmed (not ensured) by the testing and rejection oflots that fail to meet stated quality."

Begin early, develop continuously
 "Specification development must begin at the earlieststages," said Timothy Brown, PhD, group director at Diosynth-RTP, Inc.(Research Triangle Park, NC,

www.diosynthbiotechnology.com

) "Clinical experience definesthe ultimate boundaries for key safety and efficacy parameters."Clinical studies establish meaningful release parameters and keyquality attributes and are important in managing manufacturing variability.Biotechnology products are considerably more complex than syntheticproducts, said Brown. Because drug substances are heterogeneous, thereis significant concern about immunogenicity, and assay methodvariabilities require redundant tests "to get the full picture ofpurity." Nonetheless, "acceptance criteria should be flexible toaccommodate ongoing process development."

Specifications should evolve over the lifecycle of the product toreflect the state of process knowledge, said Brown. To ensure theproduct conforms to specifications, the technology transfer process isimportant regarding process knowledge and understanding; procedures formanufacturing, packaging control, testing and release of drugsubstances; and the testing and release of drug substances. "Make surewhat happens in small scale [also] happens in large scale," he said.

From a risk-management perspective, "if clinically meaningful limitsare clearly defined, they become the ultimate boundaries--thespecifications," said Brown. In addition, operating limits "should beestablished based on process capability, and changes to operatinglimits are subject to the same considerations as the original limits."

Learning from Gardasil
Discussing a case study involving Merck's "Gardasil" vaccine (aquadrivalent, virus-like particle for fighting human papillomavirus, thesole cause of cervical cancer), Robert D. Sitrin, PhD, of MerckResearch (Whitehouse Station, NJ,

www.merck.com

) demonstrated how specifications canbe set during various stages of product. Manufacturing consistency datain particular can be used to set specifications for antigens andbiotechnology products for which the dose is equivalent to the mass andthe potency is equivalent to the specific activity. "A specificationconfirms that the commercial lot is not significantly different thanpivotal clinical lots." In addition, developers should use process andanalytical variabilities and an appropriate statistical approach to setspecifications and estimate process variabilities.

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Vaccinetechnologies and industry challenges
In a symposium on new vaccine technologies, conference attendees heardthe latest developments in vaccines against infectious diseases,cancer, influenza, and potential bioterror agents. Presenters alsofocused on scale-up and manufacturing challenges and regulatory issuesduring development.

DNA vaccines
There are currently 28 clinical trials involving DNA vaccines, most forinfectious diseases, though one-third of them are cancer therapies,said Lee K. Roberts, PhD, vice-president of operations at ODC Therapy,Inc. (a Baylor Healthcare company,
Dallas, TX, www.baylorhealth.com), in a presentation on DNA anddendritic cell vaccines. The "field is starting to shift," saidRoberts, referring to changes in vaccine formulations that increasinglyinclude adjuvants, viral vectors, and cell-based platforms. Changes indelivery, including nasal and dermal routes, are also apparent.

Results from clinical studies involving DNA vaccines are promising,said Roberts. All of the 17 clinical studies (5 in melanoma or prostatecancer and 12 in infectious diseases including malaria, HIV, HBV, andinfluenza) published between 2004 and 2006 have reported the vaccine as"safe and well tolerated." These studies are offering scientists a "newperspective" about DNA vaccines, said Roberts. Specifically, DNAvaccines favor induction of a cell-mediated immune response and thisresponse is best for therapeutic applications. Clinical results alsoindicate that the efficacy of DNA vaccines depends on the route ofadministration, formulation of the DNA plasmid, and the types ofadjuvants and immune stimulators.

DNA vaccines are not without commercial and regulatory challenges, saidRoberts. First, DNA vaccines and autologous cell therapies are novelproducts in the biotechnology industry. "An effective DNA vaccineproduct may require novel formulations, adjuvants or immunestimulators, and novel drug delivery systems." Developing manufacturingschemes for these products can also be challenging. "Each cell is apotential product," says Roberts, "so manufacturers must develop arobust process to result in a consistent product." Finally, it may bedifficult to validate the quality assurance assays. Specifically,"potency assays may require surrogate markers, validation may requirethe development of a biological assay, and there are currently nostandards available. So as you develop these assays, you should bedeveloping the standards," said Roberts.

Manufacturing, fill-and-finishchallenges
"There are significantly more challenges in scaling up andmanufacturing commercial vaccines," said Ranjit R. Deshmukh, PhD,director of global technology transfer at Wyeth Biotech and Engineering(Collegeville, PA,

www.wyeth.com

).For example, in upstream processes, scale-up may not be linear. "Manyupstream processes remain older technologies that are less amenable forscale-up, such as those for egg-based vaccines. Also, live viralsystems require careful scale-up to maintain viability and controltiters."

There are also challenges in preparing facilities for vaccinedevelopment. Issues such as long lead times to set up facilities,costly investments, and the need for meeting global standards must betaken into consideration. Integrated facilities are rare, saysDeshmukh, and cross-site or even cross-country facilities are oftenneeded.

Challenges are also present in fill and finish processes. "Vaccines aretypically low fill volume but very high throughput, and some vaccinesrequire more care in filling, including live attenuated viral vaccinesand some adjuvant-containing suspensions." Manufacturing Wyeth's"Prevnar" vaccine (one of the three "billion dollar" vaccines, togetherwith Rotateq and Gardasil) requires a complex 15-step process. Ittypically takes 12 months from the start of the manufacture of one (outof seven) polysaccharides to final fill-finish and release. Long cycletimes are not uncommon for other multicomponent vaccines, and thiscould affect a company's decision to invest in capacity, says Deshmukh.

Expediting production
There are ways to expedite vaccine manufacture, however. Deshmukhsuggested defining the strain on composition early in the process,using multicomponent facilities, balancing the use of large-scaledevelopmental facilities and launch facilities, using processdevelopment strategically, and implementing "analytical excellence" indefining the product and processes. Other changes in technologies andoperations are also helping. "For example, the industry finally hasadequate financial reward for risk," he said. Moreover, the importanceof vaccines in general public health is recognized and there is agreater focus on global outreach for vaccines.

Peter Patriarca, MD, senior consultant for Biologics Consulting Group(Bethesda, MD,

www.bcg-usa.com

),and former CBER staffer, gave the final presentation of the vaccinesymposium. His talk focused on the vaccine market and its outlook andreasons why the vaccine industry has had a "disappointing hit rate" inlicensing new vaccines (

e.g.,

in 1996, 79 products were in thePhase 2stage; of those, only 11 are licensed in the United States). Patriarcaalso provided a checklist of issues "to be concerned about duringdevelopment" and provided best-approach advice for working with FDA'sOffice of Vaccine Research and Review.

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