The latest topics in Drug Development This issue IMMUNOGENICITY FOR EMEA AND FDA ………..1 CYTOKINE RELEASE ASSAYS……………………..2 EXTRACTABLE AND LEACHABLE..………………..3 CLINICAL SUPPLY SERVICE AT ALTA..…………..6 Immunochemistry ◦ (858) 558-2599 ◦ www.AltaImmunochem.com LCMS ◦ (916) 933-1640 ◦ www.Altalcms.com QTI ◦ (908) 534-4445 ◦ www.qtionline.com Intertek Pharmaceutical Services ALTA Analytical Laboratory 3985 Sorrento Valley Blvd, Suite C San Diego, CA 92121 Postage Meet Intertek representatives at these following conferences: June 1-4, 2009 ASMS Conference on Mass Spectrometry Philadelphia, PA June 21-24, 2009 2009 AAPS National Biotechnology Conference Seattle, WA July 13-17, 2009 10th Annual Land O’Lakes Bioanalytical Conference Merrimac, WI UPCOMING EVENTS Newsletter Pharmaceutical Services Pharmaceutical Services Comprehensive GLP Bioanalytical LCMS, Immunochemistry, and cGMP Analytical Services
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lular cytokine accumulation by flow cytometry, cytokine release by
ELISA or detection of secondary markers of T cell activation such as
proliferation. Although there is not yet consensus on the preferred
methods of testing or interpretation of the results, there seemed to be
general agreement that such testing should be considered on a case-
by-case basis.
Recent experience suggests that Sponsors will need to place re-
newed emphasis on selecting their FIH doses, through methods such
as MABEL calculations, and on understanding the pharmacologic
effects that might accompany those doses, especially if they may be
associated with cytokine release. For many biologics, particularly
those directed against T cells or with immunomodulatory properties,
in vitro cytokine release assays may become an important part of the
preclinical evaluation.
References:
ABPI/BIA. Early Stage Clinical Trial Taskforce, Early Stage Clinical Trial
Taskforce – Joint Association of the British Pharmaceutical Industry (ABPI)/
BioIndustry Association (BIA) Report. 2007.
BioSafe General Membership Meeting, Cytokine release assays: Current ap-proaches and considerations, in Cytokine release assays: Current approaches and
considerations. 2008: Cambridge, MA.
Duff, G.W. Expert Group on Phase One Clinical Trials (Chairman: Professor
Gordon W. Duff), Expert Group on Phase One Clinical Trials: Final report. 2006.
EMEA. European Medicines Agency (EMEA), Guideline On Strategies To Identify And Mitigate Risks For First-In Human Clinical Trials With Investiga-
FDA CDER Immunotoxicology Subcommittee meeting, Cytokine release: What
does it mean to you? , in Cytokine release: What does it mean to you? . 2008:
FDA White Oak Campus, Rockville, MD.
Gibb, F., Victim Ryan Wilson in 'Elephant man' drug trial to get £2m, in The
Times. 2008: London.
Hsu, D.H., et al., A humanized anti-CD3 antibody, HuM291, with low mitogenic
activity, mediates complete and reversible T-cell depletion in chimpanzees.
Transplantation, 1999. 68(4): p. 545-54.
Klingbeil, C. and D.H. Hsu, Pharmacology and safety assessment of humanized
monoclonal antibodies for therapeutic use. Toxicol Pathol, 1999. 27(1): p. 1-3.
Legrand, N., et al., Transient accumulation of human mature thymocytes and
regulatory T cells with CD28 superagonist in "human immune system" Rag2(-/-)
gammac(-/-) mice. Blood, 2006. 108(1): p. 238-45.
Lin, C.H. and T. Hunig, Efficient expansion of regulatory T cells in vitro and in
vivo with a CD28 superagonist. Eur J Immunol, 2003. 33(3): p. 626-38.
Rao, P.E., et al., OKT3E, an anti-CD3 antibody that does not elicit side effects or
antiidiotype responses in chimpanzees. Transplantation, 1991. 52(4): p. 691-7.
Stebbings, R., et al., "Cytokine Storm" in the Phase I Trial of Monoclonal Anti-body TGN1412: Better Understanding the Causes to Improve PreClinical Testing
of Immunotherapeutics. J Immunol, 2007. 179(5): p. 3325-3331.
Suntharalingam, G., et al., Cytokine Storm in a Phase 1 Trial of the Anti-CD28
Monoclonal Antibody TGN1412. N Engl J Med, 2006. 355(10): p. 1018-1028.
Van Wauwe, J.P., J.R. De Mey, and J.G. Goossens, OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol,
1980. 124(6): p. 2708-13.
Waibler, Z., et al. Signaling signatures and functional properties of Antihuman
CD28 superagonistic antibodies. PLoS ONE 2008;3:e1708.
Cytokine Release Assays
Alta has extensive experience in the bioanalysis of pharmaceutical compounds in ocu-
lar matrices. We have developed, validated and run GLP studies for over 40 proprie-
tary LC/MS/MS methods in a variety of ocular fluids and tissues.
In addition, we routinely run non-GLP ocular studies for our clients. We can measure
drugs in ocular tissue homogenates or in intact tissues employing high energy sonica-
tion, bead beater techniques and other more classical bioanalytical approaches.
Ocular matrices worked with to date include aqueous humor, vitreous humor, tears,
lens, retina, choroid, sclera, cornea, iris, ciliary body and eye lid.
ALTA LC/MS:
Bioanalysis in
Ocular Matrices
Call us to discuss the assays you need to satisfy your strategy
for evaluation of possible immunogenicity associated with your
compound .
We are experienced in the development of assays to deal with
the need for increased drug tolerance, confirmation assays,
and evaluation of neutralizing antibodies.
Call Joyu Lin at (858)558-2599 for a quote, or look for more
information in our next issue.
Complete Service
Offering for
Evaluation of
Immunogenicity
Intertek USA dba ALTA Analytical 1100 Windfield Way
GLP LCMS Services El Dorado Hills, CA 95762
Phone: (916) 933-1640
Fax: (916) 933-0940
Established in 1990, Alta Analytical Laboratory has been a premier provider of quantitative bioanalytical LCMS services to the
Pharmaceutical and Biotech industries.
We have been a pioneer in the application of efficient sample preparation and LC/MS/MS technologies to the analysis of drugs
and metabolites in a wide variety of biological matrices, including ocular tissues.
ALTA routinely provides GLP bioanalytical support for pre-clinical, Phase I-IV and large bioequivalence studies. In addition, we
have a dedicated project team that provides rapid turnaround for non-GLP bioanalysis in support of early discovery, pharma-
cokinetic and lead qualification studies.
For additional information, please contact us or visit www.altalcms.com
Due to an increase in client requests, we have implemented a Clinical Supply and Cold Chain Logistics Service. All services are tailored to the client’s specific need. We can provide the follow-ing for clinical and preclinical support, available for both LC/MS and immunochemistry studies:
PK lab manual – specifically designed based on the study protocol and outlines the collection, processing, storage and shipment of collected study samples per the study protocol. Included in the manual are all forms needed for notification and shipment of samples to the analytical site.
Shipping – shipping boxes, forms, labels, packing materials and dry ice delivery coordina-tion. Additional services include the coordination of shipping for both domestic and international sample shipments.
Training and On-call Support – training of the contents and use of the PK manual and kits are provided for each clinical site, if desired. Also, a 24 hour on-call service can be provided at an hourly cost.
Please contact Rhonda Johnson at
(916) 933-1640 ext 5019 or Rambod Omid at
(310) 312-3902 for a detailed quote.
NEW SERVICES FROM ALTA
Clinical Supply
and
Cold Chain Logistics
[continued from page 4]
Simply extracting materials with a series of
solvents may not provide the entire profile of
trace metals, which are potentially harmful.
However, using the universal approach, a
formulator could evaluate or screen a series
of packaging materials for total metals con-
tent.
In the examples provided, a sample of clear
glass (Fig. 1) and a butyl rubber serum stop-
per (Fig. 2) were completely acid digested
and analyzed. As can be seen in the data,
significant levels of elements such as alumi-
num (Al), boron (B), barium (Ba), calcium
(Ca), iron (Fe), potassium (K), magnesium
(Mg), sodium (Na), silicon (Si), strontium
(Sr), titanium (Ti), zinc (Zn) and zirconium
(Zr) were found.
Then using this type of total metal data, ex-
tractable or leachable levels using drug prod-
uct or solvents similar in nature to the final
product could predict the feasibility of using
the packaging materials with the drug prod-
uct. Selective metals of interest can now be
monitored, instead of tracking the entire se-
ries of metals.
Classic approaches to extractable and leach-
able (E/L) studies may not be appropriate as
some metals (ie. Os, Co) are practically in-
soluble in water. Metals such as palladium,
platinum and tin are used extensively as
catalysts. However, the inorganic forms of
these elements are relatively non-toxic ver-
sus the more soluble salt forms or organic
forms. Again, extraction of these metals may
not occur based on the solvent system se-
lected.
This is not to say that extraction of materials
with different solvent systems is not useful.
In fact, these experiments indicate levels of
metals that potentially can be extracted or
leach into a specific pharmaceutical product.
However, in most cases, the specific metals
and initial levels contained within the packag-
ing materials or container are unknown. This
type of information can be useful in setting
vendor specification for packaging materials.
SUMMARY
This work has shown that a universal ap-
proach to Controlled Extractables can be
useful :
• in the evaluation of product safety
• in the evaluation of potential product containers and closures
• in the evaluation and setting of vendor specifications