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
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Pharmaceutical Services
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Comprehensive GLP Bioanalytical LCMS, Immunochemistry,
and cGMP Analytical Services
The consequences of an im-
mune reaction to a therapeutic
protein range from transient
appearance of antibodies with-
out any clinical significance to
severe life threatening conditions. Potential clinical consequences are
severe hypersensitivity-type reactions, decrease in efficacy and in-
duction of autoimmunity, including antibodies to the endogenous form
of the protein.
Many factors may influence the immunogenicity of therapeutic
proteins. They can be considered patient-, disease- or product-
related.
In April 2008, EMEA issued a new guidance on immunogenicity
assessment of Biologics entitled “Guideline on Immunogenicity As-
sessment of Biotechnology-Derived Therapeutic Proteins”. The
scope of this new guideline included proteins, polypeptides, their
derivatives, and products of which they are components, e.g. conju-
gates excluding coagulation factors.
Although there is no recent immunogenicity “Guidance” from the
FDA, the latest dating from 1997 entitled “Guidance for Industry: S6
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuti-
cals”, a series of White Papers have been published on the subject.
The latest White Paper was published in December 2008 by G.
Shankar et al. summarized clearly all the regulations toward immuno-
genicity screening and testing.
According to the EMEA & FDA guidelines, validation of qualita-
tive immunogenicity assays for the detection of host antibodies to
macromolecules should include the following parameters:
▪ Precision: inter- and intra-run variability of the positive control
▪ Screening Cutpoint ▪ Specificity Cutpoint
▪ Sensitivity ▪ Selectivity/Interference
▪ Drug Interference ▪ Robustness
▪ Dilutional effects ▪ Stability
Adopting an appropriate strategy for assessment of unwanted
immunogenicity of biological products is essential. This include a
screening assay for identification of antibody positive samples/ pa-
tients, analytical immunochemical procedures for confirming the pres-
ence of antibodies and determining antibody specificity and functional
bioassay(s) for the assessment of the neutralizing capacity of anti-
bodies.
Relevant literature:
- “Guideline on Immunogenicity Assessment of Biotechnology-
Derived Therapeutic Proteins”. EMEA Guideline, webpage:
http://www.emea.europa.eu/pdfs/human/biosimilar/1432706en.pdf
- “Guideline on Development, Production, Characterisation and speci-
ficications for monoclonal antibodies and related products”. EMEA Guide-
line, webpage:
http://www.emea.europa.eu/pdfs/human/bwp/15765307enfin.pdf
- “Guidance for Industry: S6 Preclinical Safety Evaluation of Biotech-
nology-Derived Pharmaceuticals”. FDA Guideline, webpage: http://
www.fda.gov/cder/guidance/1859fnl.pdf
- “Recommendations on risk-based strategies for detection and charac-
terization of antibodies against biotechnology products”. Koren E. et al.
2008, Journal of Immunological Methods, Volume 333, pages 1–9
- “Recommendation For The Validation Of Immunoassays Used For
Detection Of Host Antibodies Against Biotechnology Products”. Shankar
G., et al. 2008. Journal of Pharmaceutical and Biomedical Analysis, Vol-
ume 48 (5), Pages 1267-1281.
- “Recommendations for the design, optimization, and qualification of
cell-based assays used for the detection of neutralizing antibody responses
elicited to biological therapeutics ”Gupta S. et al. 2007. Journal of Immu-
nological Methods, Volume 321, Pages 1–18.
Pharmaceutical
The Service Provider you can trust
Newsletter, May 2009
Page 1 of 7
Current Immunogenicity Guidelines for the EMEA AND FDA
Intertek USA dba ALTA Analytical GLP Immunochemistry Services
3985 Sorrento Valley Blvd, Suite C Phone: (858) 558-2599
San Diego, CA 92121 Fax: (858) 558-2600
Established in 1999, Alta offers services to the biotech and pharmaceutical indus-
tries in method development, validation and GLP sample analysis for preclinical
and clinical studies.
The immunochemistry lab has extensive expertise in dealing with various types of
therapeutic macromolecules, and with studies associated with PK, TK, immuno-
genicity, and biomarkers.
For more information, please contact us or visit www.altaimmunochem.com
Services
By Dominique Gouty, PhD
Scientific Director,
ALTA Immunochemistry
On 13 March 2006, eight healthy volunteers
were administered placebo or a monoclonal
antibody (mAb), TGN1412, as a 3‑ to 6‑-minute IV infusion at a dose of 0.1 mg/kg.
Within 90 minutes, the six who had received
TGN1412 had a systemic inflammatory re-
sponse characterized by rapid induction of
proinflammatory cytokines and accompanied
by headache, myalgia, nausea, diarrhea,
erythema, vasodilatation, and hypotension
(Suntharalingam, 2006). At 12 to 16 hours
post-dose, they became critically ill, with pul-
monary infiltrates and lung injury, renal fail-
ure, and disseminated intravascular coagula-
tion (DIC). Severe and unexpected depletion
of lymphocytes and monocytes occurred
within 8 hours, reaching a nadir at 24 hours.
They were transferred to an intensive care
unit, where they received intensive cardiopul-
monary support (including dialysis), high-
dose methylprednisolone, and an anti–
interleukin‑2 receptor antagonist antibody. Prolonged cardiovascular shock and acute
respiratory distress syndrome developed in 2
patients, who required intensive organ sup-
port for 8 and 16 days. It was soon con-
cluded that TGN1412 had caused a “cytokine
storm”. Although all six volunteers survived,
the long-term prognosis for these subjects is
unknown. One of these patients has since
had all of his toes and the tips of several
fingers amputated (Gibb, 2008).
TGN1412 was being developed by TeGenero
for use in B cell chronic lymphocytic leuke-
mia, in which T cells are deficient, and auto-
immune diseases, such as rheumatoid arthri-
tis, in which Treg cell expansion might be
beneficial. TGN1412 is a humanized IgG4ĸ
mAb directed against CD28 on T cells, re-
ferred to as a “superagonist” be-
cause it has the ability to activate
T cells without need for T cell re-
ceptor (TCR) pre-activation, result-
ing in polyclonal T cell expansion and activa-
tion and concentration-dependent IL‑2 pro-duction (Lin, 2003). In this manner,
TGN1412 promotes the proliferation of regu-
latory T cells (Treg cells), thought to be im-
portant in immune and cancer surveillance
(Lin, 2003). The fact that TGN1412 also
causes concurrent rapid and prolonged de-
pletion of CD28+ T cells from the circulation
(Legrand, 2006) was overlooked as a cause
for concern at the time. These properties are
not unique to TGN1412. In fact, cytokine
release syndrome (CRS) accompanied by T
cell depletion is the expected mechanism of
action and “black box” warnings are promi-
nently featured on the labels for alemtuzu-
mab (CamPATHÒ , against CD52) and muro-
monomab-CD3 (OKT3Ò, against CD3). Simi-
lar concerns resulted in the discontinuation of
development of visilizumab (HuM291 or Nuvi-
onÒ, against CD3) and numerous other anti-T
cell mAbs.
The “TeGenero Incident”, as it became
known, resulted in a flurry of expert review
and culminated in the release of an expert
scientific group report known as “the Duff
report” (Duff, 2006) and the issuance of the
European Medicines Agency (EMEA) Guide-
line on strategies to identify and mitigate risk
for first-in-human (FIH) clinical trials with
investigational medicinal products (EMEA,
2007). In addition, dozens of publications
appeared on related topics, such as the se-
lection of relevant species, the predictive
abilities of nonclinical testing, and strategies
for establishing FIH doses. One of the pro-
posed methods for selecting FIH doses in-
volves estimation of the minimum anticipated
biological effect [dose] level (MABEL) for
humans (ABPI/BIA, 2007).
The Duff report concluded that the preclinical
development studies that were performed
with TGN1412 did not predict a safe dose for
use in humans, even though current regula-
tory requirements were met. Understanda-
bly, much effort was spent trying to under-
stand why this was so. In their regulatory
filings, TeGenero had described cytokine
release syndrome or a cytokine storm as
possible adverse events. In human in vitro
assays using cell suspension-based systems
and in monkey toxicology studies TGN1412
had elicited minimal cytokine release. Soon
after, it was demonstrated that immobilization
(fixation) of the Fc portion of TGN1412 was
an essential requirement for robust in vitro
activation, proliferation and T cell cytokine
release from human T cells, and that monkey
T cells did not respond in comparable fashion
(Stebbings, 2007). Furthermore, despite
complete conservation of the CD28 extracel-
lular and cytoplasmic domains in monkeys
and humans, TGN1412 and other CD28 su-
peragonist mAbs are associated with sus-
tained transmembrane calcium flux in human,
but not in cynomolgus and rhesus monkey T
cells (Waibler, 2008).
T cell proliferation and cytokine (IL‑2) release (Van Wauwe, 1980). These attributes are
dependent on the Fc portion, as is the super-
agonist property of TGN1412. Attempts to
reduce these undesirable effects have led to
many different anti-CD3 mAbs, including
HuM291, being engineered to reduce Fc-
mediated effects. These efforts have been
mostly unsuccessful. Both HuM291 and
OKT3 are known for inducing marked T cell
activation, depletion and cytokine release in
humans, yet absence of a cytokine release
syndrome in chimpanzees (Hsu, 1999, Kling-
beil, 1999, Rao, 1991). Catastrophic events
did not occur in clinical trials of these similar
mAbs because the trials were not conducted
in normal volunteers, used doses that were
much lower and enrolled patients one at a
time. [continued on page 5]
In Vitro Cytokine Release Assays: Useful for Forecasting Cytokine Storms?
By Christopher Horvath, DVM, MS, DACVP
Vice President of PreClinical Sciences
Taligen Therapeutics
2
Will you be there?
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at booth #802,
2009 AAPS National Biotechnology Conference
June 21-24, 2009 - Seattle, WA
Or call (858) 558-2599 x 436
to set up a meeting!
ABSTRACT
A universal approach for determining the
extractable and leachable metals in phar-
maceutical products by Inductively Cou-
pled Plasma Mass Spectrometry (ICPMS)
is investigated. This study examines di-
gestion strategies of both packaging ma-
terials and formulated products for com-
plete trace metals analysis. Packaging
materials and drug products are evaluated
for leachable metals by stressing the ma-
terials under accelerated stability condi-
tions. Trace metal profiles of 64 elements
for several different types of packaging
materials and some common pharmaceu-
tical products are reported.
The classical approach to Controlled Ex-
tractables analysis is to expose the mate-
rial to a specific solvent (ie. water, or-
ganic, buffer)1 for a period of time at an
elevated temperature and measure the
trace metal content. While this technique
is useful, it is limited by the quantitation
limit (QL) of each metal and the volume
and nature of solvent used. Also, certain
metals at extremely low levels may not be
detected, thus there is the potential for
their presence in the drug product to go
unnoticed.
The universal approach involves a com-
plete acid digestion of the packaging ma-
terial and drug product. Sample solutions
are then analysis by ICPMS. This combi-
nation provides reduced sample prepara-
tion time, increased sensitivity and a com-
plete metals profile as the ICPMS pro-
vides for elements not typically measured
by optical emission ICP. Based upon the
nature of these materials and potential
metals, a selection tree was developed for
the appropriate type of digestion and acid
mixture for several different materials and
some common pharmaceutical products.
Exposure of the packaging material and
drug product at accelerated stability condi-
tions then provides information into any
extractable or leachable that has migrated
from the packaging into the drug formula-
tion.
RATIONALE
The focus in Pharma for extractables and
leachables tends to be in the organic
area, in which pharmaceutical products
are evaluated for organic components
which may migrate to the product. This
paper however investigates the equally
important area of inorganic analysis with
regard to this concept.
Metals are known to have either a toxic
effect based on certain elements (ie. Al,
Cd, Cr, Cu, Pb, Mn, Zn)2 or can contribute
to interactions between APIs and excipi-
ents (ie. Fe, Zn, Cu, Mn)3.
A comprehensive method of evaluating
the entire metals profile then provides a
more effective means to determine the
potential metal extractables and leach-
ables over current limited extraction tech-
niques.
The concept of a universal or comprehen-
sive method of analysis for trace metals is
based upon evaluating the material of
interest for all potential contaminates.
Unfortunately, trace metal limits and toxic-
ity data can be confusing, as limits and
toxicity is reported in literature relative to
such things as drinking water or as an
exposure limit as an air contaminate. 5,6,7,8
DISCUSSION AND RESULTS
The decision tree provided illustrates a
systematic approach to digesting and
analyzing many different types of materi-
als for trace metals using simple to com-
plex acid digestions.
The universal approach (complete diges-
tion) lends itself to a vast and diverse set
of packaging materials, trace metals and
pharmaceutical products. Current extrac-
tion techniques such as USP <381> do
not accurately reflect the entire trace met-
als profile, as extraction by autoclave or
other solvent, then measuring turbidity,
pH, heavy metals (as Pb) and then resi-
due weight can not provide the same level
of information as a complete trace metals
profile nor does this information provide
any indication of toxicity or potential metal/
product interaction.
[continued on page 6]
Universal Approach in the Determination of Extractable and Leachable Metals in Phar-
maceutical Products by ICPMS
Daniel J. Zuccarello,
Michael P. Murphy,
Richard F. Meyer and
Paul A. Winslow
QTI Analytical Services
Analyte Result
(mg/g) Analyte
Result
(mg/g)
Ag < 0.1 Na 2.4%
Al 1.6% Nb 0.4
As 0.3 Nd 0.4
Au < 0.1 Ni < 0.1
B 5.5% P < 0.1
Ba 21 Pb 1.0
Be < 0.1 Pd 1.6
Bi 0.1 Pr 0.5
Ca 361 Pt < 0.1
Cd 0.5 Re < 0.1
Ce 8.8 Rh < 0.1
Co < 0.1 Ru < 0.1
Cr 0.2 Sb 0.5
Cs < 0.1 Sc < 0.1
Cu 0.1 Se 0.1
Dy < 0.1 Si > 30%*
Er < 0.1 Sm < 0.1
Eu < 0.1 Sn < 0.1
Fe 239 Sr 1.7
Ga 1.2 Ta < 0.1
Gd < 0.1 Tb 0.2
Ge 0.5 Te < 0.1
Hf 6.0 Th 0.2
Ho < 0.1 Ti 6.7
In < 0.1 Tl < 0.1
Ir 0.2 Tm < 0.1
K 0.1% U 0.3
La 2.5 V < 0.1
Li 0.2 W 0.1
Lu < 0.1 Y 2.8
Mg 61 Yb 0.1
Mn 0.2 Zn < 0.1
Mo 4.8 Zr 206
* Si value obtained by FLAA
Fig. 1 - Trace Metal Profile of Clear Glass
Nitric/HF Digestion
Fig. 2 - Trace Metal Profile of Butyl Rubber (Grey) Lyo/Serum Stopper Three Acid Digestion
Analyte Result (mg/g)
Analyte Result (mg/g)
Ag < 0.1 Na 87
Al 0.13 % Nb < 0.1
As 3.0 Nd 1.7
Au < 0.1 Ni 1.0
B 1.7 P 43
Ba 3.6 Pb 1.1
Be < 0.1 Pd < 0.1
Bi < 0.1 Pr 0.4
Ca 640 Pt < 0.1
Cd < 0.1 Re < 0.1
Ce < 1 Rh < 0.1
Co 0.2 Ru < 0.1
Cr 2.6 Sb < 0.1
Cs < 0.1 Sc < 0.1
Cu 2.3 Se < 0.1
Dy 0.4 Si 14
Er 0.2 Sm 0.3
Eu < 0.1 Sn 0.7
Fe 325 Sr 25
Ga 0.1 Ta < 0.1
Gd 0.4 Tb < 0.1
Ge < 0.1 Te < 0.1
Hf < 0.1 Th 0.2
Ho < 0.1 Ti 0.81 %
In < 0.1 Tl < 0.1
Ir < 0.1 Tm < 0.1
K 117 U 0.1
La 2.0 V 1.3
Li 9.3 W < 0.1
Lu < 0.1 Y 1
Mg 0.93 % Yb < 0.1
Mn 7.8 Zn 81
Mo < 0.1 Zr 0.7
QTI is a FDA and DEA registered contract Analytical R&D Laboratory, operating in
accordance with cGMP regulations and associated guidance documents.
Our services include Discovery Support, Method Development/Validations as well
as Stability and Pharmaceutical Testing.
For more information, please contact us or visit www.qtionline.com
4
P.O. Box 470
291 Route 22 East
Salem Industrial Park, Bldg. 5
Whitehouse, NJ 08888-0470
Phone: (908) 534-4445
[continued from page 2]
For many mAbs, confirmation of target expression and homology and
mAb recognition of the target in a nonhuman species was considered
sufficient proof of the relevance of the species for use in nonclinical
safety studies. TeGenero had met these requirements too. Since
publication of the findings that nonhuman primates and certain in
vitro assay configurations are poor predictors of human cytokine re-
lease there has been renewed interest in identifying relevant species
and “predictive” methods. Many Sponsors have reported being re-
quested by regulatory agencies to assess whether their biotherapeu-
tics are capable of eliciting in vitro cytokine release, and whether their
chosen species are relevant. These topics have been featured in
recent FDA and Industry meetings (FDA/CDER, 2008, BioSafe,
2008), and have been the basis for platform or workshop sessions at
professional society meetings, such as ACT, SOT, and STP. Pro-
posed methods for investigating in vitro cytokine release have in-
cluded evaluating cytokine gene activation (RNA message), intracel-
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-
tional Medicinal Products (EMEA/CHMP/SWP/28367/07). 2007.
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.
PK kits – vacutainers, collection tubes, trans-fer pipets, labels and collection sheets.
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
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(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
References available upon request
Extractable and Leachable Metals
6
Q: How does ALTA differ from your
past employers?
A: ALTA has a very efficient sample log-
in system set up and nice work flow. I
also enjoy the dynamics of our team
tremendously.
Q: What can a site or sponsor do to
keep the process smooth on your end?
A: Always provide an electronic mani-
fest with your sample shipment. This
not only reduces possibilities for man-
ual error, but also cuts accessioning
time by up to 80%! That way, any sam-
ple discrepancy can also be dealt with
immediately.
Q: What is the capacity of your de-
partment?
A: With the electronic manifest pro-
vided, we can accession 2,000— 3,000
samples per day into our Laboratory
Information Management System.
Q: What is your favorite part about
the job?
A: It is interesting to see the different
pre-clinical and clinical samples coming
in from various sites.
Featured
Employee
Ryan Pinilli
Current Position:
Manager, Accessioning,
ALTA Immunochemistry
Years of Service:
4 years
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Validation
• Sample Analysis for Phase I-IV Preclinical and
Clinical Development
• Rapid Turnaround for Discovery Bioanalysis
• Ocular Tissues and Fluids
• Pegylated Small Molecules and Peptides
• Dose Formulation and Analysis
QTI Analytical Services
Phone: (908) 534-4445
• Comprehensive Elemental Analysis
• Fully Analytical Method Development and
Validation
• Pharmaceutical Stability Testing and
Storage
• Compound Characterization
• Reference Standard material Programs
• Extractable and Leachables
2009 Events
June 1-4, 2009 American Society for Mass Spectrometry (57th ASMS Conference on Mass Spectrometry)
Philadelphia, PA July 13-17, 2009 10th Annual Land O’Lakes Bioanalytical Conference
Merrimac, WI September 14-17, 2009 Applied Pharmaceutical Analysis (APA/BSAT)
Boston, MA
2009 Events
May 4-6, 2009 Immunogenicity for Biotherapeutics Meeting
San Diego, CA June 21-24, 2009 2009 AAPS National Biotechnology Conference
Seattle, WA November 8-12, 2009 AAPS Annual Meeting and Exposition
Los Angeles, CA
2009 Events
July 27 - 31, 2009 Land of Lakes 49th Annual Conference on Pharmaceutical Analysis Devil’s Head Lodge,
Merrimac, WI
November 8-12, 2009 AAPS Annual Meeting and Exposition
Los Angeles, CA