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

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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

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The immunochemistry lab has extensive expertise in dealing with various types of

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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

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at booth #802,

2009 AAPS National Biotechnology Conference

June 21-24, 2009 - Seattle, WA

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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

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Immunogenicity

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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

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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.

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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.

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[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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• Bioanalytical Methods Development and

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