Identifying Risks. Finding Solutions.

An unmet Need

Hypersensitivity Reactions (HSRs), stemming from drug infusion and medical device usage can range in severity from minor skin rash to anaphylactic shock and death. Globally, more than 3% of patients develop HSRs to marketed therapies, and the occurrence of HSRs in clinical trials can be not only dangerous for patients, but project ending and often bankrupting for companies. With the development of new and more complex therapies that are highly susceptible to HSRs, the need for preclinical HSR testing is growing. World leading health authorities, such as the FDA, EMA and WHO, acknowledge the adverse nature of these events and the need for improved prevention and management.

The CARPA Assay

SeroScience’s professional suite of immunotoxicology services center on complement activation, the innate immune system’s first-line defense against foreign objects and a system capable of eliciting anaphylaxis. The assay is named Complement Activation Related Pseudoallergy (CARPA); it is a pseudoallergic reactions because it is not IgE mediated. Our proprietary porcine model and testing protocols enable high-resolution studies of complement activation pathway-mediated HSR and the associated physiologic read-outs, providing detailed insight into the intensity with which the human complement system will react to a foreign object (drug or device). More than 20 years of supporting in vivo studies have demonstrated our proprietary system to be extremely accurate in quantifying the level of reaction expected to occur in a human as well as to develop clear guidance on appropriate dose concentration, allowing us to create custom administration protocols to mitigate undesired reactions.

In partnership with Dartmouth College, Semmelweis University and Aurigon GmbH, the SeroScience Group offers the CARPA Assay under GLP, GLP-like, or non-GLP standards depending on your needs and budget. The experiment is usually conducted on minipigs or juvenile domestic pigs (the most sensitive platforms), but may also be conducted in dogs, rats and mice depending on experiment design and purpose.

During the experiment the following parameters are acquired and analyzed:

CARPA Model.jpg
  • Pulmonary Arterial Pressure (PAP)

  • Systemic Arterial Pressure (SAP)

  • Cardiac Output (CO)

  • Heart rate (HR)

  • Electrocardiogaphy (ECG)

  • Expiratory/end-tidal Carbon Dioxide pressure (pCO2)

  • All Blood Cell Counts

  • White Blood Cell (WBC) differential

  • Coagulation Parameters

  • Skin reactions (rash, flushing)


Complement measurements are recommended and widely applied for the hemocompatibility testing of medical devices, as regulated in ISO 10993-4. ISO-1093

The U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) lists testing for complement activation among the recommended immunotoxicological as follows:  

"A pseudoallergic reaction can result from activation of inflammatory or anaphylactic mechanisms independent of antigen-specific immune responses. Pseudoallergy is known to have several causes, including but not limited to direct histamine release and complement activation (Descotes, 1986; Szebeni, 2001). This reaction is likely to be dose-related. If signs of anaphylaxis are observed in animal studies, follow-up studies should be considered. Anaphylactoid reaction can be differentiated from true IgE mediated anaphylaxis by various methods, including in vitro testing (e.g., drug-induced histamine release using a mast cell line) (Baxter et al., 1993; Toyoguchi et al., 2000). Biochemical markers of an anaphylactoid reaction can be observed in nonclinical toxicology studies (e.g., detection of serum anaphylactic complement products in animals showing signs of anaphylaxis) (Szebeni, 2001). Careful evaluation of these reactions has resulted in valuable information on biochemical markers used in clinical trials.”  See Guidance for Industry 2002.

A peer-reviewed publication referencing the above guideline also specifically comments on the phenomenon (Hastings KL 2002 Int Immunopharmacol).

The EMA refers to complement activation as a potential mechanism when adverse reactions occur upon administration of biotechnology-derived products in ICH guideline S6 (R1):  "incidence and/or severity of adverse effects, complement activation, or the emergence of new toxic effects should be considered when interpreting the data.”  See EMA CHMP ICH 731268 1998.


  • ISO 10993-4: Biological evaluation of medical devices — Part 4: selection of tests for interaction with blood, ANSI/AAMI/ISO 10993-4:2002/(R) 10 March 2009, 2009.

  • Guidance for Industry, Immunotoxicology Evaluation of Investigational New Drugs”, October 2002.

  • Hastings KL, Center for Drug Evaluation and Research, US Food and Drug Administration. Implications of the new FDA/CDER immunotoxicology guidance for drugs. Int Immunopharmacol. 2002 Oct;2(11):1613-8.

  • Preclinical safety evaluation of biotechnology-derived pharmaceuticals EMA/CHMP/ICH/731268/1998; Committee for medicinal products for human use (CHMP); June 2011)

  • Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, Patni S, Szebeni J, Weiss G. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-6.




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