**5. IVIG preparations**

In recent years, manufactures aim to develop products that provide a high-yield, safe, well tolerated and stable concentrates of polyclonal IgG. Each new intravenous immunoglobulin product has to be tested for its biochemical characterization done by standart methods focusing on purity, integrity and functionality. Efficacy must be shown by opsonization, protein A affinity chromatography and mouse protection tests. Pharmacokinetics of the product, the influence of product on vital functions, acute toxicity, anaphylactoid potential, thrombogenicity should be evaluated in rats, dogs or a rabbit models. Development of new methods for fractionation, combining processes and integrating three dedicated virus clearance steps provided fulfilling the clinical requirements for intravenous administration of second-generation intravenous immunoglobulins products (Table 2) [21].

The US Food and Drug Administration (FDA) standardized clinical trials with IVIG in patients with primary immunodeficiencies. FDA has proposed to measure the rate of serious bacterial infections during regular infusions of investigational IVIG for 12 months to avoid seasonal variations. Serious bacterial infection term has to be well defined, thus bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess were defined as serious infections [8].

The guidelines for clinical Investigation of human normal Immunoglobulin for Intravenous administration of the European Medicines Agency (EMA/CHMP/BPWP/94033/2007 rev.2) and FDA recommended that an immunoglobulin product is effective if treated patients experience less than 1.0 serious infection per year [21,34]. A new IVIG product must have 'intact IgG' which means pharmacokinetic properties of Immunoglobulin G is similar to endogeneous IgG and available other immunoglobulin preparations.
