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  • TEC12: What kind of qualification and quality assurance processes are needed for the use or maintenance of IVIG?
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What kind of qualification and quality assurance processes are needed for the use or maintenance of IVIG?

Authors: Jesús González-Enríquez, Nadine Berndt, Houria Mouas

Internal reviewers: Romana Tandara Haček, Mirjana Huic, Anna-Theresa Renner

Refer to domain search and domain methodology section.

Manufacturing and Preparation

Quality controls are required to guarantee the consistency of IVIG batches and to limit the risks of adverse reactions that have shown to be linked to the presence of certain proteins (e.g. IgA) or to biological⁄ microbial (e.g. endotoxins) or chemical (e.g. residues of viral inactivation treatments) impurities. A set of quality control assays are needed to guide manufacturers in the development of IVIG preparations, to control the conditions of production and to guarantee the quality, safety and consistency of the products. In fact, international and national Pharmacopoeias define quality assays that must be performed by manufacturers, and all assay methods should be validated {WHO, 2013} {38}. Reference preparations and WHO standards, based on plasma preparations or purified fractions, are available from the National Institute for Biological Standards and Control (NIBSC, UK), the Center for Biologics Evaluation and Research, Food and Drug Administration (CBER ⁄FDA, US), or from the European Directorate for the Quality of Medicines and HealthCare (EDQM, France). Batches should comply with the quality specifications defined and approved from regulators in the marketing authorization file of each product. Since IVIG products are manufactured using components of human blood, they may potentially contain the causative agents of hepatitis and other viral diseases, potentially even Creutzfeldt-Jacob Disease (CJD). For that reason prescribed manufacturing procedures at the plasma collection centers and plasma-testing laboratories need to be designed in that way that they reduce the risk of transmitting viral infection. Risk reducing measures include careful selection of donors for plasma pools, testing for viral markers at multiple stages which allow for the detection of plasma viruses {Baxter, 2011}{36}, and the application of rigorously validated methods of testing. Quality controls for plasma derivatives include determination of chemical parameters (like pH), protein content, content of stabilizers and residues of chemicals used for the production or viral inactivation and various safety parameters (e.g. protein identity, visual appearance) {Radosevich M, 2010}{39}.

Maintenance, storage and transport

Immunoglobulin products are supplied as solutions or as lyophilized products that need to be stored appropriately. Some IGs products require refrigeration whereas others can be stored at room temperature. As such, lyophilized products are generally stored at room temperature before reconstitution. However, all liquid IVIG products optimally require refrigerated transport and storage between 2°C and 8°C. Lower temperatures are likely to damage the product, and any IVIG liquid which has been frozen should be discarded {NZ Clinical Immunology Group, 2013}{32}. IVIG products should ideally be stored in accredited blood fridges that meet required standards. Domestic fridges and ward fridges should not be used for storage since these refrigerators are not closely monitored and accepted temperature range cannot be guaranteed. Blood products should be transported in dedicated and validated containers and be stored within glass containers, which are closed with rubber stoppers {ACT Health, 2013}{33}. It is important to follow the manufacturer’s specifications regarding storage of each product, since the recommendations may vary per IG product {NZ Clinical Immunology Group, 2013}{32}. While being stored and transported, the IVIGs should be protected from light {ACT Health, 2013}{33}.

Examples for Storage:

Kiovig (Baxter)

- Store in a refrigerator for the duration of the shelf life (36 months) (2°C – 8°C). Do not freeze.

- At room temperature: Kiovig may be stored at room temperature (below 25°C) for up to 12 months within the first 24 months. However, once stored at room temperature, the product must remain stored at room temperature and must be used within the first 24 months from the date of manufacture. The total storage time of Kiovig depends on the point of time the vial is transferred to room temperature. The new expiration date must be recorded on the package when the product is transferred to room temperature. Product cannot be stored at room temperature after 24 months from date of manufacture. Once the product has been stored at room temperature, the product should not be re-refrigerated {Baxter, 2011} {36}.

Octagam (Octapharma)

- Store in a refrigerator for the duration of the shelf life (48 months) (2°C – 8°C). Do not freeze.

- At room temperature: Octagam may be removed from the refrigerator for a single period of up to 3 months (without exceeding the expiry date) and stored at a temperature below 25°C. At the end of this period, the product should not be refrigerated again and should be disposed of {Octapharma, 2014} {35}. In certain cases, Octagam may be stored for 24 months at +2°C to +25°C from the date of manufacture {Octapharma, 2007} {34}. The date at which the product was taken out of the refrigerator should be recorded {Octapharma, 2014} {35}.

Use and documentation

Before administering IVIGs, it needs to be sure that the patient is not allergic to IGs, and not to the any of the ingredients in the product. Appropriate vaccinations should be considered for immune competent patients who receive regular/repeated treatment with IVIGs {Octapharma, 2014}{35}. It is strongly recommended that every time the patient receives a dose of IVIG the name, dose and batch number of the product are recorded in order to maintain a record of the batches used. The integrity (protective seals) and the quality of the product should always be assessed. IVIG products should not be used if the solution is cloudy, has deposits or is colored intensively. If the protective seals are not intact, the dispensing pharmacy should be notified and the product should not be given. The products should neither be used after the expiry date stated on the label {Octapharma, 2014; Baxter, 2011}{35,36}. All (refrigerated) products should be at room temperature before infusion, as adverse effects can be associated with the administration of products that are too cold. The products should be allowed to brought to room temperature by themselves and not by heating (e.g. in microwave) since this may degrade the product. However, once a product has been brought to room temperature it may not be returned to the fridge. The date the product is removed from refrigeration should be noted on the packet. It is important to note that each product should be administered once removed from refrigeration and it is for a single use in one patient only, and therefore any remaining product should be discarded and recorded as such {Baxter, 2011}{36}.

IVIG products are not generic and there are notable differences among them. They must be considered as individual therapies and choice of or decision to change a particular IVIG product needs to be done with caution {Gelfand EW, 2005; 2006}{40,41}. In the case of the product is diluted, the preparation should be used as soon as practicable, in order to reduce microbiological hazard, as the product does not contain antimicrobial preservative. If storage is necessary, the diluted preparation should be stored at 2°C to 8°C for not more than 24 hours. It is possible for lyophilized products to be prepared at more than one concentration depending on the amount of diluent added. Possibilities for different concentrations should however be specified in the manufacturer’s prescribing information. Lyophilized products should ideally be reconstituted in the infusion clinic. It is critically important to be aware of and to follow manufacturer’s guidelines, prescriber’s orders and aseptic technique when reconstituting these products {Younger MEM, 2012}{37}. IVIGs should be administered through a designated intravenous infusion, and should not be mixed with other medications or piggybacked into other infusions {Baxter, 2011}{36}. Since sterility of the IVIG is a concern, the solution should not be reconstituted until IV access has been established and it is ready to be administered. After adding the appropriate diluent to the powder by gently rotations, the vials should not be shaken to mix the solution, since this may damage the immunoglobulin proteins. Instead, the diluent should be able to dissolve the powder. It may take 5 up to 20 minutes for the powder to completely be absorbed into solution. Depending on the manufacturer, IVIG may only be stable in solution for a few hours {Rosenthal K, 2007}{42}

Another quality assurance process includes detailed documentation of IVIG infusions. This should include the patient’s current health status and any changes in this status in the period between IVIG infusions; the name, dose and the lot numbers of the product; any pre-medications which were given; time duration of infusion and specific rate titrations which were made; and any problems or adverse reactions the patient experienced during the infusion and how they were managed {Younger MEM, 2012}{37}.

González-Enríquez J et al. Result Card TEC12 In: González-Enríquez J et al. Description and technical characteristics of technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 30 June 2022]. Available from: