QA guidelines for blood products

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methods of viral removal, viral inactivation, process design and new techniques of viral removal from blood products

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QUALITY ASSURANCE GUIDELINES OF HUMAN BLOOD PRODUCTS:

QUALITY ASSURANCE GUIDELINES OF HUMAN BLOOD PRODUCTS Prepared by:- Ankit Gupta M. Pharm (QA) student

INTRODUCTION:

INTRODUCTION Human blood is the source of a wide range of medicinal products used for the prevention and treatment of a variety of often life-threatening injuries and diseases. Despite measures such as donor selection, testing of donations and of plasma pools, the transmission of blood-borne viruses by plasma and purified plasma products is still considered to constitute a risk to patients. Several procedures for virus inactivation and removal have proven to be robust and to contribute substantially to blood product safety.

Cont…:

Cont… The transmission of blood-borne viruses by plasma and purified plasma products is considered to constitute a risk to patients. The chances of transmission viral e.g. hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is still a serious problem in many areas of the world. The overall goal of the National Regulatory Authorities is to ensure that only blood products of demonstrated quality, safety and efficacy should be used.

Challenges and Issues: :

Challenges and Issues: To strengthen National Regulatory Authorities on quality assurance systems for the control of quality and safety of blood products. Need to assure quality and safety of blood and plasma globally to prevent transmission of blood-borne viral diseases via blood products. To facilitate access to and appropriate use of WHO International Reference Materials by national control laboratories or designated laboratories and manufacturers in developing countries. To promote support for the implementation of new manufacturing technologies to avoid viral contamination and other infectious agents via blood products .

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Categories of Human Blood products Concentrated red blood corpuscles. Platelets concentrates Granulocytes concentrates Fresh frozen plasma Cryoprecipitate ( concentrate of anti hemophiliac factor)

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Process of blood product Collection of blood for fractionation Inactivation of virus Pasteurization of albumin Heating of dry (lyophilized) products Heating of lyophilized products under humidified conditions (vapour heating) Solvent/detergent treatment 3 . Method of virus removal By precipitation By Nanofiltration

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Collection of blood for fractionation Plasma shall be collected form license Blood Banks and store in frozen condition at -20 °C Individual plasma shall remain in quarantine till it is tested for Hepatitis B, Hepatitis C, HIV I, HIV II Individual plasma unit shall be tested and if sample is found negative, then shall be taken up for fractionation.

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Method of Virus Inactivation Pasteurization of albumin Albumin solutions are heated as a liquid at 60 ± 0.5 °C for 10–11 hours. Sterile filtration and dispensing into final containers (glass vials). To prevent denaturation of albumin, low concentrations of sodium caprylate alone or with n acetyl tryptophan are added. Infectious virus can no longer be detected after 10 minutes of treatment.

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Heating of dry (lyophilized) products Heating at 80 °C has produced favourable results with respect to transmission of HBV, HCV, HIV and HAV. But it leads to inactivation of coagulation factor. To prevent it, manufacturer has been treating coagulation factor with solvent/detergent. Also heats final product for 30 minutes at 100 °C.

Heating of lyophilized products under humidified conditions (vapour heating):

Heating of lyophilized products under humidified conditions (vapour heating) A higher level of virus inactivation can be achieved by the addition of water vapour before initiating the heat cycle. The freeze-dried product is transferred into a stainless steel tank where an amount of water vapours is slowly added to adjust the water content to 7–8% (w/w). The tank is flushed with dry nitrogen to remove oxygen, and a pressure test is performed to ensure that the cylinder is airtight.

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This cylinder is then transferred to a heating cabinet equipped with an electric heater and heated according to the temperature regimen specified for the particular product. After vapour heating, the heating cabinet is opened from the other side, and the product is further processed . Cont…

Solvent/detergent treatment:

Solvent/detergent treatment The conditions typically used are 0.3% tri(n-butyl) phosphate (TNBP) and 1% nonionic detergent, either Tween 80 or Triton X-100. At 24 °C Organic solvent/detergent mixtures disrupt the lipid membrane of enveloped viruses. Once disrupted, the virus can no longer bind to and infect cells. For a minimum of 4 hours with Triton X-100, or 6 hours with Tween 80.

Method of virus removal 1. By precipitation:

Method of virus removal 1. By precipitation Precipitation with ethanol is the single most widely used plasma fractionation tool worldwide. Viruses, as large structures, tend to precipitate at the beginning of the fractionation process when the ethanol concentration is still relatively low. Many manufacturers separate the precipitated proteins by centrifugation whereas others have introduced filtration as an alternative. To prevent clogging of the filters, filtration is carried out using filter aids. Because these substances (diatomaceous earth or similar products) also adsorb virus.

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2. By Nanofiltration Nanofiltration removes viruses according to their size- particularly those that tend to form aggregates. Effective removal requires that the pore size of the filter be smaller than the effective diameter of the virus. Filters with a pore size that exceeds the virus diameter may still remove some virus if it is aggregated such as by inclusion in antibody/ antigen or lipid complexes.

Cont..:

Cont.. Careful monitoring of the performance of the nanofilters in every run is mandatory. Filter integrity should be ascertained before and after use, and every filter manufacturer offers test methods that have been developed specifically for this purpose. E.g.- Membranes with 15 and 35 nm pore size were reported to removal of murine xenotropic retrovirus, SV40 and pseudorabies virus from IgG and IgM solutions.

Process design:

Process design The benefit of viral inactivation and removal will be negated if the plasma fractions from preceding steps are permitted to recontamination the intermediates or products that follow; thus, the manufacturer must describe how the operating procedures reduce the likelihood of cross-contamination. Usually, decisions are made after a multidisciplinary team consisting of responsible staff from manufacturing, engineering, quality assurance and microbiology has made its recommendations. The following points illustrate how some manufacturers have addressed these cross-contamination issues.

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Cont… In-process/bulk virus inactivation (e.g. solvent/detergent, low pH, pasteurization) If bacterial growth during virus inactivation is a consideration, the solution is sterile- filtered (pore size 0.45mm or less) before treatment. On completion of the first stage of inactivation, the product is aseptically transferred (sterile coupling) into the second vessel, which is located in a safety zone, for completion of the second stage of viral inactivation.

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Cont.. All processing after virus inactivation and prior to sterile filtration and dispensing (e.g. removal of solvent/detergent or stabilizers and further purification steps) are carried out in the safety area. All the equipment used in the safety area that is in contact with the product must be GMP certified which will not recontaminate the product.

Review of newer viral inactivation methods under development:

Review of newer viral inactivation methods under development Psoralen –treated fresh frozen plasma Irradiation with ultraviolet light- Typically at a wavelength of 254nm targets nucleic acid, thus a wide variety of viruses are inactivated irrespective of the nature of their envelope. Viruses containing single stranded nucleic acids are more sensitive, because they are unable to repair damage in the absence of a complementary strand.

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Cont.. 3. Gamma-irradiation- The principal challenge in using gamma irradiation is the inactivation of the desired quantity of virus while maintaining the structural and functional integrity of blood protein. 4. Iodine - Iodine is a strong oxidizing agent and, as a result, is a powerful microbicidal agent. However, in its free form iodine is not sufficiently selective. When bound to polymers, such as polyvinylpyrrolidone, cross-linked starch the virucidal action of iodine is more controlled.

References::

References: International Conference on Harmonization. ICH Topic Q5A: Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin, adopted 1997. WHO Guidelines on Transmissible Spongiform Encephalopathies in relation to Biological and Pharmaceutical Products, Geneva, Switzerland. February 2003. Available on the Internet at: http://www.who.int/biologicals . Schreiber GB et al. The risk of transfusion-transmitted viral infections. New England Journal of Medicine, 1996, 334:1685–1690

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