Plasma fractionation processes

VALIDATION STRATEGIES FOR EXISTING PLASMA FRACTIONATION PROCESSES... 

In 1999, a Technical Workshop was held by the Parenteral Drug Association (PDA) to come up with a reasonable strategy for the validation of existing plasma fractionation processes. The workshop and subsequent effort by many led to a set of guidelines for the validation of existing plasma fractionation processes (3) that are shown below ... 

Technical Workshop Validating Plasma Fractionation Processes, PDA, February 8-9, Bethesda, MD. 

Bastek etal also tested the ability of the identified affinity peptides to purify aj-PI from effluent 11 -i- 111, a process intermediate of the Cohn plasma fractionation process with eight major protein constituents. Several of the peptides achieved yields of 70-80% with purities ranging from 42% to 77%. Purification using these peptides matched or exceeded yields and purities reported in the literature using ion exchange chromatography. 

Human blood plasma contains over 700 different proteins (qv) (1). Some of these are used in the treatment of illness and injury and form a set of pharmaceutical products that have become essential to modem medicine (Table 1). Preparation of these products is commonly referred to as blood plasma fractionation, an activity often regarded as a branch of medical technology, but which is actually a process industry engaged in the manufacture of speciaUst biopharmaceutical products derived from a natural biological feedstock (see Pharmaceuticals). 

History. Methods for the fractionation of plasma were developed as a contribution to the U.S. war effort in the 1940s (2). Following pubHcation of a seminal treatise on the physical chemistry of proteins (3), a research group was estabUshed which was subsequendy commissioned to develop a blood volume expander for the treatment of military casualties. Process methods were developed for the preparation of a stable, physiologically acceptable solution of alburnin [103218-45-7] the principal osmotic protein in blood. Eady preparations, derived from equine and bovine plasma, caused allergic reactions when tested in humans and were replaced by products obtained from human plasma (4). Process studies were stiU being carried out in the pilot-plant laboratory at Harvard in December 1941 when the small supply of experimental product was mshed to Hawaii to treat casualties at the U.S. naval base at Pead Harbor. On January 5, 1942 the decision was made to embark on large-scale manufacture at a number of U.S. pharmaceutical plants (4,5). 

Full details of this work were pubHshed (6) and the processes, or variants of them, were introduced in a number of other countries. In the United States, the pharmaceutical industry continued to provide manufacturing sites, treating plasma fractionation as a normal commercial activity. In many other countries processing was undertaken by the Red Cross or blood transfusion services that emerged following Wodd War II. In these organisations plasma fractionation was part of a larger operation to provide whole blood, blood components, and speciaUst medical services on a national basis. These different approaches resulted in the development of two distinct sectors in the plasma fractionation industry ie, a commercial or for-profit sector based on paid donors and a noncommercial or not-for-profit sector based on unpaid donors. 

Plasma fractionation is unusual in pharmaceutical manufacturing because it involves the processing of proteins and the preparation of multiple products from a single feedstock. A wide range of unit operations are utilized to accompHsh these tasks. They are Hsted in Table 3 some are common to a number of products and all must be closely integrated. The overall manufacturing operation can be represented as a set of individual product streams, each based on the processing of an intermediate product derived from a mainstream fractionation process (Fig. 1). 

Fig. 2. Typical plasma fractionation operation where Fr represents fraction. Based on processes at the Protein Fractionation Centre, Scottish National...

Process Rationale. The products of plasma fractionation must be both safe and efftcaceous, having an active component, protein composition, formulation, stabiUty, and dose form appropriate to the intended clinical appHcation. Processing must address a number of specific issues for each product. Different manufacturers may choose a different set or combination of unit operations for this purpose. 

Estimates for a number of economic aspects of plasma fractionation can be made (200—206). The world capacity for plasma fractionation exceeded 20,000 t of plasma in 1990 and has increased by about 75% since 1980, with strong growth in the not-for-profit sector (Fig. 4). The quantity of plasma processed in 1993 was about 17,000 t/yr the commercial sector accounts for about 70% of this, with over 8000 t/yr in the form of source plasma from paid donors (Fig. 5). Plant capacities and throughput are usually quoted in terms of principal products, such as albumin and Factor VIII. These figures may not encompass manufacture of other products. 

Fractionation. See also Plasma fractionation foam, 12 22 physical, 10 813-814 Fractionation methods, for particle size measurement, 18 139, 140-146 Fractionation process, in paper recycling, 21 441... 

A characteristic of the plasma etching process which is generally observed is that the etch rate of a sample decreases as the area of the sample exposed to the plasma increases This dependence of etch rate on batch size is referred to as the loading effect and an example is shown in Fig. 3.8. The reason for the loading effect is simply that the etching process consumes a significant fraction of the... 

Anticoagulants - [BLOOD, COAGULANTS AND ANTICOAGULANTS] (Vol 4) - [PROSTHETIC AND BIOMEDICALDEVICES] (Vol 20) -in ceramic processing [CERAMICS - CERAMIC PROCESSING] (Vol 5) -use in blood fractionation [FRACTIONATION, BLOOD - PLASMA FRACTIONATION] (Volll)... 

An example of the problem is the FDA recommendation that the manufacturing process for all plasma products incorporate new viral inactivation or segregation steps to reduce the risk of transmitting enveloped viruses such as HIYand Hepatitis B and C. However, the FDA also required the plasma fractionators to compare old product to new product in large... 

The properties of plasmas vary strongly with gas composition, pressure and the method and parameters of the plasma generation process. The charge carrier concentration depends on the pressure and the fractional ionization of the plasma, for instance basically on the power density. The mobility of the electrons depends on the electron temperature, which is typically several orders of magnitudes greater than the gas temperature or the temperature of the ionized species in non-thermal low temperature plasmas used for electrochemical purposes. 

However, it must be pointed out that most of these studies cited in Table 3 were performed in blood-perfused models. In buffer-perfused models, PBN adduct formed in coronary effluents could be extracted into toluene within seconds. On the contrary, in blood-perfused models, the whole-blood samples require centrifugation to obtain plasma fractions that are then extracted into solvents. The processing of blood samples involves a delay time of several minutes. Therefore, it can be argued that PBN/ OH would not survive the delay time for sample processing. The actual half-life of PBN/ OH in the blood is, however, not known. 

In a capactlvely coupled system the flow rate into the plasma is not known as precisely as for the systems described above. This is because not all monomer feed must drift into the inter-electrode gap. On the other hand the flow into the gap cannot be obtained from the knowledge of the fraction of reactor volume the inter-electrode gap represents, because the plasma polymerization process acts as a pump. 

Friedli, H. Fournier, E. Volk, T. Kistler P. "Studies on New Process Procedures in Plasma Fractionation on an Industrial Scale" Vox Sang. 1976, 31, pp 283-288. Hallstrom, B. Lopez-Leiva M. "Description of a Rotating Ultrafiltration Module" Desalination. 1978, 24, pp 273-279. 

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