Biopharmaceutical materials

Humidity Control The humidity requirement for comfort is in the range of 30-60% relative humidity (RH). If process concerns suggest another value, it should be specified as soon as possible in the design process. Biopharmaceutical materials sensitive to humidity variations or excessively high or low values may require stringent controls. 

Chromatographic methods are widely used to describe the analytical properties of different types of biopharmaceutical materials. Size, shape, charge, and hydrophobi-city may each represent properties to be characterized and used to describe the purity, impurities and degradation products, as well as the dose in the case of proteins, for example. 

Membrane-retained components are collectively called concentrate or retentate. Materials permeating the membrane are called filtrate, ultrafiltrate, or permeate. It is the objective of ultrafiltration to recover or concentrate particular species in the retentate (eg, latex concentration, pigment recovery, protein recovery from cheese and casein wheys, and concentration of proteins for biopharmaceuticals) or to produce a purified permeate (eg, sewage treatment, production of sterile water or antibiotics, etc). Diafiltration is a specific ultrafiltration process in which the retentate is further purified or the permeable sohds are extracted further by the addition of water or, in the case of proteins, buffer to the retentate. 

BioProcess stainless-steel columns are fixed bed height columns designed for the most stringent requirements in the routine production of biopharmaceuticals. Wetted materials include stainless steel, polypropylene, and EPDM. The BPSS series may be operated at pressures up to 3 bar (0.3 MPa) and are supplied with sanitary fittings of 10 or 22 mm i.d. The available column sizes and specifications for the BPSS column series are given in Table 2.18. 

Purification of biopharmaceuticals often involves the removal of materials with physical characteristics very similar to the desired product, such as failure sequences from DNA synthesis or misfolded proteins from bacterial fermentations. The contaminants, however, may have biological characteristics very different from the desired product, including different antigenicities, bioactivities, and specificities. There are even systems in which the... 

As well as overcoming many of the inherent problems associated with agriculture, plant tissue culture also offers a number of advantages over conventional animal cell culture methods currently being applied to produce biopharmaceutical proteins commercially [8], As plant culture media are relatively simple in composition and do not contain proteins, the cost of the process raw materials is reduced and protein recovery from the medium is easier and cheaper compared with animal cell culture. In addition, as most plant pathogens are unable to infect humans, the risk of pathogenic infections being transferred from the cell culture via the product is also substantially reduced. 

Figure 4.9 Scale-up of proposed biopharmaceutical production process to generate clinical trial material, and eventually commercial product. No substantive changes should be introduced to the production protocol during scale-up...

Biopharmaceutical products are also subjected to screening for the presence of viral particles prior to final product release. Although viruses could be introduced, for example, via infected personnel during downstream processing, proper implementation of GMP minimizes such risk. Any viral particles found in the finished product are most likely derived from raw material sources. Examples could include HIV or hepatitis viruses present in blood used in the manufacture of blood products. Such raw materials must be screened before processing for the presence of likely viral contaminants. 

Contaminant-clearance validation studies are of special signibcance in biopharmaceutical manufacture. As discussed in Section 7.6.4, downstream processing must be capable of removing contaminants such as viruses, DNA and endotoxin from the product steam. Contaminant-clearance validation studies normally entail spiking the raw material (from which the product is to be purihed) with a known level of the chosen contaminant and subjecting the contaminated material to the complete downstream processing protocol. This allows determination of the level of clearance of the contaminant achieved after each purihcation step, and the contaminant reduction factor for the overall process. 

Of all the possible contaminants and impurities of a biopharmaceutical product, organisms (bacteria, virus, mycoplasma) and their products (DNA, endotoxin, host protein), media components, and raw materials, it is most appropriate to use an ELISA for the HCP impurities and some of the process residuals (media components and raw materials). Impurities from media components are known or expected unlike those from the host cell. 

Overall, the development of a robust formulation with scale-up potential for Phase II studies involves integration of physicochemical, biopharmaceutical, and technical considerations. Whether a rudimentary formulated capsule or a more robust formulation closer to the commercial form will be used in Phase II studies will depend on the company policy, material cost, the complexity of clinical design, and the development strategy. 

The discovery of pharmaceuticals commences with the scanning of hundreds of compounds, whether with actual materials (irrational approach) or virtual simulations (rational approach). To discover biopharmaceuticals, we have to examine the compounds within us, for example, hormones or other biological response modihers, and determine how they affect the biological processes. In some cases, we study pathogens such as the influenza virus or bacteria to derive the vaccines. In other cases, we copy these biological response modifiers and use them as replacement therapy. 

This is especially the case for biopharmaceutical production, because the soiled materials are normally protein based, and, unlike synthetic drugs, biopharmaceutical drugs are not generally subjected to terminal sterilization. 

Both pre-clinical and clinical trials are underpinned by a necessity to produce sufficient quantities of the prospective drug for its evaluation. Depending on the biopharmaceutical product, this could require from several hundred grams to over a kilo of active ingredient. Typical production protocols for biopharmaceutical products are outlined in detail in Chapter 3. It is important that a suitable production process be designed prior to commencement of pre-clinical trials, that the process be amenable to scale-up and, as far as is practicable, that it is optimized (Figure 2.9). The material used for pre-clinical and clinical trials should be produced using the same process by which it is intended to undertake final commercial-scale manufacture. 

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