Final product fill

An overview of a typical final product filling process is presented in Figure 6.23. The bulk final product first undergoes QC testing to ensure its compliance with bulk product specifications. Although implementation of good practices during manufacturing will ensure that the product carries a low microbial load, it will not be sterile at this stage. The product is then passed through a (sterilizing) 0.22 ^m filter (Figure 6.24). The sterile product is housed (temporarily) in a sterile-product holding tank, from where it is aseptically filled into pre-sterile final product containers (usually glass vials). The filling process normally employs highly automated liquid filling systems. All items of equipment, pipework, etc. with which the sterilized product comes into direct contact must obviously themselves be sterile. Most such equipment items may be sterilized by autoclaving, and be aseptically assembled prior to the filling operation (which is undertaken under Grade A laminar flow conditions).

Figure 6.23 Final product filling. The final bulk product (after addition of excipients and final product QC testing), is filter sterilized by passing through a 0.22 |im filter. The sterile product is aseptically filled into (pre-sterile) final product containers under grade A laminar flow conditions. Much of the filling operation uses highly automated filling equipment. After filling, the product container is either sealed (by an automated aseptic sealing system), or freeze-dried first, followed by sealing

Figure 6.23 Final product filling. The final bulk product (after addition of excipients and final product QC testing), is filter sterilized by passing through a 0.22 |im filter. The sterile product is aseptically filled into (pre-sterile) final product containers under grade A laminar flow conditions. Much of the filling operation uses highly automated filling equipment. After filling, the product container is either sealed (by an automated aseptic sealing system), or freeze-dried first, followed by sealing

Figure 6.24 Photographic representation of a range of filter types and their stainless steel housing. Most filters used on an industrial scale are of a pleated cartridge design, which facilitates housing of maximum filter area within a compact space (a). These are generally housed in stainless steel housing units (b). Some process operations, however, still make use of flat (disc) filters, which are housed in a tripod-based stainless steel housing (c). All photographs courtesy of Pall Life Sciences, Ireland

Figure 6.24 Photographic representation of a range of filter types and their stainless steel housing. Most filters used on an industrial scale are of a pleated cartridge design, which facilitates housing of maximum filter area within a compact space (a). These are generally housed in stainless steel housing units (b). Some process operations, however, still make use of flat (disc) filters, which are housed in a tripod-based stainless steel housing (c). All photographs courtesy of Pall Life Sciences, Ireland

The final product containers must also be pre-sterilized. This may be achieved by autoclaving or passage through special equipment that subjects the vials to a hot WFI rinse, followed by sterilizing dry heat and UV treatment.

Figure 6.24 (Continued)

Figure 6.24 (Continued)

6.9.4 Freeze-drying

Freeze drying (lyophilization) refers to the removal of solvent directly from a solution while in the frozen state. Removal of water directly from (frozen) biopharmaceutical products via lyophi-lization yields a powdered product, usually displaying a water content of the order of 3 per cent. In general, removal of the solvent water from such products greatly reduces the likelihood of chemical/biological-mediated inactivation of the biopharmaceutical. Freeze-dried biopharmaceu-tical products usually exhibit longer shelf lives than products sold in solution. Freeze-drying is also recognized by the regulatory authorities as being a safe and acceptable method of preserving many parenteral products.

Freeze-drying is a relatively gentle way of removing water from proteins in solution. However, this process can promote the inactivation of some protein types, and specific excipients (cryopro-tectants) are usually added to the product in order to minimize such inactivation. Commonly used cryoprotectants include carbohydrates (such as glucose and sucrose), proteins (such as HSA), and amino acids (such as lysine, arginine or glutamic acid). Alcohols/polyols have also found some application as cryoprotectants.

The freeze-drying process is initiated by the freezing of the biopharmaceutical product in its final product containers. As the temperature is decreased, ice crystals begin to form and grow. This results in an effective concentration of all the solutes present in the remaining liquid phase, including the protein and all added excipients. For example, the concentration of salts may increase to levels as high as 3 mol l-1. Increased solute concentration alone can accelerate chemical reactions damaging to the protein product. In addition, such concentration effectively brings individual protein molecules into more intimate contact with each other, which can prompt protein-protein interactions and, hence, aggregation.

As the temperature drops still lower, some of the solutes present may also crystallize, thus being effectively removed from the solution. In some cases, individual buffer constituents can crystallize out of solution at different temperatures. This will dramatically alter the pH values of the remaining solution and, in this way, can lead to protein inactivation.

As the temperature is lowered further, the viscosity of the unfrozen solution increases dramatically until molecular mobility effectively ceases. This unfrozen solution will contain the protein, as well as some excipients, and (at most) 50 per cent water. As molecular mobility has effectively stopped, chemical reactivity also all but ceases. The consistency of this 'solution' is that of glass, and the temperature at which this is attained is called the glass transition temperature Tg. For most protein solutions, Tg - values reside between -40 °C and -60 °C. The primary aim of the initial stages of the freeze-drying process is to decrease the product temperature below that of its Tg - value and as quickly as possible in order to minimize the potential negative effects described above.

The next phase of the freeze-drying process entails the application of a vacuum to the system. When the vacuum is established, the temperature is increased, usually to temperatures slightly in excess of 0 °C. This promotes sublimation of the crystalline water, leaving behind a powdered cake of dried material. Once satisfactory drying has been achieved, the product container is sealed.

The drying chamber of industrial-scale freeze dryers usually opens into a cleanroom (Figure 6.23). This facilitates direct transfer of the product-containing vials into the chamber. Immediately prior to filling, rubber stoppers are usually partially inserted into the mouth of each vial in such a way as not to hinder the outward flow of water vapour during the freeze-drying process. The drying chamber normally contains several rows of shelves, each of which can accommodate several thousand vials (Figure 6.25). These shelves are wired to allow their electrical heating, cooling, and their upward or downward movement. After the freeze-drying cycle is complete (which can take 3 days or more), the shelves are then moved upwards. As each shelf moves up, the partially inserted rubber seals are inserted fully into the vial mouth as they come in contact with the base plate of the shelf immediately above them. After product recovery, the empty chamber is closed and is then heat-sterilized (using its own chamber-heating mechanism). The freeze-drier is then ready to accept its next load.

6.9.5 Labelling and packing

After the product has been filled (and sealed) in its final product container. QC personnel then remove representative samples of the product and carry out tests to ensure conformance to final product specification. The most important specifications will relate to product potency, sterility and final volume fill, as well as the absence of endotoxin or other potentially toxic substances. Detection and quantification of excipients added will also be undertaken. Product analysis is considered in Chapter 7.

Only after QC personnel are satisfied that the product meets these specifications will it be labelled and packed. These operations are highly automated. Labelling, in particular, deserves special attention. Mislabelling of product remains one of the most common reasons for product recall. This can occur relatively easily, particularly if the facility manufactures several different products, or even a single product at several different strengths. Information presented on a label should normally include:

Figure 6.25 Photographic representation of (a) laboratory-scale, (b) pilot-scale freeze-driers. Refer to text for details. Photograph courtesy of Virtis, USA

and (c) industrial-scale

Figure 6.25 (Continued)

• name and strength/potency of the product;

• specific batch number of the product;

• date of manufacture and expiry date;

• storage conditions required.

Additional information often presented includes the name of the manufacturer, a list of excipients included and a brief summary of the correct mode of product usage.

When a batch of product is labelled and packed, and QC personnel are satisfied that labelling and packing are completed to specification, the QC manager will write and sign a 'Certificate of Analysis'. This details the predefined product specifications and confirms conformance of the actual batch of product in question to these specifications. At this point, the product, along with its Certificate of Analysis, may be shipped to the customer.

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