Liquids

Although tacitly acknowledged for some time, only during the last few years have both industry experts and regulatory authorities fully acknowledged that humans working in cleanrooms are the chief source of microbial contamination. Because humans are the only significant source of contamination, it follows that they are also the greatest obstacles to the achievement of sterility assurance. It is logical, then, that contamination control technologies currently described as "advanced" focus on enhancing the control of human contamination.

For at least 20 years, the global parenteral industry has recognized that personnel are the dominant risk relative to microbial contamination in aseptically produced sterile products (1). The contamination source strength of the gowned aseptic processing operator has been estimated in several research studies. Concomitant with this awareness, we have witnessed a series of technological advances that have endeavored to mitigate this contamination risk. These advances can be roughly categorized as follows:

* separate personnel from the aseptic environment;
* limit personnel interaction with sterile materials;
* remove personnel from the aseptic environment;
* some combination of the above.

Aseptic processing is perhaps the most critical of all production activities performed within the healthcare industry (1, 2). The risks to patients are higher for aseptic processing than any other process in current use, and the technologies used for the aseptic production of sterile products are among the most complex and costly in the industry. Regulators worldwide recognize the importance of proper practices for aseptic processing and have established several guidance documents pertaining to its application (1, 3).

Firms that produce aseptic products, pharmaceuticals, or medical devices have attempted to reduce the microbial contamination risk associated with their assembly by using individually sterilized materials and packaging in pristine environments. Beginning in the 1950s, firms relied for years almost completely on cleanroom technology in which critical activities were performed by gowned personnel.

There are advantages and disadvantages to using model microorganisms in the validation of sterilizing filtration. Although filtration validation studies may demonstrate the removal of the challenge organisms (whatever they may be), those studies can only imply that any particular filter used to filter a batch of drug product will yield a sterile filtrate. Successfully passing a bubble-point test (1) (or multipoint diffusive-flow integrity test), the results of which have been correlated to successful microbial challenge testing and validation studies, provides additional assurance that a sterile filtrate has been obtained. The filter manufacturer's quality-management system and production-control program further support the validity of the sterilizing filtration process. All three elements must be present to predict the successful outcome of a particular sterile filtration event (2).

The market outlook for parenteral contract manufacturing finds itself caught between two versions of the immediate future. One scenario looks at new cancer drugs and the considerable number of biologics in late-stage testing and predicts a parade of new products, the equivalent of on-the-red-carpet attention and spiraling, higher demand. The other, frequently described by the CMOs themselves, sees steady increases over the next few years from several contributing areas, with figures more in line with the segment’s traditional, modest rates of growth. Tom Polen, senior director of marketing at Baxter Biopharma Solutions, points to the driving trend of the outsourcing of previously approved molecules, and sees growth in approved molecules from 31% to 35% by 2010. He also sees a major change in orientation.

Oral delivery is still the Holy Grail for drug products, but plenty of new drugs (and many more in development) require injection. With so many large molecules like oligonucleotides and PEGylated versions of drugs in the pipeline, and so many smaller and virtual firms developing them, the market for parenteral outsourcing remains robust.

We spoke to a number of providers and sponsors about the market for contract production of parenteral drugs, and found a very healthy outlook. “There’s rapid growth going on,” said Craig Mastenbaum, director for business development at HollisterStier Contract Manufacturing, a Spokane-WA based CMO. “There are a lot of companies—both classic pharma and newer biotechs—that are doing a lot of research. Plenty of drugs are coming out of this research, and many will reach the clinic.”

Aseptic processing is the met h od used for producing sterile products if terminal sterilizati on would advers ely affect the produ ct . Because terminal steri l i z a ti on processes k i ll microor ga n i s m s , t h ey are more certain to preven t produ ct con t a m i n a ti on than aseptic processing met h ods, wh i ch aim to exclu de microor ganisms from the operating envi ronment. Even if the active pharmaceutical ingredient is compati ble with terminal steri l i z a ti on, however, aseptic processing s om etimes is the preferred processing ch oice. For example, a drug delivery system that is incompatible with terminal sterili z a ti on may be a good ch oi ce because it redu ces the risk of contamination when the product is administered to a patient. Mi c robial contaminati on in aseptic processing is mainly caused by personnel. It is estimated that more than 99% of all microorganisms detected in cleanrooms are of human origin.

The closed vial has been developed to improve aseptic filling quality and to reduce process complexity. A ready-to-fill closed vial consists of a sterile vial provided with the stopper secured in place. The vial is filled by inserting a noncoring needle through the stopper, which is then resealed by laser.

Microbial testing is conducted in the sterile pharmaceutical industry in support of sterile product development; for in-process monitoring during aseptic processing and filling operations; and for testing finished products. The role that microbial testing plays in promoting sterility assurance of aseptically filled sterile products will be discussed.

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ASEPTIC PROCESSING Last year I wrote in these pages about the future of aseptic processing.At that time the industry was waiting for FDA to publish a replacement for its 1987 “Guideline on Sterile Drug Products Produced by Aseptic Processing” and wrestling with issues such as media-fill acceptance criteria, interventions and intervention management, environmental monitoring practices and acceptance levels, rapid microbial methods, sterility test insensitivity, regulatory harmonization, and how best to implement, control, and monitor improved aseptic processing technologies such as isolators and barrier systems.

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