Filtration and Purification in the Biopharmaceutical Industry, 3rd Edition PDF by Maik W Jornitz

Contents:

Foreword ix
Acknowledgments xi
Summary xiii
Editor…………………………………………. xv
Contributors xvii
1. Prefiltration in Biopharmaceutical Processes 1
George Quigley
2. Charge-Modified Filter Media 21
Eugene A. Ostreicher, Todd E. Arnold, and Robert S. Conway
3. Filter Designs 41
Maik W. Jornitz
4. Membrane Pore Structure and Distribution 57
Maik W. Jornitz
5. Filtrative Particle Removal 73
Ross Acucena
6. Microbiological Considerations in the Selection and Validation of Filter Sterilization 131
James A. Akers
7. Filter Configuration Choices and Sizing Requirements 141
Maik W. Jornitz
8. Stainless Steel Application and Fabrication in the Biotech Industry 169
Joseph Manfredi
9. Protein Adsorption on Membrane Filters 191
Maik W. Jornitz
10. Integrity Testing 221
Magnus Andreas Stering
11. Filter Manufacturer’s Quality Assurance and Qualifications 277
Maik W. Jornitz
12. Validation of the Filter and of the Filtration Process 295
Paul S. Stinavage
13. Extractables and Leachables Evaluations for Filters 309
Raymond H. Colton and Denise G. Bestwick
14. Media and Buffer Filtration Requirements 331
Maik W. Jornitz
15. Downstream Processing 349
Uwe Gottschalk
16. Ultrafiltration and Crossflow Microfiltration Filtration 383
Michael Dosmar, Steven Pinto, and Kirsten Jones Seymour
17. Virological Safety of Biopharmaceuticals: How Safe Is Safe Enough? 437
Hazel Aranha
18. A Rapid Method for Purifying Escherichia coli β-galactosidase Using Gel-Filtration
Chromatography 467
Lynn P. Elwell
19. Membrane Chromatography 481
Sherri Dolan and Susan Martin
20. Expanded Polytetrafluoroethylene Membranes and Their Applications 503
Michael Wikol, Bryce Hartmann, Michael Debes, Cherish Robinson, Scott Ross, and
Uwe Beuscher
21. Gas Filtration Applications in the Pharmaceutical Industry 519
Elisabeth Jander
22. Sterility Testing by Filtration in the Pharmaceutical Industry 571
Olivier Guenec
23. Bacterial Biofilms in Pharmaceutical Water Systems 587
Marc W. Mittelman
24. Ozone Applications in Biotech and Pharmaceuticals 609
Joseph Manfredi
25. Disposable Equipment in Advanced Aseptic Technology 627
Maik W. Jornitz and Peter Makowenskyj
Index 639

Prefiltration in Biopharmaceutical Processes
George Quigley, ErtelAlsop

Prefiltration Principles:
Prefiltration can be described simply as any filtration step incorporated into a manufacturing process prior to the final filtration. The usual purpose in conducting pharmaceutical filtrations is to remove objectionable particles from a fluid drug preparation. In effecting such a purification there is a concern for the rate at which the filtration takes place, and the extent to which it proceeds before the retained particles block the filter’s pores sufficiently to render further filtration so slow as to be impractical. An adequacy of particle removal is the principle goal. The rate of filtration and throughput are secondary considerations. Nevertheless, the accrual of particles on the final filter relative to its porosity and extent of filter surface determines the ongoing rate of filtration as well as its ultimate termination.

In practically all pharmaceutical and biotech processes, the final filter is a microporous membrane, which is manufactured from high-tech polymers. It is commercially available in pore size designations of 0.04–8 μm, and due to its mode of manufacture is of a narrow pore size distribution. Consequently, these filters presumably retain particles of sizes larger than their pore size ratings with great reliability,* the mechanism of particle retention being sieve retention or size exclusion. Being extremely effective at removing submicronic particles, they retain so thoroughly that with heavily loaded liquids they may not have a significant capacity to remove large volumes of particulates while maintaining sufficient fluid flow across the filter. More importantly, the more particulate matter with which the final filter is challenged and retained, the higher the differential pressure across the filter will become. This is undesirable because it is widely known that a filter performs at its highest particle retention efficiency when operated at low differential pressures (Δp). At a low Δp, the filter retains small particles through the mechanism of adsorptive sequestration. Lower operating pressure differentials will provide greater throughputs than will high Δp, because the higher pressure differentials tend to compress the filter cakes rendering them less permeable to liquids. The problem can be solved by the use of larger effective filter areas (EFAs). However, this entails the cost of the additional membrane filters. The use of prefilters accomplishes essentially the same purpose, but at a lesser expense.

In reality, therefore, the only reason for prefiltration is based on economic constraints. There are no particulate contaminants in a fluid stream that could not, at least in principle, be removed by the final sterilizing grade filter. However, the cost of filtration would increase significantly under this situation, due to the larger amount of final filtration area that would be required. Prefiltration, by this definition, is a more cost-effective means of removing the majority of the contaminants from the fluid stream prior to the final filter removing the remainder. It, therefore, becomes important to incorporate one or more levels of prefiltration so that the particulate challenge to the final filter is minimized, allowing it to operate at the highest level of efficiency.

Prefilters are not intended to be completely retentive (if they were, they would by definition be final filters). Prefilters are designed to accommodate only a portion of the particulate load, permitting the remainder to impinge upon the final filter. In the process, the life of the final filter is prolonged by the use of the prefilter, whose own service life is not unacceptably shortened in the process. Overall, the service life of the prefilter(s)/final filter assembly is extended to the point where the rate of fluid flow and its throughput volume meet practical process requirements.

Depth-type filters are usually used for prefiltrations. However, microporous membranes of higher pore size ratings may serve as prefilters for final filters of finer porosities. In such cases, it was best, however, that the liquid not be highly loaded, or that more extensive EFA be used to forestall premature filter blockage (Trotter et al., 2002; Jornitz et al., 2004).