Filtration and Purification in the Biopharmaceutical Industry, Third Edition

Maik W. Jornitz

• Publisher: CRC Press
• Year: 2019
• ISBN:
  9781351675680
• Edition: 3
• Topic: Business
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry
• Index: Business

Since sterile filtration and purification steps are becoming more prevalent and critical within medicinal drug manufacturing, the third edition of Filtration and Purification in the Biopharmaceutical Industry greatly expands its focus with extensive new material on the critical role of purification and advances in filtration science and technology. It provides state-of-the-science information on all aspects of bioprocessing including the current methods, processes, technologies and equipment. It also covers industry standards and regulatory requirements for the pharmaceutical and biopharmaceutical industries. The book is an essential, comprehensive source for all involved in filtration and purification practices, training and compliance. It describes such technologies as viral retentive filters, membrane chromatography, downstream processing, cell harvesting, and sterile filtration.

Features:

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• Addresses recent biotechnology-related processes and advanced technologies such as viral retentive filters, membrane chromatography, downstream processing, cell harvesting, and sterile filtration of medium, buffer and end product

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• Presents detailed updates on the latest FDA and EMA regulatory requirements involving filtration and purification practices, as well as discussions on best practises in filter integrity testing

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• Describes current industry quality standards and validation requirements and provides guidance for compliance, not just from an end-user perspective, but also supplier requirement

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• It discusses the advantages of single-use process technologies and the qualification needs

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• Sterilizing grade filtration qualification and process validation is presented in detail to gain the understanding of the regulatory needs

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• The book has been compilated by highly experienced contributors in the field of pharmaceutical and biopharmaceutical processing. Each specific topic has been thoroughly examined by a subject matter expert.

1

Prefiltration in Biopharmaceutical Processes

George Quigley

ErtelAlsop

CONTENTS

Prefiltration Principles

Cellulose-Based Depth Filters

The Filter Aid

The Wet-Strength Resin

Retention Mechanisms

Sieve Retention

Inertial Impaction

Brownian Motion

Adsorptive Interactions

Charge-Modified Filters

Activated Carbon

Filter Forms

Lenticular Configuration

Single-Use Disposable Devices

Fibrous Materials

Glass Fibers

Polypropylene

Examples of Applications

Active Pharmaceutical Ingredients

Blood/Plasma Products

Pretreatment and Prefiltration

Pretreatment Agents

Prefilters for Plasma/Serum

Serum Filtration

Plate-and-Frame Filtration of Serum

Plasma Fractionation

Cohn Fractionation Procedure

Albumin

Factor 9

Oral Syrups

Fermentation Solutions

Filter Selection

Filtration Trials and System Sizing

References

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).

Cellulose-Based Depth Filters

One of the most common prefilters used in biopharmaceutical processes is the cellulose-based depth filter, which is used in either a sheet format or in a lenticular cartridge format. These are very cost-effective prefilters due to the relatively inexpensive raw materials used in their manufacture and the thickness and structure of the filter matrix that is formed during the manufacturing process. The basic raw materials used in the production of these filters are cellulose fibers, inorganic filter aid, and a polymeric wet-strength resin (Figure 1.1).

FIGURE 1.1 Cellulse fiber matrix.

Cellulose pulp is available as either hardwood or softwood. Hardwood is primarily comprised of short fibers, which provide a smooth filter sheet surface. However, the short fibers create a dense structure with minimal void volume. Softwood has a longer fiber structure, which provides greater void volumes and a mechanically stronger filter sheet with a rough surface.

The void volume of the cellulose and particle retention capacity of the cellulose component of the filter is controlled by refining the cellulose fibers. Pulling the fibers apart creates more and more surface area as the cellulose fibers are fibrillated to a lower freeness. Freeness is a measurement of the ability of water to flow through the fibers; the lower the freeness, the tighter the matrix of cellulose fibers and the smaller the particle retention capacity of the filter media.

The Filter Aid

The next primary component of the filter sheet is the filter aid. The overwhelming majority of filter sheets contain Diatomaceous Earth (DE) and/or Perlite as a filter aid (Figure 1.2). These two inorganic substances are naturally occurring and mined from deposits in various parts of the world.

Perlite is volcanic ash that has a glass-like, smooth structure. The particles are relatively homogeneous in shape and they form densely within the matrix of cellulose fibers. The powder is available in various particle sizes to provide a range of porosity.

FIGURE 1.2 Example of Perlite structure.

FIGURE 1.3 Diatoms in diatomaceous earth.

DE is comprised of diatoms, which are fossilized remains of plankton. The fresh water variety of this product contains less than 20 different diatoms, while salt water DE is made up of thousands of different species. This broad range of shapes creates a less dense matrix in the cellulose fibers and therefore a greater void volume in the filter sheet. The trade-off is that the variety of shapes creates a filter sheet with less mechanical strength than a sheet made with perlite. Like perlite, DE is available in a variety of grades for various particle retention capabilities (Figure 1.3).

The Wet-Strength Resin

The final component of the filter sheet is the wet-strength resin. This ingredient serves two purposes; the first is to hold the sheet together and the second is to impart a positive charge to the internal surfaces of the filter sheet. The positive charge is referred to as zeta-potential and it allows the filter to retain particles that are smaller than the pore size by attracting them to these positively charged sites (Figure 1.4).

The components can be mixed together in different ratios to affect the performance qualities of the filter sheet, the most important of which are flow capacity and particle retention. Cellulose-based filter sheets can provide effective particle retention down to 0.1 μm. The retention rating of depth filters is stated as a nominal value, essentially meaning that it will remove at least one particle of the stated size. Most manufacturers, however, provide the rating based upon a certain percentage of particles of the stated size under standard conditions. The rating is usually based upon the filter’s ability to retain a fixed-size spherical particle at a constant differential pressure. In practice, most particles are not spherical and filtration studies should be carried out to define the ability of the filter to provide an acceptable filtrate.

FIGURE 1.4 Wet strength resin.

Retention Mechanisms

Sieve Retention

There are a number of retention mechanisms employed by depth filters. Among them are: sieving, inertial impaction, Brownian motion, and adsorption.

Sieving is the simplest form of particle retention, and results from the removal of particles that are larger than the pores that they are trying to pass through. The retention is independent of the number of particles or pores, and it is indep...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Dedication Page
• Table of Contents
• Foreword
• Acknowledgments
• Summary
• Editor
• Contributors
• 1. Prefiltration in Biopharmaceutical Processes
• 2. Charge-Modified Filter Media
• 3. Filter Designs
• 4. Membrane Pore Structure and Distribution
• 5. Filtrative Particle Removal
• 6. Microbiological Considerations in the Selection and Validation of Filter Sterilization
• 7. Filter Configuration Choices and Sizing Requirements
• 8. Stainless Steel Application and Fabrication in the Biotech Industry
• 9. Protein Adsorption on Membrane Filters
• 10. Integrity Testing
• 11. Filter Manufacturer’s Quality Assurance and Qualifications
• 12. Validation of the Filter and of the Filtration Process
• 13. Extractables and Leachables Evaluations for Filters
• 14. Media and Buffer Filtration Requirements
• 15. Downstream Processing
• 16. Ultrafiltration and Crossflow Microfiltration Filtration
• 17. Virological Safety of Biopharmaceuticals: How Safe Is Safe Enough?
• 18. A Rapid Method for Purifying Escherichia coli β-galactosidase Using Gel-Filtration Chromatography
• 19. Membrane Chromatography
• 20. Expanded Polytetrafluoroethylene Membranes and Their Applications
• 21. Gas Filtration Applications in the Pharmaceutical Industry
• 22. Sterility Testing by Filtration in the Pharmaceutical Industry
• 23. Bacterial Biofilms in Pharmaceutical Water Systems
• 24. Ozone Applications in Biotech and Pharmaceuticals
• 25. Disposable Equipment in Advanced Aseptic Technology
• Index