Manufacturing Articles

Partial-filling affinity capillary electrophoresis (PFACE) is a versatile analytical technique to probe bimolecular non-covalent interactions and to estimate binding constants between receptors and ligands. In this article we demonstrate the use of PFACE and two modifications to PFACE: flow-through PFACE and multiple-step ligand injection to examine the binding of D-Ala-D-Ala terminus peptides to vancomycin from Streptomyces orientalis and arylsulphonamides to carbonic anhydrase B.

Using a modified dispersal chamber, the authors have studied the protective efficacy of cleanroom clothing systems. Study results show that the state of a cleanroom clothing system—new or much used—influences the protection efficacy of the system. Suitable combinations of cleanroom underwear and cleanroom garments also improve the protection of the clean environment against airborne contaminants from people.

Production information is part of a company’s intellectual property and is as important as the materials the company produces. Production information must be accurate and available in real time for management to make informed decisions about the product or business, a process that must be completed with the least amount of time and cost.

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The BioPharma Operations Excellence Consortium, facilitated by Tefen Operations Management Consulting, continues to thrive, recently holding chapter meetings on two separate continents. The US East Coast Chapter met at Centocor's headquarters in Malvern, PA, while the European Chapter met at Sorono's facility in Vevey, Switzerland. Since its establishment in early 2002, over 45 leading biopharmaceutical companies have joined the forum, which operates on the basis of using the group's collective knowledge to drive each member company — and the industry as a whole — to world-class levels of operational effectiveness and efficiency.

Creation and qualification of scale-down models are essential for performing several critical activities that support process validation and commercial manufacturing. As shown in Figure 1, these activities include process characterization and production support studies that are performed to evaluate column and membrane lifetimes, demonstrate clearance of host-cell impurities and viruses, and troubleshoot manufacturing issues. While the underlying fundamentals are relatively the same as those when scaling up, some unique considerations should be taken when scaling unit operations down.1-4 The goal when scaling down is to create a small-scale or lab-scale system that mimics the performance of its large-scale (pilot or manufacturing) counterpart, when both the process parameters are varied within their operating ranges and also when a process parameter deviates outside its operating range.

Upstream and downstream processing in biomanufacturing follow different rules. Upstream processing is biology-driven, and a lot of black box issues remain to be explored. On the other hand, purification is clearly engineering-driven and can be described and simulated with the precision of mathematical models. However, despite our still-limited knowledge of cells as bioreactors, it is upstream fermentation that is setting the pace. Downstream processing is having a hard time accommodating the output of this revolution in biosynthesis development. In any case, the two separate areas must be aligned and integrated in order to manage the challenges that lie ahead. But what are those challenges, and what technical solutions are available?

THE BIOTECH SECTOR TO DATE: FULL PIPELINES AND EMPTY POCKETS

Purification and analysis of PEGylated protein pharmaceuticals presents many challenges.

The modification of proteins with polyethylene glycol (PEGylation) is an established technology that has many benefits in the biopharmaceutical industry. For instance, modifying proteins with multiple PEGs masks immunogenic sites and prevents neutralizing-antibody formation to certain proteins and therapeutic enzymes.1-3 Due to the amphiphilic nature of polyethylene glycol, PEGylation can also improve the solubility and physical-chemical stability of proteins.2,3 PEGylation can increase the circulating half-life of proteins, especially smaller peptides and proteins, which normally have a rapid glomerular filtration rate and are cleared on the basis of size. PEGs have a high Stokes-radius-to-mass ratio.

Meeting the USP requirements for minimum fill and deliverable volume is a serious concern in pharmaceutical production. Filling operations must be controlled throughout the filling cycle to ensure that the sampled filled products will meet quality control specifications based on the USP ^755& Minimum Fill or ^698& Deliverable Volume tests. The common acceptance criterion of the two USP tests is that the average content of all samples tested must not be less than 100% of the labeled amount. Such a requirement will lead to a filling volume target greater than 100% of the labeled amount. This article proposes a criterion for establishing an appropriate target fill such that a sample will have a 95% probability of passing these USP tests at 95% confidence, i.e., that the established target fill will guarantee with 95% confidence that 95 out of 100 samples will pass the USP tests.

The USP (755) Minimum Fill test

Integrate CIP and process piping in the "pencil and eraser" phase or you will have to use "hacksaw and torch" to add it later.

In biopharmaceutical and many pharmaceutical operations, post-production residues are primarily removed by chemical, rather than physical, means. Chemical cleaning is typically the most efficient mechanism for removing in-process material. Chemical cleaning methods rely on fully developed turbulent flow in pipelines and spray devices (often non-rotating sprayballs) in vessels and other processing equipment to supply rinsing and washing solutions to surfaces being cleaned. Cleaning is a mass transfer process that relies on good mixing and strong convection to produce turbulence. Turbulent flow promotes efficient mass transfer and thus is a key factor in optimizing cleaning cycles.

Drug manufacturers can take advantage of the better, faster, and smaller paradigm

The drive to develop better, faster, and smaller — in other words, more efficient — products is a universal trend in the modern world. This trend has profoundly impacted many industries from microelectronics to packaging equipment. In the biopharmaceutical industry, the need to speed and simplify the long and complex drug manufacturing processes brings additional challenges, such as meeting regulatory requirements.