The ability of an instantaneous microbial detection system (IMD-A) to monitor microbial populations in environmental air was evaluated. The IMD-A results were compared with results from conventional environmental air monitoring methods. The comparisons were carried out in controlled microbial barrier test chambers and in cleanroom environments. Additionally, microbial populations in environmental air in an unclassified environment were evaluated using the IMD-A and the all-gas impingement (AGI) method coupled with ScanRDI. In 1-m3 and 150-m3 controlled-barrier test chamber studies the mean recoveries with the IMD-A were equal to or greater than the mean recoveries obtained with the Anderson air sampler at various concentrations. The mean microbial recoveries obtained using the AGI were higher, but in the same order of magnitude, as those recovered by IMD-A.
Some general managers may think they need only an accountant and an attorney to run a business, but if you have risen through the technical ranks, you know a lot more insight is required to successfully manage an API facility. Sure, accounting and legal services are two very important items in your toolbox. Both functions tend to operate in a conservative fashion and serve to mitigate or limit risk. However, businesses do not tend to grow without taking risks. General Patton was quoted as saying, "Take calculated risks. That is quite different from being rash."
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Hood, suit, faceplate, cover shoes, gloves: these are the necessary items of clothing when operating in A- and B-grade areas. The principal purpose of protective clothing is to minimize the risk of microbiological contamination caused by personnel. Thus, protective garments should not release fibers and must be able to contain particles produced and released by the body.
But how can we ensure that protective garments are not themselves vehicles of contamination? And how can we ensure that cleaning and sterilization processes are effective and do not alter the characteristics of the garments? We attempted to answer these questions, concentrating our attention mainly on glasses (in general, on individual protection devices usually referred to as masks).
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Transgenic milk production offers a cost-effective system for the manufacturing of large amounts of complex proteins. Specifically, commercialization is near for recombinant human antithrombin (rhAT) expressed in transgenic dairy goats. The product received a positive opinion from the Committee for Medicinal Products for Human Use of the European Medicine Agency.
This article reviews the reasons why transgenic milk is a cost-effective system. Also reviewed is the earlier research on targeting heterologous proteins to the mammary glands of many different animals. The final section describes the process by which goats express rhAT in their milk at approximately 2 g/L. The human AT purified from milk is structurally indistinguishable from human plasma–derived AT with the exception of carbohydrates. Clinical studies are ongoing on the prevention of deep-vein thrombosis.
Biopharmaceutical companies around the world use disposable processing equipment for numerous reasons. According to Barres's 3rd Annual Report and Survey on Biopharmaceutical Manufacturing,1 they are to minimize or improve, in order of importance, cross-contamination, cleaning, time-to-start, capital investment, production cycle, and assurance of sterility. The priority varies, of course, according to a drug company's business objectives. For example, vaccine manufacturers regard cleaning and sterility as the most important reasons for adopting this processing model. Contract manufacturing organizations (CMOs) use disposable technologies because they minimize the risks of cross-contamination. Biotechnology manufacturing firms view disposables as a way to reduce capital investment.
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As pharmaceutical product coding regulations change, and as the threat of counterfeiting increases, drug companies are looking for better methods of product identification. Coding and marking are keys to accurate, reliable product identification that can combat counterfeiting. The latest coding and marking technologies have the added benefits of helping to provide flexible coding methods, streamline production, improve productivity, reduce costs and increase profits.
Addressing the Challenges
New and updated regulations on drug product coding, driven by security issues and emerging technologies, have left pharmaceutical manufacturers, repackers, relabelers and distributors searching for cost-effective options to comply.
Drug companies, regulators, insurers, caregivers and patients face tremendous challenges due to the growth in drug counterfeiting and need better ways to protect the integrity of the healthcare delivery system, the drug products and patient safeguards.
Almost every day, we hear another story about the spread of avian flu and the possibility that it will lead to a pandemic rivaling the disaster of 1918. Responding to this growing fear, the president recently announced a $7.1 billion plan that would include purchase of 20 million doses of vaccine to protect against the current strain of avian flu. The plan also included incentives to develop new production methods, and protection against liability claims so that vaccine makers would add U.S.-based facilities. “If a pandemic strikes, our country must have a surge capacity in place that will allow us to bring a new vaccine online quickly and manufacture enough to immunize every American against the pandemic strain,” said the president. (For more on the White House’s strategy, see my From the Editor commentary on page 12.)
Four new inhaled-insulin therapies are following Exubera (insulin) down the drug pipeline, and each one of them may eventually enjoy a significant advantage over Pfizer's groundbreaking new delivery system. But for now, Pfizer has the only drug in its class. The new inhalation system, originally developed by Nektar Therapeutics of San Carlos, California, shows a similar insulin profile to subcutaneously injected insulin, and has proven popular with patients during clinical trials. Although the drug's price had not been set at press time, strong patient uptake is fairly well assured. In part because the world's largest pharmaceutical company will put its marketing muscle behind it. But also because pulmonary delivery could boost compliance among patients who resist treatment because they fear needles or hate injections.
Manufacturing and laboratory efficiency issues have direct effects on cash flow, balance sheet, product quality and customer satisfaction. Performance behind the competition—or ahead of it—can dramatically affect shareholder value. Therefore, in the face of ever-challenging profitability and revenue goals, pharmaceutical companies and contract manufacturers alike are striving to improve and enhance their manufacturing and laboratory efficiency. A solid understanding of manufacturing costs and performance metrics among world-class companies is the first step in evaluating a company’s own current practices.
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IN BIOMANUFACTURING, EXPRESSION technology, an optimized process, and the required production capacity are all intertwined. The choice of a prolific expression technology and efforts expended to improve production processes can have a dramatic affect on the amount of capacity needed. After the push to build capacity in the past few years, contract biomanufacturers are now focusing on improving production efficiencies.
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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.
Abstract: The feasibility of using dense gas techniques such as rapid expansion of supercritical solutions (RESS) and aerosol solvent extraction system (ASES) for micronization of pharmaceutical compounds is demonstrated. The chiral nonsteroidal anti-inflammatory racemic ibuprofen is soluble in carbon dioxide at 35°C and pressures above 90 bar. The particle size decreased to less than 2 µm while the degree of crystallinity was slightly decreased when processed by RESS. The dissolution rate of the ibuprofen (a poorly water-soluble compound) was significantly enhanced after processing by RESS. The nonsteroidal anti-inflammatory drug Cu2(indomethacin)4L2(Cu-Indo); (L = dimethylformamide [DMF]), which possessed very low solubility in supercritical CO2, was successfully micronized by ASES at 25°C and 68.9 bar using DMF as the solvent and CO2 as the antisolvent. The concentration of solute dramatically influenced the precipitate characteristics.
In the manufacture of many pharmaceutical products, dry-particle blending is a critical step that directly affects content uniformity. Tumbling blenders—a common way to mix granular constituents—are hollow containers attached to a rotating shaft; the vessel is partially loaded with materials and rotated. Their main advantages are large capacities, low-shear stresses, flexibility, containment, and easy cleaning. The blenders come in a variety of geometries and sizes (ranging from a minimum of ,16 qt to a maximum .500 ft3). The convective blender is another common mixer, in which flow is created by impellers rotating within a fixed shell. The blender can impart high shear, reduce ingredient segregation, and be used for wet granulation.
Process scale-up is an increase in batch size or production capacity, usually in response to increased product demand, concerns about high production costs, or an increased need for clinical research supplies. Conversely, scale-down is a decrease in batch size or productivity.
These problems include but are not limited to dissimilar processing equipment between one scale and another; various requirements for process control at different production scales; insufficient data about equipment performance at different production scales; the complexity of pharmaceutical processing, which may involve several very different unit operations and equipment; and variations in macroscopic and microscopic properties of formulation components and products at different production scales. Additional usually in response to decreased product demand. Pharmaceutical manufacturing scales range from the laboratory to the pilot plant to full production.