Pharmaceutical Manufacturing Plant Research Articles

Evaluation of Chinese hamster ovary cell stability during repeated batch culture for large-scale antibody production

Pharmaceutical manufacturing plants can be operated continuously for several months. It is therefore important to use cells with long-term stability for the production of active ingredients. We investigated the reliability and long-term stability of an antibody-producing cell line. A recombinant Chinese hamster ovary (CHO) cell line was cultivated in spinner flasks and reactors, including a practical production-scale reactor (1600 L), for 109 days to produce monoclonal antibodies against the HM1.24 antigen. During cultivation, the cells remained stable and there was an increase in the rate of cell proliferation, yielding viable cells at high density. A decrease in cell-specific productivity was associated with this increase in the rate of cell proliferation. The cells were genetically stable and other measures of cellular function remained consistent throughout the cultivation period.

Determination and Source Apportionment of Five Classes of Steroid Hormones in Urban Rivers

We developed an original analytical method for monitoring five estrogens, nine androgens, nine progestogens, six glucocorticoids, and one mineralocorticoid in one water sample using liquid chromatography-electrospray tandem mass spectrometry, and then 45 river, 13 discharging sites, and 4 composite effluent samples were analyzed to reveal their occurrence and sources in urban rivers. Of the 45 river samples, androgens were the dominant steroids detected (total concentrations up to 480 ng/L), followed by glucocorticoids (up to 52 ng/L), progestogens (up to 50 ng/L, and estrogens (up to 9.8 ng/L). The summed concentration for each class of detected hormones in 13 discharging site samples was higher than that in river samples, up to 1887 ng/L for androgens, 390 ng/L for glucocorticoids, 75 ng/L for progestogens, and 25 ng/L for estrogens. A principal component analyses with multiple linear regression based on the profiles of all target compounds was applied to identify the source apportionment and to predict the contribution from different sources. It was found that 62.7% of the mean summed hormones were contributed by freshly discharged untreated sewage, 29.4% by treated sewage and/or naturally attenuated untreated sewage, and 7.9% by an unknown source, possibly pharmaceutical manufacturing plants.

Scheduling dispensing and counting in secondary pharmaceutical manufacturing

AbstractIn this article, we describe a general methodology for operations scheduling in dispensing and counting departments of pharmaceutical manufacturing plants. The departments are modeled as a multiobjective parallel machines scheduling problem under a number of both standard and realistic constraints, such as release times, due dates and deadlines, particular sequence‐dependent setup times, machine unavailabilities, and maximum campaign size. Main characteristics of the methodology are the modularity of the solution algorithms, the adaptability to different objectives and constraints to fulfill production requirements, the easiness of implementation, and the ability of incorporating human experience in the scheduling algorithms. Computational experience carried out on two case studies from a real pharmaceutical plant shows the effectiveness of this approach. © 2009 American Institute of Chemical Engineers AIChE J, 2009

Identification and Control of Calcium and Solids Fouling in a Packed Tower Steam Stripper

Identification and Control of Calcium and Solids Fouling in a Packed Tower Steam StripperWastewater from a solid dosage pharmaceutical manufacturing plant and research activities are combined and processed through an onsite wastewater pre-treatment system. The system consists of pH control and packed tower steam stripping. Solids accumulation and scale formation within the conveyance and treatment system adversely impacts performance. A comprehensive sampling program of the wastewater...Author(s)Patrick J. CyrEdward G. HelmigRominder P.S. SuriScott StoddardSourceProceedings of the Water Environment FederationSubjectSession 6 - Pharmaceutical Wastewater TreatmentDocument typeConference PaperPublisherWater Environment FederationPrint publication date Jan, 2009ISSN1938-6478SICI1938-6478(20090101)2009:5L.237;1-DOI10.2175/193864709793900410Volume / Issue2009 / 5Content sourceMicroconstituents ConferenceFirst / last page(s)237 - 250Copyright2009Word count172Subject keywordsScalingsteam strippingcalciumpacked towersolidsfoulingprecipitatemodeling

Quantitative analysis of nicotinic acid, nicotinamide and 3-cyanopyridine in industrial effluent by high performance liquid chromatography

A rapid and reliable high performance liquid chromatographic (HPLC) method for the simultaneous determination of heterocyclic compounds, namely nicotinic acid, nicotinamide, and 3-cyanopyridine, in industrial effluent is described. A Φ4.6 mm × 150 mm, 5 μm C-18 reversed phase stationery phase, and a methanol-acetonitrile-water tertiary mobile phase (20:20:60 v/v) were used for separation. The detection wavelength of a diode array (DAD) was set at 216 nm with a bandwidth of 16 nm. Phenol was used as an internal standard. The regression equations revealed a linear relationship between the concentration of the analytes injected and the peak area detected by DAD. The limits of detection (S/N = 3) ranged from 0.70 to 1.18 mg L−1, the recoveries ranged from 87% to 102% and the precision expressed as % RSD intra-day and inter-day varied from 0.9 to 3.9 and 1.2 to 5.6, respectively. This method is rapid, sensitive and suitable for the monitoring of nicotinic acid, nicotinamide, and 3-cyanopyridine in effluent of related pharmaceutical manufacturing plants.

Continuous granulation in the pharmaceutical industry

Traditionally the manufacturing of pharmaceutical dosage forms has been a batch-wise process and continuous processes have limited applications in a pharmaceutical manufacturing plant. However, several factors (reduction of cost, improved process efficiency, optimal use of equipment, flexibility in production capacity) are stimulating the pharmaceutical industry to investigate the opportunities offered by continuous processes. This paper discusses some of the techniques which could be implemented in a continuous granulation process of pharmaceuticals.

A 50-year historical cohort mortality study of workers in a pharmaceutical plant.

An historical cohort study was conducted of workers at a pharmaceutical manufacturing plant. The cohort mortality experience of workers ever employed at the plant over the period from 1950 to 1999 was examined. The 1958 workers accumulated 44,294 person-years of experience at the plant, and a total of 384 deaths were identified. Our findings from external comparisons based on standardized mortality ratios (SMRs) in the cohort provide no evidence of excess mortality risk from all causes combined (SMR=0.75), all cancers combined (SMR=0.96), or from certain other individual causes of death. No patterns of excess mortality risk were apparent after stratifying on age and sex or job classification. The mortality experience of this cohort was generally more favorable than that of the general population.

Modular Pharmaceutical Factories Gain Popularity

In the early 1980s, Clas Wallenborg was involved in building pharmaceutical manufacturing plants for the Swedish pharmaceutical company Kabi- Vitrum—the predecessor to Pharmacia, now Pharmacia & Up...

The Future Concept of Pharmaceutical Manufacturing Plant and Manufacturing Control

The Future Concept of Pharmaceutical Manufacturing Plant and Manufacturing Control

Control of activated sludge bulking by operating clarifiers in a series

A full scale experiment with an activated sludge process in a pharmaceutical manufacturing plant showed that the operation of two settling tanks in series, with the first tank full of sludge, resulted in selection of sludge particles which had a lower than average filament content for retention in the process. Series operation of the two clarifiers was very successful in controlling sludge bulking. The functioning of the settling tanks as selectors of sludge particles which settle and thicken well has not been considered to any great extent. Two laboratory-scale activated sludge plants fed with an artificial wastewater were operated to explore this selection function further. The SVI values were measured and assessed. At the start of operation, the SVI was about 60–80 ml/g in both of the parallel and the series plants. After eight days of the operation, the SVI started to increase rapidly in the parallel plant, and in twenty days of operation, the averaged values of SVI were 163 ml/g and 116 ml/g for the parallel and the series plants, respectively. On day 38, MLSS from two aeration tanks were interchanged. In a few days after that interchange, the SVI values in the parallel, which was originally in the series mode, rapidly increased from 130 ml/g to more than 350 ml/g(SV30 = 930 ml/g). This experiment clearly supports the hypothesis of a microorganism selection function of the settling tank and also corresponds to the results obtained from the field study.

Control of activated sludge bulking by operating clarifiers in a series

A full scale experiment with an activated sludge process in a pharmaceutical manufacturing plant showed that the operation of two settling tanks in series, with the first tank full of sludge, resulted in selection of sludge particles which had a lower than average filament content for retention in the process. Series operation of the two clarifiers was very successful in controlling sludge bulking. The functioning of the settling tanks as selectors of sludge particles which settle and thicken well has not been considered to any great extent. Two laboratory-scale activated sludge plants fed with an artificial wastewater were operated to explore this selection function further. The SVI values were measured and assessed. At the start of operation, the SVI was about 60-80 ml/g in both of the parallel and the series plants. After eight days of the operation, the SVI started to increase rapidly in the parallel plant, and in twenty days of operation, the averaged values of SVI were 163 ml/g and 116 ml/g for the parallel and the series plants, respectively. On day 38, MLSS from two aeration tanks were interchanged. In a few days after that interchange, the SVI values in the parallel, which was originally in the series mode, rapidly increased from 130 ml/g to more than 350 ml/g(SV30 = 930 ml/g). This experiment clearly supports the hypothesis of a microorganism selection function of the settling tank and also corresponds to the results obtained from the field study.

Utilization of a portable microchip gas chromatograph to identify and reduce fugitive emissions at a pharmaceutical manufacturing plant

Eli Lilly and Company utilizes a mass balance procedure to track solvent usage at its manufacturing and pilot plant locations. Although the mass balance procedure provides accurate usage information, it is not useful as a tool for rapid identification and quantitation of fugitive volatile organic compounds (VOCs). As government regulations and permitting requirements demanded more specific information, it became obvious that a system was needed for rapid identification and quantitation of fugitive VOCs. In 1991, Eli Lilly and Company investigated both technology and methodology which would identify and quantitate specific VOCs. The objective was to reduce fugitive VOC emissions by understanding both the sources of emissions and the operating parameters that allowed their occurrence. After reviewing existing technologies such as FT-IR, mass spectrometry, and gas chromatography, the company purchased five portable microchip gas chromatographs. These instruments were incorporated into a routine monitoring program that profiled various production facilities and tank farms for specific VOC emissions. Once baseline emissions were established, the instruments were strategically located to monitor the effect of various improvement activities. The result of using portable gas chromatographs to establish an emission profile was an 86% reduction in fugitive VOC emissions over a 2-year period. This article presents a portable gas chromatograph and sample interface that quantitates methyl alcohol, ethyl alcohol, acetone, acetonitrile, ethyl acetate, methylene chloride, and toluene in 2 minutes. A typical linear range for these compounds is 5 ppm to 1%. The philosophy of incorporating this technology into routine manufacturing processes will also be discussed. © 1997 John Wiley & Sons, Inc. Field Analyt Chem Technol 1:367–374, 1997

An integrated approach to the selection of optimal salt form for a new drug candidate

A general method was developed to select the optimal salt form for BMS-180431, a novel HMG-CoA reductase inhibitor and a candidate for oral dosage form development, in an expeditious manner at the onset of the drug development process. The physicochemical properties such as hygroscopicity, physical stability of crystal forms at different humidity conditions, aqueous solubility, and chemical stability of seven salts e.g., sodium, potassium, calcium, zinc, magnesium, arginine and lysine, were studied using a multi-tier approach. The progression of studies among different tiers was such that the least time-consuming experiments were conducted earlier, thus saving time and effort. A ‘go/no go’ decision was made after each tier of testing the salts, thus avoiding generation of extensive data on all available salt forms. The hygroscopicities of all BMS-180431 salts were evaluated at tier 1 and four salts (sodium, potassium, calcium and zinc) were dropped from consideration due to excessive moisture uptake within the expected humidity range of pharmaceutical manufacturing plants (30–50% R.H. at ambient temperature). The remaining three salts were subjected to the tier 2 evaluation for any change in their crystal structures with respect to humidity and the determination of their aqueous solubilities in the gastrointestinal pH range. The magnesium salt was dropped from further consideration due to humidity-dependent changes in its crystal structure and low solubility in water (3.7 mg/ml at room temperature). Arginine and lysine salts, which were resistant to any change in their crystalline structures under extremes of humidity conditions (6 and 75% R.H.) and had high aqueous solubilities (> 200 mg/ml), were elevated to tier 3 for the determination of their chemical stability. Based on solid state stability of these two salts under accelerated conditions (temperature, humidity, and presence of excipients), consideration of ease of synthesis, ease of analysis, potential impurities, etc., and input from the marketing group with respect to its preference of counter ion species, the arginine salt was selected for further development. The number of tiers necessary to reach a decision on the optimal salt form of a compound may depend on the physicochemical properties studied and the number of salts available. This salt selection process can be completed within 4–6 weeks and be easily adopted in the drug development program.

Airborne Contact Urticaria Due to Sodium Benzoate in a Pharmaceutical Manufacturing Plant

Three workers exposed to airborne contact with sodium benzoate (SB) in a pharmaceutical plant developed transient urticaria related to skin contamination with SB. Patch test responses to SB and benzoic acid (BA), without occlusion, were similar to those of three previously unexposed controls in keeping with the nonimmunologic nature of the reaction. Sweating, which lowers skin pH and increases topical BA concentration, appeared to increase the susceptibility to urticaria in two of the three workers. Ventilation and hygiene control methods designed to reduce SB skin contamination eliminated the problem in the workplace.

A User's Experience with Electric Heat Tracing

The use of electrical heat tracing systems can provide excellent flexibility in piping systems of chemical manufacturing plants located in areas subjected to subzero weather. However, eight years of experience with various types of systems in an Indiana pharmaceutical manufacturing plant has resulted in an annual concentrated effort to insure maximum performance. Challenges have arisen due to engineering design oversights, the improper installation of material, and unanticipated production techniques and ``immediate action'' procedures. Details of some of each of these challenges have been included as well as programs which have been initiated to overcome the problems. These programs have greatly improved the reliability of the heat tracing systems as well as allowing continued production operations regardless of the weather conditions throughout winter months.