Showing papers in "Pda Journal of Pharmaceutical Science and Technology in 2005"

Determination of mass and heat transfer parameters during freeze-drying cycles of pharmaceutical products.

Abstract: The principal aim of this study was to evaluate the water vapour mass transfer resistance of the dried layer and the vial heat transfer coefficient values of a pharmaceutical product during the primary drying period. First, overall vial heat transfer coefficient values, Kv, were determined by a gravimetric method based on pure ice sublimation experiments. Thus, it was possible to set up a map of the total heat flux received by each vial throughout the plate surface of our pilot scale freeze-dryer. Important heterogeneities were observed for the vials placed at the plate edges and for the vials placed at the center of the plate. As well, the same gravimetric method was also used to precisely determine the influence of main lyophilization operating parameters (shelf temperature and gas total pressure) or the vial types and sizes on these overall heat transfer coefficient values. A semi-empirical relationship as a function of total gas pressure was proposed. The transient method by pressure rise analysis (PRA method) after interrupting the water vapour flow between the sublimation chamber and the condenser, previously set up and validated in our laboratory, was then extensively used with an amorphous BSA-based formulation to identify the dried layer mass transfer resistance values, Rp, the ice front temperature, and the total heat transfer coefficient values, Kv, with or without annealing treatment. It was proved that this method gave accurate and coherent data only during the first half of the sublimation period when the totality of the vials of the set was still sublimating. Thus, this rapid method allowed estimation of, on line and in situ, the sublimation front temperature and the characterization of the morphology and structure of the freeze-dried layer, all along the first part of the sublimation period. The estimated sublimation temperatures shown by the PRA model were about 2 degrees C lower than the experimental values obtained using thermocouples inserted inside the vial, in accordance with previous data given by this method for similar freeze-drying conditions. As well, by using this method we could confirm the homogenization of the dried layer porous structure by annealing treatment after the freezing step. Furthermore, frozen matrix structure analysis (mean pore diameter) using optical microscopy and mass transfer modelling of water vapour by molecular diffusion (Knudsen regime) allowed, in some cases, to predict the experimental values of this overall mass transfer resistance directly related to the freeze-dried cake permeability.

Assessing Parallelism Prior to Determining Relative Potency

Abstract: In the course of preparing a revision to Chapter (111) of the U.S. Pharmacopeia, the revision committee came to a unanimous agreement that the method for assessing parallelism that is currently presented in (111) and in the European Pharmacopeia's Chapter 5.3 is flawed and should be replaced. The symptoms are that perfectly acceptable assay results may fail due to good precision and that obviously faulty assay results may pass due to poor precision. The flaw is that the wrong statistical technique has been used. We propose an alternative approach based on the equivalence testing paradigm that does not have these shortcomings. Equivalence testing requires the establishment of equivalence limits. Specific approaches for establishing equivalence limits are discussed.

Linking extractables and leachables in container/closure applications.

Abstract: Establishing a link between extractables and leachables may be necessary to understand, interpret, assess, quantify, or control the interaction between a drug product and its container/closure system. This paper considers the various factors that affect the rigor with which such a linkage is established and justified. Such an assessment considers the origin and/or genesis of the leachable or extractable, enumerates situations in which extractables/leachables linkages are useful, ties such situations to the drug product9s lifecycle, defines a hierarchy of linkages based on the rigor with which the linkages are established and justified, and establishes guidelines for how to determine what kind of linkage is appropriate for certain circumstances and situations. Additionally, this paper gives several examples of linkages relevant to flexible plastic drug product containers.

Design, development and qualification of a microbiological challenge facility to assess the effectiveness of BFS aseptic processing.

Abstract: A programme of work has been initiated to further the understanding of the impact of the environment surrounding a Blow/Fill/Seal (BFS) machine upon the microbiological quality of processed product. A dedicated facility (Challenge Room) has been constructed and qualified to provide for the production and containment of dispersions of micro organisms in air of a room housing an operating BFS machine of a given style and configuration. The facility achieves homogeneous distribution of generated dispersions throughout the Challenge Room air, including that within and close to the critical area in which aseptic BFS operations occur. Generated microbial dispersions can be maintained in the room over extended time periods (up to 600 min) at a desired concentration within the range 10(1) to 10(7) cfu m(-3). They can also be produced employing different cell types, including bacterial endospores, Gram-positive and Gram-negative vegetative cells and yeast cells. Effective containment of dispersions is achieved while 'cards of product' (vials in sets) are conveyed from the Challenge Room to an adjacent Packing and Storage Area. Decontamination of the room and the housed BFS machine is accomplished through exposure to chlorine dioxide gas at a concentration of 1.0 mg dm(-3) for 120 min at room temperature (approximately 23 degrees C).

Simple HPLC determination of benzalkonium chloride in ophthalmic formulations containing antazoline and tetrahydrozoline.

Abstract: A simple and rapid analytical procedure for routine quantification of n-C12H25 and n-C14H29 benzalkonium chloride (C-12 and C-14 BKC) homologs in ophthalmic formulations containing antazoline HCl and tetrahydrozoline HCl by high-performance liquid chromatography was developed and validated. The ophthalmic solution samples can be directly analyzed by reversed-phase on HiQ-Sil C18 column (4.6 mm x 150 mm, i.d., 5-microm particle size) with acetonitrile-sodium acetate buffer (pH 5.0; 0.2 M) (70:30, v/v) as mobile phase. UV Detection was carried out at 262 nm. The method was linear over the selected concentration and ranged from 0.03 to 0.10 mg/ml (r2 = 0.9999) and from 0.01 to 0.05 mg/ml (r2 = 0.9979) for C-12 and C-14 BKC homologs, respectively. The mean percent recoveries were 100.2 and 102.6 and the percent CV values were 1.3 and 3.5 for C-12 and C-14 BKC homologs, respectively. The results demonstrated the good linearity, accuracy, and precision. The method was applied to determine two commercial ophthalmic formulations, and the percent label amounts of total BKC contents were found to be 99.7 and 103.2.

Optimization of the freeze-drying cycle: adaptation of the pressure rise analysis model to non-instantaneous isolation valves.

Abstract: The principal aim of this study is to extend to a pilot freeze-dryer equipped with a non-instantaneous isolation valve the previously presented pressure rise analysis (PRA) model for monitoring the product temperature and the resistance to mass transfer of the dried layer during primary drying. This method, derived from the original MTM method previously published, consists of interrupting rapidly (a few seconds) the water vapour flow from the sublimation chamber to the condenser and analysing the resulting dynamics of the total chamber pressure increase. The valve effect on the pressure rise profile observed during the isolation valve closing period was corrected by introducing in the initial PRA model a valve characteristic function factor which turned out to be independent of the operating conditions. This new extended PRA model was validated by implementing successively the two types of valves and by analysing the pressure rise kinetics data with the corresponding PRA models in the same operating conditions. The coherence and consistency shown on the identified parameter values (sublimation front temperature, dried layer mass transfer resistance) allowed validation of this extended PRA model with a non-instantaneous isolation valve. These results confirm that the PRA method, with or without an instantaneous isolation valve, is appropriate for on-line monitoring of product characteristics during freeze-drying. The advantages of PRA are that the method is rapid, non-invasive, and global. Consequently, PRA might become a powerful and promising tool not only for the control of pilot freeze-dryers but also for industrial freeze-dryers equipped with external condensers.

Pharmaceutical Development of a Parenteral Lyophilised Formulation of the Investigational Anticancer Agent ES-285.HCl

Abstract: The aim of this study was to design stable parenteral pharmaceutical final products containing 25 mg and 50 mg ES-285HCl per dosage unit for use in phase I clinical trials ES-285HCl drug substance was fully characterised and showed very slight solubility in water The development of the pharmaceutical product, containing 2-hydroxypropyl-beta-cyclodextrin, is discussed in view of formulation optimisation and manufacture The developed freeze-dried products were found stable for at least 6 months at an accelerated storage condition of 25 +/- 2 degrees C/60 +/- 5% relative humidity and for at least 12 months at the designated long term storage condition of 5 +/- 3 degrees C, in the dark Phase I trials using ES-285HCl 25 mg/vial and 50 mg/vial final products are currently ongoing

Aseptic processing contamination case studies and the pharmaceutical quality system.

Abstract: This paper summarizes parenteral drug contamination case studies presented at industry conferences and a Food and Drug Administration advisory committee meeting in the period of 2000–2004. CGMP deficiencies associated with each contamination event are discussed. The key role of a well-functioning quality system in contamination prevention is emphasized.

Managing the microbiological quality of pharmaceutical excipients.

Abstract: The microbiological quality of the pharmaceutical excipients used to manufacture pharmaceutical and over-the-counter drug products may significantly affect the outcome of individual processing steps and the microbiological attributes of the final drug products. Unlike active pharmaceutical ingredients, excipients are purchased from multiple suppliers and in many cases are produced for the food, cosmetics, consumer products, photographic, and paint industries and not specifically for the pharmaceutical industry, so the management of their microbiological quality is less straight- forward. This article discusses the qualification of suppliers, excipient production methods, compendial standards, regulatory controls, and microbial limits testing of excipients. Emphasis is given to risk assessment associated with pharmaceutical excipients.

Stability of all-in-one standard formulae for paediatric parenteral nutrition.

Abstract: The Robert Debre Hospital pharmacy unit ensures an annual manufacturing rate of 20,000 parenteral nutrition bags. Until 1999, these bags consisted in binary admixtures, fat emulsions being administered to the patient via a “Y” connexion on the catheter. Since then, all-in-one standard formulae have been established and are manufactured using a Baxa MM23® automated compounder. The aim of this study was to assess the physico-chemical stability of all-in-one admixtures, in order to ensure patient administration safety (mainly avoiding precipitation risks between the nutrients). Three bags of each standard formula were manufactured in monocompartmental bags. Stability assays consisted in the assessment of the admixture9s (1) macroscopic aspect, (2) drop size measurement, (3) zeta potential measurement, (4) pH measurement, and (5) osmolality measurement. Tests were conducted between D0 (manufacturing day) and D10 (10 days after manufacture). All-in-one admixtures manufactured according to the established standard formulae were found to be stable for at least 10 days, provided they are kept away from light and at a temperature of +4 °C.

Bacterial Adhesion: Considerations Within A Risk-Based Approach To Cleaning Validation

Abstract: Pharmaceutical manufacturing processes are vulnerable to varying degrees of microbial challenge (hazard) quantifiable as microbial ingress, and microbial retention risks affecting raw materials and inputs to the final product. Control over these risks is exacted by both purposefully designed and incidental (or fortuitous) properties of the manufacturing processes. Within the manufacturing environment, equipment cleaning and hold processes are uniquely prone to microbial challenge yet paradoxically demonstrate the greatest potential for mitigation of these risks. Cognition of those components and contributing factors associated with microbial challenge are necessary to facilitate scientifically sound risk assessments. In the context of equipment cleaning and hold processes, risk assessments are necessary to identify and contrive conditions, which are truly worst case for the validation of the control of microbial challenge. A number of components contribute to the risk of microbial retention, yet the phenomenon of microbial adhesion to surfaces remains one of the most ubiquitous and perplexing. The dual purpose of this review is to primarily pre9cis and provide in a single reference those multi-factorial features and variables contributing to bacterial adhesion, and secondly to provide a guide for interpretation of those considerations for integration into a risk-based approach to cleaning validation.

Modeling of drug release from celecoxib-PVP-meglumine amorphous systems.

Abstract: An empirical assessment of drug release from amorphous systems of celecoxib (CEL), poly(vinyl pyrrolidone) (PVP), and meglumine (MEG) was performed and compared with that for its crystalline form. CEL–PVP (4:1 w/w) binary and CEL–PVP–MEG (7:2:1 w/w) ternary amorphous systems provided higher drug dissolution. Mathematical modeling of drug release data was found to best fit the Hixson-Crowell release model. The biphasic drug release during a 6-h duration exhibited higher release kinetics in the first phase due to the presence of drug in amorphous form. The release kinetics subdued in the latter phase due to ongoing devitrification process in amorphous systems. A comprehensive understanding of drug release from amorphous systems will accentuate the rationalized design of amorphous drug delivery systems.

Evaluating the formulae for integrated lethality in ethylene oxide sterilization using six different endospore forming strains of bacteria, and comparisons of integrated lethality for ethylene oxide and steam systems.

Abstract: Bacterial endospores from six different species of bacteria were exposed to a spectrum of ethylene oxide (EtO) sterilizing conditions. Temperature was varied from 40 to 60 °C and the ethylene oxide concentration was varied from 300 to 750 mg/L. Relative humidity was maintained at 60 ± 10% RH. The fraction negative procedure was used to determine the D value for each of the test conditions. Bacterial species tested included Bacillus atrophaeus ATCC # 9372, Bacillus smithii ATCC # 51232, Bacillus subtilis “5230” ATCC # 35021, Bacillus subtilis, DSM # 4181, Bacillus pumilus ATCC # 27142, and Geobacillus stearothermophilus ATCC # 7953. All spore preparations were inoculated on filter paper strips packaged in blue, sterilizable glassine pouches. G. stearothermophilus was the least resistant organism tested. The most resistant organisms tested were B. atrophaeus and B. subtilis “5230”. The B. subtilis “5230” strain was slightly more resistant than B. atrophaeus at conditions of 54C and EtO concentrations of 400, 600, and 750 mg/L, as well as at 60C/750mg/L EtO. The other species were between these extremes. This empirical data allowed the application of the recently published formula for converting D values from one set of conditions to another and evaluations of accuracy. The measured D values also allowed the determination of Z values based on temperature variations. These formulae, when applied to process temperatures independent of gas concentration, result in a Z value of approximately 32 °C that appears to be similar for all species tested. These data support the application of the previously published formulae 1–6 and allow the same approach to integrated lethality for ethylene oxide processes as is commonly applied to steam sterilization. A review of steam sterilization and related principles was conducted for comparison of integrated lethality for these two methods of sterilization. Errors associated with D values, Z values, extrapolation, and integrated lethality for both methods of sterilization are discussed.

Strategy for Assessing the Leachables Impact of a Material Change Made in a Container/Closure System

Abstract: Container/closure systems are extensively characterized in terms of their propensity to contribute leachable substances to the drug products they contain. Such a characterization is relevant until a change occurs in the composition or production of the container/closure system itself or the raw materials it is comprised of. When such a change occurs, it is necessary to ascertain the impact that the change would have on the validity and applicability of the previously performed leachables assessment. A general methodology for performing change control evaluations is developed in this manuscript and is illustrated via the use of a case study.

Pharmaceutical Development of a Parenteral Lyophilised Dosage Form for the Novel Anticancer Agent C1311

Abstract: C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. C1311 shows significant cytotoxic activity in vitro and in vivo toward a range of colon tumours. The aim of the present study is to develop a sterile and stable, injectable pharmaceutical product for C1311 to be used in phase I clinical trials. C1311 drug substance was structurally and analytically characterised by chromatographic, spectrometric, and diffraction techniques. C1311 was freely soluble in water, and its stability was investigated in several liquid and lyophilised formulations with or without the use of buffering, tonicity, and bulking agents. The final product, containing 100 mg/vial C1311 (as anhydrous free base), was stable for at least 3 months under accelerated storage conditions and at the designated long-term storage condition of 5 ± 3 °C in the dark. The drug is currently used in phase I clinical trials.

Nomenclature standardization for 'large pore size' virus-retentive filters.

Abstract: hat’s in a label — or name or number for that matter? A great deal, apparently. Some of today’s clothing manufacturers are intentionally labeling clothes a size or two smaller than they really are — just to cater to their customers’ vanity. Unclear nomenclature is unacceptable, however, in the more serious world of biotechnology. If a filter is counted on to remove viruses from biotech products by a size exclusion mechanism, its rating or nomenclature must be crystal clear. For example, 18–26 nm parvoviruses are unlikely to be retained on/in a “large pore size” virus–retentive filter (designed to remove retroviruses and other larger viruses).Virus filtration is a critical unit operation during the manufacture of recombinant proteins and plasma-derived biopharmaceuticals. At a conference earlier this year, Patrick Celis of the European Medicines Evaluation Agency (EMEA) remarked that virus filtration appears to be one of the most common virus clearance unit operations in bioprocessing based on their frequency in marketing authorization dossiers that he has reviewed (

Activities of the USP Analytical Microbiology Expert Committee During the 2000–2005 Revision Cycle

Abstract: Cor~s~~ltc~t~t.~ , AMB EC; '~rc!frs.so,; Urli~~rr.rir~ c~f'Pirt.~l)urgl~ Scliool of Plzarrntrc~. Chciir.. AMB E.t-pert Cottltnitte~; '~itw.tor of Genercll Po1ic.ie.r trntl Rryuir.rtncnt.s ABSTRACT: This article is a comprehensive review of the published activities of the Analytical Microbiology Expert Committee (AMB) for the 20002005 revision cycle. The major thrust of the activities during this revision cycle were directed at international harmonization. and to provide guidance in the changing field of pharmaceutical microbiol- ogy. In addition to reviewing the changes accomplished. this article discusses the rationale for many of the changes and some background information regarding new initiatives underway. Where appropriate. changes in the USP that did not fall under the direct pi~rview of the AMB Expcrt Comn~ittee (EC) but of interest to the microbiology conlniunity are also discussed.

Establishment of Critical Contamination Risk Locations (“Hot Spots”) in Environmental Monitoring by Means of Three-Dimensional Airflow Analysis and Particulate Evaluation

Abstract: A practical approach for the qualification of the surrounding environment of the critical area in aseptic processing has been developed. This method uses three-dimensional air velocity measurements combined with airborne particle monitoring. The analysis of the results obtained using the methods described in this article are beneficial in the selection of sample sites and frequencies and in refining personnel procedures and materials flow in aseptic processing. We propose that this improved qualification method can be widely applicable for both existing and new aseptic processing areas. This paper shows the results of one case study utilizing this method. The particle distribution map of a Grade B environment based upon extensive analysis was found to correspond to room airflow, as visualized by air vector mapping. The actual annual environmental monitoring data, which include airborne particles and microbes, as well as other microbial monitoring data, are also presented with respect to their relationship to the airflow pattern.

Suspension for intravenous injection: image analysis of scanning electron micrographs of particles to determine size and volume.

Abstract: The purpose of this study is to determine the size and volume of large particles in a drug suspension by performing an image analysis of digital micrographs obtained by field emission, low voltage scanning electron microscopy (FE-LVSEM). The data obtained by this method are then used to select the appropriate imaginary component of the complete refractive index necessary for the software computation of particle size distribution measured using laser light diffraction. The application of FE-LVSEM involves four major elements: 1) the use of Anodisc™ inorganic aluminum oxide membrane filters for the image analysis of drug crystal particles ≥350nm having been isolated from suspension in order to determine the area, length, width, and other particle measurements; 2) the use of either a Thornley Everhart secondary electron detector or a MCP detector in the secondary electron mode directly above the specimen so as to produce a shadow-free digital image; 3) recording digital images as viewed normal to the crystal surface and at 45° so as to image the edge of the crystal at a known angle; and 4) determination of drug particle volume from both views and the conversion of those volumes to an equivalent spherical volume.

Impact of Blow/Fill/Seal process variables in determining rate of vial contamination by air dispersed microorganisms.

Abstract: Controlled challenges of air dispersed spores of Bacillus subtilis NCIMB 8649 have been generated in a custom-built challenge room housing a Blow/Fill/Seal machine filling filter-sterilized trypticase soy broth into 5.5 cm3 low density polyethylene vials. The effects on the rate of vial contamination of systematic changes in the process variables, rate of provision of ballooning air, delay in the application of mould vacuum and duration of transfer of the open vial, have been examined. Overall, the findings show that the conditions of vial formation can affect appreciably the rate of vial contamination from airborne spores. The indications are that heat lethality, associated with the elevated temperature required for polymer extrusion and vial formation, has a role in determining such contamination.

Evaluation of peracetic acid permeation during flash sterilization through pharmaceutical plastic polymers used in cytotoxic reconstitution units.

Abstract: Peracetic acid (PAA) permeation in flash sterilization was studied using three different plastic infusion bags made of polypropylene and polyethylene, filled with glucose 5% or NaCl 0.9%. The pH was measured and acetic acid (AA) and PAA concentrations were made by reverse phase high-performance liquid chromatography (RP-HPLC). PAA was derivatized by oxidation of methyl tolyl sulfide (MTS) into methyl tolyl sulfoxide (MTSO) detected by ultraviolet (UV) absorbance at 230 nm. The technique has a sensitivity of 0.3 microg x L(-1) and was highly specific. Results showed that pH measurements remain constant and demonstrated the absence of PAA permeation, which was confirmed by the absence of AA permeation regardless of the brand tested, with both unwrapped and overwrapped infusion bags, when flash sterilization is applied. These results allow flash sterilization to be performed with unwrapped infusion bags without any risk of drug degradation by PAA. This makes compounding safer and easier, which improves productivity.

Permeation Risks with Peracetic Acid and Hydrogen Peroxide Sterilizing Agent Inside Ambulatory Pumps

Abstract: The sterilizing agent commonly used to sterilize materials for an isolator is a peracetic acid (PA) and hydrogen peroxide (HP) mixture. The permeation of this agent through ambulatory pumps should reveal a potential toxic risk for the patient and a stability modification of the drug by a pH change. Six wrapped and six unwrapped ambulatory pumps from each laboratory were introduced in the transfer chamber for the sterilizing process over 2 h 45 min. The presence of PA and HP were determined by using analytical strips. If the analytical strips of HP were positive, the level of HP was determined by using a specific spectrometric kit. No acid permeation was found in all wrapped pumps. Acid permeation was found in two samples of Ultraflow unwrapped series and in one unwrapped sample of Easypump series by the analytical strips. In other unwrapped samples, no acid permeation was detected. In four unwrapped ambulatory pumps (Accufuser, Infusor, Ultraflow, and Easypump), the analytical strips of HP were positive in the range of 0.5 to 25 mg/L, varying by laboratory. In only one sample (Surefuser), no detection of HP was found. The quantitative dosage of HP by spectrophotometry confirmed the permeation risk inside all pumps except the Surefuser. Our investigation shows that the permeation risk inside ambulatory pumps is real when pumps are unwrapped and exposed at high levels to PA and HP mixture. The results of our study recommend retaining the wrapping for the peracetic acid sterilization of the ambulatory pumps.

Endotoxin in parenteral medicines may be a risk factor in severe sepsis.

Abstract: Endotoxemia is part of sepsis and septic shock. In the terminal phase of the disease, elevated blood levels of endotoxin (ET) are commonly observed. This suggests a correlation between endotoxemia and the severity of sepsis. Proliferating microorganisms are the primary source of ET in septic patients; however, ET is also present in replacement fluids and in a variety of iv drugs and blood products. Current pharmacopoeia guidelines allow 0.5EU/ml in replacement fluids (1) and 350EU/dose (assuming 70 kg body weight) for any iv medication (2).