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PubMedDate not supplied

Studies on the scale-up of crossflow filtration devices.

This paper describes a new method that makes it possible to predict the performance of crossflow ultrafiltration and microfiltration when scaling up from small laboratory scale to process-scale systems. Using this method, one characterizes a solution's filtration properties with a specific ultrafiltration or microfiltration membrane in a laboratory-scale crossflow device. Based on experimental results at this scale, one can accurately predict scale-up performance from laboratory through clinical production to full marketing production. Given the need for biopharmaceutical engineers to rapidly predict the size and cost of full-scale filtration processes once products receive regulatory approval, this method will find wide use in the pharmaceutical industry.

Drug Industry↗
PubMed1996

Systemic delivery of peptides and proteins across absorptive mucosae.

As therapeutic peptides and proteins become readily available through rapid advances in recombinant technology, and because rapid presystemic elimination renders them ineffective when administered orally, pharmaceutical scientists are faced with the challenge of delivering these macromolecules systemically; therefore, alternative routes of delivery need to be investigated. Transmucosal delivery through absorptive mucosae represents one of these alternatives. This route has the advantage of being noninvasive and of bypassing hepatogastrointestinal clearance. The absorptive mucosae that have been investigated for delivery of peptides and proteins include buccal, nasal, pulmonary, rectal, and vaginal. Nasal delivery has been studied extensively and has been the most successful--nasal sprays for buserelin, desmopressin, oxytocin, and calcitonin are already available commercially. In general, enzyme inhibitors and permeation enhancers need to be coadministered for successful delivery of these biopharmaceuticals. Classes of enhancers used for transmucosal delivery include bile salts, dihydrofusidates, cyclodextrins, surfactants, and chelating agents. Each of these agents exerts its enhancing effects by a different mechanism, and each has been associated with adverse effects. This article discusses the physiology of each of the mucosae used, the fundamentals of transmucosal delivery, and recent progress in systemic delivery of therapeutic peptides and proteins across each of the mucosae; in an effort to highlight principles of transmucosal delivery, it also discusses the transmucosal delivery of enkephalin, calcitonin, and insulin as case studies.

Absorption↗
PubMed1996

[How can the practicing veterinarian select the best vaccine?].

To choose the best vaccine from the available vaccines is a difficult task for the veterinary practitioner. The aim of this article is to tender the practitioner criteria for making the best choice. Efficacy is the most important criterion when selecting a vaccine. The efficacy can be assessed by studying the results of well-designed vaccination-challenge experiments performed in the laboratory and of field trials. Safety is the second criterion for quality of vaccines. Other aspects that can influence the choice of a vaccine are: available documentation, the cost and biopharmaceutical data. A systematic and objective comparison of the quality criteria of vaccines will lead to the selection of the best vaccine.

Animals↗
PubMed1996

[Design of topically resorptive interferon drugs].

The current data on the development and design of topically resorptive interferon drugs are summarized. In many cases it is advisable to use topically resorptive interferon agents which allows them to topically affect a clinical process, to avoid negative sequelae seen when high-dose interferon is unjustifiably systematically given, by reducing its use to a minimum. Interferon is known to be one of the best antiviral agent, besides, it produces marked antimicrobial and antitumor effects. Whether interferon as a component of drugs can be stabilized by axillaries of various chemical nature which act as stabilizers, promoters, and carriers is dealt with. The topically resorptive formulations designed in terms of biopharmaceutical factors are described. The advantages of topically resorptive agents over other drugs are shown and hence they can be widely used in practical medicine.

Absorption↗
PubMed1996

A comparison of methods for the estimation of retroviral burden.

The presence of retroviral contamination is of vital concern in the manufacture of cell culture-derived biopharmaceuticals. These cell lines usually have A- or C-type retrovirus-like particles which are visible by transmission electron microscopy (TEM) even when infectivity (IF) or reverse transcriptase activity (RTA) cannot be demonstrated. The supernatant of the post-production cell cultures, therefore, also needs to be evaluated by TEM for viral burden. A major question, however, is how to establish a quantitative viral load estimate for the evaluation of a purification process. The FDA recommends that a purification process for viral contaminants remove or inactivate 3-5 logs over the estimated viral burden. Viral particles are difficult to identify and quantify, however, by conventional negative staining. We present a comparison of infectivity assay, reverse transcriptase assay, negative staining, and thin sectioned TEM. These assays were performed on four samples. Ultracentrifuged sediments of cleared cell-culture media were measured, fixed and processed. Thin sections were evaluated by TEM and the number of viral particles estimated by morphometric derived quantification. Retrovirus particles were easily identified and quantified when examined by TEM as compared to negative staining and correlated with the other viral assays (IF, RTA). These results demonstrate that the TEM thin section method was a superior technique to negative staining for estimating viral particle load in cell-culture supernatant. To validate further the plastic embedding with thin sectioning, we evaluated cell culture supernatants (pellets) for retroviral burden at various dilutions, from two cell lines. Morphometric determinations were made of the number of viral particles present per unit volume and compared to results obtained by infectivity assay. Since the morphometric calculation for viral density assumes even distribution of viral particles, we also evaluated and calculated viral counts on multiple thin sections taken throughout selected pellets.

Animals↗
PubMed1996

Validation of retroviral detection for rodent cell-derived products and gene therapy applications.

The availability of sensitive assays for detecting infectious murine retroviruses has become critical for the development and acceptance of a number of biopharmaceuticals, including monoclonal antibody-derived products and gene therapy vectors. Comparative studies demonstrated that the PG4 S+L- retrovirus infectivity test routinely yields higher titres than the mink cell test for xenotropic, amphotrophic and MCF murine retroviruses. A validation study for the PG4 S+L- assay demonstrated very good linearity (r2 of 0.95 to 0.99), reproducibility within a study (+/-0.35 log10 units), and precision between tests (+/-0.45 log10 units). Interference (or selectivity) in the presence of a non-specific antibody was insignificant (less than 0.2 log10 units). Sensitivity levels established from measurements as virus titres approach zero demonstrated a threshold value of 2-3 focus forming units (FFU)/ml. Two methods for increasing assay sensitivity were used including: (i) increased product samplings combined with a Poisson distribution analysis, and (ii) a 14-day co-cultivation with Mus dunni cells. Each of these methods was shown to increase sensitivity by at least one log10 unit. Murine retroviruses may also be detected by a less sensitive immunofluorescence assay (IFA) using specific monoclonal antibodies; this assay is essential for detecting certain recombinant ecotropic MuLVs. In summary, murine retroviral detection ranked by sensitivity is mink S+L- < IFA with monoclonal antibodies < PG4 S+L- < Mus dunni co-cultivation followed by PG4 S+L-.

Animals↗
PubMed1996

Evaluation of anti-viral filters.

The purification processes used to prepare medicines from human and animal cell lines provide one of the major opportunities for virus risk reduction. The purification process can be validated for its ability to remove a range of viruses and can be shown to provide a significant barrier to the transmission of viruses from cell substrates and raw materials to the patient. Ultrafiltration membranes which are manufactured with extremely tight control on pore size distribution can remove a broad spectrum of viruses with high efficiency. A scheme is described for the evaluation of anti-viral filters and the results from evaluation of two filters are presented. The experiments carried out with ultrafiltration membranes suggest that they can provide significant additional virus risk reduction factors for biopharmaceuticals.

Animals↗
PubMed1996

Process scale considerations in evaluation studies and scale-up.

This paper focuses on the scale of validation studies that are performed in order to demonstrate viral clearance in downstream processing of biopharmaceutical products. A serious concern for rDNA-derived proteins from recombinant mammalian cell cultures and monoclonal antibodies (MAbs) derived from hybridoma cultures is the potential risk from contaminating retroviral particles or adventitious viruses. Accordingly the downstream process has to be designed to reduce a potential virus load significantly: by virus removal and by virus inactivation methods. Such viral clearance is essential for drug safety- and has to be validated. This means that the design of downstream processing has to take into consideration both the capability for viral clearance and the capability for validation respectively.

Animals↗
PubMedDate not supplied

Virus retention by a hydrophilic triple-layer PVDF microporous membrane filter.

Retention of bacteriophages (phi 6, PR772, T1, and PP7) and mammalian viruses (poliovirus and influenza A virus) by a hydrophilic triple layer PVDF microporous membrane, the Ultipor VF grade DV50 membrane, was evaluated. Challenges of membrane discs or pleated filter cartridges were performed at concentrations of 10(6)-10(8) PFU/mL in one or more of the following carrier fluids: water, saline, gelatin (0.1%) in phosphate buffer, Dulbecco's Modified Eagle Medium (MEM), and MEM supplemented with 10% fetal bovine serum (MEM + 10). The data demonstrate a minimum log titer reduction (LTR) of 6 for viruses larger than 50 nm irrespective of the carrier fluid. Protein transmission levels of greater than 95% for IgG and albumin were achieved. For integral pleated filter cartridges, correlation between a nondestructive integrity test (using the forward flow integrity test method) and virus retention was demonstrated. The Ultipor VF grade DV50 filter can be applicable in the manufacture of biologicals and biopharmaceuticals, where high protein transmission and consistent viral titer reduction are desired.

Membranes, Artificial↗
PubMedDate not supplied

Cumulative viral titer reduction demonstrated by sequential challenge of a tangential flow membrane filtration system and a direct flow pleated filter cartridge.

The efficiency of sequential incorporation of two approaches to virus removal, i.e., tangential flow ultrafiltration using the Omega 300K VR Maximate System, and, direct flow microfiltration using the Ultipor VF grade DV50 virus removal filter, was evaluated using bacteriophage phi 6 in Dulbecco's modified Eagle medium (MEM) as the carrier fluid. A combined log titer reduction value of > 10 was demonstrated, with each step, individually, providing > 4.5 log reduction. Significant improvement in filter life was also demonstrated when the combined system was used. The data suggest that this system may have applications in the manufacture of biologicals and biopharmaceuticals, where there is a requirement for multiple robust methods of virus removal to ensure freedom from endogenous or adventitious viral contamination.

Drug Contamination↗
PubMed1998

[The importance of concomitant compounds in plant extracts].

Plant extracts are multi-composed mixtures that can be subdivided into main active substances and concomitant compounds. Concomitant compounds are called co-effectors because they can change the physicochemical properties of the main active substances and therefore influence the biopharmaceutical parameters, e.g. solubility and bioavailability. The composition and the properties of plant extracts depend on a multitude of different factors such as quality and degree of reduction of the plant, and the process of extraction and drying. Concomitant compounds affect the physical and chemical stability of plant extracts. The hygroscopicity also depends on the composition of the concomitant compounds. It is an important property for the further processing of the plant extract to solid dosage form, e.g. tablets. Solubility and dissolution rate can be influenced by the concomitant compounds. Both properties are important for the absorption of the active substances though in many cases the responsible substances and mechanisms are still unknown. Solubilisation by surface-active agents, formation of soluble drug-concomitant compound-associates and solid dispersion, in which the drug is finely dispersed or X-ray amorphous, are often responsible for the increased solubility. Improved wettability in the presence of the concomitant compounds results in better dissolution. Supersaturated solutions of the active substances are stabilized for months by inhibition of crystallization. Numerous examples are known for influencing the absorption by natural concomitant compounds. The absorption is enhanced by the increased amount of dissolved drug or by the alteration of membrane permeability. Adsorption or complex formation with the concomitant compounds decrease the absorption rate, in some cases also the extent of absorption.

Animals↗
PubMed1998

Chromatographic removal and heat inactivation of hepatitis A virus during manufacture of human albumin.

CSL Limited, an Australian biopharmaceutical company, has recently converted its method of manufacture for human albumin from a traditional Cohn-ethanol fractionation method to a method employing chromatographic techniques. Studies were undertaken to determine the efficiency of the chromatographic and pasteurization steps used in the manufacture of Albumex(R) (CSL's trade name for albumin) in removing and inactivating the potential viral contaminant, hepatitis A virus (HAV). The manufacturing process for Albumex(R) includes three chromatographic steps, two of which are ion-exchange steps (DEAE-Sepharose(R) Fast Flow and CM-Sepharose(R) Fast Flow) and the third is a gel-filtration step (Sephacryl(R) S200 HR). The final stage of the Albumex(R) process involves a bulk pasteurization step where product is held at 60 degrees C for 10 h. HAV partitioning experiments on the DEAE-Sepharose(R) FF and CM-Sepharose(R) FF ion-exchange and Sephacryl(R) S200 HR gel-filtration columns were performed with scaled-down models of the production-scale chromatographic Albumex(R) process. Production samples collected before each of the chromatographic steps were spiked with HAV and processed through each of the scaled-down chromatographic columns. Samples collected during processing were assayed and the log10 reduction factors calculated. Inactivation kinetics of HAV were examined during the pasteurization of Albumex(R) 5 and 20 [5% and 20% (w/v) albumin solutions] held at 60 degrees C for 10 h. Log10 reductions for HAV through the DEAE-Sepharose(R) FF, CM-Sepharose(R) FF and Sephacryl(R) S200 HR chromatographic columns were 5.3, 1.5 and 4.2 respectively, whereas a 4.4 and a greater than 3.9 log10 reduction in HAV in Albumex(R) 5 and 20 respectively were achieved during pasteurization.

Chromatography, Gel↗
PubMed1998

Chromatographic removal and heat inactivation of hepatitis B virus during the manufacture of human albumin.

The purpose of the present study was to examine the efficacy of the chromatographic and pasteurization steps, employed in the manufacture of human albumin, in the removal and/or inactivation of hepatitis B virus (HBV). Most human albumins manufactured today are prepared from donor plasma by fractionation methods that use precipitation with cold ethanol. CSL Limited, an Australian biopharmaceutical company, has recently converted its method of manufacture for albumin from a traditional Cohn fractionation method to a method employing chromatographic techniques. A step-by-step validation of virus removal and inactivation was performed on this manufacturing process, which includes a DEAE-Sepharose(R) and CM-Sepharose(R) Fast Flow ion-exchange step, a Sephacryl(R) S200 High-Resolution gel-filtration step and a bulk pasteurization step where product is held at 60 degreesC for 10 h. HBV partitioning experiments were conducted on scaled-down chromatographic columns with hepatitis B surface antigen (HBsAg) as a marker, whereas the HBV model virus, duck HBV, was used to study the inactivation kinetics during pasteurization. Reductions for HBsAg through the three chromatographic steps resulted in a total log10 decrease of 1.5 log10, whereas more than 6.5 log10 decrease in duck HBV in Albumex(R)5 was achieved during pasteurization.

Animals↗
PubMed1998

[The validity of radioimmunologic determination of bioavailability of beta-escin in horse chestnut extracts].

The bioavailability under steady state conditions of a standard, slow-release horse chestnut seed extract (HCSE)-containing product was compared with that of an analogous, fast-release test preparation (Noricaven novo) in a prospective, randomised, double-blind study in a double cross-over design. The serum concentration of beta-escin (CAS 6805-41-0) was measured by radioimmunoassay. In addition, the biopharmaceutical properties of the HCSEs present in the products were investigated, the amount and composition of the active ingredient, escin, being analysed with a validated HPLC method. The pharmacokinetics of this study were compared with the corresponding data of a similar investigation carried out under analogous conditions concerning study design, analytical methods and reference preparation. Comparison of the similar studies revealed differences in characteristic pharmakokinetic values of beta-escin in terms of a shift of the concentration time curves as could be demonstrated for the reference product. The total amounts of escin in the two products investigated did not differ significantly. However, quantitative and qualitative differences were detected in the constituents of the two different extract preparations. It is concluded that the high specificity of the validated beta-escin radioimmunoassay leads to analytical imprecision due to the variable constituents of the extract preparations used. It is necessary to test whether this problem can be solved using an analytical approach, which is specific for each extract.

Adult↗
PubMed1999

Tetrahydropalmatine poisoning: diagnoses of nine adult overdoses based on toxicology screens by HPLC with diode-array detection and gas chromatography-mass spectrometry.

BACKGROUND: Tetrahydropalmatine (THP) is a neuroactive alkaloid with analgesic and hypnotic action. Its analysis is important because cases of human poisonings have emerged as a result of unregulated use of some proprietary biopharmaceuticals containing purified THP. METHODS: We established analytical parameters for HPLC with diode-array detection (HPLC-DAD) and gas chromatography-mass spectrometry (GC-MS) for the detection of THP in serum and urine. Nine acutely THP-poisoned adults were thus screened over 16 months. RESULTS: All patients recovered quickly after mild neurological disturbance. In general, THP was metabolized rapidly and excreted as polar metabolites in urine. Serum THP was measured in five cases and found to be <0.1-1.2 mg/L (<0.3-3.4 micromol/L). Paired analyses of urine with and without glucuronidase treatment clarified the disposition of THP. Our GC-MS method with trimethylsilane derivatization identified O-desmethyl metabolites. With a uniform solid-phase extraction, the HPLC-DAD procedure detected intact glucuronide metabolites. CONCLUSION: Intact glucuronide metabolites of THP are sensitive markers for THP exposures. Our methods and findings provide practical tools and information for surveillance of intoxication caused by excessive THP intake.

Adult↗
PubMed1998

[Interspecies allometric scaling in pharmacokinetics of drugs].

Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight, ratio of organ- and body weight, breathing number, etc.). Interspecies pharmacokinetics tend to approximate, the organism, as the sum of organs and tissues according to material balance. The allometric equations for the pharmacokinetic parameters were applied to scale the data with respect to pharmacokinetic time and remove the chronological time dependency. When the data of at least three species are available, the pharmacokinetic parameters can be fit according to body weight in log-log regression. Allometric scaling is not applicable in all cases, only when the selected species has similar physiological behaviour, such as protein-binding, metabolism, etc. Valuable information for the evaluation of the effect and the biopharmaceutical characteristics may emerge from more creative data analysis based on all result collected during the preclinical evaluation of a new drug. Author examined the applicability of the interspecies scaling method in the case of a new drug depogen, using drotaverin as reference. The pharmacokinetic data were collected from mouse, rat and dog and during the evaluation human data were applied too. The usual pharmacokinetic parameters were determined (MRT, MAT, beta, etc.), the results of allometric analysis were collected and the standard deviation of measured and calculated values were given.

Animals↗
PubMed1965

HERPES ZOSTER.

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Adrenal Cortex Hormones↗