In-process Testing Research Articles

Pathogen Safety of Intravenous Rh Immunoglobulin Liquid and Other Immune Globulin Products: Enhanced Nanofiltration and Manufacturing Process Overview

Plasma products for therapeutic use pose specific challenges in manufacturing to ensure products maintain biologic activity and are safe with respect to contamination and transmission of disease-causing agents. Various processes have demonstrated effectiveness in eliminating, reducing, or inactivating viral contaminants. Recently, the possibility of transmitting variant Creutzfeld-Jakob disease (vCJD) or transmissible spongiform encephalopathies (TSE) through blood-based products has become a concern. The present study involves the validation of a hyperimmune immunoglobulin manufacturing process incorporating a nanofiltration step with a nominal pore size of 20 nm for removal of viral contaminants and other adventitious agents. Processing intermediates during the manufacture of IV Rh IgG (WinRho SDF/WinRho SDF Liquid, Cangene Corporation, Manitoba, Canada) were spiked with model viruses and processed in scaled-down procedures to validate the viral reduction capacity of each step. Anion-exchange chromatography and solvent/detergent steps are known to contribute to virus removal and inactivation. The Planova 20 N nanofiltration step was effective in reducing model viruses representing a wide range of viral morphologies with varying degrees of resistance to physicochemical inactivation. All in-process and final batch testing met current standards for production of IV Rh IgG manufactured with the previously licensed filter, which had a larger nominal pore size of 35 nm. The manufacturing process, employing a Planova 35 N filtration step, has been proactively improved by the change to a smaller-pore 20 N filter. Replacement of the 35 N filter with the 20 N filter produces a similar product while enhancing the capability for removal of smaller viruses and prions.

In-Process Functional Testing of Pixel Circuit in AM-OLEDs

This paper presents a functional testing scheme using a two-thin-film-transistor (TFT) pixel circuit of an active-matrix organic light-emitting display (AM-OLED). This pixel circuit and the co-operative electrical testing scheme can not only evaluate the characteristics of each TFT, but also determine the location of line and point defects in the TFT array. Information on defects can be used in a unique repair system that cutting and repairing these defects. Furthermore, the functional testing scheme can be applied as a part of yield management of the AM-OLED array process.

Analyzing a bioterror attack on the food supply: the case of botulinum toxin in milk.

We developed a mathematical model of a cows-to-consumers supply chain associated with a single milk-processing facility that is the victim of a deliberate release of botulinum toxin. Because centralized storage and processing lead to substantial dilution of the toxin, a minimum amount of toxin is required for the release to do damage. Irreducible uncertainties regarding the dose-response curve prevent us from quantifying the minimum effective release. However, if terrorists can obtain enough toxin, and this may well be possible, then rapid distribution and consumption result in several hundred thousand poisoned individuals if detection from early symptomatics is not timely. Timely and specific in-process testing has the potential to eliminate the threat of this scenario at a cost of <1 cent per gallon and should be pursued aggressively. Investigation of improving the toxin inactivation rate of heat pasteurization without sacrificing taste or nutrition is warranted.

Early estimation of software quality using in-process testing metrics

In industrial practice, information on post-release field quality of a product tends to become available too late in the software development process to affordably guide corrective actions. An important step towards remediation of this problem of late information lies in the ability to provide an early estimation of software post-release field quality. This paper presents the use of a suite of in-process metrics that leverages the software testing effort to provide (1) an estimation of potential software field quality in early software development phases, and (2) the identification of low quality software programs. A controlled case study conducted at North Carolina State University provides initial indication that our approach is effective for making an early assessment of post-release field quality.

Development of a HPTLC method for in-process purity testing of pentoxifylline

A HPTLC method for the separation and identification of pentoxifylline and related substances, impurities of reaction partners, and side reaction products has been developed using different mobile and stationary phases. For quantitative assay of possible by-products as impurities, LiChrospher RP-18 F254s chromatoplates, acetone-chloroform-toluene-dioxane (2:2:1:1 v/v) as a mobile phase, and detection at 275 nm were employed. Linearity (r > or = 0.997), recovery (86.5-115.5%), and determination limit (0.1-0.6%) were evaluated and found to be satisfactory. This method enables monitoring of the synthesis, as well as purity control of pentoxifylline-containing raw materials and pharmaceuticals.

To test or not to test? - Understanding electrical and mechanical tests performed on induction motors

This article explores tests available for various induction motors and analyzes the stress on the motor and value of information derived. When considering motor testing, we need to discuss both in-process testing and testing of the final product. The in-process testing focuses on stator and rotor assembly, although the integrity of other motor components can also be examined. The benefit of having information obtained from rigorous tests must be compared against the additional testing cost.

Monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs: test design and data analysis

An optimised test designed for an in vitro monocyte activation test for pro-inflammatory and pyrogenic contaminants of parenteral drugs is described, together with ways to address the inherent variability of such assays in which cells are cultured using 96-well plates. The test preparation is cultured with peripheral blood mononuclear cells (PBMNC) and the contaminants in the test article stimulate the release from the cells of the endogenous pyrogenic cytokine interleukin-6 (IL-6). The test system is in use within the pharmaceutical industry and at a national control authority for detecting pro-inflammatory and pyrogenic contaminants, including ‘rabbit-negative’ and ‘LAL-negative’ non-endotoxin pyrogens. Products tested include small molecules, biologicals and vaccines. The PBMNC/IL-6 monocyte activation test has been approved by the US FDA as an ‘end-product release test’ and also is being used for in-process testing.

Use of near-infrared spectrometry for quantitative determinations of selamectin and moisture in topical formulations

A rapid near-infrared spectrometric (NIR) method was qualified for use with the quantitative analysis of selamectin and moisture in topical formulations. Selamectin is currently marketed as a pet endectocide and is available in several formulations for cats and dogs. The use of NIR in this investigation replaces the in-process testing by liquid chromatography and concurrently provided moisture content that would otherwise only be available with additional Karl Fischer titration investigations. A seven-factor partial least square regression (PLS) of the second derivative spectra encompassing the wavelength region of 1450–2200 nm was used to quantify both selamectin and moisture content. A second three-factor PLS solely for water content was also applied and compared with the full model. This qualification confirms that this method may be used to quantitate selamectin and moisture as a process tool or to examine finished good samples. Each sample can be rapidly analyzed within 5 min on the current bench top system.

Process Development Implications of Biotin Production Scale-Up

Careful planning and construction of suitable in-process tests and isolation of new impurities observed led to quick, mechanistic-based assessments of problems seen in two steps of Biotin production scale-up and allowed for rapid changes to be made to resolve the issues. The quench of Grignard reaction mixtures with deuterium-based materials led to increased understanding of one of the main pathways for yield loss in a Grignard reaction contained with the Biotin process.

Case Studies in Blend Sampling Using a Front-Loading Thief

In-process testing is employed in pharmaceutical systems for monitoring and detecting process failures. Blend sampling is a useful in-process test. The present article outlines case studies in which sampling thieves with front-loading and side-vented mechanisms were compared. Blend uniformity analysis (BUA) using a front-loading sampling thief helped confirm or discover blend homogeneity issues and guide the product development process to rational decision points by providing quick responses to actual or impending failure with a low probability of falsely declaring a failure that is not present.

Comparison of OPLC and other chromatographic methods (TLC, HPLC, and GC) for in-process purity testing of nandrolone

A semiquantitative OPLC purity test has been developed for inprocess control of nandrolone and compared with other chromatographic methods. TLC was not sufficiently selective, a key impurity with low UV absorption could not be detected by HPLC, and nandrolone was slightly degraded during gas chromatography. OPLC proved to be a suitable means of testing for all potential impurities in nandrolone. The separation was performed by multiple development on fine-particle silica gel with cyclohexane-ethyl acetate-chloroform, 50 + 25 + 25 ( v/v ), as mobile phase. After spraying the chromatograms with sulfuric acid, then heating, the impurities could be sensitively detected by visual inspection in long-wave UV light. Detection limits were ≤0.01 μg.

EVALUATION OF AN ION EXCLUSION/DIRECT CONDUCTIVITY METHOD FOR QUANTITATING ACETIC AND LACTIC ACIDS IN PHARMA-CEUTICAL LVP BASE FORMULATIONS

Organic acids (e.g., acetic, lactic and gluconic acid) are common components in Large Volume Parenteral (LVP) base solutions. The characterization of such solution products is necessary for production control and product release. A chromatographic method, which couples separation by anion exclusion with direct conductivity detection, has been developed for this purpose. The evaluation of this method, carried out in a manner consistent with United States Pharmacopeia (USP) and International Council for Harmonization (ICH) guidelines, is summarized in this manuscript. The method meets the acceptance criteria for in-process and/or product release testing with respect to accuracy, linearity, range, precision, and specificity.

Compliance with safe practices for preparing parenteral nutrition formulations.

Compliance with the guidelines of the National Advisory Group on Standards and Practice Guidelines for Parenteral Nutrition (NAG) was studied. A questionnaire based on the NAG guidelines was developed to identify common practices used in the preparation of parenteral nutrition formulations in a variety of health care settings. The questionnaire was mailed in January 2000 to a national sample of 1445 pharmacists. There were a total of 633 usable responses, for a net response rate of 45.2% (based on 1400 deliverable surveys). Almost 80% of the respondents were employed in an urban setting, and 64.3% worked in hospitals. Relatively high compliance was reported for guidelines related to filtration (86.9% and 85.9%), verification of product stability and compatibility by a pharmacist or computer program (86.4%), evaluation of the aseptic technique of persons preparing sterile products (81.4%), and having a pharmacist assess formulations to determine whether the contents are within acceptable standard ranges (78.8%). Low compliance was reported for guidelines related to the inclusion of dosing weight on the label (15.4%), the use of amount per day as the unit of measure for labeling ingredients (26.1%), direct pharmacist-to-pharmacist communication about prescriptions when patients are transferred among health settings (33.4%), and daily in-process or end-product quality assurance testing of formulations. The NAG guidelines on parenteral nutrition formulations with which pharmacists' practice was most discrepant were the use of amount per day as the unit of measure for labeling ingredients, inclusion of the patient's dosing weight on the label, direct pharmacist-to-pharmacist communication when patients are transferred, and daily quality assurance testing.

EVALUATION OF AN ION EXCLUSION/DIRECT CONDUCTIVITY METHOD FOR QUANTITATING ACETIC AND LACTIC ACIDS IN PHARMA-CEUTICAL LVP BASE FORMULATIONS

Organic acids (e.g., acetic, lactic and gluconic acid) are common components in Large Volume Parenteral (LVP) base solutions. The characterization of such solution products is necessary for production control and product release. A chromatographic method, which couples separation by anion exclusion with direct conductivity detection, has been developed for this purpose. The evaluation of this method, carried out in a manner consistent with United States Pharmacopeia (USP) and International Council for Harmonization (ICH) guidelines, is summarized in this manuscript. The method meets the acceptance criteria for in-process and/or product release testing with respect to accuracy, linearity, range, precision, and specificity.

Significance of controlling crystallization mechanisms and kinetics in pharmaceutical systems

Metastable thermodynamic states are frequently encountered in pharmaceutical systems, in the intentional or unintentional creation of supersaturation, in the crystallization of desired solid-state modifications, and in the control of solid-phase conversions during isolation, manufacturing, storage, and dissolution.1-4 Some examples in which metastable states are encountered include solid solutions, freeze-concentrated solutions, solutions of weak acids or bases exposed to a pH change, solutions prepared by dissolving a solid-state modification with a higher solubility (higher free energy), and residual solutions during filtration, granulation, and drying. Because crystallization provides a way of reducing the free energy of metastable thermodynamic states, the extent to which metastable states can be maintained is determined by the crystallization mechanisms and kinetics.5-16 What is surprising, however, is that despite the important role that crystallization has in process control and in determining solid-phase outcomes, crystallization phenomena are often neglected in the pharmaceutical industry until a problem is encountered. While emphasis is often given to the knowledge of equilibrium phase diagrams with the purpose of identifying the concentration and temperature regions of thermodynamic stability of solid phases, information on crystallization processes can only be obtained by combining studies of thermodynamic properties with kinetic measurements. Cases of unwanted or previously unknown nucleation events abound. Dunitz and Bernstein17 documented cases of “disappearing or elusive polymorphs” that provide evidence for the consequences of poor process control in crystallization of polymorphic systems. The recent shortage in the supply of capsules of the HIV protease inhibitor Norvir (indinavir), due to the sudden formation of a crystalline structure different from the one harvested for months,18 illustrates the decisive role that nucleation mechanisms and kinetics have on crystallization. Nichols and Frampton19 have reported considerable efforts that failed to crystallize the metastable polymorph of paracetamol as described in the initial publication of the crystal structure.20 The critical role of crystallization kinetics in determining the appearance of crystalline modifications is also recognized by the FDA and described in the guidelines for the manufacture of drug substances:21 “Appropriate manufacturing and control procedures (including in-process testing when needed) should be established for the production of the desired solid-state form(s). It should be emphasized that the manufacturing process (or storage condition) is responsible for producing particular polymorphs or solvates; the control methods merely determine the outcome.” Even when the parameters that regulate crystallization phenomena are neglected, the illusion of process control is motivated by a crystallization process that yields the desired productssolid phase modification, shape, or size distributionsand by the robust analytical methods used for solid state characterization. This situation is greatly complicated by the recent emphasis on an exclusively * Corresponding author. Tel: 734-763-0101. Fax: 734-763-2022. e-mail: nrh@umich.edu. † University of Michigan. ‡ Dupont Pharmaceuticals. July 1999

Low T/sub c/ superconductive circuits fabricated on 150-mm-diameter wafers using a doubly planarized Nb/AlO/sub x//Nb process

We have used a doubly planarized all-refractory technology for superconductive electronics (DPARTS) process to fabricate mixed-signal circuits that have more than 200 junctions per circuit and operate at 2 GHz. A 150-mm-diameter wafer can produce more than 400 chips, each 5 mm on an edge. The junctions had a critical current density of 1.7 kA/cm/sup 2/. The wafers were evaluated at room temperature, both in- and post-process. In-process testing was used to detect parameter shifts during processing, while post-process testing used an automated testing station to test more than 3500 structures across each completed wafer and thus establish a large set of statistical data for studying the spread and targeting of parameter values. The circuits were fabricated in a class-10 clean room in which 0.25 /spl mu/m CMOS and CCD devices were also produced. The DPARTS process could also be used for sub-/spl mu/m fabrication, as it includes optical lithography with an i-line stepper; chemical-mechanical planarization at two levels; a self-aligned via process; and dry, anisotropic etching for all metal etching and via definition steps. The use of 150-mm-diameter wafers ensures that this process will be able to exploit technological advances in the standard silicon tool set as improvements become available. The results demonstrated here are a necessary precondition to yielding large volumes of superconductive electronic circuits containing devices with sub-/spl mu/m dimensions.

The Challenge of Managing Quality Control/Quality Assurance for Loosely Structured and Virtual Biopharmaceutical Companies

Managing quality control (QC)/quality assurance (QA) is a challenge in biopharmaceutical manufacture and product release. While many of the quality systems which are applied to biopharmaceutical products are also employed in the control of chemical pharmaceutical products and traditional biological products, there are special QC/QA concerns associated with the control of biopharmaceutical products. The main component that is used in the production process is a living organism which has been genetically altered. The manufacturing processes used to produce biopharmaceuticals, whether recombinant DNA methods or hybridoma technologies, can be fairly complicated with extended production times. Adequate in-process testing, thorough process validation, and a comprehensive assessment of final product quality using a complete battery of analytical methodologies, is needed to demonstrate lot-to-lot consistency. How a biopharmaceutical company that is not a fully integrated pharmaceutical company, but instead either...

In-Process Proof Testing of Cutting Tools in Interrupted Turning

AbstractThis paper proposes IPT (In-process Proof Testing) as a new method for improving the reliability of cutting tools in interrupted cutting. Theoretical basis for the IPT method is first described by applying fracture mechanics and statistics, then interrupted CNC turning experiments with the use of IPT are carried out on ceramic tools. The cutting edge is preliminarily subjected to cutting force greater than that expected in actual cutting, so that weak tools are eliminated, while surviving tools are successively used in service. Performance of the proposed method is discussed in terms of tool life reliability and machining economics.

Instrumentation: Ingenuity abounds: Trends: In-field diagnostics, in-plant and in-process testing, and smarter portables

In-field diagnostics, in-plant and in-process testing, and smarter portables are instanced as current trends.

Report on results of a collaborative assay of BCG vaccines organized by the International Association of Biological Standardization

In a collaborative assay initiated by the International Association of Biological Standardization 13 laboratories investigated the properties of 10 freeze-dried BCG vaccines made in different ways by different producers which met the requirements of the World Health Organization. The in vitro tests with respect to the dry weight of the bacteria, the number of culturable particles and the stability during storage at 37 °C gave results which showed statistically significant differences between vaccines as well as between laboratories. The use of a reference vaccine in the tests for the number of culturable particles did not improve the precision of the results. These tests are useful as in-process tests to assure the producer that his vaccine will consist of the required amount of bacteria of which a high percentage is living. It was found that all vaccines had a survival of more than 25% after 1 month at 37 °C with the exception of two vaccines in rubber-stoppered vials. The two in vivo tests, determining skin reactivity in guinea-pigs and multiplication of BCG in spleens of mice, resulted in nearly the same ranking of the vaccines with respect to their virulence, differing from that of the in vitro tests. In the skin reactivity test the simultaneous injection of both the reference vaccine and a test vaccine into the same animal achieved the elimination of the inter-laboratory variation of the results.