Process Validation Studies Research Articles

MyBeST-A Web-Based Survival Prognostic Tool for Women with Breast Cancer in Malaysia: Development Process and Preliminary Validation Study.

Women with breast cancer are keen to know their predicted survival. We developed a new prognostic model for women with breast cancer in Malaysia. Using the model, this study aimed to design the user interface and develop the contents of a web-based prognostic tool for the care provider to convey survival estimates. We employed an iterative website development process which includes: (1) an initial development stage informed by reviewing existing tools and deliberation among breast surgeons and epidemiologists, (2) content validation and feedback by medical specialists, and (3) face validation and end-user feedback among medical officers. Several iterative prototypes were produced and improved based on the feedback. The experts (n = 8) highly agreed on the website content and predictors for survival with content validity indices ≥ 0.88. Users (n = 20) scored face validity indices of more than 0.90. They expressed favourable responses. The tool, named Malaysian Breast cancer Survival prognostic Tool (myBeST), is accessible online. The tool estimates an individualised five-year survival prediction probability. Accompanying contents were included to explain the tool's aim, target user, and development process. The tool could act as an additional tool to provide evidence-based and personalised breast cancer outcomes.

O-204 Non-invasive AI image analysis unlocks the secrets of oocyte quality and reproductive potential by assigning ‘Magenta’ scores from 2-dimensional (2-D) microscope images

Abstract Study question Can an Artificial Intelligence (AI) software tool, utilizing 2-D image analysis of mature oocytes, prospectively correlate an oocyte score to utilizable blastocyst development? Summary answer Oocyte Magenta scores show a statistically significant difference in blastocyst development between the highest (7.1-10) and lowest (1.0-4.0) scored oocytes [46.1% vs 26.6%; p < 0.005]. What is known already Unlike sperm (WHO 2010) or embryos (Gardner blastocyst grading), there is no validated visual oocyte scoring system used in clinical practice. Embryologists have been unsuccessful in correlating oocyte morphological features to reproductive potential. A valuable oocyte scoring system should be able to correlate higher scores with improved embryological outcomes. Although not possible by the human eye, a non-invasive oocyte AI assessment tool (Magenta) has accomplished this feat in retrospective studies. This study applied the Magenta network at two IVF clinics in real-time; representing one of the few prospective AI studies in our field, and the only one focusing on oocytes. Study design, size, duration This prospective, multi-center study was conducted from September - November 2021 by TRIO Fertility (Toronto, Canada) and CARE Fertility (Sheffield and Nottingham, UK), utilizing the oocyte AI image analysis tool, Magenta. Magenta was created with a convolutional neural network trained on 16,373 oocyte images and corresponding outcomes. Inclusion criteria was all IVF-ICSI patients who consented to participate without severe male factor (testicular or epididymal sources). Results are based on 392 images of oocytes (46 patients). Participants/materials, setting, methods Non-invasive, light microscope images were taken of mature oocytes post-denudation, prior to ICSI, utilizing an image capture software. Images were uploaded and analyzed by Magenta, scoring each oocyte on a scale of 1-10, and remained in a blinded folder to the IVF clinics. De-identified patient outcomes were collected to analyze blastocyst development correlation with Magenta scores. Oocytes were handled as per good laboratory practice, without extended periods outside the incubator or disruption to standard protocols. Main results and the role of chance Oocyte images were analyzed by Magenta to score each oocyte on a scale of 1-10. There was a total of 46 patients representing 392 oocytes from both TRIO (26, 280) and CARE (20, 112). The scoring spectrum was divided into 3 tiers (1.0-4.0: 188 oocytes; 4.1-7.0: 128 oocytes; 7.1-10: 76 oocytes). A utilizable blastocyst was defined as a Gardner grade of 2BB or greater on Day 5 or 3BB or greater by Day 6 of embryo development and of adequate quality for transfer, freezing or PGT-A biopsy. The blastocyst development (positivity) rate was 26.6% (1.0-4.0), 32.0% (4.1-7.0) and 46.1% (7.1-10), with mean Magenta scores of 2.4, 5.5 and 8.2, respectively. The lowest and highest tier of Magenta scores were accordingly found to have the lowest and highest blastocyst rates, which was statistically significant (p-value < 0.005) by a Two-Proportions Z-test. Overall, oocytes that developed into a utilizable blastocyst had a higher mean Magenta score (5.0) than oocytes that did not develop into a utilizable blastocyst (4.3); (p-value <0.05) by a Welch’s Two Sample t-test. Limitations, reasons for caution Sample size is currently limited for this ongoing, prospective study. Therefore, additional male factor (non-surgical sperm sources) and possible poor images have not been removed from the current analysis. Furthermore, AI neural network accuracy is restricted by the amount of data it is trained on. Wider implications of the findings Magenta has enabled visual oocyte assessments that will provide IVF-ICSI patients with insights into their oocyte quality; resulting in counselling benefits and the ability to make more informed, personalized decisions regarding future treatment plans. AI will inevitably improve the IVF process and prospective validation studies are critical in its evolution. Trial registration number Not applicable.

Assessment of outcomes associated with a Moodle-based lesson design for a research course in pharmacy education: An experimental pilot process validation study

Background: This study aims to evaluate the effectiveness of an online Moodle-based lesson for pharmacy students developed and designed for a research course focused on different methodologies, study variables, and research process applications. Methods: An experimental research methodology was used to determine the effectiveness of the Moodle-based lesson. All fourth term Pharm.D. students were required to complete and provide self-reflection reports. The outcome variables were cluster-based completion time, earned score, subjective feedback on contents, gender differences, and performance. Mean values were used to conduct statistical analysis, and a logistic regression model was applied to identify the significance of independent variables. Results: A total of 35 students completed the Moodle-based lesson. The mean earned score for the module was 81.0%, with an average completion time of 28.5 (range 26.8-30.1) hours. Females showed completion in less time compared to males. The reported knowledge and understanding showed a significant (p<0.001) pre-post increase in mean percentages in all three clusters. The intragroup pool analysis also reported significant (p<0.001) differences among gender and performance. The general feedback was limited to technical difficulties and self-reflection questions. Conclusions: The findings of this study showed that the online Moodle-based lesson module for a research course is an effective and validated tool to improve the knowledge and understanding of pharmacy students.

OPTIMIZATION & VALIDATION OF BILAYER TABLET FABRICATED BY ANTIHYPERTENSIVE DRUGS

The objective of this study was to systematically conduct the process validation studies pertaining to the manufacturing activities of Bilayer tablet. The optimization of critical process steps and acceptance criteria at various stages of the process is referred in the validation report. The specifications of raw materials used in the manufacturing of Bilayer tablets of antihypertensive drugs have been derived from the monograph or previous history. The tolerance limits for the process parameters and the acceptance criteria for the various tests performed on in-process samples are derived from the FRND inputs. The physical characteristics of the final product are based on actual production scale, as some of these processes cannot be simulated in the laboratory. This research was carried out to produce a Bilayer tablet of antihypertensive drug. The immediate release Bilayer tablet of Telmisartan, Amlodipine besylate & Hydrochlorothiazide (40+5+12.5 mg) was successfully prepared. This combination Therapy indicated for the treatment of severe hypertension & coronary heart disease. Therefore, the purpose of performing optimization study for Antihypertensive drug form facility to provide necessary assurance for consistent quality product has been fulfilled.
 Keywords: Telmisartan, Amlodipine besylate, Bilayer tablet, Hydrochlorothiazide, optimization and validation.

Selenite Cystine Agar for Enumeration of Inoculated Salmonella Serovars Recovered from Stressful Conditions During Antimicrobial Validation Studies.

Process validation studies often require the inoculation of select foodborne pathogens into targeted foods to determine the lethality of the process or antimicrobial ingredients, and quantitative recovery of surviving inoculum bacteria helps to make those assessments. Such processes introduce various stressors on the inoculated challenge microorganisms whereby traditional selective media are too harsh to enumerate the remaining viable and injured population quantitatively. Innate antibiotic resistance of challenge organisms has often been used to establish simple selective media (i.e., Tryptic Soy Agar/TSA + antibiotics) for recovering inoculated strains, but sometimes antibiotic resistant background microorganisms are higher than desired. Salmonella Thompson 120, Salmonella Heidelberg F5038BG1, Salmonella Hadar MF60404, Salmonella Enteritidis H3527, and Salmonella Typhimurium H3380 were characterized for antibiotic resistance and acid adaptation in Tryptic Soy Broth containing 0%, 0.25%, or 1.0% glucose. Sodium pyruvate was evaluated for recovery after stress but no enhancing effect was observed, possibly because the strains were acid-adapted. Selenite Cystine Broth, traditionally used as a selective enrichment broth, was used as the basis for Selenite Cystine Agar (SCA) in combination with three antibiotics to which our Salmonella are resistant. Serovars of Salmonella, both individually and in mixtures, were enumerated on TSA, SCA, Xylose Lysine Desoxycholate (XLD), and Hektoen Enteric (HE) selective agars (all containing the same antibiotics) after conditions of nutrient starvation, desiccation, acid stress, and thermal stress. The data show that quantitative enumeration of our Salmonella serovars on SCA was not significantly different (p > 0.05) than those achieved on TSA for all tested stress categories. Levels of Salmonella enumerated on XLD and/or HE were significantly different (p < 0.05) than on TSA and SCA and often more than 1–2-log lower, consistent with the inhibition of injured cells. These data confirm that SCA (+ antibiotics) is a suitable selective medium for enumeration of these acid-adapted Salmonella serovars as challenge organisms recovered from various conditions of stress.

DEM Investigation of the Influence of Particulate Properties and Operating Conditions on the Mixing Process in Rotary Drums: Part 2—Process Validation and Experimental Study

The process of homogenization of particulates is an indispensable part of many industrial processes, and, therefore, it is necessary to pay a special attention to this area and develop it. This paper deals with a complex study of homogenization of particulate matters in a rotary drum in terms of shape, size, and density of particles. In addition, the influence of operating parameters, such as drum filling capacity, rotational speed, and drum filling pattern are also investigated. Studies of reproducibility of discrete element method simulations, effects of rotary drum sizes or effects of drum volumetric filling to the mixture homogeneity index were also carried out. In general, the least satisfactory values of the homogeneity index resulted from the mixing of particles with different densities. The dominating factor of homogenization was the drum filling-up degree. The course of the homogeneity index in 140, 280, and 420 mm drums was very similar and after five revolutions of the drum, identical values of the homogeneity index were achieved for all the drum diameters. The optimal drum filling-up degree is at 40–50% for the spherical particles and 30–40% for the sharp-edged particles. The repeatability of simulations showed the maximum relative standard deviation of the homogeneity index at 0.6% from ten simulation repetitions with the same parametric conditions.

Rationale and Design of a Novel Method to Assess the Usability of Body-Worn Absorbent Incontinence Care Products by Caregivers.

The purpose of this study was to develop and test a new method to measure the usability of absorbent incontinence care products from the caregivers' perspective and to investigate if the method can be used to differentiate between product types in a product change. Process evaluation and validation study. Product developers and end users participated in designing the new method. Thereafter, professional caregivers acted as testers of the new method, ranking usability when performing absorbent product changes on patients in a simulated nursing home care environment, assisted by third-party research institute moderators. Design and evaluation of a new method designed to assess the usability of body-worn absorbent incontinence care products for lay caregivers were completed. The evaluation included formative and summative evaluations of effectiveness (product fit), efficiency (time and physical workload), and satisfaction. A person-centered approach aimed at including all subjects and settings to generate a single usability score for decision making and product benchmarking. Experienced caregivers changed 4 types of products: (1) disposable body-worn pads with mesh briefs (2-piece system); (2) disposable all-in-one briefs; (3) disposable, T-shaped, and belted brief; and (4) disposable pull-up pants on simulated patients in standing or lying position. Each product change was performed by 1 unassisted experienced caregiver. The probability of success as a score for each product type was calculated across the 4 metrics and reported with 95% confidence intervals (CIs). Descriptive and inferential statistics were developed assuming a binary statistical model, using the weighted scores from each of the factors. An overall usability score was calculated. The method we developed discriminated between usability of different product types. The overall score for the disposable pull-up product (90%; CI: 83%-97%) was better (P < .05) than for the disposable T-shaped brief (83%; CI: 77%-89%), the disposable brief (53%; CI: 45%-61%), and the disposable body-worn pad with mesh pant (61%; CI: 56%-66%) in standing patients. For lying patients, the overall score for the disposable T-shaped brief product (81%; CI: 73%-89% was better (P < .05) than the disposable brief (65%; CI: 45%-61%) and the disposable body-worn pads with mesh brief (62%; CI: 55%-69%). Reliability was evaluated quantitatively in terms of measurement uncertainties in the results. The method we described demonstrated differentiation of usability based on product type indicating concurrent validity. Further testing in diverse real-world care environments is needed to evaluate and confirm the validity and to assess reliability of this method in the research setting.

Prospective Process Validation Study of Glibenclamide 2.5 mg Tablets

Prospective Process Validation Study of Glibenclamide 2.5 mg Tablets

Precooking as a Control for Histamine Formation during the Processing of Tuna: An Industrial Process Validation

An experiment to validate the precooking of tuna as a control for histamine formation was carried out at a commercial tuna factory in Fiji. Albacore tuna (Thunnus alalunga) were brought on board long-line catcher vessels alive, immediately chilled but never frozen, and delivered to an on-shore facility within 3 to 13 days. These fish were then allowed to spoil at 25 to 30°C for 21 to 25 h to induce high levels of histamine (>50 ppm), as a simulation of "worst-case" postharvest conditions, and subsequently frozen. These spoiled fish later were thawed normally and then precooked at a commercial tuna processing facility to a target maximum core temperature of 60°C. These tuna were then held at ambient temperatures of 19 to 37°C for up to 30 h, and samples were collected every 6 h for histamine analysis. After precooking, no further histamine formation was observed for 12 to 18 h, indicating that a conservative minimum core temperature of 60°C pauses subsequent histamine formation for 12 to 18 h. Using the maximum core temperature of 60°C provided a challenge study to validate a recommended minimum core temperature of 60°C, and 12 to 18 h was sufficient to convert precooked tuna into frozen loins or canned tuna. This industrial-scale process validation study provides support at a high confidence level for the preventive histamine control associated with precooking. This study was conducted with tuna deliberately allowed to spoil to induce high concentrations of histamine and histamine-forming capacity and to fail standard organoleptic evaluations, and the critical limits for precooking were validated. Thus, these limits can be used in a hazard analysis critical control point plan in which precooking is identified as a critical control point.

Thermal death kinetics in dry air of Diplodia seriata fungus inoculated in vitro in pruned vine shoots

The upsurge in fungal diseases that cause grapevine wood rot in young and adult plants remains a major concern for the wine sector. Since pruned vine shoots act as a reservoir of these fungi, there is a need for sanitization methods that can prevent their spread, avoiding plant reinfection. In this work, the effectiveness of dry heat treatments for the disinfection of pruning waste has been investigated. The thermal death of two inocula of Diplodia seriata fungus, associated to black dead arm disease, was studied in vitro at four different temperatures (40, 50, 60 and 65 °C) for different time periods (20, 40, 60, 90, 120 and 150 min) in a dry air incubator. Obtained data confirmed that inhibition increased as a function of temperature and exposure time. First-order and Weibull models were compared to describe D. seriata fungus survival curve kinetics, with high R 2 values (0.923 and 0.930, respectively) and high significances (p < 0.001). Both models predict that the time required to reach 99 % mortality at 65 °C would be 143 min, slightly higher than the experimentally determined minimum time of 120 min. The thermal death kinetics data reported herein has direct applications in process design and validation studies of other grapevine-pruning-waste sanitization methodologies.

A measure of medical tourism destination brand equity

Purpose Given the increasing dominance of medical tourism on the service economy of some of the developing nations, as a pioneering attempt, this study aims to develop a consumer-based brand equity (CBBE) measurement scale for the medical tourist destinations (city/hospital). Design/methodology/approach Following the traditional marketing construct development process (qualitative study, purification study and validation study), in the present study, two sets of large and independent samples were assessed to judge the dimensionality of the measure. Findings A well-validated measurement scale was developed as an amalgamation of four dimensions, namely, awareness, perceived quality, brand loyalty and authenticity to assess CBBE of medical destinations. Practical implications To reduce the financial and physical risk associated with the purchase of treatment, the customers may rely on “authenticity” of the service providers to select a treatment destination. The outcomes would help medical administrators/managers to focus more on developing “assurance” by increased reliability, responsiveness and tangibles to attract the medical tourists to a large extent. Originality/value The study is a pioneering attempt to develop a scale for measuring CBBE for medical tourist destinations. The study aligns with earlier CBBE scales in terms of the first three elements, namely, brand awareness, loyalty and perceived quality. However, based on predictive validity, the study puts forth five interrelated first order attributes, namely, “trust”, “value for money”, “quality of residents”, reliability and soft issues (like friendliness and ease of process) as contributing factors to a so far unexplored dimension, “brand authenticity”.

Validation of Baking To Control Salmonella Serovars in Hamburger Bun Manufacturing, and Evaluation of Enterococcus faecium ATCC 8459 and Saccharomyces cerevisiae as Nonpathogenic Surrogate Indicators

This study was conducted to validate a simulated commercial baking process for hamburger buns to destroy Salmonella serovars and to determine the appropriateness of using nonpathogenic surrogates (Enterococcus faecium ATCC 8459 or Saccharomyces cerevisiae) for in-plant process validation studies. Wheat flour was inoculated (∼6 log CFU/g) with three Salmonella serovars (Typhimurium, Newport, or Senftenberg 775W) or with E. faecium. Dough was formed, proofed, and baked to mimic commercial manufacturing conditions. Buns were baked for up to 13 min in a conventional oven (218.3°C), with internal crumb temperature increasing to ∼100°C during the first 8 min of baking and remaining at this temperature until removal from the oven. Salmonella and E. faecium populations were undetectable by enrichment (>6-log CFU/g reductions) after 9.0 and 11.5 min of baking, respectively, and ≥5-log-cycle reductions were achieved by 6.0 and 7.75 min, respectively. D-values of Salmonella (three-serovar cocktail) and E. faecium 8459 in dough were 28.64 and 133.33, 7.61 and 55.67, and 3.14 and 14.72 min at 55, 58, and 61°C, respectively, whereas D-values of S. cerevisiae were 18.73, 5.67, and 1.03 min at 52, 55, and 58°C, respectivly. The z-values of Salmonella, E. faecium, and S. cerevisiae were 6.58, 6.25, and 4.74°C, respectively. A high level of thermal lethality was observed for baking of typical hamburger bun dough, resulting in rapid elimination of high levels of the three-strain Salmonella cocktail; however, the lethality and microbial destruction kinetics should not be extrapolated to other bakery products without further research. E. faecium demonstrated greater thermal resistance compared with Salmonella during bun baking and could serve as a conservative surrogate to validate thermal process lethality in commercial bun baking operations. Low thermal tolerance of S. cerevisiae relative to Salmonella serovars limits its usefulness as a surrogate for process validations.

Construction of Nontoxigenic Mutants of Nonproteolytic Clostridium botulinum NCTC 11219 by Insertional Mutagenesis and Gene Replacement.

Group II nonproteolytic Clostridium botulinum (gIICb) strains are an important concern for the safety of minimally processed ready-to-eat foods, because they can grow and produce botulinum neurotoxin during refrigerated storage. The principles of control of gIICb by conventional food processing and preservation methods have been well investigated and translated into guidelines for the food industry; in contrast, the effectiveness of emerging processing and preservation techniques has been poorly documented. The reason is that experimental studies with C. botulinum are cumbersome because of biosafety and biosecurity concerns. In the present work, we report the construction of two nontoxigenic derivatives of the type E gIICb strain NCTC 11219. In the first strain, the botulinum toxin gene (bont/E) was insertionally inactivated with a retargeted intron using the ClosTron system. In the second strain, bont/E was exchanged for an erythromycin resistance gene using a new gene replacement strategy that makes use of pyrE as a bidirectional selection marker. Growth under optimal and stressed conditions, sporulation efficiency, and spore heat resistance of the mutants were unaltered, except for small differences in spore heat resistance at 70°C and in growth at 2.3% NaCl. The mutants described in this work provide a safe alternative for basic research as well as for food challenge and process validation studies with gIICb. In addition, this work expands the clostridial genetic toolbox with a new gene replacement method that can be applied to replace any gene in gIICb and other clostridia. The nontoxigenic mutants described in this work provide a safe alternative for basic research as well as for food challenge and process validation studies with psychrotrophic Clostridium botulinum In addition, this work expands the clostridial genetic toolbox with a new gene replacement method that can be applied to replace any gene in clostridia.

Validation of the manufacturing process used to produce long-acting recombinant factor IX Fc fusion protein.

Recombinant factor IX Fc (rFIXFc) fusion protein is the first of a new class of bioengineered long-acting factors approved for the treatment and prevention of bleeding episodes in haemophilia B. The aim of this work was to describe the manufacturing process for rFIXFc, to assess product quality and to evaluate the capacity of the process to remove impurities and viruses. This manufacturing process utilized a transferable and scalable platform approach established for therapeutic antibody manufacturing and adapted for production of the rFIXFc molecule. rFIXFc was produced using a process free of human- and animal-derived raw materials and a host cell line derived from human embryonic kidney (HEK) 293H cells. The process employed multi-step purification and viral clearance processing, including use of a protein A affinity capture chromatography step, which binds to the Fc portion of the rFIXFc molecule with high affinity and specificity, and a 15 nm pore size virus removal nanofilter. Process validation studies were performed to evaluate identity, purity, activity and safety. The manufacturing process produced rFIXFc with consistent product quality and high purity. Impurity clearance validation studies demonstrated robust and reproducible removal of process-related impurities and adventitious viruses. The rFIXFc manufacturing process produces a highly pure product, free of non-human glycan structures. Validation studies demonstrate that this product is produced with consistent quality and purity. In addition, the scalability and transferability of this process are key attributes to ensure consistent and continuous supply of rFIXFc.

Thermal death kinetics of B. stearothermophilus in coriander leaf puree

Coriander leaves are widely used in culinary throughout the world. Thermal death kinetics of Bacillus stearothermophilus in coriander leaf puree was investigated at varying levels of pH (4.5–8.5) and processing temperatures (105–145 °C). The thermal death kinetics data was statistically treated using non-linear regression. The first order kinetics model provided a good description of the heat inactivation of B. stearothermophilus in coriander puree for the entire range of temperatures tested and was therefore found to be appropriate for predictive purposes. The effect of temperature on death rate was modelled using Arrhenius equation (coefficient of determination R2 > 0.90). This study utilised the principles of predictive microbiology in real food and thus will be useful for process design and validation studies.

High-pressure Food Processing

High pressure processing (HPP) of foods offers a commercially viable and practical alternative to heat processing by allowing food processors to pasteurize foods at or near room temperature. Pressure in combination with moderate temperature also seems to be a promising approach for producing shelf-stable foods. This paper outlines research needs for further advancement of high pressure processing technology. Kinetic models are needed for describing bacterial inactivation under combined pressure-thermal conditions and for microbial process evaluation. Further, identification of suitable surrogate organisms are needed for use as indicator organisms and for process validation studies. More research is needed to evaluate process uniformity at elevated pressure-thermal conditions to facilitate successful introduction of low-acid shelf-stable foods. Combinations of non-thermal technologies with high pressure could reduce the severity of the process pressure requirement. Likewise, processing equipment requires improvements in reliability and line-speed to compete with heat pasteurization lines. More studies are also needed to document the changes in animal and vegetable tissue and nutrient content during pressure processing, from types of packaging, and from storage.

Photochemical treatment of plasma with amotosalen and UVA light: process validation in three European blood centers

A photochemical treatment (PCT) process has been developed to inactivate pathogens and white blood cells (WBCs) in therapeutic plasma. Process validation studies were performed in three European blood centers under routine operating conditions. Each center prepared 30 apheresis and 30 to 36 whole blood-derived plasma units for PCT. Each whole blood-derived plasma unit contained a mixture of two to three matched donations. After removal of pretreatment control samples (control fresh-frozen plasma [C-FFP]), 546 to 635 mL of plasma was treated with 15 mL of 6 mmol per L amotosalen, 3 J per cm(2) UVA treatment, and removal of residual amotosalen with a compound adsorption device. After processing, plasma samples (PCT-FFP) were withdrawn, frozen at -60 degrees C within 8 hours of collection, and assayed for coagulation factors and residual amotosalen. A total of 186 units of plasma were processed. The mean prothrombin time (12.2 +/- 0.6 sec) and activated partial thromboplastin time (32.1 +/- 3.2 sec) of PCT-FFP were slightly prolonged compared to C-FFP. Fibrinogen and Factor (F)VIII were most sensitive to PCT (26% mean reduction). PCT-FFP, however, retained sufficient levels of fibrinogen (217 +/- 43 mg/dL) and FVIII (97 +/- 29 IU/dL) for therapeutic plasma. Mean levels of FII, FV, FVII, F IX, FX, FXI, and FXIII in PCT-FFP were comparable to C-FFP (81%-97% retention of activity). Antithrombotic proteins were not significantly affected by PCT with retention ranging between 83 and 97 percent. Mean residual amotosalen levels were 0.6 +/- 0.1 micromol per L. Process validation studies in three European centers demonstrated retention of coagulation factors in PCT-FFP within the required European and respective national standards for therapeutic plasma.

Validation Studies in European Blood Centers To Evaluate Processing Whole-Blood-Derived or Apheresis Plasma Using the INTERCEPT Blood System Intended for Commercialization.

Introduction: INTERCEPT plasma (I-FFP) for transfusion is prepared with a photochemical treatment (PCT) system using amotosalen (S-59) and long-wavelength UVA light to inactivate a broad spectrum of blood-borne pathogens. For Phase 3 clinical trials, 6 US blood centers prepared an inventory of ~10,000 I-FFP units by processing ~250 mL whole blood-derived (WB) or apheresis (APH) plasma units using a prototype PCT system. In these trials, I-FFP effectively supported patients with congenital and acquired coagulopathies or TTP. The prototype PCT system has been modified to treat up to 635 mL of plasma in a single PCT process, yielding up to three ~200 mL doses while maintaining pathogen inactivation efficacy. This modified PCT system intended for commercialization was evaluated in process validation studies in 3 European blood centers under routine operating conditions. After processing with the commercial PCT system, the effect on coagulation factor activity and retention was assessed in APH plasma (Blood 2004; 104:746a) and, as reported here, in WB plasma.Methods: Whole blood and/or APH plasma units were collected at 3 European blood centers. Three-unit pools (~600 mL) of WB plasma were prepared. APH plasma (~600 mL) was collected using Autopheresis C (Baxter) or MCS+(Haemonetics) devices. Blood bank personnel processed a total of 60 WB plasma pools and 90 APH plasma units using the commercial PCT system. Baseline and I-FFP plasma samples were collected, frozen below -60°C, and sent to Cerus for assay of factors I (fibrinogen), II, V, VII, VIII, IX, X, XI, and XIII, proteins C (PC) and S (PS), and antithrombin III (AT). Alpha-2 antiplasmin (AP) was assayed by a reference laboratory. Comparative data from a representative subset of I-FFP units prepared for the Phase 3 trials using the prototype PCT system were obtained from samples collected during PCT processing and stored at ≤−70°C. Retention of activity is expressed as the proportion (%) of pre-treatment (baseline) activity remaining after PCT.Results: Retention of coagulation factor activity in WB and APH I-FFP prepared with the commercial PCT system (Comm) was 73–76% of baseline fibrinogen and FVIII activity, and 80–97% of baseline for factors II, V, VII, IX, X, XI, XIII, PC, PS, AT, and AP (Table). Retention of activity in I-FFP prepared with the commercial PCT system was similar to that of I-FFP prepared with the clinical prototype.Conclusion: The PCT system intended for commercialization provides multiple I-FFP doses with a single PCT process. Retention of coagulation factor activity in WB and APH plasma processed with the commercial PCT system was similar to that of I-FFP used in Phase 3 trials to effectively support patients with congenital and acquired coagulopathies or TTP. [Display omitted]

The INTERCEPT Blood System for Plasma: Process Validation Studies of Coagulation Factor Activity and Yield in Two European Blood Centers.

Introduction: INTERCEPT Plasma (I-FFP) is prepared as FFP for transfusion using photochemical treatment (PCT) with amotosalen HCl (S-59, 150 μM) and UVA light (3J/cm2) to inactivate a broad spectrum of blood-borne pathogens. Phase 3 clinical trials, supported with an inventory of > 19,000 I-FFP units processed in 200 mL/unit with a prototype set, demonstrated retention of coagulation factor activities and hemostatic function in I-FFP for support of patients with congenital and acquired coagulopathies or TTP. For commercial introduction, the clinical prototype I-FFP system has been improved to treat up to 650 mL of plasma in a single, less time-consuming, PCT process yielding up to three 200 mL I-FFP doses per PCT process. The effects of this modified process on coagulation factor activity and yield were evaluated in two European blood centers under routine operating conditions.Methods: A total of 60 plasma units (approximately 600 mL/unit) were collected using the Autopheresis C device (Baxter-Fenwall) at Haukeland University Hospital and the Institute of Immunology and Transfusion Medicine, University of Lübeck. I-FFP units were prepared at each center by blood bank personnel using the improved set. Baseline and I-FFP samples were collected, frozen (<−60 °C) and sent to Cerus for assay of: Fibrinogen (F I), and Factors II, V, VII, VIII, IX, X, XI, XIII, proteins C (PC) and S (PS), and antithrombin (AT).α-2 antiplasmin (AP) was assayed in a reference laboratory.Results: Fibrinogen (mg/dL) and coagulation factor activities (IU/dL) are expressed as the mean ±SD (Table). The post-PCT yield for each coagulation factor activity in I-FFP units prepared with the improved set (Improved) is expressed as a proportion (%) of total pre-treatment coagulation factor activity per FFP unit (Baseline). Comparative yield data for I-FFP used in Phase 3 studies (Prototype) were obtained by testing 275 plasma units randomly selected from 19,000 units prepared for use in clinical trials with the protype set at 6 U. S. blood centers.Conclusions: I-FFP prepared with the improved system retained 78–79% of baseline Fibrinogen and FVIII activity, and 82%–95% of baseline Factors II, V, VII, IX, X, XI, XIII, PC, PS, AT, and AP. Clinical trials have shown that I-FFP provided sufficient levels of coagulation factor activities for treatment of congenital and acquired coagulopathies and for therapeutic plasma exchange of TTP. The improved set, intended for commercialization, provides multiple I-FFP doses with a single PCT process. Using the improved processing set, coagulation factor activities and yields were similar to those for I-FFP used in Phase 3 clinical trials.Activity (IU)F IF IIF VF VIIF VIIIF IXBaseline300±54100±17135±23112±25142±4497±15I-FFP238±4898±16131±2291±20111±3883±13Yield (%)F IF IIF VF VIIF VIIIF IXImproved79±590±490±482±378±585±4Prototype78±690±595±482±577±788±5Activity (IU)F XFXIFXIIIPCPSATAPBaseline115±17107±20121±20120±21100±20100±11104±13I-FFP103±1696±18115±20104±1996±1996±1085±8Yield (%)F XFXIFXIIIPCPSATAPImproved90±389±595±586±395±595±382±8Prototype90±390±699±3100±8103±692±290±3F XIII, PC, PS, AT (n=34); AP (n=14)

Anticipating the effects of technological change: A new era of dynamics for human factors

Human factors studies the intersection between people, technology and work, with the major aim to find areas where design and working conditions produce human error. It relies on the knowledge base and research results of multiple fields of inquiry (ranging from computer science to anthropology) to do so. Technological change at this intersection (1) redefines the relationship between various players (both humans and machines), (2) transforms practice and shifts sources of error and excellence, and (3) often drives up operational requirements and pressures on operators. Human factors needs to predict these reverberations of technological change before a mature system has been built in order to steer design into the direction of cooperative human-machine architectures. The quickening tempo of technology change and the expansion of technological possibilities has largely converted the traditional shortcuts for access to a design process (task analysis, guidelines, verification and validation studies, etc.) into oversimplification fallacies that retard understanding, innovation, and, ultimately, human factors' credibility. There is an enormous need for the development of techniques that gain empirical access to the future-that generate human performance data about systems which have yet to be built.