Consecutive Lots Research Articles

Lot-to-lot consistency, immunogenicity, and safety of the Ad26.ZEBOV, MVA-BN-Filo Ebola virus vaccine regimen: A phase 3, randomized, double-blind, placebo-controlled trial

ABSTRACT This phase-3, double-blind, placebo-controlled study (NCT04228783) evaluated lot-to-lot consistency of the Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Participants were randomized (6:6:6:1) to receive the two-dose regimen from three consecutively manufactured lots of Ad26.ZEBOV on Day 1 paired with three consecutively manufactured lots of MVA-BN-Filo on Day 57 (Groups 1–3) or two doses of placebo (Group 4). An additional cohort also received an Ad26.ZEBOV booster or placebo 4 months post-dose 2. Equivalence of the immunogenicity at 21 days post-dose 2 between any two groups was demonstrated if the 95% confidence interval (CI) of the Ebola virus glycoprotein (EBOV GP)–binding antibody geometric mean concentration (GMC) ratio was entirely within the prespecified margin of 0.5–2.0. Lot-to-lot consistency (i.e., consecutive lots can be consistently manufactured) was accomplished if equivalence was shown for all three pairwise comparisons. Results showed that the primary objective in the per-protocol immunogenicity subset (n = 549) was established for each pairwise comparison (Group 1 vs 2: GMC ratio = 0.9 [95% CI: 0.8, 1.1], Group 1 vs 3: 0.9 [0.8, 1.1], Group 2 vs 3: 1.0 [0.9, 1.2]). Equivalence of the three groups for the Ad26.ZEBOV component only was also demonstrated at 56 days post-dose 1. EBOV GP–binding antibody responses (post-vaccination concentrations >2.5-fold from baseline) were observed in 419/421 (99.5%) vaccine recipients at 21 days post-dose 2 and 445/460 (96.7%) at 56 days post-dose 1. In the booster cohort (n = 39), GMCs increased 9.0- and 11.8-fold at 7 and 21 days post-booster, respectively, versus pre-booster. Ad26.ZEBOV, MVA-BN-Filo was well tolerated, and no safety issues were identified.

Mathematical Models and Optimal Algorithms for Lot Scheduling Considering Job Splitting and Due Dates in Green Logistics

Lot scheduling is a promising manufacturing mode in green logistics that can efficiently save energy and reduce production costs. It has been widely applied to integrate circuit tests in semiconductor factories, textile processing in garment workshops, etc. Each processing lot is of a fixed capacity and identical processing time, and completes more than one job simultaneously. Jobs with sizes and due dates are allowed to be arbitrarily split and processed in consecutive lots. They are delivered immediately upon completion. To the best of our knowledge, in the domain of lot scheduling, there exist no mathematical programming models that describe the above features simultaneously. In this work, we focus on the single machine environment and mainly consider two lot scheduling problems with the objectives of minimizing the maximum lateness and the total tardiness, respectively. For the problems, we first propose new mixed integer linear programming models (solved by commercial solvers), which enable a systematic understanding of the studied problems and serve as a mathematical programming basis for more complicated problems. We then prove that the Earliest Due-Date (EDD) first rule and the Shortest Processing Time (SPT) first rule can optimally solve the two problems, respectively, provided that the due dates and job sizes are agreeable, i.e., a later due date indicates a larger size of job. Experimental results show the efficiency of our methods and managerial insights are drawn.

Consistency of immunogenicity in three consecutive lots of a tetravalent dengue vaccine candidate (TAK-003): A randomized placebo-controlled trial in US adults

BackgroundWe conducted a trial to demonstrate immunogenic equivalence of three consecutive manufacturing lots of Takeda’s tetravalent dengue vaccine candidate, TAK-003, and further assessed its safety and reactogenicity. MethodsHealthy US adults (n = 923) randomized 2:2:2:1 to four groups received two doses of one of three TAK-003 lots or placebo on Days 0 and 90, with follow-up to Day 270. Primary endpoint evaluated lot-to-lot equivalence of geometric mean neutralizing titers at Day 120 against each of 4 dengue serotypes in baseline seronegative participants. Solicited local and systemic, and unsolicited adverse events (AEs) were assessed for 7, 14 and 28 days after each dose, respectively. Serious AEs (SAE) were monitored throughout the study. ResultsEight of 12 prespecified equivalence comparisons were met in the per-protocol set but failed marginally in the other 4 mainly due to loss of statistical power following higher than anticipated baseline seropositivity and drop-out rates. All three TAK-003 lots elicited high rates of tetravalent dengue seropositivity (96.7 %, 93.0 % and 97.5 % at Day 120; 91.0 %, 80.5 % and 85.7 % at Day 270) and had similar reactogenicity profiles with no vaccine-related SAEs. ConclusionsThe three lots of TAK-003 were immunogenic for all four dengue serotypes and well tolerated in healthy adults. Despite not meeting all equivalence comparisons, no major differences were observed between lots and the data support acceptable consistency of the manufacturing process.Trial registrationClinicalTrials.gov identifier: NCT03423173.

Chicken bed reuse.

Aviculture is a developed and important industry worldwide. However, it is an industry that produces solid waste such as bedding. As an attempt to reduce environmental impact and productive activity costs, beds are reused by several consecutive lots which can increase microorganism concentration and lead to unsanitary conditions. In this regard, it is essential to adopt a litter pre-treatment during the gap sanitary period between lots to avoid passing problems to the birds from the current flock to the subsequent flock and to guarantee the litter quality. Several factors must be considered to guarantee that there is minimal damage to chicken production. Therefore, this literature review aims to approach the main factors that affect the thermal comfort and chicken litter quality, as well as alternatives used as an alternative biological treatment to guarantee its reuse quality.

Optimum design of generalized adaptive sampling plan for solid supplier-buyer purchasing partnership with yield-driven validation

A flexible, effective scheme to operate successive lot disposition is critical for developing a solid supplier–buyer relationship. The consecutive lots' yields from in-control, automated manufacturing processes contribute substantial, valuable yield-record information. Feeding this information back into the inspecting compliances and decision criteria improves the sampling plans’ performance and supplier–buyer resources allocation. The existing multiple-lot dependent state plan (MDSP), however, engenders an adverse situation. It situates higher inspection costs and lower lot-sentencing standards when an increase of cumulative-lot yields considers in a lot-sentencing decision. This adversity significantly impacts a long-lasting supplier–buyer partnership. A recently developed adaptive MDSP (AMDSP) has resolved the adversity. But its sentencing rules administer a wide range of marginally satisfactory yields. To mitigate these, in this paper we propose a generalized AMDSP (GAMDSP) validated by the process yield-driven index. The process-yield-validated GAMDSP contains combinatorial mathematical treatment that activates its manufacturing traceability to historical lot-yield levels. When encompassing more preceding lot-yield histories in the decision, the GAMDSPs manifest the benefit of inspecting sample reduction. The GAMDSPs also increase the lot-acceptance yield standards and show lot sentencing with a narrow range of marginally satisfactory yields. Besides, they are sufficiently flexible. By manipulating their adaptive mechanisms, the GAMDSPs can convert into a specific sampling plan that is suitable for the different stages of supply chain management. Finally, a case study demonstrates the applicability of our proposed GAMDSPs.

Safety, Immunogenicity and Lot-to-Lot Consistency of Sabin-Strain Inactivated Poliovirus Vaccine in 2-Month-Old Infants: A Double-Blind, Randomized Phase III Trial.

Background: The Sabin-strain-based inactivated poliovirus vaccine (sIPV) plays an important role in poliomyelitis eradication in developing countries. As part of the phase III clinical development program, this study aimed to evaluate the safety, immunogenicity and lot-to-lot consistency of the sIPV in 2-month-old infants. Method: We conducted a phase III, randomized, double-blind, positive-controlled trial in which 1300 healthy infants were randomly assigned to four groups in a 1:1:1:1 ratio to receive one of the three lots of the sIPV or the control IPV at 2, 3 and 4 months of age. Serum samples were collected before the first dose and 30 days after the third dose of vaccination to assess the immunogenicity. Solicited local and systemic reactions were recorded within 7 days and unsolicited adverse events within 30 days after each vaccination. Results: Of the 1300 randomized infants, 1190 infants completed the study and were included in the per-protocol population. The seroconversion rates in the three lots of the sIPV were 95.67%, 97.03% and 95.59%, respectively, for type 1; 94.33%, 93.73% and 92.88%, respectively, for type 2; and 98.67%, 99.67% and 99.32%, respectively, for type 3. The ratios of GMTs for poliovirus types 1, 2 and 3 of each pair of lots were all between 0.67 and 1.50, therefore meeting the predefined immunological equivalence criteria. For the seroconversion rate of poliovirus types 1, 2 and 3, the pooled sIPV group was non-inferior to the IPV group. The incidence of solicited and unsolicited adverse reactions (ARs) was similar in the pooled sIPV lots and the IPV group, and most of them were mild to moderate in severity. Non-vaccine-related serious adverse events (SAEs) were reported. Conclusions: Three consecutive lots of sIPV demonstrated robust and consistent immunogenicity. The safety and tolerability of the sIPV was acceptable and similar to that of the IPV.

A note on the single machine CON and CONW problems with lot scheduling

We study extensions of the classical single machine common due-date (CON) and common due-window (CONW) assignment problems to the setting of lot scheduling. In the CON problem, all the jobs share a common due-date, and jobs completed prior to or after the due-date are penalized according to their earliness/tardiness. In CONW, there exists a time interval, such that jobs completed within this interval are not penalized. In both cases the due-date/due-window are decision variables. In lot scheduling, a number of customer orders of different sizes may be processed in the same lot. We allow order splitting between consecutive lots. The objective is to find the order allocation to lots, such that the total cost of earliness, tardiness and due-date/due-window is minimized. Given $$n$$ orders, and under the very realistic assumption that the lot capacity is of the order of $$n$$ , we introduce polynomial time dynamic programming algorithms for both extensions. Our numerical tests indicate that both algorithms can easily solve medium-size problems.

Bias and uncertainty of the International Normalized Ratio determined with a whole blood point-of-care prothrombin time test device by comparison to a new International Standard for thromboplastin

BackgroundWhole blood point-of-care PT/INR test devices, e.g. CoaguChek XS, are calibrated by their manufacturers. In the Netherlands, each new lot of test strips for CoaguChek XS is validated by a group of anticoagulant clinics collaborating with a Coagulation Reference Laboratory. In 2017, a new International Standard for recombinant human thromboplastin (coded rTF/16) has been established by the World Health Organization. AimTo assess uncertainty of the validation procedure and the magnitude of the INR bias of a series of consecutive lots of test strips imported in the Netherlands. MethodsCoaguChek XS test strip INR results were compared to INRs determined with the new International Standard rTF/16. Comparisons were made with variable numbers of blood samples obtained from patients treated with vitamin K-antagonists. Relationships between CoaguChek XS and rTF/16 results were determined with orthogonal regression analysis. The relationships were used to assess bias and uncertainty of bias. ResultsAverage bias between CoaguChek XS test results and rTF/16 depends on the INR level. Overall, there was a trend of increasing bias and increasing uncertainty with increasing INR values. Along the sequence of 47 consecutive lots, a temporary fluctuation of bias was observed. At an INR level of 3.0 the average bias was less than 10% in all cases, but at an INR of 4.0 there were 5 lots with average bias between 10 and 15%. ConclusionValidation of test strips is useful to assess bias but depends on availability of fresh patients' samples and traceability to an accepted Reference Measurement System.

Single machine lot scheduling with optional job-rejection

We consider single machine lot scheduling problems. A number of customer orders of different sizes may be processed in the same lot. Splitting orders between consecutive lots is allowed. Three scheduling measures are considered: makespan, total completion time and total weighted completion time. In all cases, the goal is minimizing the relevant scheduling measure, subject to an upper bound on the total permitted rejection cost. All three problems studied here are NP-hard. We introduce efficient pseudo-polynomial dynamic programming algorithms for all cases. Our numerical tests indicate that the proposed algorithms can solve efficiently large-size problems.

Single machine lot scheduling with non-uniform lot capacities and processing times

In this paper, we investigate the single machine lot scheduling problem in which each lot contains one or more jobs (or part of jobs). Jobs with different sizes are splittable and should be processed in consecutive lots. Any completed (part of a) job is delivered to the customer on its completion. We generalize the problem studied in Zhang et al. (Inf Process Lett 142:46–51, 2019) such that lots may have different capacities and processing times, and the sizes of jobs are unbounded. We show that for this generalized case, the WSPT (Weighted Shortest Processing Time first) rule is still optimal for both minimizing total weighted completion time and minimizing total weighted discounted completion time.

Lot scheduling on a single machine to minimize the (weighted) number of tardy orders

We consider a single machine lot scheduling problem. A number of customer orders of different sizes may be processed in the same lot. We consider first the setting that splitting orders between consecutive lots is allowed. We focus on minimizing the number of tardy orders. A polynomial time solution algorithm is introduced for this problem. We then study the extension to minimizing the weighted number of tardy orders. This problem is NP-hard, and a pseudo-polynomial dynamic programming is provided and tested. We also study the setting of no-split. The problem of minimizing the number of tardy orders in this context is proved to be strongly NP-hard, and an efficient heuristic is introduced.

Single-machine lot scheduling with variable lot processing times

This research addresses single-machine lot scheduling problems, with a focus on minimizing the total weighted completion time. The following properties for the lots are assumed: the lots have the same capacity, each lot may contain several orders of different sizes, the size of each order is less than or equal to the identical capacity, and orders must be processed at most in two consecutive lots. To date, lot scheduling researchers have assumed that all lots have identical processing times. In this study, variable lot processing times are considered; specifically, the setting where the processing time of the lots is position dependent, reflecting general position-dependent processing time properties, e.g. learning/ageing effects. Three special cases are examined: minimizing the total completion time, minimizing the makespan, and minimizing the linear combination of the makespan and the total completion time. All problems are shown to be solved in polynomial time.

A Study of 2-dose Vaccine Regimen Using 3 Consecutive Lots of Ad26.ZEBOV and MVA-BN-Filo in Adult Participants

A Study of 2-dose Vaccine Regimen Using 3 Consecutive Lots of Ad26.ZEBOV and MVA-BN-Filo in Adult Participants

Alternative light colors in suckling piglet creep area: preference and validation tests in swine maternity

ABSTRACT: We performed a two-stage experiment: a preference and a validation test in swine litters, to determine whether suckling piglets preferred alternative light colors in their creep area over white light; we also determined whether the preferred color affected piglet behavior. In the first stage, five trials of two consecutive days were performed, each at 21-day intervals. In each trial, 40 piglets, from three to five days old, from four F1 sows (Large White x Landrace), were distributed in four treatments, in a paired scheme, receiving the following treatments: Treatment GR: white light vs. green light ; Treatment BL: white light vs. blue light; Treatment YE: yellow light vs. white light; Treatment RD: white light vs. red light. For the validation test, three consecutive lots of eight F1 sows (Large White x Landrace) and their corresponding maternity were used, remaining from birth under the influence of treatments T_Gr and T_Wh, totaling three replicates. T_Gr corresponded to four creep areaswith green LED light and T_Wh to four nurseries with white LED light. The piglets showed a significant preference only for white over blue. Among the alternative colors, piglets significantly preferred green. In the validation stage, there was no significant effect of colors on the mean percentage of permanence of the piglets inside the creep areas over all evaluated periods. Piglets between two and five days of age prefer green lighting;however,in the creep area, the light color used did not influence piglet behavior.

Lot-to-lot consistency study of an Escherichia coli-produced bivalent human papillomavirus vaccine in adult women: a randomized trial

ABSTRACT An Escherichia. coli-produced HPV-16/18 bivalent vaccine has been proved to be well-tolerated and highly efficacious against diseases associated with vaccine HPV types. As a part of the multi-center, randomized, double-blind phase III clinical trial, this lot-to-lot consistency study aimed to assess the safety and immunogenicity consistency of this novel HPV vaccine, which is also one of the objectives of the phase III trial. A total of 3689 healthy women aged 18–45 years were enrolled and randomly assigned 1:1:1 to three lots of the HPV vaccine groups. The primary outcomes were the IgG antibody level at 1 month after the last dose (month 7). In the immunogenicity per-protocol set (PPS), almost all of the participants seroconverted at month 7 and remained seropositive at month 42. For each paired comparison of the three lot groups, the two-sides of 90% CIs of GMC ratios for both IgG and neutralizing antibodies for HPV-16 and HPV-18 at month 7 were within the equivalence interval [0.5, 2]. Lot consistency was also demonstrated at month 42. The majority of recorded solicited reactions were mild or moderate. The incidences of solicited reactions of Lot 2 and Lot 3 were slightly higher than Lot 1. However, the incidences of solicited reactions of ≥ grade 3 and solicited reactions by symptoms were all similar among the three lot groups. None of the SAEs was considered related to vaccination by the investigator. In conclusion, this study demonstrates lot-to-lot consistency of the 3 consecutive lots of the E. coli-produced HPV-16/18 bivalent vaccine.

Single machine lot scheduling to minimize the total weighted (discounted) completion time

In this work, we investigate the problem of single machine lot scheduling where each lot contains one or more jobs and is of identical processing time. Jobs with different sizes are splittable and shall be processed in consecutive lots. Any completed (part of a) job is delivered to the customer on its completion. We prove that the WSPT (Weighted Shortest Processing Time first) rule is optimal for both models of minimizing total weighted completion time and minimizing total weighted discounted completion time.

Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

BackgroundModified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.MethodsThe trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.ResultsBetween March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.ConclusionsThe neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.Trial registrationClinicalTrials.gov NCT01144637

Completion Time Analysis of Wafer Lots in Single-Armed Cluster Tools With Parallel Processing Modules

We analyze the completion time of wafer lots in single-armed cluster tools with parallel processing modules (PMs) by considering the lot switching operation. To effectively assign wafer lots and dispatch overhead hoist transports (OHTs) to manufacturing tools, it is crucial to obtain the completion time of wafer lots. However, estimating the completion time is not straightforward, due to the concurrent processing of two consecutive wafer lots during lot switching operation, which often increases wafer sojourn times in PMs. In this paper, we derive closed-form expressions of the completion time of wafer lots in single-armed cluster tools with parallel PMs. We assume that the robot unloads wafers in the order of their loading sequence. We then experimentally show that the formulas derived can be used even when processing time variation exists or another robot task sequence, which is of first-in first-out (FIFO), is assumed. Note to Practitioners —Due to the larger wafer size and circuit width reduction, cluster tools often perform the lot switching operation with each pair of consecutive wafer lots. In addition, since most tools are operated with parallel chambers, concurrent processing with two different wafer lots occurs frequently. Such transient periods in operating tools make it hard to estimate the completion time of wafer lots. In this paper, we derive closed-form expressions to obtain the completion time of wafer lots in single-armed cluster tools with parallel chambers. We further show that the formulas can be used with processing time variation or the FIFO rule. With the formulas, OHTs can be sent just-in-time to tools to load or unload wafer cassettes, and wafer lots can be assigned while minimizing the transient periods. In addition, the estimated completion time can be utilized in the planning and scheduling of wafer fabrication processes.

Lot-to-lot stability of antibody reagents for flow cytometry

The fluorescence detected using fluorochrome-labelled monoclonal antibodies depends not only on the abundance of the target antigen, but amongst many other factors also on the effective fluorochrome-to-antibody ratio. The diagnostic approach of the EuroFlow consortium relies on reproducible fluorescence intensities over time.A capture bead system for mouse immunoglobulin light chains was utilized to compare the mean fluorescence intensity of 1323 consecutive antibody lots to the currently used lot of the same monoclonal antibody. In total, 157 different monoclonal antibodies were assessed over seven years. Median relative difference between consecutive lots was 3.8% (range: 0.01% to 164.7%, interquartile range: 1.3% to 10.1%). The relative difference exceeded 20% in 8.8% of all comparisons. FITC labelled monoclonal antibodies (median relative difference: 2.1%) showed a significantly smaller variation between lots than antibodies conjugated to PE (3.5%), PECy7 (3.9%), PerCPCy5.5 (5.8%), APC (5.8%), APCH7 (7.4%), and APCC750 (14.5%). Reagents labelled with Pacific Blue (1.4%), Pacific Orange (2.4%), HV450 (0.7%), and HV500 (1.7%) demonstrated more consistent results compared to conjugates of BV421 (4.1%) and BV510 (16.2%). Additionally, significant differences in lot-to-lot fluorescence stability amongst antibodies labelled with the same fluorochrome were observed between manufacturers.These observations might guide future quality recommendations for the production and application of fluorescence-labelled monoclonal antibodies in multicolor flow cytometry.

Methods for Accumulating Construction and Material Quality Test Results and Their Effect on Acceptance Decisions

AbstractMany state departments of transportation are currently shifting more acceptance sampling and testing responsibilities to contractors because of a shortage of personnel at highway agencies and intensive construction schedules. The practice of using contractor-performed test results for acceptance decisions is referred to here as contractor acceptance testing (CAT). Studies have shown the need for improving the power of the statistical process used to validate the contractor’s test results. A potential improvement to CAT is to accumulate contractor’s and agency’s test results of consecutive lots to increase sample size and consequently increase the power of the statistical tests used to verify the contractor’s test results. In this study, two different types of cumulative sampling methods (i.e., continuous cumulative and chain lot) are applied to actual test results obtained from the Kansas Department of Transportation (KDOT), which includes contractor-performed test results and agency-performed tes...