Raw Material Release Research Articles

Diagnosis to determine the root cause of unproductive times in the release of ascorbic acid as a raw material

The present work was carried out in a company dedicated to the elaboration of medicines and food supplements, in which a diagnosis was made in the raw material release process, specifically, in ascorbic acid; where the critical points of the release process that presented a difference in time (unproductive time) were detected in the analysis of the parameters of each test of the raw material with respect to the established time. The objective of this work was to determine the root causes of unproductive times that affect the release of raw material; the methodology used was a study of times and movements, process flow diagrams and route diagrams. During development, the proposal for traceability formats of the characteristics of the raw material was designed.

Characteristic Curves and Cycle Time Control of Re-Entrant Lines

The characteristic curve (CC) of a production system is a function describing the behavior of cycle time ( CT ) versus throughput ( TP ). In systems with unlimited buffers, this function typically has a knee-type shape. Operating the system below the knee is not efficient, since TP can be increased without an appreciable increase in CT . Operating above the knee is also counterproductive— CT becomes extremely large without a significant increase of TP . Thus, the desirable operating point is at the knee. In order to operate the system at or close to the knee, some knowledge of its CC is necessary. In this paper, an analytical/empirical method for calculating CCs of single-product re-entrant lines is developed using the so-called bottleneck workcenter model of systems at hand. Based on this method, open- and closed-loop raw material release policies, which ensure operating at the desired point of CC, are provided. The development is carried out in terms of the First Buffer First Served (FBFS) and Last Buffer First Served (LBFS) dispatch policies, although CCs for other dispatch policies can be investigated in a similar manner. In addition, it is shown by simulations that the method developed can be used for evaluating CC of a model of a scaled-down wafer fab, which includes multiple workcenters and batching, as long as the severity of the bottleneck workcenter is sufficiently high.

Toxicidade ambiental de efluentes advindo de diferentes laboratórios de uma farmácia magistral

Há uma crescente preocupação com os chamados “poluentes emergentes” na produção de medicamentos. Eles chegam ao meio ambiente a partir do descarte doméstico ou a partir das sobras geradas na produção de fármacos. Em pequenas concentrações da ordem de microgramas por litro ou inferiores, ou seja, concentrações não efetivas a curto prazo em termos de resposta biológica em seres humanos, podem causar grandes impactos no meio ambiente pela exposição crônica. O objetivo deste trabalho foi avaliar o risco de contaminação de efluentes pelo lançamento dos dejetos brutos da produção de medicamentos em pequena escala, por farmácias de manipulação, com base na avaliação da ecotoxicicidade pelo biomonitoramento de algas Euglena gracilis, e investigar os impactos apresentados sobre o comportamento e as alterações no processo de fotossíntese. Amostras de quatro laboratórios de diferentes demandas foram analisadas. As alterações comportamentais (velocidade de subida à superfície, r-value e velocidade de movimento) das algas foram biomonitoradas pelo NG-TOX e os parâmetros de fotossíntese foram medidos com o fluorímetro de pulso e amplitude modulada (PAM). Os resultados demonstraram que o efluente do laboratório de hormônios, que teve uma baixa produção semestral, apresentou pouco impacto, já o efluente do laboratório de psicotrópicos, mesmo com demanda intermediária, apresentou impacto significante sobre o comportamento e a atividade fotossintética das algas. A diferença de comportamento observada entre os diferentes setores de fármacos demonstra que os impactos e os possíveis riscos ambientais são diferentes para cada setor. A demanda e as diferentes substâncias manipuladas podem ser determinantes na classificação de risco e na escolha dos métodos de descontaminação.

Production Lead Time in Serial Lines: Evaluation, Analysis, and Control

Production Lead Time $\mbi (LT)$ is the average time a part spends in the system, being processed or waiting for processing. In systems with unlimited buffers, $\mbi LT$ may be orders of magnitude larger than the total processing time, leading to serious economic and quality problems. At present, no systematic analytical methods for evaluation, analysis, and control of $\mbi LT$ in systems with machines having up- and downtime characterized by continuous random variables are available. This paper is intended to develop such methods. Specifically, we address synchronous serial lines with exponential machines and derive formulas for $\mbi LT$ as a function of machine parameters and raw material release rate. Using these formulas, we develop methods for open- and closed-loop raw material release, which result in the desired $\mbi LT$ . For asynchronous exponential lines, we provide an upper bound on $LT$ . For non-exponential lines (e.g., Weibull, gamma, and log-normal), we offer an empirical formula for $\mbi LT$ as an affine function of the coefficient of variation. The results reported in this paper enable a new paradigm for production systems management, namely: manage a production system so that the desired $\mbi LT$ is ensured, while the throughput is maximized.

Raw material release rates to ensure desired production lead time in Bernoulli serial lines

Production systems are often managed to maximise their production rate (). In some cases, this leads to excessive work-in-process and, as a result, long production lead time (). This issue is of particular importance in systems with ‘unlimited’ buffer space, where may also become unlimited. The question addressed in this paper is: What should be the release rate of raw materials so that the desired is obtained, while is maximised? We answer this question for serial lines with infinite buffers and machines obeying the Bernoulli reliability model. Specifically, given a serial line, we quantify the set of attainable s (feasible set), and for each point in the feasible set provide the release rate (as a function of machine parameters) that guarantees the desired lead time, while maximising the production rate. In addition, we offer a feedback control law that enforces the desired system behaviour. The development is based on a recursive aggregation procedure that leads to analytical estimates of . The accuracy of these estimates is evaluated by simulations and is shown to be acceptable for practical applications (well within 5%). The results obtained offer small- and mid-size enterprises the possibility of managing their production lead time, when neither limited buffers nor kanban/CONWIP systems are available, by releasing raw materials on, say, an hourly basis.

Production Lead Time Problem: Formulation and Solution for Bernoulli Serial Lines

This paper is intended to formulate the so-called production lead time problem as the problem of throughput optimization under a constraint on production lead time. A solution is provided for serial lines with Bernoulli machines and infinite buffers. Specifically, analytical formulas are derived for raw material release rates, which guarantee the desired lead time, while maximizing the throughput. Based on this solution, a method for selecting design parameters of kanban- and CONWIP-controlled systems, which ensure the desired lead time, is provided.

Case Study: A Novel Bacterial Contamination in Cell Culture Production--Leptospira licerasiae

Leptospira licerasiae, a novel bacterial contaminant found in Genentech cell culture manufacturing operations, poses a challenge to current microbial control strategies in upstream cell culture processes, as this microorganism is fully capable of passing through 0.1 μm sterilizing-grade filtration and is not detectable by standard microbiological methods described in major pharmaceutical compendia for microbial screening and quantification required for release of raw materials, in-process intermediates, and finished products in biopharmaceutical production. The root cause investigation was greatly aided by the genetic identification of the contaminant and subsequent confirmation by cultural method and real-time polymerase chain reaction assay from the affected product batches. The purpose of this case study is to share knowledge on the novel contaminant, L. licerasiae, and potential routes of contamination in the cell culture manufacturing environment from a series of investigations involving root cause analysis, impact assessments, risk assessment, and global corrective and preventative action, as well as to provide guidance on the detection and prevention of Leptospira contamination with the intent to aid the industry to continually improve microbial control strategies for the benefit of patients. Leptospira licerasiae, a novel bacterial contaminant found in cell culture manufacturing operations, poses a challenge to current microbial control strategies in upstream cell culture processes because this microorganism is capable of passing through 0.1 μm sterilizing-grade membrane filters and is not detectable by standard microbiological methods used in biopharmaceutical production. The root cause investigation was greatly aided by the genetic identification of the contaminant and subsequent confirmation by cultural method and real-time polymerase chain reaction assay from the affected product batches. The purpose of this case study is to share knowledge on the novel contaminant, L. licerasiae, and potential routes of contamination in the cell culture manufacturing environment from a series of investigations to provide the industry with guidance on the detection and prevention of Leptospira contamination.

CWIPL II, a mechanism for improving throughput and lead time in unbalanced flow line

Critical WIP loops II (CWIPL II) is a proposed material flow control mechanism for an unbalanced flow line environment. CWIPL II is based on CWIPL and it determines critical loops in unbalanced lines. The WIP of critical loops identifies the time of releasing raw material to the line. CWIPL II proposed a new classification for unbalanced flow line which is ‘near unbalanced flow line’ and ‘perfect unbalanced flow line’. In near unbalanced line, there is one bottleneck and a raw material release to the line if ‘WIP of the bottleneck’ or ‘WIP upstream the bottleneck’ is less than defined level. In perfect unbalanced line there are multiple bottleneck and a raw material release to the line if ‘WIP upstream the slowest machine’ or ‘WIP between two primary bottleneck’ is less than defined level. Like CWIPL, the necessary condition for releasing the raw material is ‘idleness of the first machine’. CWIPL II is compared with CONWIP and TOC by simulation. Different scenarios are employed in the comparison analysis. The scenarios address variables such as number of machines, processing time distribution, WIP target level. Location of slowest machine and location of two primary bottlenecks are considered in examples. Simulation results and statistical tests of 141 numerical examples show that CWIPL II improves lead time in near unbalanced line and throughput in perfect unbalanced line compared with TOC. Because of the trade off between line throughput and lead time, the mechanism that improves one of them while maintaining the other at previous level is valuable. It is shown that CWIPL II has improved TOC in the cases that TOC hasn’t improved CONWIP.

Mapping and Identification of Biopharmaceutical Grade Cell Culture Media by MEKC

This paper describes a rapid micellar electrokinetic capillary chromatographic (MEKC) method for the mapping and identification of biopharmaceutical grade cell culture media. The method has been validated and we currently use it as an identity test for raw material release testing of cell culture media. The MEKC method is capable of resolving components of cell culture medium with specificity, matching the sample profile with the expected component profile, and precision. The precision of the assay was shown by comparison of peak migration times and relative peak areas of three injections of test media on each of three days. The intra-day and inter-day peak migration times and UV214 nm responses (% total peaks areas) of the assay were within acceptable ranges. The intermediate precision (% Relative Standard Deviation) of peak migration times was less than 3%. The intermediate precision (% Relative Standard Deviation) of relative percent peak areas was less than 10% for major peaks present. A linear relationship between response (% total peaks areas) and the concentration of the cell culture medium was observed, with the average correlation coefficient of >0.96 for major peaks (each accounting for greater than 2% of total peaks areas). Based on the identification by chromatographic profile, linearity, and precision, the MEKC method for the mapping of cell culture media components is suitable for the intended use.

Characterization and Release of Raw Materials Used in Upstream Processes for Production of Monoclonal Antibodies by Mammalian Cell Culture

Characterization and Release of Raw Materials Used in Upstream Processes for Production of Monoclonal Antibodies by Mammalian Cell Culture

Raw material release time control for complex make-to-order products with stochastic processing times

This paper considers a make-to-order manufacturing system producing complex products with multiple resource constraints, multiple levels of product structures, and stochastic processing times. The objective is to find the optimal raw material release times by minimising the expected sum of work-in-progress holding costs, product earliness costs and product tardiness costs. An evolution strategy-based planning tool is developed, in which the performance measure is evaluated by stochastic discrete event simulation. The tool is applied to an illustrative example that includes wide, deep and complex product structures and to a case study using data obtained from an industrial company that manufactures capital goods. It is demonstrated that the solutions produced perform substantially better than those produced by the backward scheduling based on infinite capacity, and also significantly better than those produced by the same search method based on deterministic processing times. More benefit can be achieved if the system has a higher degree of uncertainty.

Molecular detection of bacterial indicators in cosmetic/pharmaceuticals and raw materials

PCR assays were compared with standard microbiological methods for rapid detection of the United States Pharmacopoeia (USP) bacterial indicators in artificially contaminated samples of raw materials and cosmetic/pharmaceutical products. DNA primers containing the specific sequences of the uidA gene of the b-glucuronidase enzyme for Escherichia coli, the membrane lipoprotein gene oprL for Pseudomonas aeruginosa, and the 16S ribosomal gene for Staphylococcus aureus were used for detection in the PCR reaction. Contaminated samples were incubated for 24 h at 35°C. After incubation in broth media with and without 4% Tween 20, samples were streaked on selective growth media. After 5‐6 days, all microbial indicators were morphologically and biochemically identified using standard methods while detection and identification by the PCR-based assays was completed within 27‐30 h. Rapid PCR detection of E. coli, S. aureus, and P. aeruginosa will allow a faster quality evaluation and release of raw materials and cosmetic/pharmaceutical products sensitive to microbial contamination.

A one year controlled release implant for the luteinizing hormone releasing hormone superagonist RS-49947. II. Clinical performance results

A small macroporous nonerodible matrix implant supplying therapeutic levels of the decapeptide drug RS-49947 ([ d-Nal(2) 6,aza-Gly 10]-luteinizing hormone releasing hormone) for one year is described and analyzed. The implant is indicated for estrus or male sexual behavior suppression (reversible chemical castration), or for the treatment of sex hormone dependent diseases in the canine or feline. These small (55 mg) slab devices are implanted below the ventral surface skin of the animal through a small incision, and can be removed or replaced at the end of one year of therapy. The optimal system contains 41% of water soluble drug raw material (33.6% theoretical of RS-49947 free base) dispersed in Silastic 382 silicone elastomer. Plasma levels of drug and clinical performance parameters in the canine are presented for the optimal formulation and for formulations containing higher (44% drug solubles) and lower (39% drug solubles) percentages of drug raw material. Formulations containing 39% or 41% of drug raw material release in vivo by an unanticipated apparent zero order release mechanism. Comparison of clinical and in vitro data suggests that in vivo itmechanisms may control drug release rates from these systems. In vitro data for these implants are consistent with current knowledge of macroporous implants, while the in vivo data show anomalous drug release durations and profile shapes. Hypotheses for the differences between in vitro and in vivo drug release are presented. The drug raw material used to manufacture these implants exhibits a unique morphology, which may further complicate understanding of the in vivo release results. In vitro data for these systems give some insight into in vivo release, although the mechanisms of in vitro and in vivo drug release apparently differ.

Automatización de la estación neumática PN-2800 mediante la plataforma CompactLogix de Alien Bradley

El presente artículo describe la automatización de la estación neumática PN-2800 mediante la plataforma Compactlogix de Allen Bradley, misma que es parte integral del Laboratorio de Control Industrial del Departamento de Eléctrica y Electrónica de la Escuela Politécnica del Ejército(ESPE), denominado C.I.M.2000. La estación NEUMATICA PN-2800, cumple con la función primordial de proporcionar la materia prima para la ejecución de los diversos procesos dentro del C.I.M.2000, para lo cual mantiene un sistema completamente autónomo, en relación a la ejecución de los pasos necesarios para el despacho de la materia prima solicitada. La actualización de la estación NEUMATICA PN-2800, admite mantener varios modos de operación, con una HMI que permite al usuario entender y manejar el control de la estación de una manera fácil y adecuada aportando de esta manera al entendimiento, desarrollo y funcionalidad de los procesos industriales encontrados en muchas empresas.Para éste proyecto se efectuó la migración de la plataforma MODICON, con el PLC 984 COMPACT A130, a la plataforma COMPACTLOGIX con el PLC 1768-L43A de ALLEN BRADLEY; y se observó una amplia optimización de la estación neumática, directamente relacionada con tiempos de optimización, flexibilidad en los procesos realizados como son pedidos mixtos de materia prima, así como también la reducción de cableado. A través de un único Cable de red y aprovechando la infraestructura de red Ethernet, se hizo la transferencia de información y comunicación con las otras estaciones del Laboratorio CIM y en especial con la estación Central, logrando así mejorar el cableado utilizado anteriormente con el PLC 984 COMPACT A130 en la plataforma MODBUS.