Production of clavulanic acid and cephamycin C by Streptomyces clavuligerus under different fed-batch conditions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Modelling and optimization of the cephalosporin C production bioprocess in a fed-batch bioreactor with invert sugar as substrate

Cephalosporin C production process optimization was studied based on four experiments carried out in an agitated and aerated tank fermenter operated as a fed-batch reactor. The microorganism Cephalosporium acremonium ATCC 48272 (C-10) was cultivated in a synthetic medium containing glucose as major carbon and energy source. The additional medium contained a hydrolyzed sucrose solution as the main carbon and energy source and it was added after the glucose depletion. By manipulating the supplementary feed rate, it was possible to increase antibiotic production. A mathematical model to represent the fed-batch production process was developed. It was observed that the model was applicable under different operation conditions, showing that optimization studies can be made based on this model. (C) 1999 Elsevier B.V. Ltd. All rights reserved.

Advanced production scheduling for batch plants in process industries

An Advanced Planning System (APS) offers support at all planning levels along the supply chain while observing limited resources. We consider an APS for process industries (e.g. chemical and pharmaceutical industries) consisting of the modules network design (for long–term decisions), supply network planning (for medium–term decisions), and detailed production scheduling (for short–term decisions). For each module, we outline the decision problem, discuss the specifi cs of process industries, and review state–of–the–art solution approaches. For the module detailed production scheduling, a new solution approach is proposed in the case of batch production, which can solve much larger practical problems than the methods known thus far. The new approach decomposes detailed production scheduling for batch production into batching and batch scheduling. The batching problem converts the primary requirements for products into individual batches, where the work load is to be minimized. We formulate the batching problem as a nonlinear mixed–integer program and transform it into a linear mixed–binary program of moderate size, which can be solved by standard software. The batch scheduling problem allocates the batches to scarce resources such as processing units, workers, and intermediate storage facilities, where some regular objective function like the makespan is to be minimized. The batch scheduling problem is modelled as a resource–constrained project scheduling problem, which can be solved by an efficient truncated branch–and–bound algorithm developed recently. The performance of the new solution procedures for batching and batch scheduling is demonstrated by solving several instances of a case study from process industries.

Production of polyhydroxyalkanoates from oil-containing substrates

Different oil-containing substrates, namely, used cooking oil (UCO), fatty acids-byproduct from biodiesel production (FAB) and olive oil deodorizer distillate (OODD) were tested as inexpensive carbon sources for the production of polyhydroxyalkanoates (PHA) using twelve bacterial strains, in batch experiments. The OODD and FAB were exploited for the first time as alternative substrates for PHA production. Among the tested bacterial strains, Cupriavidus necator and Pseudomonas resinovorans exhibited the most promising results, producing poly-3-hydroxybutyrate, P(3HB), form UCO and OODD and mcl-PHA mainly composed of 3-hydroxyoctanoate (3HO) and 3-hydroxydecanoate (3HD) monomers from OODD, respectively. Afterwards, these bacterial strains were cultivated in bioreactor. C. necator were cultivated in bioreactor using UCO as carbon source. Different feeding strategies were tested for the bioreactor cultivation of C. necator, namely, batch, exponential feeding and DO-stat mode. The highest overall PHA productivity (12.6±0.78 g L-1 day-1) was obtained using DO-stat mode. Apparently, the different feeding regimes had no impact on polymer thermal properties. However, differences in polymer‟s molecular mass distribution were observed. C. necator was also tested in batch and fed-batch modes using a different type of oil-containing substrate, extracted from spent coffee grounds (SCG) by super critical carbon dioxide (sc-CO2). Under fed-batch mode (DO-stat), the overall PHA productivity were 4.7 g L-1 day-1 with a storage yield of 0.77 g g-1. Results showed that SCG can be a bioresource for production of PHA with interesting properties. Furthermore, P. resinovorans was cultivated using OODD as substrate in bioreactor under fed-batch mode (pulse feeding regime). The polymer was highly amorphous, as shown by its low crystallinity of 6±0.2%, with low melting and glass transition temperatures of 36±1.2 and -16±0.8 ºC, respectively. Due to its sticky behavior at room temperature, adhesiveness and mechanical properties were also studied. Its shear bond strength for wood (67±9.4 kPa) and glass (65±7.3 kPa) suggests it may be used for the development of biobased glues. Bioreactor operation and monitoring with oil-containing substrates is very challenging, since this substrate is water immiscible. Thus, near-infrared spectroscopy (NIR) was implemented for online monitoring of the C. necator cultivation with UCO, using a transflectance probe. Partial least squares (PLS) regression was applied to relate NIR spectra with biomass, UCO and PHA concentrations in the broth. The NIR predictions were compared with values obtained by offline reference methods. Prediction errors to these parameters were 1.18 g L-1, 2.37 g L-1 and 1.58 g L-1 for biomass, UCO and PHA, respectively, which indicates the suitability of the NIR spectroscopy method for online monitoring and as a method to assist bioreactor control. UCO and OODD are low cost substrates with potential to be used in PHA batch and fed-batch production. The use of NIR in this bioprocess also opened an opportunity for optimization and control of PHA production process.

A Petri Nets-based Scheduling Methodology forMultipurpose Batch Plants.

This article presents an optimization methodology of batch production processes assembled by shared resources which rely on a mapping of state-events into time-events allowing in this way the straightforward use of a well consolidated scheduling policies developed for manufacturing systems. A technique to generate the timed Petri net representation from a continuous dynamic representation (Differential-Algebraic Equations systems (DAEs)) of the production system is presented together with the main characteristics of a Petri nets-based tool implemented for optimization purposes. This paper describes also how the implemented tool generates the coverability tree and how it can be pruned by a general purpose heuristic. An example of a distillation process with two shared batch resources is used to illustrate the optimization methodology proposed.

Batch scheduling in process industries: an application of resource-constrained project scheduling

The paper deals with batch scheduling problems in process industries where final products arise from several successive chemical or physical transformations of raw materials using multi–purpose equipment. In batch production mode, the total requirements of intermediate and final products are partitioned into batches. The production start of a batch at a given level requires the availability of all input products. We consider the problem of scheduling the production of given batches such that the makespan is minimized. Constraints like minimum and maximum time lags between successive production levels, sequence–dependent facility setup times, finite intermediate storages, production breaks, and time–varying manpower contribute to the complexity of this problem. We propose a new solution approach using models and methods of resource–constrained project scheduling, which (approximately) solves problems of industrial size within a reasonable amount of time.

ISA S88 / Loose Coupling Based Solution for Production Control Software Reusability

A solution for the problem of reusability of software system for batch production systems is proposed. It is based on ISA S88 standard that prescribes the abstraction of elements in the manufacturing system that is equipment, processes and procedures abstraction, required to make a product batch. An easy to apply data scheme, compatible with the standard, is developed for management of production information. In addition to flexibility provided by the S88 standard, software system reusability requires a solution supporting manufacturing equipment reconfigurability. Toward this end a coupling mechanism is developed. A software tool, including these solutions, was developed and validated at laboratory level, using product manufacturing information of an actual plant.

A production planning system for plastic footwear in a seasonal market

Modern injection-moulding machinery which produces several, pairs of plastic footwear at a time brought increased production planning problems to a factory. The demand for its footwear is seasonal but the company's manning policy keeps a fairly constant production level thus determining the aggregate stock. Production planning must therefore be done within the limitations of a specified total stock. The thesis proposes a new production planning system with four subsystems. These are sales forecasting, resource planning, and two levels of production scheduling: (a) aggregate decisions concerning the 'manufacturing group' (group of products) to be produced in each machine each week, and (b) detailed decisions concerning the products within a manufacturing group to be scheduled into each mould-place. The detailed scheduling is least dependent on improvements elsewhere so the sub-systems were tackled in reverse order. The thesis concentrates on the production scheduling sub-systems which will provide most. of the benefits. The aggregate scheduling solution depends principally on the aggregate stocks of each manufacturing group and their division into 'safety stocks' (to prevent shortages) and 'freestocks' (to permit batch production). The problem is too complex for exact solution but a good heuristic solution, which has yet to be implemented, is provided by minimising graphically immediate plus expected future costs. The detailed problem splits into determining the optimal safety stocks and batch quantities given the appropriate aggregate stocks. It.is found that the optimal safety stocks are proportional to the demand. The ideal batch quantities are based on a modified, formula for the Economic Batch Quantity and the product schedule is created week by week using a priority system which schedules to minimise expected future costs. This algorithm performs almost optimally. The detailed scheduling solution was implemented and achieved the target savings for the whole project in favourable circumstances. Future plans include full implementation.

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P < 0.001) and increased consistency between donors compared with FBS-based culture. FBS-based culture showed an inter-batch production range of 0.9 and 5 days per dose compared with 0.5 and 0.6 days in SFM for each BM-hMSC donor line. The consistency between donors was also improved by the use of PRIME-XV SFM, with a production range of 0.9 days compared with 19.4 days in FBS-based culture. Mean cell diameter has also been demonstrated as a process metric for BM-hMSC growth rate and senescence through a correlation (R² = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes.

Liikevaihdon ja materiaalivirtojen kasvun vaatimukset logistiikkakeskukselle

Incap Furniture Oy on koottavien mäntyhuonekalujen sopimusvalmistaja. Yrityksen tavoitteena on saavuttaa 70 miljoonan euron liikevaihto Kärsämäen tehtaalla vuonna 2008. Suurin osa komponenttituotannosta ostetaan alihankintaverkostosta ja valmiit tuotteet pakataan logistiikkakeskuksessa. Diplomityön tavoitteena oli selvittää miten kasvavat materiaalivirrat saadaan tulevaisuudessa käsiteltyä Kärsämäen tehtaan logistiikkakeskuksessa Työn teoriaosassa on ensin käsitelty mahdollisuuksia vähentää kokoonpanon puutetilanteita ostotoimintaa kehittämällä. Teoriaosassa esitellään lisäksi varastonohjausmenetelmiä, sekä yleisesti varastoinnin tehtäväkenttää. Empiirisessä osassa analysoitiin annettujen tietojen avulla vuoden 2008 tavoitetilaa, sekä simuloitiin tavoitetilan materiaalivirtoja suhteessa logistiikkakeskuksen kapasiteettiin. Kasvavat materiaalivirrat pakottavat kehittämään logistiikkakeskuksen toimintaa. Eräluonteisen toiminnan vuoksi kaikkien komponenttien kohdalla on pyrittävä MRP ohjaukseen. Komponenttientilauseriä on pyrittävä pienentämään vastaamaan todellista tarvetta. Kriittisille A- ja B- komponenteille tarvitaan lisäksi puskurivarastot tasaamaan toimitusajan vaihtelua ulkomaantoimituksissa. Pakkauseristä yli jäävät C nimikkeet tulee varastoida jatkossa erillään logistiikkakeskuksesta ja korkeavarastosta. D- ja E-nimikkeitä ei kannata tuoda ulkomailta, eikä niitä ole kannattavaa varastoida lainkaan. Pakkaamon täytyy toimia tulevaisuudessa kolmessa vuorossa ja korkeavaraston työjonoa on lyhennettävä kolmesta vuorokaudesta 4-6 työvuoroon. Edellä mainituilla toimenpiteillä ja toimitusten aktiivisella seurannalla saavutetaan toimintaympäristö, jolloin logistiikkakeskuksen kapasiteetti riittää materiaalivirtojen kasvaessa.

Joustava hitsausautomaatio piensarjatuotannossa

Kustannuspaineet, tuotteiden laatuvaatimukset ja lisääntyvässä määrin myös ammattitaitoisen työvoiman pula lisäävät robotisoinnin käyttötarvetta hitsauksessa. Tämä työ on tehty edellä mainituista lähtökohdista ja käsittelee robottihitsausjärjestelmän suunnitteluprojektia, joustavaa hitsausautomaatiota ja robotiikan soveltamista. Näkökohtana on Savonia-ammattikorkeakoulun sekä Pohjois-Savon alueen yritysten tutkimus-, kehitys- ja koulutustoiminnan tarpeet. Joustavuus on hitsausjärjestelmän päätavoite, jolla pyritään vastaamaan asiakasohjautuvan yksittäis- ja piensarjatuotannon haasteisiin. Ratkaisua yksittäis- ja piensarjatuotteiden kokonaistaloudelliseen hitsaukseen on haettu hitsausrobotin rinnalle lisätyllä apurobotilla, jonka päätehtävä on kappaleenkäsittely, mutta sitä voidaan käyttää myös mm. robotisoituun leikkauksen ja särmäykseen. Tavallisuudesta poikkeavaa järjestelmäratkaisua on perusteltu sillä, että ohjaus- ja ohjelmointitekniikan sekä kehittyneen anturoinnin myötä on robottien käytettävyys parantunut ja aiempaa haasteellisempien robottijärjestelmien toteuttaminen on tullut näin mahdolliseksi. Lisäksi virtuaalimallinnus, simulointi ja etäohjelmointi ovat työkaluja, joita voidaan käyttää mm. tuotannon laadun ja tehokkuuden parantamiseen. Työssä esitetty robottiaseman suunnittelu alkaa järjestelmän määrittelystä, vaatimuslistan laadinnasta sekä visioinnista ja päättyy kolmen järjestelmävaihtoehdon vertailuun. Esitetyillä järjestelmävaihtoehdoilla on haettu mahdollisuutta yhdistää yleensä erillisinä toteutettuja työvaiheita yhteiseen soluun. Tuotannon joustavuus on ollut tuotantokapasiteettia tärkeämpi laitteistokokoonpanon valintaperuste.

Tuotekustannuslaskentamenetelmät eri tuotantomuodoissa

Lähtökohta työlle on John Fogelholmin vuonna 2001 julkaisema tutkimus tuotekustannuslaskentamenetelmien soveltuvuuksista eri tuotantoprosesseihin. Työn tavoitteena on tutkia, mitä uutta vuoden 2001 jälkeen aiheesta on kirjoitettu ja uudistaa näiden tietojen pohjalta Fogelholmin tutkimus nykypäivään. Aihetta lähdettiin tutkimaan laaja-alaisen kirjallisuuskatsauksen avulla, jossa tarkoituksena oli selvittää, mitkä tuotekustannuslaskentamenetelmistä ovat kaikkein eniten käytössä nykypäivän yrityksissä sekä millaisia ominaisuuksia yleisimmät tuotantoprosessit omaavat. Tämän jälkeen saatuja tuloksia sovellettiin käytäntöön erilaisten tutkimusten, artikkeleiden sekä omien päätelmien pohjalta tutkien, mitkä yleisimmistä tuotekustannuslaskentamenetelmistä sopivat parhaiten kuhunkin tuotantoprosessiin. Saatujen tulosten pohjalta rakennettiin yhteenvetotaulukko, josta voidaan havaita, mitä muutoksia aiheeseen liittyen on tapahtunut vajaan kymmenen vuoden aikana. Tutkimuksen tuloksista voidaan nähdä, että tuotantoprosessit jaotellaan nykyisin miltei samalla tavoin kuin aikaisemminkin, mutta laskentamenetelmissä on tapahtunut enemmän muutoksia modernin kustannuslaskennan käytön lisäännyttyä.

Produktentwicklung von Druckgussteilen

Die Produktentwicklung von Druckgussteilen kann flexibel, wirtschaftlich und schnell durch die Herstellung von RP-Unikaten und Metallabgüssen aus Keramikschalen realisiert werden. Dieser Weg eignet sich vor allem für komplexe Bauteile und macht eine Produkterprobung mit qualitativ deutlich verbesserter Aussagekraft trotz reduzierter Entwicklungskosten möglich. In Abgrenzung zum Sandguss, muss die Konstruktion der Bauteile nicht verändert werden. 
Durch eine gezielte Wärmebehandlung wird die Vergleichbarkeit der mechanischen Eigenschaften von Prototypen zu späteren Serienteilen möglich. Technisch sinnvolle Änderungen sind leicht und flexibel realisierbar, da werkzeuglos gefertigt wird. Für unerreichbare Hohlräume und Hinterschnitte kann in diesem Verfahren mit Keramikkernen als Einleger gearbeitet werden. Auch diese Kerne können werkzeuglos hergestellt werden. Ein Verzicht auf technisch Sinnvolles aus Kostengründen ist damit hinfällig.
In der Konstruktion ergeben sich neue Freiheitsgrade, so dass Ziele im Leichtbau, die Einsparung von Verbindungstechnik oder die erhöhte Materialeffizienz realisierbar werden. Die so entwickelten Bauteile sind insgesamt qualitativ hochwertiger und bilden die technischen Anforderungen bestmöglich ab. Damit kann die für die Erprobung benötigte Zahl der Prototypen verringert werden. 
Je komplexer die Geometrie der Bauteile, je stärker kommen die beschriebenen Effekte zum Tragen. Diese Aussage gilt für die Produktentwicklung und für Kleinserien, die herkömmlich zu teuer und zu schwer im Druckguss oder Schmiedeverfahren produziert werden

Competitive edge through operations management

A view has emerged within manufacturing and service organizations that the operations management function can hold the key to achieving competitive edge. This has recently been emphasized by the demands for greater variety and higher quality which must be set against a background of increasing cost of resources. As nations' trade barriers are progressively lowered and removed, so producers of goods and service products are becoming more exposed to competition that may come from virtually anywhere around the world. To simply survive in this climate many organizations have found it necessary to improve their manufacturing or service delivery systems. To become real ''winners'' some have adopted a strategic approach to operations and completely reviewed and restructured their approach to production system design and operations planning and control. The articles in this issue of the International journal of Operations & Production Management have been selected to illustrate current thinking and practice in relation to this situation. They are all based on papers presented to the Sixth International Conference of the Operations Management Association-UK which was held at Aston University in June 1991. The theme of the conference was "Achieving Competitive Edge" and authors from 15 countries around the world contributed to more than 80 presented papers. Within this special issue five topic areas are addressed with two articles relating to each. The topics are: strategic management of operations; managing change; production system design; production control; and service operations. Under strategic management of operations De Toni, Filippini and Forza propose a conceptual model which considers the performance of an operating system as a source of competitive advantage through the ''operation value chain'' of design, purchasing, production and distribution. Their model is set within the context of the tendency towards globalization. New's article is somewhat in contrast to the more fashionable literature on operations strategy. It challenges the validity of the current idea of ''world-class manufacturing'' and, instead, urges a reconsideration of the view that strategic ''trade-offs'' are necessary to achieve a competitive edge. The importance of managing change has for some time been recognized within the field of organization studies but its relevance in operations management is now being realized. Berger considers the use of "organization design", ''sociotechnical systems'' and change strategies and contrasts these with the more recent idea of the ''dialogue perspective''. A tentative model is suggested to improve the analysis of different strategies in a situation specific context. Neely and Wilson look at an essential prerequisite if change is to be effected in an efficient way, namely product goal congruence. Using a case study as its basis, their article suggests a method of measuring goal congruence as a means of identifying the extent to which key performance criteria relating to quality, time, cost and flexibility are understood within an organization. The two articles on production systems design represent important contributions to the debate on flexible production organization and autonomous group working. Rosander uses the results from cases to test the applicability of ''flow groups'' as the optimal way of organizing batch production. Schuring also examines cases to determine the reasons behind the adoption of ''autonomous work groups'' in The Netherlands and Sweden. Both these contributions help to provide a greater understanding of the production philosophies which have emerged as alternatives to more conventional systems -------for intermittent and continuous production. The production control articles are both concerned with the concepts of ''push'' and ''pull'' which are the two broad approaches to material planning and control. Hirakawa, Hoshino and Katayama have developed a hybrid model, suitable for multistage manufacturing processes, which combines the benefits of both systems. They discuss the theoretical arguments in support of the system and illustrate its performance with numerical studies. Slack and Correa's concern is with the flexibility characteristics of push and pull material planning and control systems. They use the case of two plants using the different systems to compare their performance within a number of predefined flexibility types. The two final contributions on service operations are complementary. The article by Voss really relates to manufacturing but examines the application of service industry concepts within the UK manufacturing sector. His studies in a number of companies support the idea of the ''service factory'' and offer a new perspective for manufacturing. Harvey's contribution by contrast, is concerned with the application of operations management principles in the delivery of professional services. Using the case of social-service provision in Canada, it demonstrates how concepts such as ''just-in-time'' can be used to improve service performance. The ten articles in this special issue of the journal address a wide range of issues and situations. Their common aspect is that, together, they demonstrate the extent to which competitiveness can be improved via the application of operations management concepts and techniques.