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Virtually all chemical reactions in biological systems are catalyzed by macromolecules called enzymes. A defined mixed culture involvesinoculation of the substrate with morethan one pure culture. Solid state fermentation as an enzyme production technique is not without difficulties that must be overcome. The preparation of a solid substrate, often with pretreatment to decrease the particle size or increase the availability of nutrients in the substrate.
A cooking step which sterilizes or at least pasteurizes the substrate and causes the absorption of water into the substrate particles. The Alltech solid state fermentation programThe many advantages of enzyme production by SSF have convinced Alltech that it is a valuable technology for the production of enzymes. The development of a SSF fermentation program at Alltech is intended to produce a more useful enzyme employing a procedure with economics that make it practical for the animal feed and fuel ethanol industries. Treatment of type 2 diabetes mellitus by viral eradication in chronic hepatitis C: Myth or reality?
Increasing multimorbidity with age often makes it necessary to prescribe several drugs for one patient at a time.
A necessary consequence of this is the danger that interactions between drugs will lead to serious adverse effects or will reduce the therapeutic effect of some compounds. This CME article gives examples of interactions at the pharmacodynamic level, mainly using the example of nonsteroidal anti-inflammatory drugs (NSAIDs). The term “pharmacodynamic interactions” refers to interactions in which drugs influence each other’s effects directly. Platelet-related interactions—It is generally known that simultaneous administration of NSAIDs increases the COX-1-mediated inhibition of thromboxane synthesis and hence the risk of gastrointestinal bleeding in a synergistic manner.
Long-term clinical observations confirm these ex vivo observations (e5), which appear also to hold for naproxen (e6). Increased gastrointestinal bleeding also occurs when selective serotonin reuptake inhibitors (SSRIs) such as citalopram are taken simultaneously with NSAIDs (e7). Interactions with the vascular system—NSAIDs can reduce the blood-pressure-lowering effect of ACE inhibitors. Other interactions of inhibitors of the renin–angiotensin system (RAAS)—The aldosterone-antagonistic effect of ACE inhibitors and AT1-receptor antagonists can, in combination with potassium-sparing diuretics or specific aldosterone antagonists such as spironolactone and eplerenone, induce dangerous hyperkalemia or renal failure. With pharmacodynamic interactions, it is not possible to demonstrate a simple systematics as it is in pharmacokinetic interactions; instead, they require a careful weighing up of which drug groups cause desired and which undesired effects, which can in turn either potentiate or weaken each other (Table 1). Reciprocal influencing of absorption, distribution in the various compartments, metabolization, and elimination can affect the effective concentrations at their sites of action. The systematics are becoming increasingly better understood, so that some of the interactions of various drugs can be well predicted, partly with the help of computer programs, at least for certain drug groups (12). Multidrug efflux transporters such as P-glycoprotein (P-gp, ABCB1) were first described as one of the causes of chemotherapy resistance in tumors. An example of a typical drug interaction at the P-gp level is the much higher bioavailability of the cardiac glycoside digoxin when accompanied by oral administration of the calcium antagonist verapamil. P-gp induction can, on the other hand, accelerate efflux transport and reduce the bioavailability of drugs.
In addition to P-gp, the efflux transporters ABCC2 (MRP2) and ABCG2 (BCRP) are also responsible for the efflux transport of many medical drugs and can be subject to interactions with inhibitors.
The opposite also occurs: inhibition of uptake transporters leads to a reduction in bioavailability. Interactions with CYP3A4 are particularly marked, since this isoenzyme has a particularly broad substrate spectrum (e15). Anticoagulants—The most relevant interactions are those relating to drugs with a narrow therapeutic spectrum, such as ciclosporin or phenprocoumon. For vitamin K antagonists, however, coadministration of broad-spectrum antibiotics such as amoxicillin (alone or with clavulanic acid) or doxycycline appears to be a determinant of bleeding events.
The flavonoid naringin, contained in citrus fruits (especially grapefruit), also inhibits CYP3A4 and thus can increase the availability of a number of other drugs. Fluvoxamine, on the other hand, inhibits CYP1A2 and can thus increase the toxicity of theophylline or clozapine. The inhibition of CYP2D6 can also reduce the formation of active metabolites of codeine into morphine or tramadol into O-desmethyltramadol. Apart from the pharmacokinetic interactions, another aspect to consider with SSRIs is potentiation of the serotonergic effects.
Quinolones—Quinolones such as ofloxacin and ciprofloxacin are primarily inhibitors of CYP1A2, which is also involved in metabolism of theophylline or clozapine.
In addition to inhibiting CYP2C19, omeprazole leads to reduced induction of CYP1A2 (23, e23). While lansoprazole is also able to induce CYP1A2, this interaction was not observed with pantoprazole (24). A significant influence of omeprazole on the bioavailability of the HIV protease inhibitor atazanivir was observed, not mediated by cytochrome P450, but as a consequence of the rise in pH.
Professor Cascorbi has received fees for preparing medical educational events from Novartis, MSD, and Sanofi-Aventis.
Gallagher PF, Barry PJ, Ryan C, Hartigan I, O’Mahony D: Inappropriate prescribing in an acutely ill population of elderly patients as determined by Beers’ Criteria. Thomsen LA, Winterstein AG, Sondergaard B, Haugbolle LS, Melander A: Systematic review of the incidence and characteristics of preventable adverse drug events in ambulatory care.
Schuler J, Duckelmann C, Beindl W, Prinz E, Michalski T, Pichler M: Polypharmacy and inappropriate prescribing in elderly internal-medicine patients in Austria.
Schalekamp T, Klungel OH, Souverein PC, de Boer A: Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins. Abrahamsen B, Eiken P, Eastell R: Proton pump inhibitor use and the antifracture efficacy of alendronate. Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G: Acute heart transplant rejection due to Saint John’s wort. Bertz RJ, Granneman GR: Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Penning-van Beest FJ, Koerselman J, Herings RM: Risk of major bleeding during concomitant use of antibiotic drugs and coumarin anticoagulants. Shakeri-Nejad K, Stahlmann R: Drug interactions during therapy with three major groups of antimicrobial agents. Dilger K, Zheng Z, Klotz U: Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline. Meyer UA: Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs.
Hudson M, Baron M, Rahme E, Pilote L: Ibuprofen may abrogate the benefits of aspirin when used for secondary prevention of myocardial infarction.
Hauta-Aho M, Tirkkonen T, Vahlberg T, Laine K: The effect of drug interactions on bleeding risk associated with warfarin therapy in hospitalized patients.
Edwards NC, Steeds RP, Chue CD, Stewart PM, Ferro CJ, Townend JN: The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.
Geick A, Eichelbaum M, Burk O: Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. Lane RM: Pharmacokinetic drug interaction potential of selective serotonin reuptake inhibitors. Ferslew KE, Hagardorn AN, Harlan GC, McCormick WF: A fatal drug interaction between clozapine and fluoxetine. Rocha A, Coelho EB, Sampaio SA, Lanchote VL: Omeprazole preferentially inhibits the metabolism of (+)-(S)-citalopram in healthy volunteers. Institute of Clinical and Experimental Pharmacology at the University Medical Center Schleswig-Holstein:Prof.
Chemical reactions in vivo rarely proceed at perceptible rates in the absence of enzymes while reaction rates increase as much as a million times when enzymes are present.
Strict aseptic conditions arenot followed; and selective pressuressuch as water content and inoculationrate are used to control contamination.
Examples of substrates are cereal grains, wheat bran, and wheat straw.b) Substrates require less pretreatment compared to liquid fermentation. The majority of commercially profitable processes involve fungi, however.b) Removal of metabolic heat can be a problem in large scale fermentations. Potential interactions can arise at any age in life, but the frequency of polypharmacy in older life increases the risk substantially. One study, in which hospital personnel on an intensive care unit were informed of drug interactions by written drug information based on a computerized clinical decision support system, was very successful, reducing the number of interactions from 66% to 54% and the number of unwanted events from 44% to 25% (e4) (Box 1). When the effect of one drug is impeded by another, the effects of these drugs are antagonistic.
For example, if fluoroquinolones are combined with macrolides such as erythromycin, this can result in QT prolongation.
A particular property of the acidic anti-inflammatory ibuprofen is its specific, reversible binding to COX-1, which prevents acetylsalicylic acid (ASA) from acetylating the serine residue at position 529 of the COX-1 protein. Accordingly, patients with coronary heart disease on ASA prophylaxis should not take ibuprofen or naproxen on a regular basis.
SSRIs inhibit the transport of serotonin into the platelets, leading to further impairment of function and doubling of the risk of bleeding. The main mechanism is via a reduction in glomerular perfusion through a reduction of local prostaglandin E2 synthesis with corresponding reactive secretion of renin. After the introduction of spironolactone for the treatment of cardiac failure, the number of hospitalizations for hyperkalemia increased markedly (11). The causes can be formation of complexes, competition for uptake transporters, or induction of metabolizing enzymes and efflux transporters (Figure 1). Quantification of the extent of the interaction, however, is not usually subject to any simple rule, such as in dose adjustment of renally eliminated drugs depending on the patient’s glomerular filtration rate. The bisphosphonates used in osteoporosis, such as alendronate, have a very low bioavailability of only 0.5% to 2%.
P-gp-mediated efflux transport also contributes to reducing the responsiveness of lymphocytes to HIV protease inhibitors.
For ciclosporin, this means that simultaneous administration of the tuberculostatic rifampicin can lead to subtherapeutic concentrations.
An example is inhibition by repaglinide of the uptake of metformin via the organic cation transporter OCT1 (e14).
Most metabolic interactions are due to competition for the cytochrome P450 enzyme (CYP), which is expressed in the liver and catalyzes the phase I oxidation of more than half of all medical drugs (16). Some of the CYP3A4 substrates, inhibitors, and inducers are identical with those of P-gp, indicating a synergistic defense mechanism against foreign matter that has developed in the course of evolution (Tables 3 and 4).
As already mentioned, vitamin K antagonists can trigger life-threatening hemorrhage and contribute to the incidence of medical drug-related hospitalizations. The cause is less inhibition of the metabolism, more possibly a change in coagulation status given the underlying pyretic infection (17). In a study carried out in healthy volunteers, the bioavailability of orally administered midazolam did not return to normal until 3 days after the subjects drank one glass of grapefruit juice (e17).
It has been shown in large studies that the inhibition of CYP2D6-mediated activation of the anti-estrogen tamoxifen to endoxifen through SSRIs is associated with increased breast cancer mortality (18).
It is known that simultaneous administration of moclobemide can trigger serotonin syndrome and is contraindicated for that reason. Simultaneous administration of, for example, ciprofloxacin and theophylline can lead to a rise in the plasma concentration of theophylline, with corresponding clinical symptoms of cardiac and gastrointestinal unwanted effects (19). An example is citalopram, the metabolization of which is slowed down by omeprazole (e21), and the risk of unwanted effects such as QT prolongation rises.
Knowledge of which enzymatic metabolic path is clinically relevant to the metabolization of a drug, whether it is the substrate of a drug transporter, and whether it inhibits or induces these proteins, makes it possible to predict pharmacokinetic interactions.
Three basic types of reactors can be distinguished based on the mixing regime and the aeration mode. Two isolates have gone through a rigorous screening and selection process and are currently used extensively in the program.
The high rate of prescribed drugs in elderly patients (65-year-old patients take an average of 5 drugs) increases the likelihood of drug interactions and thus the risk that drugs themselves can be the cause of hospitalization.
Prescription peaks in the 75- to 84-year-old group; a European study showed among patients with a mean age of 81 years that 34% to 68% were taking six drugs or more (2).
Meta-analyses of the reasons for inpatient admission to medical wards showed that in 7% of cases serious drug interactions were the cause for admission or for prolonged hospital stays (3, e1, e2). The combination of ACE inhibitors with potassium-sparing diuretics such as amiloride can increase potassium retention so strongly that life-threatening hyperkalemia ensues.


Irreversible and hence long-lasting inhibition of COX-1-mediated thromboxane A2 synthesis by ASA can thus be prevented and the cardiac risk of patients with coronary heart disease can increase (8).
The SSRI-mediated impairment of platelet function can also increase the risk of bleeding due to vitamin K antagonists such as warfarin and phenprocoumon (9, e8).
In a controlled clinical study, the blood pressure of healthy volunteers treated with lisinopril rose by 7 to 9 mmHg when they were given piroxicam (e9). Apparently there now exists an increased awareness of this potential problem, however; although, according to the guidelines of the European Society of Cardiology (ESC), aldosterone antagonists are the drug of choice for patients with NYHA class II heart failure, alongside RAAS inhibitors, and consequently are being used more widely, more recent studies do not show significant hyperkalemia when they are used in combination with RAAS inhibitors (e11, e12). Ritonavir, which causes many side effects at high doses, simultaneously inhibits P-gp and also the drug-metabolizing cytochrome P450 3A4 (CYP3A4). Rifampicin binds intracellularly to the nuclear receptor PXR, one of the main regulators of transcriptional control of P-gp expression (14, e13) (Figure 2). The cause could be interactions with older macrolide antibiotics such as erythromycin and clarithromycin, which inhibit cytochrome P450 3A4, important in the metabolization of phenprocoumon. The clinical relevance of phenprocoumon is debated, but, at the least, excessive amounts of citrus fruits should be avoided in patients receiving anticoagulation treatment with vitamin K antagonists. In everyday practice, however, one must also watch out for interactions between antidepressants and common medical drugs such as certain beta-blockers. The bioavailability of quinolones themselves can be markedly restricted if they are given at the same time as bivalent or trivalent cations, such as are contained in antacids or zinc or iron formulations (Box 4). Recently, a discussion has arisen about the consequences of its interaction with the platelet aggregation inhibitor clopidogrel.
Inhibitors of certain cytochrome P450 enzymes can influence the bioavailability of a whole group of drugs metabolized by the same enzyme, while inducers usually contribute to a loss of effectiveness. The name ‘enzyme’, meaning ‘in yeast’, was not used until 1877; however much earlier it was suspected that biological catalysts were involved in the fermentation of sugar to form alcohol.
This problem can be lessened by using organisms that are heat tolerant.c) The solid nature of the substrate presents problems in monitoring process parameters.
These include tray bioreactors, packed bed reactors, and agitated bioreactors.The simplest SSF reactor is the tray. To avoid serious consequences so far as possible from the outset, therefore, requires the ability to make better predictions about drug interactions.
Interactions of nonsteroidal anti-inflammatory drugs (NSAIDs) are demonstrated below as an example of pharmacodynamic interactions. It was recently reported that these important interactions of NSAIDs are also true for AT1-receptor blockers (10). Multivalent cations can also form complexes with tetracycline or quinolones and also reduce the bioavailability of levothyroxine; simultaneous intake of calcium-containing foods or neutralizing antacids containing aluminum or magnesium ions, must therefore be avoided. The fixed combination of ritonavir with, for example, 200 mg lopinavir improves the bioavailability of the protease-inhibiting substance and the efflux of lopinavir out of the lymphocytes, thus reducing the breakdown in the liver. Other PXR ligands, and thus inducing drugs, are the anticonvulsants carbamazepine (oxcarbazepine to a lesser extent), phenobarbital, and phenytoin, and the HIV therapeutic efavirenz.
Fluoxetine and paroxetine also inhibit the metabolism of the beta-blocker metoprolol and can thus cause lowering of blood pressure, bradycardia, and other undesired effects. When triptans such as sumatriptan are used at the same time, there is an additional risk of coronary artery constriction and hypertension. Clopidogrel is a prodrug that is metabolized to its active metabolites in two steps, and CYP2C19 plays an essential part in this. At a dose of 20 mg, omeprazole results in a 36% increase in the half-life of diazepam and a 27% reduction in its clearance; giving 40 mg omeprazole increases the half-life by 130% and clearance by 54%. According to the safety information, increasing the atazanivir dose to 400 mg does not compensate for the impact of omeprazole on atazanivir exposure. As a general principle, drugs that are metabolized more quickly and have a lower bioavailability carry a higher potential risk of interactions. Changes in pH are not easily identified and controlled in SSF; and the control of moisture content and substrate concentrations is extremely difficult.
In a tray bioreactor a relatively thin layer of substrate is spread over a large horizontal area. The authors regarded 36% of the drugs as unnecessary and 30% as inappropriate for elderly people (see recommendations in the PRISCUS list [5]). Low-dose ASA, on the other hand, appears to have no effect on arterial blood pressure (e10).
Recently, a reduction of the protective properties of alendronate with reference to avoiding hip fractures was observed when proton pump inhibitors were given at the same time (13). So far, however, the attempt to overcome the chemoresistance of tumors by inhibiting efflux transporters, especially by means of P-glycoprotein, has been unsuccessful. The calcium channel blockers verapamil and azole antimycotics can be highly potent CYP3A4 inhibitors. Interaction must be expected for several days after the last administration of SSRIs, because of their long half-life (Box 3). Lansoprazole also inhibits the metabolization of diazepam, although more weakly; this evidence did not appear for pantoprazole (e22). For this reason, neither PPIs nor, presumably, H2-receptor blockers should be used simultaneously with atazanivir. Predicting pharmacodynamic interactions often requires a deeper understanding of the mechanisms of action; but here too a certain system can be recognized, just as for pharmacokinetic interactions.
Heat production, oxygen consumption and carbon dioxide are parameters that can be measured.d) Many important basic scientific and engineering aspects are poorly understood. There is no forced aeration, although the base of the tray may be perforated and air forced around the tray. Examples of pharmacodynamic interactions are simultaneous administration of a NSAID and phenprocoumon (additive interaction), or of aspirin and ibuprofen (antagonistic interaction). For 10% of the patients, adverse drug effects were regarded as the reason for their inpatient admission, and in 18.7% a drug interaction very probably played a part in these effects (6). These study results thus indicate that SSRIs increase the risk of bleeding associated with vitamin K antagonists as much as NSAIDs do. John’s wort extract led to such a pronounced fall in ciclosporin concentration that an acute transplant rejection occurred (15). Ketoconazole inhibits the cytochrome P450 system so strongly that it is now used as a standard inhibitor in the clinical development of medical drugs, in order to test interactions with CYP3A4 among others. Electronic prescribing systems that can alert the user early on to possible interactions and can assist with drug selection and dosage are helpful.
Little is known about the mode of growth of fungi within substrate masses composed of irregularly shaped solid particles.e) Cultivation times are often longer.
A point that is becoming more and more critical for many consumers is that the organism is a non-genetically modified organism (non-GMO) able to produce phytase at a significant level for commercial production. Since the absolute number of bleeding events under SSRI treatment is quite low, however, simultaneous treatment with SSRIs and anticoagulants or NSAIDs should chiefly be avoided in at-risk patients with a known history of bleeding (e7). A similar association was found in carriers of the nonactive genetic variants of CYP2C19 (21, e20).
In 1860, Louis Pasteur postulated that enzymes are linked with the structure of the yeast cell. Internal temperature may vary with ambient temperature; or the tray may be placed in a temperature-controlled room.
Predicting pharmacodynamic interactions often demands a deeper understanding of the mechanisms of effect.
One of the frequent causes here is incorrect or wrongly adjusted dosages, especially in patients with reduced kidney function (7).
Bleeding complications during treatment with fluconazole among others have also been reported in patients on warfarin anticoagulation therapy.
Both the CYP2C19*2-splice-site variant and the *3 missense variant lead to a complete loss of effect of the protein. The ability of enzymes to function outside a cell has greatly increased their use in a large variety of commercial products and reactions.
Tray bioreactors have been used successfully at laboratory, pilot, semi-commercial and commercial scale (Ahmed et al, 1987; Hesseltine, 1987). The SSF growth environment is conducive to overproduction of a number of different enzymes; and genetic engineering is not required for production of large amounts. A British study of 3695 patients demonstrated that almost 15% of the patients suffered adverse drug effects during their stay in hospital, which in a quarter of these cases prolonged the hospital stay. In this case, the increased bioavailability of warfarin is due to fluconazole-mediated inhibition of CYP2C9 (e16). Among white people, 3% are homozygote CYP2C19*2 carriers, while *3 carriers contribute to the “poor metabolizer” status of people of Asian origin. In contrast, submerged liquid systems generally use GMOs designed for overproduction of a particular enzyme.The second organism currently being studied extensively is Rhizopus oryzae, which produces glucoamylase. Once sex, age, and type of ward (medical, surgical) were taken into account, the number of simultaneously prescribed drugs was the only significant predictor (7). A systematic meta-analysis of follow-up studies confirmed the association between CYP2C19 polymorphisms and platelet inhibition by clopidogrel, but clinically no significant effect on the risk of cardiovascular events was shown (22).
The world annual sales of industrial enzymes was recently valued at $1 billion (Bron et al., 1999).
Glucoamylase sequentially cleaves glucose molecules from the nonreducing end of a starch molecule and is used extensively in the ethanol industry. In a survey in Sweden, the contribution of drugs to overall mortality was estimated at 3%; gastrointestinal and central nervous bleeding alone contributed a third of the incidence (e3). The US Food and Drug Administration (FDA) points out in the safety information on clopidogrel that the drug will have reduced effectiveness in CYP2C19 nonmetabolizers. Three quarters of the market is for enzymes involved in the hydrolysis of natural polymers, of which about two-thirds are proteolytic enzymes used in the detergent, dairy and leather industries; and one third are carbohydrases used in the animal feed, baking, brewing, distilling, starch and textile industries.
The organism is not genetically modified and has been naturally selected for overproduction of glucoamylase.
With regard to interactions, the FDA recommends choosing the proton pump inhibitor pantoprazole rather than omeprazole, if possible. Detergent manufacturers use 45% of all industrial enzymes produced in spot remover and detergent products containing proteases and lipases. The German drug information, without mentioning any drugs by name, advises against the simultaneous use of strong CYP2C19 inhibitors. Food processing enzymes including "-amylases, glucose isomerase and pectinases account for about 45% of enzyme usage.
The temperature of the incoming air can be changed to aid in temperature regulation of the substrate (Narahara et al., 1984).
This organism is currently being used in lab scale and pilot scale tray fermentations and deep bed lab scale fermentations.
The starch processing industry uses half of the enzymes in the food industry, approximately 25% are used by the dairy industry and 10% by the brewers, fruit juice and wine producers. The advantage of packed bed reactors is that they remain simple while allowing better process control than trays.
Completion of these studies will allow the organism to be used at a commercial level.STANDARDIZATION OF THE PROCESS AT SMALL SCALEThe selection of strains involves SSF on a small scale. The textile and paper industry (6%) uses primarily amylases and hemicellulases and the leather industry (2%) uses proteases.
The first is a rotating drum reactor consisting of a horizontal or inclined cylinder that rotates around a central axis and causes a tumbling motion of the substrate. In these flasks the typical moisture, temperature and extraction conditions as well as the length of fermentation and inoculation rate have been determined and maximized. Mixing is gentle, although problems can arise if microorganisms are sensitive to the agitation. As the understanding of enzymes and their properties has grown, so have both their use and their effectiveness as feed supplements. Temperature control is difficult because the reactor is difficult to water jacket (Lonsane et al., 1985). In addition to thin layer tray systems, deep bed systems of 30–50 cm will be used in production. The purpose of using enzymes in monogastric animals is to improve availability of nutrients in feedstuffs.
The second type of agitated fermenter, a stirred reactor, has the reactor placed either on a horizontal or a vertical axis.
In order to determine if organisms are suitable for growth in deep layer fermentations, lab scale deep layer fermenters have been designed. The result is improved feed utilization and reduced impact of anti-nutritional components.Methods for production of commercial enzymesIndustrial enzymes are produced by plants, animals, and microbes.


Horizontal reactors are similar to rotating drums except the mixing is provided by an internal scraper or paddles, rather than rotation of the reactor. By far the most exploited for the use of industrial enzymes has been the microbial population. Short generation times and high yields, together with the fact that microorganisms produce extracellular enzymes, which are easy to harvest, make microbes the enzyme source of choice.
Production of enzymes by microorganisms has also expanded because of the vast amounts of genetic information now available.
The airflow, relative humidity of the air, and oxygen content within the chamber can all be measured. Several industrially important microbial genomes have been sequenced; and the understanding of gene expression systems in microorganisms is much more advanced when compared to other gene expression systems. This knowledge has made it possible to select a variety of microorganisms suitable for enzyme production with traditional submerged liquid fermentation (Bailey and Ollis, 1986).
An alternative fermentation method for enzyme production is solid substrate fermentation (Mitchell and Lonsane, 1992).SUBMERGED LIQUID FERMENTATIONSubmerged liquid fermentations are traditionally used in the United States for the production of microbially derived enzymes. With this system we are able to generate data that reflect the heat produced during the fermentation and determine the amount of air required to maintain temperature in the target range. Submerged fermentation involves submersion of the microorganism in an aqueous solution containing all the nutrients needed for growth. A research team led by Chaim Weizmann in Great Britian developed a process for production of acetone by submerged liquid fermentation using Clostridium acetobutylicum, which eventually led to the first large-scale aseptic fermentation vessel (Stanbury et al., 1995). These systems can produce data on the success of the fermentation in deep layers and the amount of heat produced during the fermentation.SCALE-UP STUDIESThe scale-up step is a crucial linkage in the process since it determines whether the process will operate at a commercial scale.
The first large-scale aerobic fermenters were used in central Europe in the 1930s for production of compressed yeast (de Becze and Liebmann, 1944). The scale-up should theoretically result in the same overall performance that can be achieved in the laboratory. In 1943, the British government decided that solid substrate fermentation was inadequate for the production of penicillin. This is rarely the case since a number of additional parameters influence the fermentation. This decision forced the development of liquid fermenters that are aseptic and contain adequate aeration and agitation. Construction of the first large-scale plant to produce penicillin by liquid fermentation began in 1943 (Callahan, 1944).Organisms used in submerged fermentationsFermentation using bacillus species accounts for about half of the world’s production of industrial enzymes.
The main classes of bacillus enzymes and the strains used to produce them are listed in Table 2. The initial system designed was a plexiglass chamber able to hold 12 trays that hold up to 200 g of substrate. Although bacillus species are the primary enzyme-producing organisms, other microbes are also used. In order to gain more information from tray fermentations, a second-generation tray fermenter was designed and built by the Departmento de Biotechnologia, Universidad Autonoma Metroplitana Iztapalapa. Through genetic modifications the bacterium Escherichia coli is able to produce insulin and human growth hormones. Four trays fit inside the reactor and conditioned air is forced in at the lower left portion of the reactor.
Other microorganisms used on an industrial scale include Saccharomyces cerevisiae for ethanol production and the fungi Aspergillus and Trichoderma for carbohydrase production.Table 2. The reactor is equipped with thermocouples, flow meter, oxygen sensor and relative humidity sensor. With the development of genetic engineering techniques, organisms can be engineered to produce high yields of a great variety of products.
Data acquisition equipment allows better understanding of heat and carbon dioxide production. The genetic manipulation of genomes is common for organisms used in submerged liquid fermentations.Fermenter designThe main function of a fermenter is to provide a controlled environment for growth of microorganisms in order to obtain a desired product. Pilot scale tray fermentation system.Alltech is interested in production of enzymes in deep layers as well as thin layer tray systems. Two important criteria for a submerged liquid fermenter include the ability to operate aseptically for a number of days and provide adequate aeration and agitation to meet the metabolic requirements of the microorganism. Many different types of fermenters have been described in the literature, but very few proved satisfactory for industrial aerobic fermentations. The most common designs are based on a stirred upright cylinder with sparger aeration (Stanbury et al., 1995). Fermenter sizes can range from flasks used in the laboratory to production fermenters of 8,000 liters or more (Figure 1).Fermenter operationMany biochemical processes involve batch growth of cell populations.
After seeding a liquid medium with an inoculum of living cells, only gas is added or removed from the culture as growth proceeds. Typically in such a batch reactor, the concentrations of nutrients, cells and products vary with time as growth proceeds. During the fermentation, temperature, oxygen, carbon dioxide, airflow and relative humidity can be monitored.
In addition, it is often desirable to add liquid streams to a batch bioreactor as the reaction process occurs. The reactor will enable studies to determine if organisms can perform in deep layers at pilot scale levels and develop an understanding of heat production.Figure 6. This can be done to add precursors for desired products, to add regulating compounds such as inducers at a point in the batch operation, to maintain low nutrient levels to minimize catabolite repression or to extend the stationary phase by nutrient addition (Baily and Ollis, 1986). A pilot scale deep bed fermenter.DESIGN AND CONSTRUCTION OF THE SSF PLANTThere is no information available in the literature on SSF with respect to the theoretical and experimental comparisons of different kinds of bioreactors, methods for controlling cultivation parameters, automation, design and scale up criteria or downstream processing options. When the fermenter is used in this manner it is known as a ‘fed-batch’ fermentation.Figure 1.
The design process for large scale production of enzymes has been based on information obtained in lab scale and pilot scale studies as well as experience gained in the areas of fermentation and downstream processing.From the data generated and the scant literature available it became apparent that for initial production a tray fermentation system would reach optimum production levels in the shortest amount of time.
Deep tank liquid fermenter (250 liter).The success of a fermentation depends upon the existence of defined environmental conditions for biomass and product formation.
The data generated in the lab and pilot tray systems were used in the development of a production tray fermentation system.
The temperature, pH, degree of agitation, oxygen concentration in the medium and other factors may need to be kept constant during the process. This facility houses pretreatment, inoculation facilities, fermentation facilities, and downstream processing facilities. Table 3 lists the variety of process sensors included in a submerged liquid fermentation.SOLID SUBSTRATE CULTIVATIONIn addition to submerged liquid fermentation, an ancient fermentation technology known as solid substrate fermentation is also used to produce enzymes. Solid substrate fermentations are generally characterized by growth of microorganisms on water-insoluble substrates in the presence of varying amounts of free water (Mitchell and Lonsane, 1992). The initial phase of the design was intended for construction of a facility that will contain about 10,000 trays.Future potentialMost profitable applications of SSF are confined to Asian and African countries and are scarce elsewhere in the world.
A resurgence of interest has occurred in western and European countries in response to the everincreasing demand for economy in enzyme production.
The facility in Serdan is believed to be the first commercial enzyme production facility in North America that uses SSF technology. The future of the SSF program at Alltech includes the development of new strains for enzyme production, to enhance current enzyme systems and development of new enzyme applications. The most profitable applications of SSF are in Asian and African countries where SSF processes have been perfected over long periods.
The use of a variety of waste products will be investigated as well as the potential for using inert supports for fermentation. The SSF technology also has the potential to be used for purposes other than enzyme production. Solid substrate fermentation has been largely neglected since the 1940s; and negligible research and development efforts have been made.
Other metabolites such as ethanol, flavors, and other microbial by-products can be produced. Solid substrate fermentations also include a number of well known microbial processes such as soil growth, composting, silage production, wood rotting and mushroom cultivation. In addition, many familiar western foods such as mold-ripened cheese, bread, sausage and many foods of Asian origin including miso, tempeh and soy sauce are produced using SSF. Beverages derived from SSF processes include ontjom in Indonesia, shao-hsing wine and kaoliang (sorghum) liquor in China and sake in Japan (Mudgett, 1986).
Table 5 gives examples of foods that involve an SSF process at some point in production.Table 5. Tempeh production has been established on a small scale in the US (Hesseltine, 1987) because it has been accepted as a meat substitute by vegetarians. Mushrooms are cultivated in western countries; and soy sauce production has become highly industrialized and is widely used across the world. Kikkoman Foods has built a state-of-the-art facility completed in 1998 for soy sauce production in Folsom, California.General features of solid substrate fermentationThe single most important feature of SSF is the low moisture content of the medium, which makes SSF very different from submerged liquid cultures.
Water is essential for microbial growth; and the limited water in SSF has several consequences. It is adsorbed and to some extent held tightly; and there may even be some free water in the interior and on the surface.
Evaporative cooling is the most effective cooling method, although this will reduce water availability (Trevelyan, 1974). Proper temperature conditions during the fermentation are a balance between the need for heat removal and the necessity of keeping the substrate sufficiently moist to support growth. The insoluble substrates used in SSF are composite and heterogeneous products from agriculture or by-products of agro-industries. For many processes, substrates are chosen because they are readily available and therefore inexpensive. The macromolecular portion often provides a structural matrix for the substrate as well as serve as the carbon and energy source (e.g. If the macromolecule serves as a structural matrix only, the carbon and energy source is provided by a non-structural macromolecule such as starch or a smaller, soluble compound (e.g.
The data suggest that microbial physiology and regulation within the cell are influenced by the fermentation environment (Viniegra-Gonzalez, 1997). A glucosidase produced by Aspergillus phoenicis in SSF was more thermotolerant than when produced in submerged liquid fermentation (Deschamps and Huet, 1984).
A phytase produced by SSF (Allzyme Phytase, Alltech Inc.) also contained a mixture of activities not found in enzyme preparations from submerged culture systems (Table 6). The complex nature of feedstuffs makes these side activities beneficial to the animal industry (Classen, 1996). Comparison of enzyme activities of two commercially available phytases.Microorganisms for solid state fermentationBacteria, yeast and fungi can all grow on solid substrates and have applications in SSF processes.
However, filamentous fungi are the best adapted species for SSF and dominate in the research and practical applications around the world. Bacterial SSF fermentations are rarely used for large scale enzyme production, but are very important in nature and in the fermented food industry. In composting, moist solid organic wastes are decomposed by a succession of naturally-occurring microorganisms. The fermentative yeast Endomycopsis burtonii is involved in the production of a traditional Indonesian fermented food, tape (Steinkraus, 1983).Filamentous fungi are the most important group of microorganisms for enzyme production in SSF. The hyphal mode of growth gives a major advantage to filamentous fungi over unicellular microorganisms in the colonization of solid substrates and the utilization of available nutrients. This makes the action of hydrolytic enzymes very efficient and allows penetration into most solid substrates. Fungi cannot transport macromolecular substrates across the cell wall, so the macromolecule must be hydrolyzed externally into soluble units that can be transported into the cell (Knapp and Howell, 1980).Figure 2. Effect of phytase enzyme source on reducing sugar release from four substrates at recommended use rates (abMeans differ, PFigure 3.
Effect of phytase enzyme source on amino nitrogen release from four substrates at recommended enzyme use rates (abMeans differ, PFigure 4.
Effect of phytase enzyme source on phosphate release from four substrates at recommended enzyme use rates (abMeans differ, PMany submerged liquid fermentations are performed using pure cultures.The substrate is sterilized and then inoculated with a single culture.



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