By V. Ramon. University of the Sciences in Philadelphia. 2018.
Risk assessment is especially critical when changes are the risks associated with a product or process buy zebeta 10mg on-line, made to validated processes or systems to ensure the integ- mitigates those risks deemed unacceptable cheap 5 mg zebeta mastercard, and rity of the product is preserved as the risk profile evolves. Thus, an effective risk as- decision-making within a company regarding a sessment will ensure that maximal resources are directed product’s quality and provide greater assurance to a towards products, equipment, and processes deemed high company’s stakeholders of the ability to deliver the risk and minimal resources towards those deemed low risk. In this paper, the authors describe risk-assessment tools used in Less-formal tools for managing change control Risk management tools provide the necessary means by change control. It is, therefore, important to select the appropriate tool based on the objective and scope the assess- ment. The greater the risk and complexity of the system (or process) under review, the greater the level of formality and detail is required of the risk tool (see Figure 1). There are two primary goals in the assessment of risk when managing change: to assure that a company is not taking on 80 Pharmaceutical Technology OctOber 2012 PharmTech. These critical param- Current state Proposed state overall risk parameter rationale profile eters will serve as the input into the risk assessment process. Identify critical parameters for the system under re- into consideration the nature (i. Determine what the differences between the current The overall risk profile may be increased if the proposed and proposed states mean from a risk-based perspec- change increases variability, reduces reproducibility or ro- tive (i. Evaluate whether changes to overall risk profile are ac- versely, the exposure to overall risk may be reduced if the ceptable. Overall risk may remain following attributes as critical parameters: bioburden speci- the same if the change does not affect that particular critical fications, environmental exposure, vessel type, and vessel parameter or if it is proven or expected to be equivalent to 82 Pharmaceutical Technology OctOber 2012 PharmTech. Overall risk Acceptability Severity The risk associated with the critical parameter Minor Moderate Critical Low is acceptable. Medium High High The risk associated with the critical parameter may be acceptable provided additional actions are taken Medium (e. Additional risk control measures are Low Low Medium required to reduce risk to within an acceptable level. As with any risk assessment, available data To continue the hypothetical example in Table I, the overall should be cited as justification for the conclusions drawn. The critical parameter surrounding change is acceptable from a risk-based perspective. In general, the introduction of a new product-contact material, however, the proposed change is acceptable if the overall risk profile has increases risk and should be examined more thoroughly. If the overall risk profile, however, has increased for should be pursued, individual risks associated with the pro- the majority of critical parameters that were assessed, the pro- posed state (change) are not thoroughly explored through posed change should not be accepted until additional analyses this tool. These individual risks are best assessed through are conducted or risk mitigation measures are pursued. Ahunji Aoki, Hyogo University of Health Sciences, Japan Me and my Rotavapor Experience evaporation from the market leader The Rotavapor® System is a unique combination of cunning system conﬁgu- ration and trend-setting design. The beneﬁts of working with the Rotavapor® System are: simple installation process, easy to use, time saving, sustainable, central process control and many more. Determine qualitative scales for insufficient Minor capacity (50L) likelihood and severity rankings. Identify critical parameters for the system under re- difficult to assign a likelihood score if there is no available view. Rank each potential failure for likelihood and severity tive approach and assign a likelihood score of “certain” to using the criteria established in Step 1. Two qualitative scales will be developed, each con- Because in this example the overall risk is driven primarily taining three potential scores. The likelihood scale addresses by a lack of data, mitigation efforts would focus on biocom- how likely is it that the failure will occur, given the cur- patibility testing to better understand the implications of rent controls in place. Once this action is taken, from remote (unlikely) through average (likely) to certain it is expected that overall risk would then be reduced to an (very likely or unknown). The severity scale ranges from minor (in- Conclusion significant impact) through moderate (moderate impact) to To ensure that the quality system and associated processes critical (significant impact). The application of quality risk management whether mitigation measures are required. Low-risk items principles and tools facilitate this understanding, allowing may not require any mitigation activities or resource ex- for more comprehensive strategy development and informed penditure, whereas high-risk items will require additional decision-making. It is not always, however, necessary to per- risk control measures to reduce risk to an acceptable level. Returning to the hypothetical saline solution scale-up, For simple systems and processes as well as for changes that the risk team would first brainstorm potential failures as- are well understood, less-formal tools such as the compari- sociated with each critical parameter for the saline solution son matrix and risk estimation matrix provide a comprehen- process. For example, the batch could fail the bioburden sive picture of the associated risk in an easily applied format. This article is the fifth a proposal for the analytical assessment and control of both drug paper in the series and focuses on specifications. These recommendations take into consideration the differences in clinical trials in early development versus those in later development and provide a starting point to stimulate discussion on specifications in early development. Due to the high attrition rate in early develop- Frank Swanek works in Analytical Development, both at ment, consistent specifications that ensure patient safety are desir- Boehringer Ingelheim Pharmaceuticals Inc. Trone works in and corresponding synthetic and formulation process undergo Analytical Development–Small Molecule at Millennium Pharmaceuticals, Inc.
The effect of particle size on dissolution rate and bioavailability has been alluded to above and is discussed in detail in Section 6 buy discount zebeta 10 mg line. These formulation additives may alter drug dissolution rates by such mechanisms as increasing the wetting of the dosage form order zebeta 10 mg overnight delivery, aiding rapid disintegration of the dosage form, forming poorly absorbable drug-excipient complexes and altering the pH. The effect of formulation factors on the dissolution rate for absorption routes other than the oral route is discussed in the relevant chapters. Drug degradation is generally a first order process and can be described by the following equation: (Equation 1. Solvolysis involves drug decomposition through a reaction with the solvent present, for example water, ethyl alcohol or polyethylene glycol. These solvents act as nucleophilic agents and attack electropositive centers of the drug molecule. Other degradation reactions include photolysis, racemization, and decarboxylation. The stability of the drug to degradative enzymes is of particular importance in vivo, as discussed above. Pharmacokinetics is the study of how drugs enter the body, reach the site of action and are removed from the body, i. Elimination is defined as the process of removal of the drug from the body, which may involve metabolism and/or excretion. The pharmacokinetic aspects of a drug are obviously just as important as its pharmacodynamics, when considering therapeutic efficacy. For many drugs this occurs by simple diffusion of the unionized form across cell membranes (see Section 1. When drugs are given by iv administration, there is an extremely high initial plasma concentration and the drug may rapidly enter and equilibrate with well-perfused tissues such as the lung, adrenals, kidneys, liver and heart. Subsequently, the drug enters poorly perfused tissues such as skeletal muscle, connective tissue and adipose tissue. As the concentration of drug in the poorly perfused tissues increases, there is a corresponding decrease in the concentration in the plasma and well-perfused tissues. Many drugs show an affinity for specific binding sites on plasma proteins such as albumin and α1-acid glycoprotein, which results in a reversible association, with some important consequences in therapeutics: • Drug binding lowers the concentration of free drug in solution, and thus the concentration of drug available to act at the receptor. This can result in the need to use high doses to compensate for drug wasteage, which is expensive. Unwanted deposition may also result in toxicity problems, arising from drug action at non-target sites. Classic examples of toxic side-effects resulting from unwanted drug distribution are found in cancer chemotherapy. The chemotherapeutic agent, a cytotoxic poison, lacks specificity and has the potential to kill all cells, both normal and malignant. The drug exploits the difference in the turnover of cancer cells, which is very much greater than normal cells. However, rapidly dividing normal cells, for example the hair follicles, and the cells of the gastrointestinal tract, are also susceptible to attack. This gives rise to typical side-effects associated with cancer chemotherapy such as hair loss and acute gastrointestinal disturbances. In the early 1900s Paul Ehrlich (who has been described as the father of drug delivery and therapeutics) pioneered the idea of the “magic bullet” approach, whereby therapy “could learn to aim”. The inherent premise of this concept is to try to improve therapy by targeting the drug to the site of action, thereby removing unwanted toxic sideeffects and minimizing drug wastage. It generally involves the transformation of a lipid-soluble drug (which can cross membranes and thus reach its site of action) into a more polar, water-soluble compound which can be rapidly eliminated in the urine. Metabolic processes have considerable implications for successful drug delivery: • Metabolic activity may result in premature degradation of the active moiety, prior to its arrival at the active site. Metabolic activity may also constitute a considerable biochemical barrier to drug absorption. As described above, extensive enzymatic degradation of labile drugs in the gastrointestinal tract can severely limit their oral bioavailability. Specific tubular uptake processes exist for carbohydrates, amino acids, vitamins etc. Drugs may pass from the tubule into the plasma if they are substrates for the uptake processes, or if they are lipid soluble (this process is highly dependent on the prevailing pH, see Section 1. Depending on the drug and the disease state, the timing of therapy may be optimal as either zero-order controlled release, or variable release. Considerable advances in controlling drug release from delivery systems have been made; such systems are described in detail in Chapters 3, 4 and 16. By effective management of the dose size and the dose frequency, it is possible to achieve therapeutic steady-state levels of a drug by giving repeated doses. An example of the type of plasma profile obtained after repeated oral dosing of a drug is shown in Figure 1. However, multiple oral dosing is associated with disadvantages: • The drug concentration does not actually remain constant in the plasma, but fluctuates between maximum (peak) and minimum (trough) values (Figure 1. These fluctuations in plasma concentration may mean that drug levels may swing too high, leading to toxic side-effects; alternatively drug levels may fall too low, leading to a lack of efficacy.
The infusion rate of a drug solution can be programmed by a portable computer with specialized software which transmits instructions by radiotelemetry to the pump generic 5mg zebeta otc. The pump is driven by a step motor cheap zebeta 5mg online, controlled by signals from the micropocessor and is capable of delivering infusate at varying rates (0. The programmer provides the implantable pump with versatile delivery patterns, including a straight continuous-flow pattern or a more complex pattern that allows a varying dose at different times of the day to meet the patient’s changing metabolic requirements. The SynchroMed pump is approved for use in: • chemotherapy (using floxuridine, doxorubicin, cisplatin, or methotrexate); • the treatment of chronic, intractable cancer pain (using morphine sulfate); • osteomyelitis treatment (using clindamycin); • spasticity therapy (using the muscle relaxant, baclofen). The pressure of the roller heads on the tubing in the peristaltic pump causes intensive shear stresses which lead to stability problems for labile peptides and proteins. A patented solenoid motor controls the piston movement, to aspirate insulin from the reservoir chamber into the piston chamber and then push it through the insulin delivery catheter. A hand-held programmer can change the pumping rate to administer the desired insulin dose to the diabetic patient. Many conventional insulin preparations are prone to denaturation when exposed to body fluids and temperature, or when agitated (see Section 1. The ensuing aggregation and precipitation may cause blockage of the catheter attached to the pump. However, the Minimed pump uses an insulin formulation, developed by Hoechst, which includes a small amount of Genapol (polyethylene glycol and polypropylene glycol), to increase the stability of the polypeptide. Infusate is placed in the inner drug reservoir chamber and Freon propellant in the outer chamber (Figure 4. When the Arrow pump is implanted subcutaneously, it is warmed by the patient’s body temperature so that the propellant-containing chamber expands and exerts pressure on the movable bellows. Infusate is thus forced out of the reservoir chamber to an attached catheter through a filter and flow restrictor. This mechanism allows the delivery of infusate at a fairly constant rate to surrounding tissues or blood vessels. It should be noted, however, that the vapour pressure exerted by the outer chamber can be affected by changes in altitude/elevation or body temperature. The Infusaid pump is another fixed-rate implantable pump that shares many similar features, including the Freon pumping principle, with the Arrow pump. Indeed, there now exists bio-responsive implantable systems, and implants for gene therapy; such advances are described in Chapter 16 (New Generation Technologies). However, despite the striking advances in this field, implantable systems will always be limited by the invasive nature of this therapy. A company is trying to develop a reservoir-type polymeric implant for the controlled release of estradiol for 3 months. Which techniques would you recommend to the company to increase the drug release rate? A new steroidal drug is allowed to pass through a siloxane membrane (surface area=23. Provided that the drug release rate is constant, calculate the flux (F) that is defined as the amount of a solute flowing through a membrane per unit time. The release rate of a drug from conventional non-degradable matrix-type polymeric implant usually decreases over time. What is the main reason for developing a reservoir/matrix hybrid-type polymeric implant? Which polymer is most extensively used as non-degradable nonporous membrane to develop reservoir-type polymeric implants? Which of the following is/are an example(s) of non-biodegradable matrix-type implant? What is the principle that has been utilized in the development of the Alzet and the Duros implant pumps in which a drug solution or suspension is confined in a semi-permeable membrane that allows only water molecules to move through it? The release rate (dM/dt) of a drug from an osmotic pump can be described as C (dV/dt)d where Cd is the drug solubility in its reservoir compartment. The effective surface area, permeability coefficient, thickness, and osmotic reflection coefficient of the semi-permeable membrane used for the pump are 3. If we change the reservoir medium and osmotic agent to increase C ofd the drug from 100 to 300 mg/ml and to increase ∆π from 100 to 300 atm, by how much will the release rate of the drug increase? The most important routes of injection of these sterile products are intramuscular (im), intravenous (iv) and subcutaneous (sc). The detailed description of 106 these areas of pharmaceutics lie outside the remit of this text and the reader is refered to information provided in the further reading section of Chapter 1. This chapter focuses on advanced drug delivery and targeting systems administered via the parenteral route and serves to provide the reader with a basic understanding of the principal approaches to drug targeting.
These will often appear as colored (orange or pink) runny or clammy looking gunk in with the rice 10mg zebeta free shipping. Bacterial infections may also give off a kind of putrid odor discount 5 mg zebeta overnight delivery, but of course you should not be taking the lids off the jars at all during this stage. Now, the rice itself will get very soft as a result of the pressure cooking, and the initial shaking of the jar may smear gel-looking gunk all over the insides of the jar. But by comparing with the rest of the jars you should be able to tell the difference between this gunk and a bacterial infection. It should take anywhere from 2 weeks to 1 month for the mycelia to completely permeate the rice medium, then it will start getting these stringy looking or fan shaped runners in the white fuzzy growth. Of course at all stages be on the lookout for any possible contaminants in the mycelia. By the way, as the mycelia mature, they may start staining blue in spots, due to bruising, I think—so don’t mistake this for a mold infection, but keep a close eye on any change in color from the white coloring. The ‘shrooms first appear as tiny white pinheads and then the caps will darken (in P. When the ‘shrooms are growing the lids on the jars should be very loose to allow for air exchange. Also, mushrooms grow best in an environment with a humidity of over 90%, so if you think that your ‘shrooms may need a more moist environment, one thing to do is to simply use a spray bottle to spray boiled or distilled water directly onto the lids of the jars. I find that the moisture condenses inside the jars and runs down the inside of the jars, moisturizing the mycelia. Another possible method is to replace the lids with a double layer of paper towel which is misted daily—although I would think that not having an actual lid on the jar would invite contamination. To harvest an individual mushroom, wash your hands well—I use rubbing alcohol, too. You may need to use a pair of sterilized tweezers to do this, which is what I do—I avoid placing germy hands inside the jars. If it is too difficult to harvest them using those methods, you can clean you hands, wash a small knife (preferably with anti-bacterial soap), dip the blade in alcohol, flame it for several seconds, then use the tip of the sterilized knife to cut the mushroom as close to the rice cake as possible. The blue staining that is common in psychedelic mushrooms is evidence of oxidation—meaning that the active ingredients (psilocin and psilocybin) are being oxidized, too—rendering the ‘shrooms inactive. While refrigeration is recommended, freezing fresh mushrooms should be avoided, since the expansion of the freezing water in the cells ruptures the cell walls and thus opens them up for oxidation. Mushrooms that were frozen while fresh may be an attractive blue color, but they are inactive.... Storage of fresh mushrooms should be in a breathable container such as a paper bag stored in a refrigerator, avoid putting fresh ‘shrooms in a ziploc bag, as they may become slimy or moldy—ugh! One way to dry them is by placing them on a cookie sheet in an oven on the lowest temp. My main problem with dried shrooms is that in my experience they are not any-where near as potent as fresh ‘shrooms. I believe the reason for this is that the two psychoactive ingredients (psilocin and psilocybin) are present in equal amounts in fresh shrooms. My current favorite method is to blend 3-4 fresh ones in a blender with orange juice—the effects are fantastic and the taste is tolerable. I believe this is due in part to the fact that the shrooms are almost completely liquified by the blending process, releasing the “good stuff” into the orange juice and making it more readily absorbed by the stomach. Remember though, that dairy products may delay/block the absorption of certain substances. Another method of ingestion is to boil the shrooms, fresh or dried (or a rice cake) in a couple cups of water for about 5 minutes (until they have sunk), and then either add a tea bag for hot tea, or make Kool-Aid with the cooled water (straining out the shrooms, of course). Sprinkling fresh or dried shrooms (chopped) onto pizza, or into spaghetti sauce is another treat—fun for a “shroom party”. Since psilocin and psilocybin are soluble in both water and alcohol, soaking shrooms in any liquor will release these active ingredients into the liquor, making for a powerfully intoxicating liquor mix. I should mention again that once shroom production has really tapered off (and you’ll be able to tell) after 2 - 3 months, the rice cake can be eaten/used, if you closely examine it and decide that there is no green or black mold contaminant present. I should note that the rice cake will probably be all kinds of funky colors—a mix of white, steel blue, gray, maybe even purple in places from spores falling on it! A single rice cake is enough for 2 - 4 people to trip on, although 2 is probably the better figure. Some of my best trips were on half a rice cake chopped up and cooked in an omelete! That’s what I love about the rice-cake method—when the shrooms stop growing there’s no waste! Speaking of no waste, if I ever had a rice cake that I didn’t want to risk eating I might use it to innoculate a compost pile or a pasture full of cow shit by inserting a small piece into each cow-pie or into the compost pile.
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