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In developing countries discount clonidine 0.1 mg amex blood pressure 2, hundreds order genuine clonidine line prehypertension a literature-documented public health concern, sometimes thou- sands 0.1mg clonidine for sale blood pressure scale, of frms control tiny shares of the same generic clonidine 0.1mg on line arrhythmia guidelines. These vendors handle a wide variety of products sold in an even wider variety of packaging. Retailers in developed countries would fnd it logistically impossible to buy their stock, in its many different packages, directly from manufacturers (Yadav et al. The drug distribution system in low- and middle-income countries has the same basic steps as that described in Figure 5-1, but with more intermediaries between the manufacturer and patient (Yadav and Smith, 2012). Instead of having one coordinated distribution chain that reaches the whole country, there are many small chains and many small companies at every step (Yadav and Smith, 2012). Figure 5-2 describes the drug fow for public, private, and nongovernmental organizations, and their separate, but sometimes overlapping, intermediaries. A comparison of Figures 5-1 and 5-2 and Table 5-1 illustrate some important differences in drug distribution in developing and developed countries. For example, a few large frms generally control the national wholesale market in developed countries. Cardinal Health, McKesson, and AmerisourceBergen distribute 90 percent of drugs sold in the United States; four or fve major frms distribute to 90 percent of the market in West- ern Europe and Japan (Yadav and Smith, 2012). In developing countries, hundreds, even thousands, of companies control tiny shares of the drug wholesale market (Yadav and Smith, 2012). Excessive fragmentation is an important difference between developed and developing countries’ drug distribution systems. In developed countries, comparatively few large frms control the market and regulatory authorities require some chain of custody documentation. Sometimes multiple par- allel distribution systems of varying effciency run in the same country. Countering the Problem of Falsified and Substandard Drugs 199 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 200 Copyright © National Academy of Sciences. Regulatory Strong, well-defned laws and Weak fragmented regulatory structure overall good ability to enforce structures, ill-defned laws regulations. Prescription Prescription drugs can only Retail drug shops often adherence be dispensed with a formal dispense medicines and also prescription. Balance of power Buyer (insurance companies or Balance of power is tilted in the system national health system) monopoly toward the manufacturer creates good balance of power and the distribution channel. In the United States, purchase with out-of-pocket pharmacy beneft managers and funds and have little bargaining drug formularies are commonly power. Box 5-1 describes the confusing drug distribution systems often found in humanitarian emergencies. In sub-Saharan Africa, a government-owned-and-operated central medical store manages the distri- bution of drugs, transporting goods around the country in a government- owned feet. Donors and developing-country governments favor this system, wherein the central store manager can neither hire people with business experience nor fre incompetent workers (Yadav, 2010). Ineffcient supply chain management directly drives up costs and causes drug stock-outs in Copyright © National Academy of Sciences. Despite its many stops along the way, only at one of the fnal destinations did a volunteer doctor notice fungal spores contaminating the product (Caudron et al. The infusions had been distributed so widely and haphazardly that, despite a product recall, only 15 per- cent were ever collected (Caudron et al. Such problems are not uncommon during emergencies, when quality control throughout long supply chains becomes difcult. The dangers of poorly regulated drugs lead some bodies, such as the European Commission’s Directorate-General for Humanitarian Aid, to stipulate that quality-assurance guidelines not be relaxed during emer- gencies, even though quality-assurance steps can slow down response (Pomatto and Schuftan, 2006). After the tsunami in Sri Lanka, only 50 percent of the drugs donated had expiration dates on them; of that half, 5 percent had already expired or would expire within days; 62 percent of the medication labels were not in English, the language of the Sri Lankan health system (Mahmood et al. Such inappropriate drug donations cause serious problems because disposing of such drugs, especially in large quantities, is a lengthy and expensive project (Pomatto and Schuftan, 2006). After the 2000 foods in Venezuela, 70 percent of the drugs donated for humani- tarian assistance needed to be destroyed, requiring the government to pay $16,000 to cover the extra personnel needed to sort the donations (Hechmann and Dune-Birouste, 2007). During emergencies, little about patients, their diagnoses, or medi- cal history is collected at most health facilities. Drug quality signals can be difcult to spot when infrastructure is disrupted: Patients are seen quickly and only minimal information is recorded. The World Health Organization published its “Guidelines for Drug Donations” in 1996 after particularly problematic donations during the Bosnian War (Berckmans et al. At times the guidelines are followed closely; for example, humani- tarian emergencies in East Timor and Gujarat State saw few inappropri- ate donations (van Dijk et al. As Chapter 4 explained, this drug scarcity in turn creates a vacuum for poor-quality products to fll. Of course, donor demands alone do not drive the costs of supply chain management in developing countries. In India, for example, nearly 70 percent of the population lives in rural areas, where the health posts may be few and lacking in staff, electricity, and supplies (Langer and Kelkar, 2008). The costs of drug distribution in India are two to three times greater than in the United States or the European Union, despite vastly lower labor costs (Langer and Kelkar, 2008). Supply chain managers are always concerned with the last-mile problem: the disproportionately expensive and ineffcient fnal leg on the distribution chain. Managing the drug distribution system in developing countries means containing the costs of the last mile, moving medicines to patients quickly, and keeping records of all transactions between the manufacturer and the consumer. Around the world, drug wholesale is a common point of vulnerability to falsifed and substandard medicines. In some countries, including the United States, there are also large regional wholesalers (Fein, 2012; White and Bothma, 2009). They often serve independent pharmacies or hospitals and may have strong distribution networks (Levy, 2006). As Figure 5-1 suggests, the distinction between the primary and second- ary wholesalers is not always clear. Primary wholesalers may, for example, buy products from secondary wholesalers as well as manufacturers (Ziance, 2008). The back-and-forth sales are common among drug wholesalers, who buy and sell medicines to accommodate market demand. That is, when they see a medicine is scarce in one region, they can buy the same medicine from other wholesalers that may be fush with it. Sometimes secondary wholesalers fll a void; they supply to rural phar- macies or markets that national or regional wholesalers do not reach. But they choose stock based on demand forecasts, price, margin, and their customers’ willingness to pay (Yadav, 2009). There are three major national wholesalers, a few regional wholesalers, and thousands of secondary wholesalers.
Thus order clonidine now arrhythmia of heart, 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 order clonidine 0.1 mg on line blood pressure medication classes, equipment order clonidine cheap blood pressure medication diabetes, and processes deemed high company’s stakeholders of the ability to deliver the risk and minimal resources towards those deemed low risk order clonidine once a day blood pressure lower number. 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. Hovione’s comprehensive approach provides multiple particle engineering technologies to address your speciﬁc development needs. Our experienced team of scientists and engineers applies state-of-the-art principles and tools to improve bioavailability. With a proven track record of commercialization, Hovione will drive your molecule from early clinical to market. To learn more about how Hovione can overcome the solubility issues that stand in the way of your success, visit hovione. These tests can be performed to collect information for Inno vative Solutions product and process understanding, or to allow for tighter control (i. If the tox batch is also intended to be used in a clinical study, Coupons there is an advantage in that the qualification of impurities for the clinical studies is inherently assured. As development progresses towards commercialization, specifications may be introduced. Internal testing may have target acceptance criteria tighter than the release testing criteria. Description, or appearance, is a test describing the analytical methods is assessed. The recommended early phase acceptance criteria is often a recommended range is 97. This testing ensures that the drug being dosed is potency factor that takes into account related substances, residual traceable to the same chemical entity that was qualified in the solvents, moisture, counterion, and inorganic impurities present. In early phase development, there is limited exposure to the ous impurity scenarios to illustrate the utilization of the proposed clinical candidate and low numbers of individuals participate in early clinical identification and qualification thresholds and their these early clinical studies.
The models shown in Figure 1-31 both well represent actual plasma concentrations of a drug after a dose purchase generic clonidine pills heart attack movie review. Would you expect that a large drug molecule that does not cross physiologic membranes very well and is not lipid soluble to have a relatively high or low volume of distribution? When plotting plasma drug concentration (y-axis) versus time (x-axis) purchase clonidine with american express arrhythmia recognition posters, what are the advantages of using a natural log scale for the y-axis rather than a linear scale? Identify the components of body fluids that make up extracellular and intracellular fluids and know the percentage of each component buy clonidine with a mastercard blood pressure vitals. Describe the difference between first- and zero-order elimination and how each appear graphically order clonidine 0.1mg fast delivery blood pressure for infants. We assumed that no drug was being removed from the tank while we were determining volume. In reality, drug concentration in the body is constantly changing, primarily due to elimination. This flux makes it more difficult to calculate the apparent volume in which a drug distributes. One way to calculate the apparent volume of drug distribution in the body is to measure the plasma concentration immediately after intravenous administration before elimination has had a significant effect. The concentration just after intravenous administration (at time zero, t0) is abbreviated as C0 (Figure 2-1). The volume of distribution can be calculated using the equation: (See Equation 1-1. If two concentrations have been determined, a line containing the two values and extending through the y-axis can be drawn on semilog paper. Both the direct measurement and back-extrapolation approaches assume that the drug distributes instantaneously into a single homogeneous compartment. The volume of distribution is an important parameter for determining proper drug dosing regimens. Often referred to as the apparent volume of distribution, it does not have an exact physiologic significance, but it can indicate the extent of drug distribution and aid in determination of dosage requirements. For example: the larger the volume of distribution, the larger a dose must be to achieve a desired target concentration. To understand how distribution occurs, you must have a basic understanding of body fluids and tissues (Figure 2-2). The fluid portion (water) in an adult makes up approximately 60% of total body weight and is composed of intracellular fluid (35%) and extracellular fluid (25%). If a drug has a volume of distribution of approximately 15-18 L in a 70-kg person, we might assume that its distribution is limited to extracellular fluid, as that is the approximate volume of extracellular fluid in the body. If a drug has a volume of distribution of about 40 L, the drug may be distributing into all body water, because a 70-kg person has approximately 40 L of body water (70 kg × 60%). If the volume of distribution is much greater than 40-50 L, the drug probably is being concentrated in tissue outside the plasma and interstitial fluid. If a drug distributes extensively into tissues, the volume of distribution calculated from plasma concentrations could be much higher than the actual physiologic volume in which it distributes. For example, by measuring plasma concentrations, it appears that digoxin distributes in approximately 440 L in an adult. Because digoxin binds extensively to muscle tissue, plasma levels are fairly low relative to concentrations in muscle tissue. For other drugs, tissue concentrations may not be as high as the plasma concentration, so it may appear that these drugs distribute into a relatively small volume. Blood refers to the fluid portion in combination with formed elements (white cells, red cells, and platelets). Plasma refers only to the fluid portion of blood (including soluble proteins but not formed elements). When the soluble protein fibrinogen is removed from plasma, the remaining product is serum (Figure 2-3). These differences in biologic fluids must be recognized when considering reported drug concentrations. The plasma concentration of a drug may be much less than the whole blood concentration if the drug is preferentially sequestered by red blood cells. Clinical Correlate Most drug concentrations are measured using plasma or serum that usually generate similar values. It is more relevant to use plasma or serum than whole blood measurements to estimate drug concentrations at the site of effect. However, some drugs such as antimalarials are extensively taken up by red blood cells. In these situations, whole blood concentrations would be more relevant, although they are not commonly used in clinical practice. Concentration resulting immediately after an intravenous injection of a drug is referred to as C0. Plasma drug concentrations are affected by the rate at which drug is administered, the volume in which it distributes, and its clearance. Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body). It indicates the volume of plasma (or blood) from which the drug is completely removed, or cleared, in a given time period. In Figure 2-4, the amount of drug (the number of dots) decreases but fills the same volume, resulting in a lower concentration. Another way of viewing the same decrease would be to calculate the volume that would be drug-free if the concentration were held constant. Drugs can be cleared from the body by many different mechanisms, pathways, or organs, including hepatic biotransformation and renal and biliary excretion. Total body clearance of a drug is the sum of all the clearances by various mechanisms. For an agent removed primarily by the kidneys, renal clearance (Clr) makes up most of the total body clearance. For a drug primarily metabolized by the liver, hepatic clearance (Clm) is most important. A good way to understand clearance is to consider a single well-perfused organ that eliminates drug. Blood flow through the organ is referred to as Q (mL/minute) as seen in Figure 2-6, where Cin is the drug concentration in the blood entering the organ and Cout is the drug concentration in the exiting blood. Organs that are very efficient at eliminating a drug will have an extraction ratio approaching one (i. The drug clearance of any organ is determined by blood flow and the extraction ratio: organ clearance = blood flow × extraction ratio or: 2-2 If an organ is very efficient in removing drug (i. The equations noted previously are not used routinely in clinical drug monitoring, but they describe the concept of drug clearance. Examination of a single well-perfused organ to understand clearance is a noncompartmental approach; no assumptions about the number of compartments have to be made.