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Appendix A Glossary Active pharmaceutical ingredient (API): Any substance or mixture of sub- stances that is part of a drug (medicinal) product, intended to furnish phar- macological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure and function of the body. Adulteration: The alteration of a product by deliberately adding something not ordinarily a part of it. Adverse drug reaction: A harmful result of drug therapy that is neither intended nor expected in normal therapeutic use. Anthelmintic resistance: The ability of worms to survive treatment at the generally effective recommended dose. Antibiotic: A drug that fights bacterial infections. Anti-Counterfeiting Trade Agreement (ACTA): An initiative signed on Oc- tober 1, 2011, by key trading partners to strengthen the international legal framework for effectively combating global proliferation of commercial- scale counterfeiting and piracy. It calls for strong legal frameworks and innovative provisions to deepen international cooperation and to promote strong intellectual property rights enforcement practices. 309

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310 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Anti-infective: A substance that aids the immune system by inhibiting infec- tive microorganisms by destroying their cell wall, slowing their growth, or interfering with DNA synthesis. Antimalarial: Drugs designed to prevent or cure malaria. Antimicrobial: A substance that kills or inhibits the growth of microorganisms. Antimicrobial resistance: The ability of microorganisms that cause disease to withstand attack by antimicrobial medicines. Antiparasitics: A class of medications that treat parasitic diseases. Antiretroviral drugs: Drugs used to treat people infected with the human immunodeficiency virus. Artemisinin: A drug used to treat malaria derived from the Artemisia An- nua plant family. It and its derivatives are a group of drugs that possess the most rapid action against the disease. Artemisinin-based combination therapy: A combination of artemisinin or one of its derivatives with an antimalarial drug or drugs of a different class. Artesunate: An artemisinin-derived drug used in the treatment of malaria. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spec- troscopy: A well-established, nondestructive method for determining the chemical composition of materials based on their chemical bonding. Beta-lactam antibiotics: A broad class of antibiotics, consisting of all antibi- otic agents that contain a beta-lactam nucleus in their molecular structure. This includes penicillin derivatives, cephalosporins, monobactams, and carbapenems. Most beta-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Bioavailability: Bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the sys- temic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavail- ability is 100 percent. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of

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APPENDIX A 311 the essential tools in pharmacokinetics, as bioavailability must be consid- ered when calculating dosages for nonintravenous routes of administration. Bioequivalent: The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equiva- lents becomes available at the site of drug action, when administered at the same molar dose under similar conditions in an appropriately designed study. Black market: A market of goods or services that operates outside the for- mal market, not supported by an established state power. Blister packet: Perforated packaging used for drugs and other consumer products. Blockbuster drugs: Popular drugs that generate at least $1 billion in annual sales for the company that creates them. British Pharmacopoeia: Established in 1864, the British Pharmacopoeia provides authoritative official standards for pharmaceutical substances and medicinal products in the United Kingdom and many other countries that have adopted it. Bulk property: A property that does not depend on the size or amount of a sample. For example, density is a bulk property because it does not depend on the amount of substance tested. A bulk property may also be called an intensive property. Central medical store: Primarily found in developing countries, it is the Ministry of Health’s procurement arm and national medical store. Central medical stores are generally responsible for the procurement, quality assur- ance, storage and distribution of drugs, vaccines, disinfectants, dressings, and related medical supplies for government health facilities and some nongovernment organizations. Chain of custody: A document intended to guarantee the integrity of a drug product along the distribution chain. Chromatography: A method for separating a mixture into its constituent substances. The separation is based on differential partitioning between a mobile and stationary phase. Subtle differences in a compound’s partition- ing result in differential retention on the stationary phase, thus effecting

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312 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS the separation. This method is used to separate mixtures such as drugs for accurate and precise analysis. Civil liability: The potential responsibility for payment of damages or other court enforcement in a lawsuit. Colorimetry: The experimental measurement of the amount of color pro- duced by a colorimetric reagent and a sample. Compounding: The creation of a particular pharmaceutical produce to fit the unique needs to a patient. To do this, compounding pharmacists combine or process appropriate ingredient using various tools. This may be done for medically necessary reasons, such as to change the form of the medication from a solid pill to a liquid, to avoid a nonessential ingredi- ent that the patient is allergic to, or to obtain the exact dose(s) needed of particular active pharmaceutical ingredient(s). It may also be done for more optional reasons, such as adding flavors to a medication or otherwise altering taste or texture. Compulsory license: Also known as statutory license of mandatory collec- tive management, provides that the owner of a patent or copyright licenses the use of their rights against payment either set by law or determined through some form of arbitration. In essence, under a compulsory license, an individual or company seeking to use another’s intellectual property can do so without seeking the rights holder’s consent, and pays the rights holder a set fee for the license. The principal requirement for the issues of a compulsory license under TRIPS is that attempts to obtain a license under reasonable commercial terms must have failed over a reasonable period of time. TRIPS also provides that the requirements for a compulsory license may be waived in certain situations, in particular cases of national emer- gency or extreme urgency or in cases of public noncommercial use. Contract manufacturing: The manufacturing of a product by an organiza- tion or company other than the marketing company. Convenience sample: A type of nonprobability sampling which involves the sample being drawn from the part of the population that is close to hand. That is, a sample population selected because it is readily available and convenient. The researcher using such a sample cannot scientifically make generalizations about the total population from this sample because it would not be fully representative.

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APPENDIX A 313 Counterfeit: A drug that bears an unauthorized representation of a reg- istered trademark on a product identical or similar to one for which the trademark is registered. Crude active ingredients: Chemicals that have not undergone the appropri- ate purification steps required to meet pharmacopeial standards or manu- facturer’s dossier requirements. Degraded: The deterioration of an active pharmaceutical ingredient in a drug. It can be a result of high temperatures exceeding label requirements, resulting in decreased potency and efficacy. Density: The ratio of an object’s mass to its volume. Developing country: A nation with a low living standard, undeveloped in- dustrial base, and low human development index relative to other countries. Development bank: A national or regional financial institution designed to provide medium- and long-term capital for productive investment, often accompanied by technical assistance in developing countries. Diffusion-ordered proton nuclear magnetic resonance spectroscopy: A type of nuclear magnetic resonance spectroscopy that can identify the various types of ingredients in a mixture by taking advantage of differences in mo- lecular mass. It separates the nuclear magnetic resonance signals of different components according to their diffusion coefficient. Direct ionization: The impulses alpha and beta particles apply to orbital electrons to ionize, or completely remove an electron from an atom follow- ing the transfer of energy from a passing charged particle. Specific ioniza- tion, the number of ion pairs formed per unit path length for a given type of radiation, is a measure of the intensity of ionization. Because of their double charge and relatively slow velocity, alpha particles have a high spe- cific ionization and a relatively short range in matter (a few centimeters in air and only fractions of a millimeter in tissue). Beta particles have a much lower specific ionization than alpha particles and, generally, a greater range. Direct-to-pharmacy: A supply chain model where manufacturers sell di- rectly to pharmacies. Directly Observed Treatment–Short Course (DOTS): The internationally recommended strategy for tuberculosis control. It is a standardized treat-

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314 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS ment regimen directly observed by health care or community workers. It has been recognized as a highly efficient and cost-effective strategy to control the disease. Disintegration: The process of breaking up a solid dosage form in water or simulated gastric solution. Dispensary: A place where medicine or medical or dental treatment is dispensed. Dissolution: The process by which a substance is dissolved. Distribution chain: A series of businesses or organizations involved in trans- porting, storing, and selling goods from the manufacturer to consumers. Diversion: The unlawful channeling of products from a legitimate, parallel marketed, subsidized supply chain into other, unsubsidized markets. Doha Declaration: A declaration adapted by World Trade Organization members in 2001. It affirms the right of all countries to protect public health and enhance access to medicines for poor countries. Drug: A substance used as a medication or in the preparation of medication. Drug pedigree: A statement of origin that identifies each prior sale, pur- chase, or trade of a drug, including the date of those transactions and the names and addresses of all parties to them. Drug potency: The extent to which a drug product contains the specified amount of active ingredient. Drug resistance: The reduction in effectiveness of a drug in curing a disease or condition due to mutations in the target organism. Economies of scale: Factors that cause the average cost of production to fall as the volume of output increases. Efficacy: The ability of a drug to produce the desired therapeutic effect. Electromagnetic spectrum: The entire range of wavelengths or frequencies of electromagnetic radiation extending from gamma rays to the longest radio waves, including visible light.

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APPENDIX A 315 Electronic product code: A radio frequency identification code, attached to a product, that contains a wide range of information unique to that item and may include the manufacturer, stock-keeping unit, product informa- tion, and batch number. This allows tracking a particular item throughout all stages of the supply chain. Electrospray ionization-mass spectrometry (ESI-MS): An ionization tech- nique that uses electrical energy to assist the transfer of ions from solution into the gaseous phase before they are subjected to mass spectrometric analysis. This technique is used to ionize small amounts of large or labile molecules such as peptides, proteins, organometallics, and polymers. The multiply charged ions then enter the analyzer. The most obvious feature of an ESI spectrum is that the ions carry multiple charges. This characteristic reduces their mass-to-charge ratio compared to a singly charged species and facilitates obtaining mass spectra for large molecules. E-pedigree: An electronic record that documents a drug’s pedigree. Epidemiologic transition: A theory that focuses on the complex change in patterns of health and disease and on the interactions between these patterns and their demographic, economic and sociologic determinants and consequences. The transition portion of the theory is concerned with changes in population growth trajectories and composition, especially in the age distribution from younger to older. It also takes into account the changes in patterns of mortality, including increasing life expectancy and reordering of the relative importance of different causes of death. Excipient: A pharmacologically inactive substance used along with the ac- tive pharmaceutical ingredients in the formulation of a medication. Expert review panel: A panel of independent experts, who review the po- tential risks and benefits associated with the use of finished pharmaceutical products or diagnostic products. The panel makes recommendations as to whether the products may be procured. Fake: Widely used as a synonym for falsified in this report and by other scholars. Falsified: A drug that falsely represents a product’s identity or source or both.

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316 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Finished product: A finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture, including packaging in its final container and labeling. Forensic chemistry: A field of chemistry focused on analyzing substances in support of law enforcement. Formal market: An official market, as recognized by a government. Formulary: A list of medications approved under a particular insurance policy. A national formulary contains a lists of medicines that are approved for prescription throughout the country, indicating which products are in- terchangeable. It includes key information on the composition, description, selection, prescribing, dispensing, and administration of medicines. Those drugs considered less suitable for prescribing are clearly identified. Formulation: A mixture of substances prepared according to a specific for- mula; included in a capsule, a pill, a tablet, or an emulsion. Fraudulent: A product claiming particular qualities with intent to deceive. Friability: A measure of the ability of a solid substance to be reduced to smaller pieces with tumbling. Fourier-transform infrared spectrometry: A measurement technique whereby infrared spectra are collected based on nondispersive spectral measurements. As with all other infrared spectral measurements, this technique can identify unknown materials, determine the quality or consistency of a sample, and determine the amount of components in a mixture. Gas chromatography: A common type of chromatography used in ana- lytical chemistry for separating and analyzing compounds that can be vaporized without decomposition. It is typically used to test the purity of a particular substance or separate different components of a mixture. In some situations, gas chromatography may help identify a compound. Gas chromatography-mass spectrometer (GC-MS): A tool used for the iden- tification and quantitation of volatile and semi-volatile organic compounds in mixtures. The GC-MS consists of two parts: the gas chromatograph and the mass spectrometer. The gas chromatograph separates the molecules in the sample, allowing some of them to pass into the mass spectrometer more rapidly than others. When the molecules move into the mass spectrometer, they are ionized into fragments and each molecule is identified based on

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APPENDIX A 317 mass and charge. The GC-MS spectrometer helps separate and determine the individual elements and molecules in a sample. It is used for the quan- titation of drugs and provides forensic investigators the ability to identify individual substances that may be found within a very small test sample. Good manufacturing practices: A system for ensuring that products are consistently produced and controlled according to quality standards. It is designed to minimize the risks involved in any pharmaceutical production that cannot be eliminated through testing the final product. Gray market: A supply channel that is unofficial, unauthorized, or unin- tended by the original manufacturer. Hard currency: A globally traded currency that is expected to serve as a reliable and stable store of value. Herd immunity: A situation in which a sufficient proportion of a population is immune to an infectious disease (through vaccination or prior illness) to make its spread from person to person unlikely. Even individuals not vaccinated (such as newborns and those with chronic illnesses) are offered some protection because the disease has little opportunity to spread within the community. High-performance liquid chromatography (HPLC): A technique used to separate a mixture of compounds to identify, quantify, and purify the indi- vidual components of the mixture. This technique relies on pumps to pass a pressurized liquid and a sample mixture through a column filled with a sorbent, leading to the separation of the sample components. The active component of the column, the stationary sorbent, is typically a granular material made of solid particles, 2-50 micrometers in size, which may be coated. The components of the sample mixture are separated from each other due to partitioning differences with the sorbent particles. The pres- surized liquid is typically a mixture of solvents (e.g., water, acetonitrile, or methanol) and is referred to as the mobile phase. Its composition and temperature play a major role in the separation process by influencing the partitioning between sample components and stationary sorbent. HPLC is one of the most powerful tools in analytical chemistry. Depending on the detection system and stationary phase used, it has the ability to separate, identify, and quantitate compounds present in any sample that can be dis- solved in a liquid. Compounds in trace concentrations as low as parts per trillion can be separated and with appropriate detectors may be identified using this technique. HPLC can be, and has been, applied to numerous

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318 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS samples such as pharmaceuticals, food, nutraceuticals, cosmetics, environ- mental matrices, forensic samples, and industrial chemicals. Illegal: Not authorized by law. Illegitimate: Illegal drugs not in accordance with accepted standards. Used in this report and by some scholars as a parent category for falsified and substandard drugs. Information asymmetry: Condition in which at least some relevant infor- mation is known to some but not all parties in a transaction. Information asymmetry causes markets to become inefficient, since all the market par- ticipants do not have access to the information they need for their decision making processes. Infrared spectroscopy: The spectroscopy that deals with the infrared region of the electromagnetic spectrum, that is, light with a longer wavelength and lower frequency than visible light. It covers a range of techniques, mostly based on absorption spectroscopy. As with all spectroscopic techniques, it can be used to identify and study chemicals. A common laboratory in- strument that uses this technique is a Fourier transform infrared (FTIR) spectrometer. Infrastructure: The basic physical and organizational structures needed or the operation of a society or enterprise, or the services and facilities neces- sary for an economy to function. It can be generally defined as the set of interconnected structural elements that provide the framework supporting an entire structure of development. It is an important term for judging a country or region’s development. The term typically refers to the technical structures that support a society, such as roads, bridges, water supply, sew- ers, electrical grids, telecommunications, and so forth. Innovator drug: Generally the pharmaceutical product that was first au- thorized for marketing (normally as a patented product) on the basis of documentation of efficacy, safety, and quality according to requirements at the time of the authorization. Intellectual property: The ownership of creations of the mind. It includes inventions, literary and artistic works, symbols, names, images, and designs used in commerce. Intermediaries: The parties involved in the distribution of pharmaceuticals. They include distributers, stockists, and retailers.

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APPENDIX A 319 International nonproprietary name:  The official nonproprietary or generic name given to a pharmaceutical substance, as designated by WHO. International pharmacopoeia: A pharmacopoeia published by the WHO, established in collaboration with members of the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Prepara- tions and with other specialists, intended to serve as source material for reference or adaptation by any WHO Member State wishing to establish pharmaceutical requirements. Lifestyle drug: A term commonly applied to medications that treat non-life- threatening and nonpainful conditions such as baldness, impotence, wrin- kles, erectile dysfunction, or acne, which the speaker perceives as either not medical problems at all or as minor medical conditions relative to others. Linear barcode: One-dimensional barcodes made up of lines and spaces of various widths, creating specific patterns. These patterns represent stock- keeping unit numbers and batch numbers, which can be easily and quickly read by computer scanners. Low- and middle-income countries: Countries with a gross national income per capita of less than $12,475. Manufacturing dossier: An entire collection of records and documents that a manufacturer holds for a particular product, which is generally submit- ted to a regulatory authority as part of a marketing authorization request. Marginal cost: The change in total cost that arises when the quantity pro- duced changes by one unit. Market authorization: An official document issued by the competent drug regulatory authority for the purpose of marketing or free distribution of a product after a satisfactory evaluation for safety, efficacy, and quality. Mass spectrometer: An instrument used to measure the precise masses and relative amounts of atomic and molecular ions. In order to measure the characteristics of individual molecules, a mass spectrometer converts them to ions so that they can move and be manipulated by external electric and magnetic fields. The molecules of interest are first introduced into the ionization source of the mass spectrometer, where they are first ionized to acquire positive or negative charges. The ions then travel through the mass analyzer and arrive at different parts of the detector according to their mass-to-charge ratio. After the ions make contact with the detector, usable

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320 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS signals are generated and recorded by a computer system. The computer displays the signals graphically as a mass spectrum showing the relative abundance of the signals according to their mass-to-charge ratio. Mass spectrometry: An analytical technique that measures the mass-to- charge ratio of charged particles. It can provide both qualitative (structure) and quantitative (molecular mass or concentration) information on analyte molecules after their conversion to ions. This technique is used for deter- mining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of mol- ecules, such as peptides and other chemical compounds. Medicine: A substance or preparation used in treating a disease. Medicines registration: A system that subjects all pharmaceutical products to premarketing evaluation, marketing authorization, and postmarketing review to ensure that they conform to required standards or quality, safety, and efficacy established by national authorities. The outcome of the medi- cines registration process is the issuance or the denial of a pharmaceutical product marketing authorization or license. Medicrime Convention: The first international treaty established by the Council of Europe against counterfeit medical products and similar crimes involving threats to public health. The Convention makes it an offense to manufacture counterfeit medical products; supply, offer to supply, and traffic counterfeit medical products; falsify documents; manufacture or sup- ply medicinal products without proper authorization; and market medical devices that do not comply with conformity requirements. Microfluidics: The science and technology of systems that process or ma- nipulate small amounts of fluids, using channels with dimensions of tens to hundreds of micrometers. Microscopy: The technical field of using microscopes to examine samples and objects that cannot be seen with the unaided eye. Monograph: A written set of assessment methods and standards that are used to define an acceptable or compliant article (e.g., drug substance, drug product, excipient, or food chemical). Monographs are used to help control the quality of pharmaceutical, dietary supplement, and food ingredient products.

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APPENDIX A 321 Near-infrared reflectance spectroscopy: An analytical technique used for chemical analyses. It may be used to identify or quantify organic com- pounds by measuring the absorption of near infrared light by chemical bonds in organic materials. Nonprobability sample: Also called a nonrandom sample, wherein the se- lected units have an unknown probability of being selected. Nonprobability samples cannot be used to infer from the sample to the general population. Any generalizations obtained from a nonprobability sample must be filtered through one’s knowledge of the topic being studied. Nosocomial infections: An infection whose development is favored by a hospital environment, such as one acquired by a patient during a hospital visit or one developing among hospital staff. Such infections include fungal and bacterial infections and are aggravated by the reduced resistance of individual patients. Nuclear magnetic resonance (NMR) spectroscopy: A technique that uses radiofrequency radiation to induce transitions between different nuclear spin states of samples in a magnetic field. NMR spectroscopy can be used for quantitative measurements, but it is most useful for determining a com- pound’s unique structure and identifying the carbon-hydrogen framework of an organic compound. OECD countries: Thirty-four countries that signed the Convention on the Organisation for Economic Co-operation and Development. They are Australia, Austria, Belgium, Canada, Chile, Czech Republic, Denmark, Es- tonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Japan, Korea, Luxembourg, Mexico, the Netherlands, New Zealand, Norway, Poland, Portugal, Slovak Republic, Slovenia, Spain, Sweden, Swit- zerland, Turkey, the United Kingdom, and the United States. Opportunity cost: The cost of an action measured in terms of the value of the next best alternative action. For example, if capital is used for one pur- pose, the opportunity cost is the value of the next best purpose the capital could have been invested in. Osmolarity: The number of osmoles or particles of solute per liter of solution. Parallel importation: The importation of a product without the permission of the intellectual property owner. Parallel imports are imports of a pat- ented or trademarked product from a country where it is already marketed.

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322 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Patent: A set of exclusive rights granted to an inventor or assignee for a limited period of time in exchange for the public disclosure of the invention. Patent infringement: A violation of the rights secured by a patent. Pathogen: A bacterium, virus, or other microorganism that can cause disease. pH: The degree of acidity in a solvent. Pharmaceutical: A drug with medicinal property. Pharmaceutical crime: Involves the manufacture, trade and distribution of fake, stolen or illicit medicines and medical devices. It encompasses the counterfeiting and falsification of medical products and their packaging and associated documentation, as well as theft, fraud, illicit diversion, smuggling, trafficking, the illegal trade of medical products, and the money laundering associated with it. Pharmacist: A person who is licensed to prepare, sell, dispense drugs and compounds, and write prescriptions. They are also referred to as chemists or druggists. Pharmacopeia: A compilation of monographs that define quality assessment and requirements for acceptable products and the preparation of compound medicines. Compliance with it generally is mandated by the laws of a sover- eign state, and it is published by the authority of a government or a medical or pharmaceutical society. Pharmacovigilance: The science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. Postmarket surveillance: The process by which a drug’s safety and quality is monitored on an ongoing basis after it is approved. Price elasticity: The responsiveness, or elasticity, of the quantity demanded of a good or service to a change in its price. Primary packaging: Packaging in direct contact with the product, intended to protect one or more items and, if needed, to keep it sterile until use.

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APPENDIX A 323 Procurement: The process of purchasing or otherwise acquiring any phar- maceutical product, vaccine, or nutraceutical for human use. Procurement agency: Any organization purchasing or otherwise acquiring any pharmaceutical product, vaccine, or nutraceutical for human use. Quality: The suitability of either an active pharmaceutical ingredient or a pharmaceutical product for its intended use. This term includes such at- tributes as identity, strength, and purity. Quality assurance: A wide-ranging concept covering all matters that indi- vidually or collectively influence the quality of a product. With regard to pharmaceuticals, quality assurance can be divided into five major areas: development, quality control, production, distribution, and storage. Quality control: The sampling, specification, testing, organization, docu- mentation, and release procedures that ensure the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality-control laboratory: A laboratory capable of testing product quality. Radio frequency identification (RFID): A wireless non-contact system that uses radio frequency electromagnetic fields to transfer data from a tag attached to an object, for the purposes of automatic identification and tracking. Raman spectroscopy: A technique used to observe vibrational, rotational, and other low-frequency modes in a system. It relies on inelastic scattering of monochromatic light, usually from a laser in the visible, near infrared, or near ultraviolet range. The laser light interacts with molecular vibrations, phonons or other excitations in the system, resulting in the energy of the laser photons being shifted up or down. The shift in energy gives informa- tion about the vibrational modes in the system. Reflectance: The measure of the proportion of light or other radiation strik- ing a surface that is reflected off it. Reflectance spectroscopy: A spectroscopic technique that measures the un- absorbed portion of a beam of light that is shone on the surface of a mate- rial, such as a drug product. Reflectance spectroscopy is used for samples that are difficult or inconvenient to analyze by transmission techniques. The

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324 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS samples can usually be analyzed as is without the need for preparation or modification, but the radiation absorbed is generally limited to the surface or a very limited depth of the sample. Refractive index: The measurement of the bending of a ray of light as it passes from one medium into another. Salting: The process by which legitimate and fake drugs are mixed at wholesale. Sampling frame: A list or other device used to define a researcher’s popula- tion of interest. It defines a set of elements from which a researcher can select a sample of the target population. Secondary ion mass spectrometry (SIMS): A technique used in materials science and surface science to analyze the composition of solid surfaces and thin films. This technique sputters the surface of a specimen with a focused primary ion beam and collects and analyzes ejected secondary ions. The mass-to-charge ratios of these secondary ions are measured with a mass spectrometer to determine the elemental, isotopic, or molecular composi- tion of the surface. Due to the large variation in ionization probabilities among different materials, SIMS is generally considered to be a qualitative technique, although quantitation is possible with the use of standards. SIMS is the most sensitive surface analysis technique, with elemental detection limits ranging from parts per million to parts per billion. Serialization: The assignment and placement of unique markings on a pack- age. Unique codes are placed on each unit packaged, using variable data printers or preprinted labels or cartons, and then read by a vision system. These unique codes are uploaded to an event repository database that can be accessed by various parties, including pharmacists, law enforcement of- ficials, and even consumers after the product is shipped and sold. Slum: A heavily populated urban area characterized by substandard hous- ing and squalor. Small- and medium-sized enterprise (SME): Nonsubsidiary, independent firms that employ fewer than a given number of employees. This number varies across national statistical systems. The most frequent upper limit is 250 employees, as in the European Union. However, some countries set the limit at 200 employees, while the United States considers SMEs to include firms with fewer than 500 employees.

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APPENDIX A 325 Small molecule: The term that describes a low-molecular-weight organic compound. Solid dose formulation: A mixture of active pharmaceutical ingredients and nondrug components in solid form, such as a pill, tablet, or capsule. Solubility: The ability of a substance to dissolve and form a homogeneous substance. Spectrometer: An instrument used for measuring the interaction of light with a substance (e.g., absorption, refraction, reflection, etc.). Spectrometry: The determination of wavelengths or frequencies in a spectrum. Spectroscopy: The study of the absorption and emission of light and other radiation by matter. Standard operating procedure (SOP): Detailed, written instructions to achieve uniformity of the performance of a specific function in pharmaceu- tical processing and for related clinical studies. The focus is the repeated application of unchanged processes and procedures and its documentation in order to segregate origins, causes and effects. Stringent regulatory authority: A national drug regulatory authority that participates in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Countries with stringent regulatory agencies include the United States, European Union member states, and Japan, and observers of ICH through legally binding mutual agreements. Observers of ICH include Australia, Canada, Iceland, New Zealand, Norway, and Switzerland. Substandard: A drug that fails to meet national specifications outlined in an accepted pharmacopeia or in the manufacturer’s dossier. Substandard drugs are usually made by legitimate, known manufacturers and are the result of quality system failures. Supply chain: A system of organizations, people, technology, activities, information, and resources involved in moving a product or service from supplier to customer. Supply chain activities transform natural resources, raw materials, and components into a finished product that is delivered to the end customer.

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326 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS Surveillance: A key component of epidemiology, it can be defined as the ongoing collection, analysis, interpretation, and dissemination of health- related data. Surveillance is one of a number of methods used by epidemi- ologists to gather information on a disease. Tandem mass spectrometry: A technique involving multiple rounds of mass spectrometry, usually separated by some form of molecule fragmentation. For example, one mass analyzer can isolate one peptide from many entering a mass spectrometer. A second mass analyzer then stabilizes the peptide ions while they collide with a gas, causing them to fragment by collision-induced dissociation. A third mass analyzer then sorts the fragments produced from the peptides. An important application using tandem mass spectrometry is in protein identification. Tandem mass spectrometry enables a variety of experimental sequences. Many commercial mass spectrometers are designed to expedite the execution of such routine sequences as selected reaction monitoring (SRM) and precursor ion scanning. In SRM, the first analyzer allows only a single mass through and the second analyzer monitors for multiple user-defined fragment ions. SRM is most often used with scanning instruments where the second mass analysis event is duty cycle limited. These experiments are used to increase specificity of detection of known molecules, notably in pharmacokinetic studies. Precursor ion scanning re- fers to monitoring for a specific loss from the precursor ion. The first and second mass analyzers scan across the spectrum as partitioned by a user- defined m/z value. This experiment is used to detect specific motifs within unknown molecules. Task shifting: The rational redistribution of tasks among health workforce teams. Specific tasks are moved, where appropriate, from highly qualified health workers to health workers with shorter training and fewer qualifica- tions in order to make more efficient use of the available human resources for health care delivery. Technology transfer: A process for the transfer of information or technol- ogy between a technology supplier and a recipient. It can range from the exchange of technical knowledge through formal documentation, such as a license to exploit a patent, or through technical know-how and assistance in reverse engineering an imitation of a product. Tendering: The process by which a procurement agency invites potential suppliers to bid for a contract. Tertiary packaging: Extra packaging intended to protect one or more wrapped items during transport and storage.

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APPENDIX A 327 Thin layer chromatography (TLC): A chromatography technique used to separate mixtures. TLC is performed on a sheet of glass, plastic, or alumi- num foil, which is coated with a thin layer of adsorbent material, usually silica gel, aluminum oxide, or cellulose. This layer of adsorbent is known as the stationary phase. After the sample has been applied to a plate, a solvent or solvent mixture (known as the mobile phase) is drawn up to the plate via capillary action. Because different analytes ascend the TLC plate at different rates depending on their partitioning between the phases, separation is achieved. This technique is used in synthetic chemistry for identifying compounds, determining their purity, and following the progress of a reaction. Specific examples of TLC’s applications include drug analysis, analyzing ceramides and fatty acids, detection of pesticides or insecticides in food and water, analyzing the dye composition of fibers in forensics, as- saying the radiochemical purity of radiopharmaceuticals, and identification of medicinal plants and their constituents. Tiered pricing: The concept that different classes of buyers are charged dif- ferent prices for the same product. Tiered production: The production of different-quality product lines for different markets. Time-of-flight mass spectrometry: A method of mass spectrometry in which an ion’s mass-to-charge ratio is determined via a time measurement. In this technique, ions are accelerated by an electric field of known strength. This acceleration results in an ion having the same kinetic energy as any other ion that has the same charge. The velocity of the ion depends on the mass- to-charge ratio. The time that it subsequently takes for the particle to reach a detector at a known distance is measured. This time will depend on the mass-to-charge ratio of the particle (heavier particles reach lower speeds). From this time and the known experimental parameters, the mass-to-charge ratio of the ion can be determined. Track-and-trace: The process of determining past and current locations of a unique item. It gives manufacturers, distributors, and pharmacies a systemic method to detect and control counterfeiting, drug diversions, and mishandling. Trade dress: Visual characteristics of the appearance of a product or its packaging. Trademark: Any word, name, symbol, device, or any combination, used or intended to be used to identify and distinguish goods and services of one

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328 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS seller or provider from those of others, and to indicate the source of the goods and services. Trademarks are registered with the sovereign state and that registration may be used to protect it. Trademark infringement: A violation of the exclusive rights of a trademark without the authorization of the trademark owner or licensee. Infringement may occur when one party uses a trademark that is identical or confusingly similar to a trademark owned by another party, in relation to products or services that are identical or similar to the products or services that the registration covers. Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement: Enforced since 1995, the TRIPS agreement is a multilateral agreement on intellectual property. It sets global minimum standards for protecting and enforcing nearly all forms of intellectual property rights, including those for patents. Transport costs: Costs associated with transporting goods. Two-dimensional (2D) barcode: A graphical image that stores information with both horizontal and vertical lines. It can store large amounts of data on a variety of goods and products. Ultraviolet-visible spectroscopy: A technique that examines electronic transitions and allows the wavelength and maximum absorbance of com- pounds to be determined. This technique is routinely used in analytical chemistry for the quantitative determination of different analytes, such as transition metal ions, highly conjugated organic compounds, and biological macromolecules. Uniformity of dosage: The degree of uniformity in the amount of the drug substance in dosage units. United States Adopted Names: Unique nonproprietary names assigned to generic pharmaceuticals marketed in the United States. United States Adopted Names Council: A five-member council consisting of one member from each sponsoring organization (the American Medical Association, the U.S. Pharmacopeial Convention, and the American Phar- macists Association), one from the U.S. Food and Drug Administration, and another member-at-large. It is responsible for selecting simple, informative, and unique nonproprietary names for drugs by establishing logical nomen- clature classifications based on pharmacological and chemical relationships.

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APPENDIX A 329 Unregistered: A product that lacks market authorization from the national regulatory authority. Though it may be of good quality, an unregistered product is illegal. U.S. Pharmacopeia Convention: A scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed, and consumed worldwide. Uterotonic drugs: Medications given to cause a woman’s uterus to con- tract or to increase the frequency and intensity of contractions. The three uterotonic drugs used most frequently are oxytocins, prostaglandins, and ergot alkaloids. Vibrational spectroscopy: The collective term used to describe two ana- lytical techniques—infrared and Raman spectroscopy. Infrared and Raman spectroscopy are nondestructive, noninvasive tools that provide informa- tion about the molecular composition, structure, and interactions within a sample. These techniques measure vibrational energy levels associated with the chemical bonds in a sample. The sample spectrum is unique, like a fingerprint, and vibrational spectroscopy is used for identification, char- acterization, structure elucidation, reaction monitoring, quality control, and quality assurance. Visual inspection: The standard first step in any drug quality assessment. It is the inspection of a suspected substandard or falsified pharmaceutical product: looking for differences in color, size, shape, tablet quality, and packaging, and comparing it to an authentic product. World Health Organization (WHO) essential medicine: Medicines that satisfy the priority health care needs of a population. They are selected according to disease prevalence, evidence on efficacy and safety, and com- parative cost-effectiveness. World Health Organization (WHO) Model Quality Assurance System for procurement agencies: A system that assists procurement agencies to pro- cure safe, effective pharmaceuticals of suitable quality. World Health Organization (WHO) prequalification: A service provided to guide United Nations agencies in procuring good-quality products. The prequalification procedures established by the WHO include inspections, dossier reviews, etc., intended to assure the quality, safety, and efficacy of medicinal products.

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330 COUNTERING THE PROBLEM OF FALSIFIED AND SUBSTANDARD DRUGS World Health Organization (WHO) prequalification program: A program managed by the WHO that prequalifies pharmaceutical and other health products that are considered to be acceptable for procurement by the United Nations and specialized agencies, and laboratories for quality con- trol of such products. X-ray diffraction: A technique used by chemists to examine the physico- chemical makeup of unknown solids. Samples of solids are illuminated with X-rays of a fixed wavelength and the intensity of the reflected radiation is recorded. These data are then analyzed for the reflection angle to calculate the inter-atomic spacing, allowing chemists to identify possible matches to the sample. X-ray fluorescence: The emission of characteristic secondary (or fluorescent) X-rays from a material that has been excited by bombarding the sample with high-energy X-rays or gamma rays. It is widely used for elemental analysis to distinguish between authentic and falsified drugs.