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Carnegie Mellon University.

Among the various bioimaging modalities order super viagra no prescription erectile dysfunction causes symptoms and treatment, fluorescence optical imaging technolo- gies are powerful analytical methods not only in vitro but also in vivo buy super viagra cheap online erectile dysfunction treatment miami. The main diseases in which pro- teases or their inhibitors are involved include cancer, inflammation, diseases of the vasculature, Alzheimer’s disease as well as infectious diseases. Therefore it is important to know which protease degrades where, when, and under what phys- iological conditions to better understand the onset and progression of these dis- eases. Accurate protease detection systems constitute crucial tools not only for drug Application of Near Infrared Fluorescence Bioimaging in Nanosystems 377 screening systems used to identify drugs that target proteases, but also for the early diagnosis of diseases such as cancer, in order to enable the successful treatment of patients. Many approaches have been developed to visualize protease activities utilizing peptide chemistry. The most common detection method for protease activ- ity is the use of peptide protease substrates containing chromophores at their ter- mini. Cleavage between the peptide substrates and chromophores by activated proteases results in significant absorbance changes. Although this system is sen- sitive, its application is limited due to modest fluorescent changes that are too weak for using bioimaging systems. This activatable probe possessing the cleavable peptide linkage is optically silent in its quenched state and becomes highly fluorescent after the proteolysis of protease substrate linkers by the target protease. The peptide linkers therefore were chosen from families of possible protease enzyme substrate. Using this platform, specific molecular events in vivo have been imaged for specific diseases and processes including breast cancer (34), E-selectin as a proinflammatory marker (35), atherosclerosis (36), thrombin activity (37), etc. Detailed characteristics and properties of various activatable nanoprobes will not be discussed herein, because they have been extensively reviewed elsewhere (19,38–40). Apoptosis, a programmed cell death process in multicellular organisms, plays a key role in the pathogenesis of many disorders, such as autoimmune and 378 Kang et al. The majority of effective anticancer therapies including most anticancer drugs and gamma-irradiation exert their lethal effect by inducing apoptosis. Therefore a defective apoptotic pathway in cancer cells often leads to treatment failure. Given the central role of apoptosis, it would be desirable to have a noninvasive imaging method to monitor this process in cancer patients undergoing chemotherapy and radiation treatments as well as for the develop- ment of apoptosis-related new drugs (49,50). Proteins in cellular systems that detect specific moieties or recognize specific local environments have been employed for bioimaging in the following manners: (i) an unaltered protein itself has a specific interaction with a local site (53–55), (ii) genetically engineered protein are generated expressing a specific recep- tor (56–57), and (iii) generation of monoclonal antibodies (58). As protein indicator, Annexin V, C2-domain of synaptotagmin I, has been derived to detect apoptotic 380 Kang et al. The use of genetically engineered proteins has been established as an imag- ing indicator by Tannous and colleagues (56). Biotinylated fusion protein was imaged using streptavidin-mediated fluorophore as an imaging indicator. This platform technique provided imaging tools of tumors, expressing metabolically biotinylated membrane surface receptor. Recently, various biomarkers-modified nanosystem-based imaging probes (nanoprobes) have been extensively studied in molecular imaging field. Nanoprobes have yielded new strategies for designing imaging probes that effi- ciently detect target biomolecules or diagnose diseases. These nanoprobes have large surface, prolonged plasma half-life, enhanced stability, improved target- ing, and reduced nonspecific binding, etc. Therefore, various biomarkers, such as peptides, proteins, antibodies, and aptomers, etc. Nanosystem-based new imaging probes provide some advantages, including (i) a long circulation in the bloodstream, (ii) the ability to attach a high number of biomarkers to the polymer, (iii) a lack of immunogenicity and toxicity, and (iv) the ability to cross leaky endothelial barriers in tumors (59). This polymer-based targeted agent has a high binding specificity (20–30-fold over nonspecific uptake) and has been used to image E-selectin expression on human endothelial cells (60). Biotin-bearing cells and biotinylated cell membrane were imaged by using fluorescently labeled streptavidin. These techniques can trace the fate of biomolecules or drugs directly, and noninvasively. Silica-based multimodal/multifunctional nanoparticles for bioimaging and biosensing applications. Adenovirus-mediated gene expression imaging to directly detect sentinel lymph node metastasis of prostate cancer. Synthesis, characterization, and biological prop- erties of cyanine-labeled somatostatin analogues as receptor-targeted fluorescent probes. Earlier, more accu- rate assessment of disease presence, disease course, and efficacy of disease treatment. Effect of polymer molecular weight on the tumor targeting characteristics of self-assembled glycol chitosan nanoparticles. Tumor targetability and antitumor effect of docetaxel- loaded hydrophobically modified glycol chitosan nanoparticles. Hydrophobically modified glycol chitosan nanoparticles- encapsulated camptothecin enhance the drug stability and tumor targeting in cancer therapy. A new atherosclerotic lesion probe based on hydropho- bically modified chitosan nanoparticles functionalized by the atherosclerotic plaque targeted peptides. Physicochemical characteristics of pH-sensitive poly(l-histidine)-b-poly(ethylene glycol)/poly(l-lactide)-b-poly(ethylene glycol) mixed micelles. Thermal cycling enhances the accumulation of a temperature-sensitive biopolymer in solid tumors. In vivo imaging of tumors with protease- activated near-infrared fluorescent probes. Design, synthesis, and characterization of urokinase plasminogen-activator-sensitive near-infrared reporter. Optical visualization of cathepsin K activity in atherosclerosis with a novel, protease-activatable fluorescence sensor. In vivo imaging of thrombin activity in experimen- tal thrombi with thrombin-sensitive near-infrared molecular probe. Fluorescence imaging with near-infrared light: New technological advances that enable in vivo molecular imaging. Optical imaging of matrix metalloproteinase–2 activity in tumors: Feasibility study in a mouse model 1. Imaging of differential protease expression in breast cancers for detection of aggressive tumor phenotypes. In vivo imaging of protease activity in arthritis: A novel approach for monitoring treatment response. A near-infrared-fluorescence-quenched gold-nanoparticle imaging probe for in vivo drug screening and protease activity determination. Synthesis and characterization of a small, membrane- permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. Biochemical and in vivo characterization of a small, membrane-permeant, caspase-activatable far-red fluorescent peptide for imaging apoptosis. Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V-Cy5.

World Federation Against Drugs (2011) Global commission on drug policy offers inaccurate order super viagra in united states online doctor for erectile dysfunction in gurgaon, reckless buy super viagra 160 mg cheap erectile dysfunction causes prostate, vague drug legalization proposal. Responses from the Advisory Council on the Misuse of Drugs to questions for consultation. House of Commons Home Affairs Select Committee The government’s drugs policy: is it working? London: The Royal Society for the Encouragement of Arts, Manufactures and Commerce. Wood E, Werb D, Kazatchkine M et al (2010) Vienna declaration: a call for evidence-based drug policies. Rosmarin A & Eastwood N (2012) A quiet revolution: drug decriminalisation policies in practice across the globe. European Monitoring Centre for Drugs and Drug Addiction (2011) Annual report 2011. European Monitoring Center for Drugs and Drug Addiction (2001) European legal database on drugs. Uzbekistan: United Nations Office on Drugs and Crime, Regional Office for Central Asia. Greenwald G (2009) Drug decriminalization in Portugal: lessons for creating fair and successful drug policies. Hughes C & Stevens A (2010) What can we learn from the Portuguese decriminalization of illicit drugs? European Monitoring Centre for Drugs and Drug Policy (2011) Drug policy profiles – Portugal. King County Bar Association Drug Policy Project (2005) Effective drug control: toward a new legal framework. Health Officers Council of British Columbia (2005) A public health approach to drug control. The Health Officers Council of British Columbia (2011) Public health perspectives for regulating psychoactive substances: what we can do about alchohol, tobacco, and other drugs. Grover A (2010) Report of the Special Rapporteur on the Right of Everyone to the Enjoyment of the Highest Attainable Standard of Physical and Mental Health (Item 69(b) of the provisional agenda of the sixty-fiftession of the United Nations General Assembly). House of Commons Home Affairs Select Committee The government’s drugs policy: is it working? The Advisory Group on Drug and Alcohol Education (2008) Drug education: an entitlement for all a report to government by the advisory group on drug and alcohol education. Faggiano F, Vigna-Taglianti F, Versino E et al (2005) School-based prevention for illicit drugs use. Lloyd C, Joyce R, Hurry J et al (2000) The effectiveness of primary school drug education. Home Office (2009) Blueprint drugs education: the response of pupils and parents to the programme – executive summary. Joseph Rowntree Foundation (2005) Random drug testing of school children: a shot in the arm or a shot in the foot for drug prevention. Her Majesty’s Government (2010) Drug strategy 2010: reducing demand, restricting supply, building recovery: supporting people to live a drug free life. National Institute on Drug Abuse (2006) Evaluation of the national youth antidrug media campaign: 2004 report of findings. National Institute for Health and Clinical Excellence (2006) Drug use prevention among young people: a review of reviews. Department of Health (2000) Vulnerable young people and drugs: opportunities to tackle inequalities. Hammersley R, Marsland L & Reid M (2003) Substance use by young offenders: the impact of the normalisation of drug use in the early years of the 21st century. Fishbein M, Hall-Jamieson K, Zimmer E et al (2002) Avoiding the boomerang: testing the relative effectiveness of antidrug public service announcements before a national campaign. House of Commons Home Affairs Select Committee The government’s drugs policy: is it working? Jaffe J & O’Keeffe C (2003) From morphine clinics to buprenorphine; regulating opioid antagonist treatment of addiction in the United States. Haasen C, Verthein U & Degkwitz P (2007) Heroin-assisted treatment for opioid dependence: randomised controlled trial. National Institute for Health and Clinical Excellence (2007) Methadone and buprenorphine for the management of opioid dependence. Her Majesty’s Government (2010) Drug strategy 2010: reducing demand, restricting supply, building recovery: supporting people to live a drug free life. Robins L (1993) Vietnam veterans rapid recovery from heroin addiction: a fluke, or normal expectation? Recovery Orientated Drug Treatment Group, National Treatment Agency for Substance Misuse (2012) Medications in recovery. Hubbard R, Marsden M, Rachel J et al (1989) Drug abuse treatment: a national study of effectiveness. Bell J, Dru A, Fischer B et al (2002) Substitution therapy for heroin addiction Substance Use and Misuse 37: 1145-74. Romelsjö A, Engdahl B, Stenbacka M et al (2010) Were the changes to Sweden’s maintenance treatment policy 2000-06 related to changes in opiate-related mortality and morbidity? De Maeyer J, Vanderplasschen W & Broekaert E (2010) Quality of life among opiate-dependent individuals: a review of the literature. Moffatt S, Weatherburn D & Donnelly N (2005) What caused the recent drop in property crime? Rosenbaum M (1985) A matter of style: variation among methadone clinics in the control of clients. General Accounting Office (1990) Methadone maintenance: some treatment programs are not effective; greater federal oversight needed. Report to the chairman, Select Committee on Narcotic Abuse and Control, House of Representatives. De Maeyer J, Vanderplasschen W, Camfield L et al (2011) A good quality of life under the influence of methadone: a qualitative study among opiate-dependent individuals. Bell J, Chan J & Kuk A (1995) Investigating the effect of treatment philosophy on outcome of methadone maintenance. Bell J, Butler B, Lawrance A et al (2009) Comparing overdose mortality associated with methadone and buprenorphine treatment. Bell J, Shanahan M, Mutch C et al (2007) A randomised trial of effectiveness and cost effectiveness of observed versus unobserved administration of buprenorphine-naloxone for heroin dependence. Barau K, Thirion X, Micallef J et al (2001) Comparison of methadone and high dosage buprenorphine users in French care centres.

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At these doses super viagra 160 mg line erectile dysfunction drug, the leukopenia is mild to moderate in most patients but more severe in around 30% of patients (Hornedo & Van Echo generic 160 mg super viagra mastercard erectile dysfunction just before intercourse, 1985). Myelo- suppression is usually more severe in previously treated patients, and is much more severe with high doses of amsacrine (600–1000 mg/m2). Stomatitis and mucositis become more frequent with higher doses (> 120 mg/m2) (Slevin et al. Hepatoxicity has been reported, typically manifest as transient increases in serum bilirubin concentration and/or hepatic enzyme activity, but lethal hepatotoxicity has also been reported (Appelbaum & Shulman, 1982). Phlebitis occurred in up to 17% of patients in early studies with amsacrine (Legha et al. The more common effects were alterations in the electro- cardiogram and arrhythmia, but cardiomyopathy and congestive heart failure also occurred (Weiss et al. Amsacrine has been used safely in patients with pre- existing arrhythmia when a serum potassium concentration of > 4 mmol/L was main- tained (Arlin et al. Toxic effects on the gastrointestinal and central nervous system were observed at lethal doses in dogs (6. In subsequent studies, evidence of cardiotoxicity was not seen in rats (Kim et al. Intravenous dosing of rats at 1 or 3 mg/kg bw per day for five days resulted in hair loss, diarrhoea and leukopenia; these effects were reversible (Pegg et al. Local tissue reactions were seen when the drug was administered subcutaneously or intramuscularly to guinea-pigs or rabbits, but similar effects were seen after admin- istration of the vehicle alone, suggesting that the acidity of the vehicle (see above) may have been responsible (Henry et al. Skin rashes in personnel involved in bulk formulation of amsacrine prompted further studies in experimental animals. In the Magnussen and Kligman maximization test, amsacrine was extremely sensitizing to the skin of guinea-pigs when given as a challenge dose by direct application, while the vehicle alone produced almost no response. The animals were not sensitized for systemic anaphylaxis, however, and there was no detectable induction of antibodies in rabbits (Watson et al. There was no effect on post-spermatogonial stages and little effect on stem cells, and the sperm counts had recovered by day 56 (da Cunha et al. Eye, jaw and other skeletal malformations were observed in the fetuses at all doses. An increased frequency of resorptions and decreased fetal weight were observed at the intermediate and high doses (Ng et al. Day-10 rat embryos [strain not specified] cultured for 24 h in vitro were exposed for the first 3 h to amsacrine at concentrations of 10 nmol/L to 1 μmol/L. A dose-related increase in the frequency of malformations was observed at doses of 50–500 nmol/L, and 100% of the embryos were malformed at 500 nmol/L. The malformations consisted mainly of hypoplasia of the prosencephalon, microphthalmia and oedema of the rhombencephalon. Similar malformations were observed in the same system with etoposide (see the monograph on etoposide). Comparison of the concen- trations necessary to produce lethality and malformations in 50% of fetuses showed that amsacrine was 10 times and 20 times more potent, respectively, than etoposide (Mirkes & Zwelling, 1990). In a study reported only as an abstract, male mice were treated with a maximum tolerated dose of 15 mg/kg bw [no further details given] amsacrine and showed no signs of dominant lethal mutation. The positive effects required a dose of about 800 μg/plate, which is higher than those tested in mammalian cells. In Saccharomyces cerevisiae strain D5, amsacrine failed to induce the mitochondrial ‘petite’ mutation, but it was an effective mitotic recombinogen when testing was done under conditions permitting cell growth. The Chinese hamster cell line xrs-1 was hypersensitive to amsacrine treatment (Caldecott et al. Amsacrine caused chromosomal aberrations in cultured Chinese hamster cells, in various rodent cell lines, in HeLa cells and in cultured human peripheral blood lymphocytes. Fluorescence in-situ hybridization techniques revealed a high frequency of dicentrics and stable trans- locations in amsacrine-treated human peripheral blood lymphocytes. Additionally, amsacrine induced micronuclei and chromosomal aberrations in the bone marrow of non-tumour-bearing male and female mice. In male ddY mice, amsacrine increased the incidence of micro- nuclei in both hepatocytes and peripheral blood reticulocytes. In one study, amsacrine caused chromosomal aberrations, but no sister chromatid exchange in blood lym- phocytes of patients treated with this drug by intravenous infusion. Amsacrine induced sister chromatid exchange in Chinese hamster cells and in human lymphocytes in vitro. It had no effect in Droso- phila melanogaster in the wing spot test or in the white–ivory assay, which provide a measure of somatic crossing-over or recombination. Although there is evidence that amsacrine causes point mutations in bacteria, it does not appear to do so in mammalian cells, possibly because the concentrations necessary to evoke these events would be lethal to mammalian cells. In two of three studies, it induced primarily small colony mutants at the Tk locus in mouse lymphoma L5178Y cells; although these events were classified as gene mutations (Jackson et al. Mutations at the Hprt locus in V79 cells paralleled chromosomal events as measured by micronucleus formation (Wilson et al. Neither frameshift nor base pair-substitution mutational events could be unequivocally associated with this treatment. The extent of amsacrine-induced mutation varies among cell lines, depending on their susceptibility to apoptosis, or programmed cell death, which is a means of ensuring that genetically damaged cells do not survive to form progeny and acts as an alternative pathway to mutagenesis. Fluorescence in-situ hybridization techniques revealed that amsacrine caused both aneuploidy and polyploidy in a Chinese hamster–human cell hybrid. Polyploidy was also demonstrated by cytogenetic techniques in Chinese hamster ovary cells and, by flow cytometry, in murine erythroleukaemic cells. Amsacrine also mutates germ cells: dominant lethal events were seen in female but not in male mice. Treatment of meiotic cells with amsacrine can disrupt the structure of the synaptonemal complex, a meiosis-specific structure that is essential for accurate recombination and chromosomal segregation. For example, exposure of preleptotene mouse germ cells to amsacrine led to an aberrant multi-axial configuration of the synaptonemal complex (Ferguson et al. This provides indirect evidence that amsacrine interferes with meiotic recombination and is a probable aneuploidogen in meiotic cells. Three mechanisms have been identified to explain the mutagenicity and carcinogenicity of amsacrine. Most of the muta- tional events reported in mammalian cells, including point mutations, chromosomal deletions and exchanges and aneuploidy, can be explained by this activity. Amsacrine does not inhibit bacterial topoisomerases and may not mutate bacterial cells by the same mechanism as mammalian cells. It possesses readily oxidizable functions: The anilino ring of amsacrine can be reversibly oxidized, either chemically or microsomally, to produce a quinone diimine (Jurlina et al. DeMarini and Lawrence (1992) suggested that the induction of prophage reflects this activity of the drug. Nevertheless, none of the mutations seen with amsacrine is of the type usually associated with reactive oxygen species. In a single study in rats given amsacrine by intravenous administration, small-intestinal adenomas and adenocarci- nomas were induced in a dose-dependent fashion in males and females, and a few adenocarcinomas of the large intestine were seen in males and females at the high dose. The occurrence of intestinal carcinomas in rats of each sex and the occurrence of skin tumours after intravenous administration of a chemical are unusual.

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The equipment used for manufacturing manufacturer 160mg super viagra amex erectile dysfunction doctor orlando, distributor quality super viagra 160mg impotence under 40, and holder human food should not be used to man- of food shall at all times utilize quality ufacture nonhuman food-grade animal control operations that reduce natural feed or inedible products, unless there or unavoidable defects to the lowest is no reasonable possibility for the con- level currently feasible. Subpart G—Production and Process Con- Subpart K—Production and Process Control trol System: Requirements for Compo- System: Requirements for Manufac- nents, Packaging, and Labels and for turing Operations Product That You Receive for Pack- 111. Subpart M—Holding and Distributing Subpart I—Production and Process Control System: Requirements for the Batch 111. Component means any substance in- Subpart A—General Provisions tended for use in the manufacture of a dietary supplement, including those §111. Com- (a) Except as provided by paragraph ponent includes dietary ingredients (as (b) of this section, you are subject to described in section 201(ff) of the act) this part if you manufacture, package, and other ingredients. Examples of con- of Columbia, or the Commonwealth of tact surfaces include containers, uten- Puerto Rico. An ingredient in- retail establishment does not include a cludes, but is not necessarily limited warehouse or other storage facility for to, a dietary ingredient as defined in section 201(ff) of the act. This defini- Representative sample means a sample tion includes species that: that consists of an adequate number of (1) May have public health signifi- units that are drawn based on rational cance; criteria, such as random sampling, and (2) May cause a component or dietary that are intended to ensure that the supplement to decompose; sample accurately portrays the mate- (3) Indicate that the component or di- rial being sampled. Reserve sample means a representa- Physical plant means all or any part tive sample of product that is held for of a building or facility used for or in a designated period of time. Examples of product versely affecting the product or its complaints are: Foul odor, off taste, ill- safety for the consumer. I (4–1–10 Edition) the water vapor pressure of the sub- could result in microbial contamina- stance divided by the vapor pressure of tion of any components, dietary sup- pure water at the same temperature. In addition to this part, you must These hygienic practices include the comply with other applicable statutory following: provisions and regulations under the (1) Wearing outer garments in a man- act related to dietary supplements. If of any material, including components, hand jewelry cannot be removed, it dietary supplements, and contact sur- must be covered by material that is faces used in the manufacture, pack- maintained in an intact, clean, and aging, labeling, or holding of a dietary sanitary condition and that effectively supplement. Such measures include the protects against contamination of following: components, dietary supplements, or (1) Excluding from working in any contact surfaces; operations that may result in contami- (5) Maintaining gloves used in han- nation any person who, by medical ex- dling components or dietary supple- amination, the person’s acknowledge- ments in an intact, clean, and sanitary ment, or supervisory observation, is condition. You must keep the organisms, filth, or any other extra- grounds of your physical plant in a neous materials, including perspira- condition that protects against the tion, hair, cosmetics, tobacco, chemi- contamination of components, dietary cals, and medicines applied to the skin. Each person who is identified to parking lots so that they do not con- perform quality control operations stitute a source of contamination in must be qualified to do so and have dis- areas where components, dietary sup- tinct and separate responsibilities re- plements, or contact surfaces are ex- lated to performing such operations posed; from those responsibilities that the (3) Adequately draining areas that person otherwise has when not per- may contribute to the contamination forming such operations. The plumbing in your and adequate under the conditions of physical plant must be of an adequate use. Guard or guide for use in bathrooms or hand-washing dogs are allowed in some areas of your facilities. You must dispose dogs will not result in contamination of sewage into an adequate sewage sys- of components, dietary supplements, or tem or through other adequate means. You must provide your (2) You must take effective measures employees with adequate, readily ac- to exclude pests from the physical cessible bathrooms. The bathrooms plant and to protect against contami- must be kept clean and must not be a nation of components, dietary supple- potential source of contamination to ments, and contact surfaces on the components, dietary supplements, or premises by pests; and contact surfaces. You must migants, fungicides, or rodenticides, provide hand-washing facilities that unless you take precautions to protect are designed to ensure that an employ- against the contamination of compo- ee’s hands are not a source of contami- nents, dietary supplements, or contact nation of components, dietary supple- surfaces. You must convey, not become a component of the dietary store, and dispose of trash to: supplement. You must position decision, reprocessing, or are assign one or more employees to super- awaiting disposal after rejection; vise overall sanitation. Each of these (3) Separating the manufacturing, supervisors must be qualified by edu- packaging, labeling, and holding of dif- cation, training, or experience to de- ferent product types including dif- velop and supervise sanitation proce- ferent types of dietary supplements dures. Any physical plant you use in the (d) Be designed and constructed in a manufacture, packaging, labeling, or manner that prevents contamination of holding of dietary supplements must: components, dietary supplements, or contact surfaces. Your physical plant must have, where they may contaminate compo- and you must use, separate or defined nents, dietary supplements, or contact areas of adequate size or other control surfaces; systems, such as computerized inven- (iv) Equipment that controls tem- tory controls or automated systems of perature and humidity, when such separation, to prevent contamination equipment is necessary to ensure the and mixups of components and dietary quality of the dietary supplement; and supplements during the following oper- (v) Aisles or working spaces between ations: equipment and walls that are ade- (1) Receiving, identifying, holding, quately unobstructed and of adequate and withholding from use, components, width to permit all persons to perform dietary supplements, packaging, and their duties and to protect against con- labels that will be used in or during the tamination of components, dietary sup- manufacturing, packaging, labeling, or plements, or contact surfaces with holding of dietary supplements; clothing or personal contact. I (4–1–10 Edition) equipment must be located and oper- Subpart D—Equipment and ated in a manner that minimizes the Utensils potential for microorganisms and par- ticulate matter to contaminate compo- §111. You must calibrate: (iii) Made of nontoxic materials; (1) Before first use; and (iv) Designed and constructed to (2) At the frequency specified in writ- withstand the environment in which ing by the manufacturer of the instru- they are used, the action of compo- ment and control; or nents or dietary supplements, and, if (3) At routine intervals or as other- applicable, cleaning compounds and wise necessary to ensure the accuracy sanitizing agents; and and precision of the instrument and (v) Maintained to protect compo- control. When partment; and the surfaces are wet-cleaned, they (ii) Must have an automated device must be sanitized, when necessary, and for regulating temperature or an auto- thoroughly dried before subsequent mated alarm system to indicate a sig- use. When use to measure, regulate, or record cleaning and sanitizing is necessary, temperatures, hydrogen-ion concentra- you must clean and sanitize all contact tion (pH), water activity, or other con- surfaces before use and after any inter- ditions, to control or prevent the ruption during which the contact sur- growth of microorganisms or other face may have become contaminated. If contamination must be: you use contact surfaces in a contin- (i) Accurate and precise; uous production operation or in con- (ii) Adequately maintained; and secutive operations involving different (iii) Adequate in number for their batches of the same dietary supple- designated uses. In your tions are consistently met; documentation, you must: (b) Determine the suitability of the (i) Identify the instrument or control equipment by ensuring that your calibrated; equipment is capable of operating sat- (ii) Provide the date of calibration; isfactorily within the operating limits (iii) Identify the reference standard required by the process; used including the certification of ac- (c) Routinely calibrate, inspect, or curacy of the known reference standard check the equipment to ensure proper and a history of recertification of accu- performance. Your quality control per- racy; sonnel must periodically review these (iv) Identify the calibration method calibrations, inspections, or checks; used, including appropriate limits for (d) Establish and use appropriate accuracy and precision of instruments controls for automated, mechanical, and controls when calibrating; and electronic equipment (including (v) Provide the calibration reading or software for a computer controlled readings found; process) to ensure that any changes to (vi) Identify the recalibration meth- the manufacturing, packaging, label- od used, and reading or readings found, ing, holding, or other operations are if accuracy or precision or both accu- approved by quality control personnel racy and precision limits for instru- and instituted only by authorized per- ments and controls were not met; and sonnel; and (vii) Include the initials of the person (e) Establish and use appropriate con- who performed the calibration and any trols to ensure that the equipment recalibration. These controls must be ap- inspections, and checks of automated, proved by quality control personnel. The peti- with dietary supplements must be safe tion must set forth the scientific ra- and suitable for its intended use and tionale, and must be accompanied by must not be reactive or absorptive or the supporting data and information, for proposed alternative testing that otherwise affect the safety or quality will demonstrate that there is no mate- of the dietary supplement. To do so, you must tions to provide sufficient assurance either: that the product you receive is ade- (i) Conduct appropriate tests or ex- quately identified and is consistent aminations; or with your purchase order. In such a case, you must may adulterate or that may lead to document why, for example, any com- adulteration of the finished batch of ponent and in-process testing, exam- the dietary supplement. To do so: ination, or monitoring, and any other (1) You must select one or more es- information, will ensure that such ex- tablished specifications for identity, empted product specification is met purity, strength, composition, and the without verification through periodic limits on those types of contamination testing of the finished batch; and that may adulterate or that may lead (2) Your quality control personnel to adulteration of the dietary supple- must review and approve the docu- ment that, if tested or examined on the mentation that you provide under finished batches of the dietary supple- paragraph (d)(1) of this section. No fin- product that you receive for packaging ished batch of dietary supplements or labeling as a dietary supplement may be released for distribution unless (and for distribution rather than for re- it complies with §111. I (4–1–10 Edition) (5) Documentation for why any com- identity, purity, strength, or composi- ponent and in-process testing, exam- tion of a dietary supplement; ination, or monitoring, and any other (b) Reviewing and approving the doc- information, will ensure that a product umentation setting forth the basis for specification that is exempted under qualification of any supplier; §111. To do so, quality control per- must include: sonnel must perform operations that (a) Reviewing and approving all lab- include: oratory control processes associated (a) Approving or rejecting all proc- with the production and process con- esses, specifications, written proce- trol system; dures, controls, tests, and examina- (b) Ensuring that all tests and exami- tions, and deviations from or modifica- nations required under §111. I (4–1–10 Edition) modifications to the master manufac- ensure that specifications established turing records; under §111. I (4–1–10 Edition) (c) You must quarantine components (c) You must quarantine packaging before you use them in the manufac- and labels before you use them in the ture of a dietary supplement until: manufacture of a dietary supplement (1) You collect representative sam- until: ples of each unique lot of components (1) You collect representative sam- (and, for components that you receive, ples of each unique shipment, and of of each unique shipment, and of each each unique lot within each unique unique lot within each unique ship- shipment, of packaging and labels and, ment); at a minimum, conduct a visual identi- (2) Quality control personnel review fication of the immediate containers and approve the results of any tests or and closures; examinations conducted on compo- (2) Quality control personnel review nents; and and approve the results of any tests or (3) Quality control personnel approve examinations conducted on the pack- the components for use in the manufac- aging and labels; and ture of a dietary supplement, including (3) Quality control personnel approve approval of any treatment (including the packaging and labels for use in the in-process adjustments) of components manufacture of a dietary supplement to make them suitable for use in the and release them from quarantine. I (4–1–10 Edition) (1) Identify specifications for the erence to the physical location of the points, steps, or stages in the manufac- actual or representative label; turing process where control is nec- (h) Written instructions, including essary to ensure the quality of the die- the following: tary supplement and that the dietary (1) Specifications for each point, supplement is packaged and labeled as step, or stage in the manufacturing specified in the master manufacturing process where control is necessary to record; and ensure the quality of the dietary sup- (2) Establish controls and procedures plement and that the dietary supple- to ensure that each batch of dietary ment is packaged and labeled as speci- supplement that you manufacture fied in the master manufacturing meets the specifications identified in record; accordance with paragraph (b)(1) of (2) Procedures for sampling and a this section. I (4–1–10 Edition) (4) Approved and released, or re- ment (and for distribution rather than jected, the packaged and labeled die- for return to the supplier); and tary supplement, including any repack- (5) Packaged and labeled dietary sup- aged or relabeled dietary supplement. These precautions in- or dietary supplements, by, for exam- clude: ple: (a) Performing manufacturing oper- (1) Filters or strainers, ations under conditions and controls (2) Traps, that protect against the potential for (3) Magnets, or growth of microorganisms and the po- (4) Electronic metal detectors. You must do (a) You must make and keep records this using any effective means, includ- required under this subpart K in ac- ing the following: cordance with subpart P of this part. You must clearly identify, hold, and control under a quarantine system for (a) You must hold reserve samples of appropriate disposition any packaged dietary supplements in a manner that and labeled dietary supplement that is protects against contamination and de- rejected for distribution. You must identify and quarantine re- (a) You must make and keep records turned dietary supplements until qual- required under this subpart N in ac- cordance with subpart P of this part. Subpart O—Product Complaints You may salvage a returned dietary supplement only if quality control per- §111.