K. Arokkh. Greenville College.

Formulations of Semisolid Drugs 159 Flurandrenolide Topical Film Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0 discount fluticasone online master card asthma resources. Add and dissolve flurandrenolide in propylene including water over a period of 20–30 minutes buy generic fluticasone 500mcg asthma treatment that is not a steroid, glycol, glycerine, and ethyl alcohol. Fluticasone Propionate Ointment Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 0. Transfer the drug mixture from step 3 into the manufacturing vessel from step 2 while mixing. Melt microcrystalline wax, hard paraffin, and Mix and homogenize for 10 minutes under vac- sorbitan sesquioleate in a fat-melting vessel at uum at 0. Cool to a temperature of 25°–30°C with con- turing vessel through stainless steel filter. Disperse fluticasone propionate in propylene glycol, mix, and homogenize at a temperature of 40°–45°C. Each gram of ointment contains fluti- 11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1, casone propionate 0. The topical corticosteroids constitute a class of pri- Fluticasone Propionate Cream Fluticasone propionate cream 0. Each gram of cream con- difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopro- tains fluticasone propionate 0. Fluticasone Propionate Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 0. Transfer the drug mixture of step 5 into step 4 1000 in a fat-melting vessel at 70°C. Add purified water to the manufacturing vessel cream to contain labeled amount of drug per and heat to 70°–80°C. Transfer the fat phase of step 1 through a stain- with product identification label. Formulations of Semisolid Drugs 161 Foscarnet Cream Bill of Materials Scale (mg/100 g) Item Material Name Quantity/kg (mg) 3. Melt items 2, 3, and 5 at 70°C in a small con- step 2 to the step 3 while stirring. Transfer the ointment to stainless steel drum filter to mixer and cool it down to 50°C. Formulations of Semisolid Drugs 163 Gentamicin Sulfate Cream Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Quantity of gentamicin sulfate per batch will vary according to the actual potency. While homogenization is in progress, set the steel filter while mixing at speed 10 rpm, vac- temperature at 25°C so that the cream temper- uum 0. Stop the homogenizer, set the mixer at temper- cream in stainless steel container and fill. Gentamicin Sulfate Ointment Gentamicin sulfate ointment is a sterile, topical anti-infective (equivalent to 3. Gentamicin sulfate is the sulfate salt of gentamicin tamicin sulfate equivalent to 0. Immediately The suppository mass is manufactured at a temperature of transfer the hot mass to the heated storage ves- 120°C. Care must be taken to see that molten suppository sel or heated vessel of suppository filling mass does not accidentally spill on the person. Glycerin Suppositories Bill of Materials Scale (mg/suppository) Item Material Name Quantity/1000 Suppositories (g) 900. Formulations of Semisolid Drugs 165 Glycolic Acid Cream Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 3. Gramicidin, Neomycin, Nystatin, and Triamcinolone Ointment Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Rinse homogenizer with liquid paraffin and add heat to 70°C to melt; transfer to Becomix rinsings. Mix till ointment is smooth, transfer to a stain- twice with fine-gap setting to make smooth dis- less steel vessel, and fill. Charge items 1, 2 (balance quantity), 3, and 6 in a separate stainless steel vessel and homogenize 166 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Halobetasol Propionate Cream and Ointment The cream contains halobetasol propionate, a synthetic halobetasol propionate in a cream base of cetyl alcohol, corticosteroid for topical dermatological use. The corti- glycerin, isopropyl isostearate, isopropyl palmitate, ste- costeroids constitute a class of primarily synthetic steroids areth-21, diazolidinyl urea, methylchloroisothiazolinone, used topically as an anti-inflammatory and antipruritic methylisothiazolinone, and water. Heparin Gel-Cream Bill of Materials Scale (g/100 g) Item Material Name Quantity/kg (g) 0. Formulations of Semisolid Drugs 167 Hexachlorophen Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 45. While both solutions are at 65°–70°C, form the primary emulsion by pumping the aqueous solu- 1. Strain olive oil through voile cloth or equivalent tion from step 5 into the oil mixture from step 3 into a suitable stainless steel-jacketed tank. Homogenize primary emulsion through a Troy ate mix, add cetyl alcohol, lanolin, petrolatum, Mill, or similar device, into the balance of aque- and polysorbate 40 with mixing. Add and dissolve hexachlorophene in the oil emulsion should strained through voile cloth or mix, then add and disperse the simethicone. Cool emulsion to 40°–50°C with agitation glycerin, methylparaben, and borax as purified under vacuum. Reserve 4 mL of solution from step 5 in a separate container to rinse equipment in step 2. Other formulations include base containing sorbitan sesquioleate, water, aquaphor, cream, which contains hydrocortisone acetate 1% or 2. Hydrocortisone Ointment Bill of Materials Scale (mg/100 g) Item Material Name Quantity/kg (g) 1. In a separate vessel, disperse item 1 in item 3, using a spatula, in a water bath maintained at 60°C. Hydrocortisone Acetate Suppositories Hydrocortisone acetate is a corticosteroid designated blended hydrogenated vegetable oil base. Dissolve item 2 in balance of item 9 and a vessel after passing through stainless steel sieve portion of item 5 in a separate vessel and and heat to melt. Hydrocortisone Butyrate Cream and Ointment The cream, ointment, and topical solution contain the base consisting of cetostearyl alcohol, ceteth-20, mineral topical corticosteroid hydrocortisone butyrate, a nonflu- oil, white petrolatum, citric acid, sodium citrate, propylpa- orinated hydrocortisone ester. It has the chemical name raben and butylparaben (preservatives), and purified water. Transfer the oil phase to the aqueous phase in a mixer vessel through mesh by vacuum while stirring at manual mode, 10 rpm, temperature 60°C. Formulations of Semisolid Drugs 171 Hydrocortisone Cream Bill of Materials Scale (mg/g) Item Material Name Quantity/kg (g) 70. Heat items 7 and 8 until the active ingredient is dissolved, mix with 1/2, and continue to stir 1. Hydrocortisone Cream Bill of Materials Scale (mg/100 g) Item Material Name Quantity/kg (g) 1.

In June 1896 generic 100 mcg fluticasone with amex asthma symptoms tiredness, production was approved for laboratories in Bordeaux order fluticasone paypal asthmatic bronchitis 490, Marseilles and Montpellier, with Charles Nicolle’s laboratory in Rouen following a year later. While the law also allowed for the commission to approve imported serum, this was apparently never done. Thus, while the aims of the government (announced and supposed) does not explain the exclusion of German serum from the French market, it seems less surprising in light of the way the legislation was put into effect. Indeed, the indirect control exercised by the Pasteur Institute over the serum commission meant that the commission was likely to put into practice a policy in line with the thinking in the Institute. According to early announcements by Emile Roux immediately following his triumph at the International Congress of Hygiene in Budapest in September 1894, the Pasteur Institute was going to be the only producer of the serum in France. With their prospective capacity to produce the serum, Roux saw no reason that the serum should not be the exclusive property of the Institute, like the rabies vaccine. There were several signifcant differences between the diphtheria serum and the rabies vaccine however, frst that the method for producing serum was not secret and was not as delicate and dangerous (at least in principle) as for the rabies vaccine. Second, the economic and public health stakes were much higher in the case of the serum, as diphtheria affected a much larger population. Thus, 11 The Serum Commission was initially composed of the following members: Brouardel, Monod, Proust, Chantemesse, Bompard, Delaunay-Belleville, Bergeron (Secretaries of the Académie de médecine), Nocard, Duclaux, Straus, Grancher (ordinary members of the Académie de médecine), and Pouchet, Ogier, Thoinot, Netter (Members of the Comité consultatif d’hygiène). In the end, however, what sank Roux’s plans was a more mundane technical problem; the length of time it took to prepare a horse for producing the serum. For the period when the Pasteur Institute started its production, this period was at the very least a month, and was much longer in the case of some horses. This meant that between September 10 when the discovery was announced with great fanfare in the newspapers, and the beginning of January 1895 there was a drastic shortage of serum, despite the purchase of over a hundred horses in the wake of Roux’s high profle announcement of the serum. The Pasteur Institute was therefore obliged to limit its distribution of the serum during this initial period to the Paris area hospitals. The effect of this serum rationing was a multiplication of producers within France, something that Roux did not want, but was obliged to accept, and even actively support. We can take the example of what happened in Lyon to illustrate the developments outside Paris. Following Emile Roux’s announcement at Budapest, Dr Gabriel Roux, the homonymic director of the Bureau d’Hygiène was charged by Lyon’s mayor with obtaining serum for the city. Roux wrote to the Pasteur Institute in Paris, but received a disappointing reply: The Pasteur Institute tersely replied to me that the antitoxic serum would not be sent out to the provinces within the next two months, and then would only be delivered to hospitals and patients signed up with the ‘Bureaux de bienfaisance’. The task was entrusted to Saturnin Arloing, a professor at both the medical and the veterinary schools. The project quickly took on a larger scope than simply the production of serum, with Roux conceiving an integrated microbiology laboratory for pathological analysis. Indeed, this was a common feature of the provincial centers I have been able to look at, Grenoble, Lyon and Nancy in particular. While the serum institutes were set up to produce serum for local needs (generally supplying a signifcant but local region) they also developed a diagnostic capacity, often in the same building. The creation of a microbiology laboratory for diagnosis tempted many into research. The fnal step taken by Nancy, and possibly other serum producers as well, was to organize courses in microbiology based on the model of the Pasteur Institute, where many of the staff had themselves received their initial training. Thus, the indirect result of Paris’s initial inability to supply the provinces was not only the de-localization of serum production with regional centers (usually with only two or three horses) supplying local demand funded by the municipality or public donations, but also the introduction of veritable regional Pasteur institutes. The irony of this situation was that these regional centers found themselves in the same situation as the Pasteur Institute, needing to wait three months to have immunized horses ready to produce the serum. Thus, although he started the immunization process in November 1894, Arloing was only able to supply the Lyon hospitals with locally produced serum in February 1895, by which time a generous supply was available from Paris. This scenario was repeated all over France, with the result that the Pasteur 12 ‘Rapport de M. It is interesting to note, however, that this competition was not at all on the German model of different for- proft private enterprises. Although they were sometimes private charitable foundations, these provincial producers were never for-proft companies, and often had the appearance of an extra department attached to a city’s medical school. I now want to return to the point I was elaborating above and relate it to the developments in Lyon. In the second half of 1895, the serum commission could no longer enforce the monopoly of the Pasteur Institute as by now there was a range of regional producers that were already well established. Furthermore, these regional producers were academically respectable enterprises usually supported by local notables and more or less closely associated with the medical faculty. The moment in which a Parisian monopoly would have been possible – stretching from September to October 1895 – had now passed. The pastorians were obliged to accept the existence of the provincial producers, which were often run by medical doctors trained in serum production at the Institute itself, and were usually intimately – if not directly – linked to medical faculties around the country. Nevertheless, the producers outside Paris approved by the serum commission were, it seems, limited to ‘friends’ of the Pasteur Institute. It is in this context that we can pose the question about the non-approval of German serum, along with the absence of any private producers. Unfortunately, although we can raise this question, we are not in a position to give any conclusive response. In the absence of the archives of the serum commission, we cannot know who was applying for permission to produce or supply diphtheria serum, and, more importantly, who was being refused, and why. Judging by the outcome, however, it is reasonable to conclude that the pastorians instrumentalized the serum commission to keep a tight control on the producers, limiting them to a network of more or less intimate associates of the Institute. A subsidiary question that presents itself, therefore, is whether the Ministry of the Interior intended to give so much power to the pastorians via the commission, or whether this indirect regulatory control of the Pasteur Institute was an accident that depended on the particular circumstances in which the commission was constituted. After all, just as in the case of the regional producers, the only place to learn about microbiology in France at the end of the nineteenth century was the Pasteur Institute, in particular the course offered by Roux and later Martin. In practical terms, the Pasteur Institute already exercised a monopoly over the expertise in this feld in France, a situation exacerbated by the reluctance of medical faculties to take an active interest in it. This meant that the majority of medical doctors who specialized to some degree in microbiological research had been trained at the Institute and so were favourably disposed to it and may well have enjoyed privileged relationships of exchange and support. This was the case with Grancher or Nocard – two members of the serum commission – for example, who maintained intimate links with the Pasteur Institute throughout their lives. Thus, had the Ministry wished to keep the Institute from exercising infuence over the commission, it would have been extremely diffcult to recruit appropriately qualifed members. To continue the analysis from the perspective of ‘satisfcing’, therefore, I would argue that from a technical or more precisely ‘technocratic’ point of view, the government had no choice but to entrust the oversight of serum production to the Pasteur Institute. First, I would suggest that the regulation of April 1895 does not represent an absolute minimum that can be directly opposed to the much heavier and more intrusive German solution. One can easily imagine a hands-off approach dispensing with government approval, and simply applying a regime of post-hoc policing of dangerous substances (including ineffective serum in this case). Nevertheless, French regulation does appear to have been a kind of necessary minimum in light of certain exigencies I have pointed out in the text, in particular the high mortality associated with the disease and its prominent public image as the scourge of honest families. Furthermore, the idea of forming a commission to provide the government with an expert opinion on which to base its opinion was quite standard.

The Global Fund explains the goal of good procurement as supplying medicine “meeting agreed quality standards at the lowest possible price and in accordance with national and international laws” (Global Fund purchase fluticasone 500mcg without prescription asthma severity classification, 2009 best buy for fluticasone asthma treatment new zealand, p. Government agencies procuring medicines have to reconcile a tension between quality and price (Torstensson and Pugatch, 2012). The frms that offer the cheapest prices may do so by buying impure ingredients or cutting corners in formulation. Good procurement dictates that the cheapest tenders are not accepted Copyright © National Academy of Sciences. Chinese provincial procurement, for example, is known for “pressuring manufacturers to produce the lowest cost possible while preserving their profts” (Burkitt, 2012). These agencies face pressure to supply medicines for entire populations on tight budgets; sometimes there is added demand to support local manufacturers (Dickens, 2011; Torstensson and Pugatch, 2012). Openness in procurement can bal- ance these pressures by exposing unnecessarily high costs or bad quality, but transparency, which also includes vetting procurement offcers for con- ficts of interest, auditing suppliers, documenting decisions, and scrutinizing procurement agents, adds costs to the process (Torstensson and Pugatch, 2012). In Argen- tina, for example, a health transparency program brought down the pro- curement costs of medicines (Lewis, 2006). Reducing costs of procurement would be especially helpful in the poorest countries, which tend to spend a higher proportion of their health budget on drugs and where medicines are often expensive (Torstensson and Pugatch, 2012). In a study of 36 low- and middle-income countries, Cameron and colleagues found that public procurement agencies in the western Pacifc, Africa, and the former Soviet bloc pay an average of 34 to 44 percent above the international reference prices (Cameron et al. Donors may attempt to cover unmet demand for drugs, though donor procurement also has problems. Many European donors ask their recipients to assure quality of medicines procured with donated funds (Moore et al. Proper precaution in the medicines procurement process can prevent poor-quality products from infltrating the market. Good procurement involves separating the various steps of procurement process identifed in Table 4-2. Good procurement also puts a strong emphasis on controlling corruption and promoting transparency. Recommendation 4-2: Procurement agencies should develop a plan, within the next 3 to 5 years, to comply with the World Health Orga- nization’s Model Quality Assurance System for procurement agencies and work to remove any barriers to compliance. The model draws on the accumulated experience of these agencies’ procure- ment experts and combines advice on the procurement of medicines, vac- cines, diagnostic kits, and devices. The model focuses on four key activities: prequalifcation of pharmaceutical products and manufacturers and drug purchase, storage, and distribution. At its launch in 2006, the model had an aspirational element; it de- scribed standards that few if any of the international procurement agencies were able to maintain at that time. In the past 6 years, large procurement agencies have made great progress toward meeting the standards laid out in the model (van Zyl et al. The committee sees the model quality assurance system as a useful independent standard to assess procurement agencies. The system is a practical tool that can be used by national and international procurement agencies. Pharmaceutical procurement almost always means working with foreign suppliers; a practice that exceeds capacity of national regulators, who cannot hope to inspect foreign manufacturers as they would domestic ones. Good procurement also means that only organi- zations that follow the model system should import medicines. Small-scale importation and procurement by small actors threaten the medicines supply chain. Countering the Problem of Falsified and Substandard Drugs 149 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 150 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 151 Copyright © National Academy of Sciences. District hospitals and health posts in poor countries will not likely meet the model standards for premises, equipment, or staffng any time in the near future (Dickens, 2011). In the meantime, if full preselection of quality suppliers is not possible, interim solutions such as a two-envelope system can help reduce bias to- ward the cheapest frms. In this system, used by the Delhi hospital system, bidders submit their technical statement of work and their costs in sepa- rate, sealed envelopes (Chaudhury et al. Only if the quality controls are suffcient do they open the second envelope, containing the project budget. Ultimately, medicine procurement is complicated and requires consid- erable investment in staff and procedures. Cutting corners in procurement creates opportunities for substandard products to infltrate the supply chain. Therefore, smaller organizations such as district health offces should be free to choose the products and amounts they need from licensed, national wholesalers or importers, but they should not procure directly from manufacturers. The committee recognizes that licensing wholesalers and importers requires political will. It might take time to build momentum for this step, as discussed further in Chapter 5. Therefore, the committee recommends that national and international procurement agencies take 3 to 5 years to develop and implement their compliance plans. These agencies can develop their quality- assurance system within the next 5 years. The regulatory authority can then license national procurement agencies to buy medicines directly from manu- facturers. Instead, these organizations will be able to order their medicines from licensed procurement agencies, thereby making more effcient use of their staff and budgets and avoiding the dangers of primary procurement. Use of prescreening and prequalifcation is recommended for procurement agencies with limited capabilities. Prequalifcation must include quality assurance and quality testing through product and manufacture assessments, including testing of batches. Have management information systems in place to monitor actual supply and payment of drugs as well as post-supply quality. Estimates of medicines needed should be based on data like past use, morbidity records, and consumption predictions. Procurement Stage Procurement should be transparent, following formal written procedures and clear public selection criteria. International competitive bidding ensures economy efciency and transparency and should be used. Quality assessment of drugs upon receipt, including lab testing, inspection of shipments, and certifcate of analysis of delivered products. Post-Procurement Stage Continue to monitor quality of received drugs through independent testing.

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