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Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic

Identifieur interne : 000985 ( Pmc/Curation ); précédent : 000984; suivant : 000986

Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic

Auteurs : Márcia Lúcia De Mário Marin [Brésil] ; Bruno Barbosa Do Carmo Oliveira [Brésil] ; Sonia Lucena Cipriano [Brésil] ; Carlos Alberto Suslik [Brésil] ; Joel Faintuch [Brésil]

Source :

RBID : PMC:2999699

Abstract

AIMS:

Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand.

METHODS:

During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases.

RESULTS:

The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent.

DISCUSSION:

Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances.

CONCLUSION:

The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery.


Url:
DOI: 10.1590/S1807-59322010001100004
PubMed: 21243276
PubMed Central: 2999699

Links toward previous steps (curation, corpus...)


Links to Exploration step

PMC:2999699

Le document en format XML

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<p>During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases.</p>
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<title>RESULTS:</title>
<p>The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent.</p>
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<p>Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances.</p>
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<journal-title>Clinics</journal-title>
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<article-id pub-id-type="pmc">2999699</article-id>
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<article-id pub-id-type="publisher-id">cln_65p1081</article-id>
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<article-title>Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic</article-title>
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<contrib contrib-type="author">
<name>
<surname>de Mário Marin</surname>
<given-names>Márcia Lúcia</given-names>
</name>
<xref ref-type="aff" rid="af1-cln_65p1081">I,</xref>
<xref ref-type="aff" rid="af2-cln_65p1081">II</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>do Carmo Oliveira</surname>
<given-names>Bruno Barbosa</given-names>
</name>
<xref ref-type="aff" rid="af1-cln_65p1081">I</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cipriano</surname>
<given-names>Sonia Lucena</given-names>
</name>
<xref ref-type="aff" rid="af3-cln_65p1081">III</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Suslik</surname>
<given-names>Carlos Alberto</given-names>
</name>
<xref ref-type="aff" rid="af4-cln_65p1081">IV</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Faintuch</surname>
<given-names>Joel</given-names>
</name>
<xref ref-type="aff" rid="af5-cln_65p1081">V</xref>
</contrib>
<aff id="af1-cln_65p1081">
<label>I</label>
Pharmacotechnical Service, Pharmacy Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.</aff>
<aff id="af2-cln_65p1081">
<label>II</label>
São Camilo University Center, São Paulo, SP, Brazil.</aff>
<aff id="af3-cln_65p1081">
<label>III</label>
Pharmacy Division, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.</aff>
<aff id="af4-cln_65p1081">
<label>IV</label>
Central Institute, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.</aff>
<aff id="af5-cln_65p1081">
<label>V</label>
Department of Gastroenterology, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.</aff>
</contrib-group>
<author-notes>
<corresp id="c1-cln_65p1081">E-mail:
<email>marciamarin@hcnet.usp.br</email>
Tel.:
<phone>55 11 3133-9531</phone>
</corresp>
</author-notes>
<pub-date pub-type="ppub">
<month>11</month>
<year>2010</year>
</pub-date>
<volume>65</volume>
<issue>11</issue>
<fpage>1081</fpage>
<lpage>1086</lpage>
<history>
<date date-type="received">
<day>22</day>
<month>6</month>
<year>2010</year>
</date>
<date date-type="rev-recd">
<day>5</day>
<month>7</month>
<year>2010</year>
</date>
<date date-type="accepted">
<day>2</day>
<month>8</month>
<year>2010</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright © 2010 Hospital das Clínicas da FMUSP</copyright-statement>
<copyright-year>2010</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">
<license-p>
<pmc-comment>CREATIVE COMMONS</pmc-comment>
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (
<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>
) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</license-p>
</license>
</permissions>
<abstract>
<sec>
<title>AIMS:</title>
<p>Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand.</p>
</sec>
<sec>
<title>METHODS:</title>
<p>During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clínicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases.</p>
</sec>
<sec>
<title>RESULTS:</title>
<p>The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent.</p>
</sec>
<sec>
<title>DISCUSSION:</title>
<p>Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality-control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances.</p>
</sec>
<sec>
<title>CONCLUSION:</title>
<p>The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery.</p>
</sec>
</abstract>
<kwd-group>
<kwd>Oseltamivir</kwd>
<kwd>Influenza pandemic</kwd>
<kwd>H1N1</kwd>
<kwd>Hospital pharmacy</kwd>
<kwd>Physico-chemical tests</kwd>
</kwd-group>
<counts>
<page-count count="6"></page-count>
</counts>
</article-meta>
</front>
<floats-group>
<fig id="f1-cln_65p1081" position="float">
<label>Figure 1</label>
<caption>
<p>Fusion point tests of Oseltamivir phosphate.</p>
</caption>
<graphic xlink:href="cln-65-11-1081-g001"></graphic>
</fig>
<fig id="f2-cln_65p1081" position="float">
<label>Figure 2</label>
<caption>
<p>HPLC confirmation of the active ingredient (Oseltamivir phosphate).</p>
</caption>
<graphic xlink:href="cln-65-11-1081-g002"></graphic>
</fig>
<fig id="f3-cln_65p1081" position="float">
<label>Figure 3</label>
<caption>
<p>Estimation of the product shelf-life.</p>
</caption>
<graphic xlink:href="cln-65-11-1081-g003"></graphic>
</fig>
<fig id="f4-cln_65p1081" position="float">
<label>Figure 4</label>
<caption>
<p>Final inspection and labeling.</p>
</caption>
<graphic xlink:href="cln-65-11-1081-g004"></graphic>
</fig>
<table-wrap id="t1-cln_65p1081" position="float">
<label>Table 1</label>
<caption>
<p>Composition of the Oseltamivir bottles defined by the Central Pharmacy of Hospital das Clínicas.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Ingredient</td>
<td align="center" valign="bottom" rowspan="1" colspan="1">Amount</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Oseltamivir phosphate</td>
<td align="center" valign="top" rowspan="1" colspan="1">985 mg *</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Sodium benzoate **</td>
<td align="center" valign="top" rowspan="1" colspan="1">50 mg</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Distilled water ****</td>
<td align="center" valign="top" rowspan="1" colspan="1">50 ml ***</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tfn1-cln_65p1081">
<p>(*) Equivalent to 750 mg of oseltamivir; Final concentration 15 mg/mL; (**) Preservative agent; (***) Actual volume 51 ml in order to comply with legislation; (****): Volume sufficient for 50 ml;</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="t2-cln_65p1081" position="float">
<label>Table 2</label>
<caption>
<p>Manufacturer recommended dosage adopted in the pandemic context.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<td align="left" valign="bottom" rowspan="1" colspan="1">Body Weight</td>
<td align="left" valign="bottom" rowspan="1" colspan="1">Daily prescription</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">0- 1 month</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">2.0 mg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">1- 3 months</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">2.5 mg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">3-12 months</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">3 mg/kg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">15 kg</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">30 mg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">>15 kg to 23 kg</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">45 mg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">>23 kg to 40 kg</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">60 mg 12/12 h</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">>40 kg and adults</td>
<td align="left" char="." valign="top" rowspan="1" colspan="1">75 mg 12/12 h</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="t3-cln_65p1081" position="float">
<label>Table 3</label>
<caption>
<p>Manufacturing flowchart.</p>
</caption>
<table frame="hsides" rules="groups">
<thead>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Material</td>
<td align="center" valign="bottom" rowspan="1" colspan="1">Features and purposes</td>
<td align="center" valign="bottom" rowspan="1" colspan="1">Routines</td>
</tr>
</thead>
<tbody>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Solid ingredients</td>
<td align="left" valign="top" rowspan="1" colspan="1">Raw materials</td>
<td align="left" valign="top" rowspan="1" colspan="1">Weights, physico-chemical properties, date and time of arrival and processing, expiry date</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Oseltamivir phosphate</td>
<td align="left" valign="top" rowspan="1" colspan="1">Active substance</td>
<td align="left" valign="top" rowspan="1" colspan="1">Net drug content, solubility, pH, fusion point</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Distilled water</td>
<td align="left" valign="top" rowspan="1" colspan="1">Dissolving medium</td>
<td align="left" valign="top" rowspan="1" colspan="1">pH, total oxidants, electrical conductivity, other physico-chemical properties, lot and time of preparation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Dissolution and homogenization</td>
<td align="left" valign="top" rowspan="1" colspan="1">Oseltamivir phosphate and sodium benzoate (preservative)</td>
<td align="left" valign="top" rowspan="1" colspan="1">Mixing in steel reactor, filtration, pH, particulate matter and visual inspection</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Final product</td>
<td align="left" valign="top" rowspan="1" colspan="1">End point</td>
<td align="left" valign="top" rowspan="1" colspan="1">Lot, packaging, labeling and storage, shelf life</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Residues and rejected materials</td>
<td align="left" valign="top" rowspan="1" colspan="1">Useless and hazardous byproducts</td>
<td align="left" valign="top" rowspan="1" colspan="1">Registration of weights, volumes and materials, discarding according to GMP and environmental legislation</td>
</tr>
<tr>
<td align="left" valign="top" rowspan="1" colspan="1">Documentation</td>
<td align="left" valign="top" rowspan="1" colspan="1">Quality Control and GMP</td>
<td align="left" valign="top" rowspan="1" colspan="1">Initial and final time of each operation, yield, losses , packaging, labeling and storage, protocol nonconformities and technical problems</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="tfn2-cln_65p1081">
<p>Abbreviations: GMP: Good manufacturing practices;</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
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