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SEMINARIO INTERNACIONAL LAS GMP DEL SIGLO XXI

Incripciones en el Colegío Químico Farmacéutico del Perú
Día 7 de Noviembre 2009
Hora: 4 - 8

Quality by Design (QbD) - Contribution by Excipients Manufacturers

The International Pharmaceutical Excipients Council Europe (IPEC Europe) has published a document with questions and answers on the topic of Quality by Design (QbD).

Since excipients are used in the manufacture of medicinal products and have an influence on the properties of the product and on the production process, QbD in the development of medicinal products can also be relevant to excipients manufacturers. Therefore, suppliers have increasingly to fulfil the task of assisting manufacturers of medicinal products in reaching their QbD aims.

For this reason, a small working group has created a questions-and-answers document on QbD. This Q&A document is meant to give advice and guidance on general questions that are addressed at an early stage and also intends to try to harmonise the answers and comments from both sides and to promote and facilitate the co-operation in this field.

A total of 28 questions are listed, some of which are asked by the suppliers and the remaining ones by the users in the pharmaceutical industry.

The 28 questions are grouped in five topics bearing the following titles:

I. Effective communication between suppliers and users
II. Development of the dosage form
III. Questions related to excipient CQAs (critical quality attributes)
IV. Equipment- and production-related questions
V. Supply of samples

The topics addressed include among others "Design Space", "Critical Quality Attributes (CQAs)", "Functionality Related Characteristics (FRCs)", "Change Control Notification Process", or the protection of confidential information.

The complete document can be found here.

QbD is also the focus topic of the University of Heidelberg QbD/PAT Conference 2009, to be held in Heidelberg, Germany, from 29 September to 1 October 2009. The programme can be found at www.pat-conference.org.

Author:
Dr Günter Brendelberger
On behalf of the European Compliance Academy (ECA)

Biodisponibilidad y Bioequivalencia

Biodisponibilidad Y Bioequivalencia

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Un sustituto para el popular 'Sintrom'

EN PACIENTES CON FIBRILACIÓN AURICULAR
Un sustituto para el popular 'Sintrom'
Dabigatran podría ser más efectivo y menos incómodo para el paciente
Los expertos consideran que podría suponer un cambio en la práctica clínica
Actualizado domingo 30/08/2009 18:46 (CET)

CRISTINA G. LUCIO
BARCELONA.- Para evitar el riesgo de trombos, muchos pacientes con fibrilación auricular –la arritmia del corazón más frecuente- toman habitualmente anticoagulantes como warfarina (Aldocumar es su nombre comercial) o acenocumarol (el conocido Sintrom). Esta terapia exige controles periódicos para ajustar las dosis y la renuncia a determinados fármacos y alimentos para evitar interacciones. Además, eleva las posibilidades de que el enfermo sufra una hemorragia. Una alternativa presentada en el Congreso Europeo de Cardiología que se celebra en Barcelona podría ser una opción segura y menos incómoda para el paciente.
Dabigatran, desarrollado por Boehringer Ingelheim, "es globalmente más eficaz, más seguro y más fácil de usar para el enfermo [ya que hace necesaria la monitorización cada tres o cuatro semanas para calibrar la dosis adecuada]", ha explicado a elmundo.es Josep Brugada, presidente de la Sociedad Europea de Arritmias y coordinador en España de una investigación (RE-LY) que ha comparado la eficacia del medicamento (un inhibidor de la trombina que dificulta la formación de coágulos) con la de la warfarina.
Coincidiendo con su presentación en Barcelona, los detalles de este trabajo se han publicado en la edición on-line de la revista 'The New England Journal of Medicine'.
Un amplio estudio
En total, se analizó una muestra de 18.113 pacientes con fibrilación auricular que presentaban un riesgo alto de sufrir ictus. Estos enfermos, procedentes de 951 centros sanitarios de 44 países -incluida España- fueron divididos en tres grupos. Parte de ellos recibieron una dosis de 110 mg de dabigatran dos veces al día; a otro grupo se le indicaron 150 mg del fármaco bajo la misma pauta y el resto siguió una terapia con warfarina con controles de ajuste periódicos.
El objetivo principal del trabajo era comprobar el efecto de la medicación sobre el riesgo de ictus y, de forma secundaria, la incidencia de hemorragias graves.
Tras un seguimiento que duró como media dos años, los investigadores comprobaron que, comparados con los pacientes que tomaban warfarina, aquellos que recibieron la dosis de 110 mg de dabigatran presentaban similares tasas de ictus, pero menos incidencia de hemorragias (el riesgo se redujo un 20%).
Por su parte, quienes habían estado en tratamiento con la dosis de 150 mg habían sufrido una menor incidencia de accidentes cerebrovasculares y embolias sistémicas (una disminución del 34%) y una tasa de hemorragias similar a la de los pacientes con la terapia anticoagulante clásica.
Esto, según Brugada, sugiere que "la dosis de dabigatran podría establecerse en función del perfil de cada paciente". Así, quienes tuvieran más riesgo de ictus podrían beneficiarse de la dosis más alta del producto, mientras que la cantidad óptima del producto para los que temieran en mayor medida las hemorragias sería la de 110 mg.
Ambas dosis se asociaron con una reducción significativa del riesgo de sangrado intracraneal, un trastorno relacionado con la fibrilación auricular.
Riesgos
El trabajo también puso de manifiesto que los pacientes en tratamiento con la dosis dabigatran presentaban un riesgo ligeramente más alto de sufrir infartos de miocardio y sangrado gastrointestinal.
Los autores no han podido esclarecer la causa del aumento del riesgo coronario entre los pacientes con el nuevo fármaco, aunque sugieren que podría deberse a un efecto cardioprotector de la warfarina.
Tanto Brugada como Antoni Martínez, jefe del servicio de cardiología del Hospital Parc Taulí de Sabadell y otro de los investigadores del estudio, insisten en remarcar que "el riesgo apreciado fue muy bajo y globalmente, los pacientes que tomaron dabigatran presentaban menos complicaciones importantes".
El fármaco, que ya está autorizado en España para prevenir tromboembolismos venosos en personas que reciben prótesis de cadera o rodilla –se comercializa como Pradaxa-, sólo se asoció con un efecto secundario significativo: la dispepsia –molestias gástricas-, aunque su incidencia fue frecuente.
En sus conclusiones, publicadas en la revista médica, los autores de esta investigación subrayan que no han encontrado signos de daño hepático causado por el medicamento. Ximelagatran, un fármaco de la misma familia de dabigatran fue retirado hace tres años después de que se asociara su uso a problemas graves de hígado.
En un editorial que acompaña a este trabajo en el 'New England', Brian F. Gage, de la Universidad de Washington (EEUU) subraya el perfil prometedor del fármaco, sobre todo en su dosis más alta.
Según sus palabras, aunque los pacientes que llevan un buen control de la warfarina, no tienen por qué encontrar mayores beneficios en un fármaco "que exige tomar dos pastillas diarias y presenta un riesgo más alto de efectos secundarios distintos de las hemorragias", este medicamento sí puede ser una opción óptima "para aquellos enfermos con fibrilación auricular que presentan al menos otro factor de riesgo para sufrir un ictus".
"En mi opinión, para los pacientes con fibrilación auricular, este fármaco supondrá una revolución terapéutica. Los anticoagulantes orales clásicos suponían una carga asistencial muy importante y desde la comunidad médica llevábamos años esperando un sustituto", ha comentado Martínez.
Boehringer Ingelheim, que ha patrocinado el estudio RE-LY, espera tener el producto en el mercado en el plazo de un año. Entre sus perspectivas de futuro está la de comprobar si el fármaco también es efectivo en otros pacientes que habitualmente toman anticoagulantes, como los enfermos con prótesis valvulares.

HPLC Method Development and Validation for Pharmaceutical Analysis
Mar 1, 2004
By: Ghulam A. Shabir
Pharmaceutical Technology Europe

SEE THE FULL ARTICLE HERE OR CLICKIN ON THE IMAGE

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The wide variety of equipment, columns, eluent and operational parameters involved makes high performance liquid chromatography (HPLC) method development seem complex. The process is influenced by the nature of the analytes and generally follows the following steps:


step 1 - selection of the HPLC method and initial system
step 2 - selection of initial conditions
step 3 - selectivity optimization
step 4 - system optimization
step 5 - method validation.


Figure 1: A flow diagram of an HPLC system.

Depending on the overall requirements and nature of the sample and analytes, some of these steps will not be necessary during HPLC analysis. For example, a satisfactory separation may be found during step 2, thus steps 3 and 4 may not be required. The extent to which method validation (step 5) is investigated will depend on the use of the end analysis; for example, a method required for quality control will require more validation than one developed for a one-off analysis. The following must be considered when developing an HPLC method:



keep it simple
try the most common columns and stationary phases first
thoroughly investigate binary mobile phases before going on to ternary
think of the factors that are likely to be significant in achieving the desired resolution.

Mobile phase composition, for example, is the most powerful way of optimizing selectivity whereas temperature has a minor effect and would only achieve small selectivity changes. pH will only significantly affect the retention of weak acids and bases. A flow diagram of an HPLC system is illustrated in Figure 1.


Table I: HPLC detector comparison.

HPLC method development Step 1 - selection of the HPLC method and initial system. When developing an HPLC method, the first step is always to consult the literature to ascertain whether the separation has been previously performed and if so, under what conditions - this will save time doing unnecessary experimental work. When selecting an HPLC system, it must have a high probability of actually being able to analyse the sample; for example, if the sample includes polar analytes then reverse phase HPLC would offer both adequate retention and resolution, whereas normal phase HPLC would be much less feasible. Consideration must be given to the following:

Sample preparation. Does the sample require dissolution, filtration, extraction, preconcentration or clean up? Is chemical derivatization required to assist detection sensitivity or selectivity?

Types of chromatography. Reverse phase is the choice for the majority of samples, but if acidic or basic analytes are present then reverse phase ion suppression (for weak acids or bases) or reverse phase ion pairing (for strong acids or bases) should be used. The stationary phase should be C18 bonded. For low/medium polarity analytes, normal phase HPLC is a potential candidate, particularly if the separation of isomers is required. Cyano-bonded phases are easier to work with than plain silica for normal phase separations. For inorganic anion/cation analysis, ion exchange chromatography is best. Size exclusion chromatography would normally be considered for analysing high molecular weight compounds (.2000).


Table II: The basic types of analytes used in HPLC.

Gradient HPLC. This is only a requirement for complex samples with a large number of components (.20–30) because the maximum number of peaks that can be resolved with a given resolution is much higher than in isocratic HPLC. This is a result of the constant peak width that is observed in gradient HPLC (in isocratic HPLC peak width increases in proportion to retention time). The method can also be used for samples containing analytes with a wide range of retentivities that would, under isocratic conditions, provide chromatograms with capacity factors outside of the normally acceptable range of 0.5–15.

Gradient HPLC will also give greater sensitivity, particularly for analytes with longer retention times, because of the more constant peak width (for a given peak area, peak height is inversely proportional to peak width). Reverse phase gradient HPLC is commonly used in peptide and small protein analysis using an acetonitrile–water mobile phase containing 1% trifluoroethanoic acid. Gradient HPLC is an excellent method for initial sample analysis.

Column dimensions. For most samples (unless they are very complex), short columns (10–15 cm) are recommended to reduce method development time. Such columns afford shorter retention and equilibration times. A flow rate of 1-1.5 mL/min should be used initially. Packing particle size should be 3 or 5 μm.

Detectors. Consideration must be given to the following:


Do the analytes have chromophores to enable UV detection?
Is more selective/sensitive detection required (Table I)?
What detection limits are necessary?
Will the sample require chemical derivatization to enhance detectability and/or improve the chromatography?

Fluorescence or electrochemical detectors should be used for trace analysis. For preparative HPLC, refractive index is preferred because it can handle high concentrations without overloading the detector.

UV wavelength. For the greatest sensitivity λmax should be used, which detects all sample components that contain chromophores. UV wavelengths below 200 nm should be avoided because detector noise increases in this region. Higher wavelengths give greater selectivity.

Fluorescence wavelength. The excitation wavelength locates the excitation maximum; that is, the wavelength that gives the maximum emission intensity. The excitation is set to the maximum value then the emission is scanned to locate the emission intensity. Selection of the initial system could, therefore, be based on assessment of the nature of sample and analytes together with literature data, experience, expert system software and empirical approaches.

Six Sigma a New Paradigma for the Pharmaceutical Industry

Introduction To Six Sigma

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Tobacco Plant Helps Sprout Norovirus Vaccine

Aug 27, 2009By: Maribel RiosePT--the Electronic Newsletter of Pharmaceutical Technology

Scientists modified a tobacco plant to produce a vaccine for norovirus, the viral infection sometimes called the “cruise ship virus.” Researchers led by Charles Arntzen, PhD, a biologist and codirector of the Center for Infectious Diseases and Vaccinology at Arizona State University, believe the novel plant biotechnology methods may someday facilitate rapid development of vaccines for other viruses such as H1N1 influenza, especially when the virus has mutated beyond the effectiveness of established vaccines.
The norovirus is well-known to mutate constantly, a condition, says Arntzen, that makes it a moving target for vaccine developers. “With plant-based vaccines, we can generate the first gram quantities of the drug and do clinical tests within eight to 10 weeks. We could easily scale that up for commercial use in a two to four month period,” said Arntzen in a press release.
The plants were engineered to produce high levels of viruslike nanoparticles in the plants. These nanoparticles are approximately the same size as the norovirus (25 nm), but do not contain the infectious material of the virus. They are made up of only the outer surface of the protein that is recognized by the human immune system, and thereby stimulate an immune response to fight an infection should it occur.
Production costs related to the purification and formulation of plant-based vaccines are also generally lower than those for cell-based vaccines because of the absence of infectious agents. “There are no viruses in plants that can infect humans, so you don’t have to worry about viral removal,” explains Arntzen. “Mammalian and insect-based vaccines are tried and true—some have barely changed in nearly 60 years,” says Arntzen. But that doesn’t necessarily mean they are the best in terms of manufacturing costs or flexibility. It simply means that the industry is not accustomed to using plant biotechnology.

Liofilizacion

Liofilizacion

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