PHARMACEUTICAL BIOEQUIVALENCE - Qualification ANVISA: July 12, 2001.
THE BIOEQUIVALENCE / BIOAVAILABILITY STUDY: It is applied to new, similar and generic products. ANVISA regulates this study through several resolutions. The results are obtained by the Pharmacokinetic curve where the ABSORPTION curve and the EXCRETION curve are compared within the limit of 80 to 125%.
The bioequivalence study study still can not be defined by the "iv / iv" (in-vitro / in-vivo) relation. In vitro measurements help to predict the possible outcome for this study, but values such as particle size, metabolism of each volunteer, among others, can only be observed with the so-called pilot test (a study with few volunteers in the design scaled by Center). In the case of particle size of the pharmaceutical active, the complicating factor is the difficulty in determining this measure in the reference drug. Other factors, however equal, between Test and Reference formulation, are the pharmaceutical excipients or inputs of different origins and processes in their suppliers, in this way the kinetics of absorption and excretion can differentiate. In this last one, one of the methodologies that allows to observe the characteristics of enthalpy solubility (exotherm and endotherm) is the obtaining of comparative thermograms by DSC (differential scanning calorimetry), which will allow to evaluate if the energies of solubilization of the formulated are even.
In vivo mechanisms depend on the biotite of the volunteer and on the availability of the drug to the systemic environment. To begin the study protocol is required by CEP / CONEP.
SINEB (National Information System for Pharmaceutical Equivalence and Bioequivalence Studies): The studies to be carried out or performed must be inserted in this system "online" of ANVISA, to be valid and prior knowledge. To initiate a study of Bioequivalence it is necessary to have completed the study of Pharmaceutical Equivalence which is also inserted in SINEB.
The PDC (Comparative Dissolution Profile) study required for the Bioequivalence / Bioavailability study is also mandatory in SINEB
CLINIC: Own clinical unit and clinical body with several medical specialties, usually directed according to the study drug. It has 36 hospital beds, ICU, recreation room, own Uniform, Dispensation, Food with Nutritionist, Surveillance exams, among others. The studies are accompanied by health professionals, such as nurses, nursing assistants, nursing technicians and physicians.
Protocol performed by Doctors and Pharmacists, in several clinical designs: 2x2, replicated 3x3, 4x4, stepped, parallel, association study.
· Studies with drugs of high complexity and high intra-individual variability.
· Study of drugs of various therapeutic classes, including oncological, hormones, oral aerosols and nasal sprays. The protocols are submitted directly to the CEP (Ethics and Research Committee) or also submitted to ANVISA for prior approval of the study or study design..
The T&E Analytical center works only with healthy volunteers, ie not patient.
We offer more than 200 validated methods in biological matrices (blood, plasma and urine) with extremely low quantification limits, using methodologies such as: LCMSMS.
During the study it was followed by a statistic developed internally at the T & E Center, after the conclusion of the study, the WinNonLin software was used in its most recent version, thus achieving results in accordance with ANVISA standards. Below is a mean curve of all participating volunteers considered bioequivalent in their parameters.
Note from ANVISA: certifications from October 8, 2014 follow RDC No. 56, October 2014, according to which the statistical step is no longer considered an isolated step of the bioequivalence study. The RDC mentioned above also explains that statistics are included in the clinical stage, since it participates in study planning activities, sample size, among others. CETER continues to control the information of those responsible for the statistical area, but there is no publication on the website, for the reasons explained above.
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As técnicas analíticas estão em função das características da molécula e de sua concentração estimada no fluído biológico (sangue, plasma, urina, fezes, fluído lacrimal).
The analytical techniques are based on the characteristics of the molecule and its estimated concentration in the biological fluid (blood, plasma, urine, feces, lacrimal fluid)
The most commonly used method is the Liquid-Liquid extraction, but other extractions such as SPE (Solid Phase Extraction), SPME (Solid Phase Micro Extraction), SBE (Stil Bar Extraction) and others may be used to obtain the Quantification Limit wanted. Both for organic and for metals.
Quantification Limits range from nanograms / mL, picograms / mL to phentograms / mL. The T & E center has equipment with sufficient detectability for even phentograms / mL
· Gas-phase Chromatography (GC-FID-ECD-TCD-MS-Head Space);
· Liquid phase chromatography (UPLC or HPLC-UV / Vis; Fluorescence; ELSD); Determination of peak purity using DAD;
· LC-MS / MS: Mass Spectrometry coupled to HPLC or UPLC; (API 5500, Waters Quattro Premier XE for fast column and 3μm at 600barr on HPLC and Waters TQD with UPLC);
· ICP-OES (Induced-Simultaneous and Sequential Plasma); AA - (Atomic Absorption) and FC (flame photometry).
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