T&E - Analítica






PHARMACEUTICAL BIO EXEMPTION

 

ABOUT BIO EXEMPTION

   BIO EXEMPTION may be defined as not requiring a relative bioavailability or "in vivo" bioequivalence study for the registration of a medicinal product by the health authority when an appropriate in vitro assay may replace the in vivo study. This is fully justified in ethical terms by the reduction of trials for medicinal products employing humans.

    In 1995, the Biopharmaceutical Classification System (BCS) was created to provide a regulatory tool to replace certain bioequivalence studies with in vitro dissolution tests, which will certainly reduce the exposure of healthy volunteers to drugs that are candidates for bioequivalence tests, as well as reduce costs and time required for pharmaceutical product development processes. SCB classifies drugs according to physico-chemical properties, such as solubility and permeability.

   A drug is considered highly soluble when the dose/solubility ratio is greater than or equal to 250 mL, i.e., when the higher dose is soluble in aqueous medium within the known pH range. The pH range is 1 to 7.5 at 37°C and the triplicate of the experiments is to be done.

   Permeability is considered high when 90% or more of the administered oral dose is absorbed in the small intestine. This parameter is determined by pharmacokinetic studies, intestinal perfusion in humans and / or by cell culture.

 

In August 2011, ANVISA published the Resolution - RDC No. 37, which provides for the Guide for exemption and substitution of studies of relative bioavailability / bioequivalence and gives other measures.

 

Section I

Goal:

Article 2 This Resolution is intended to establish the requirements for exemption and substitution of relative bioavailability / bioequivalence studies.

 

Section II

Scope

Article 3 This Resolution applies to all manufacturers of generic drugs, similar and new. Single paragraph. In the case of new medicinal products, the scope of this standard is limited to:

     I.        Bio exemption for the other dosages, in cases where studies of relative bioavailability are required, as provided in Resolution RDC No.136/03, which provides for registration of new medicinal products and their subsequent amendments;     

   II.        Bio exemption based on the biopharmaceutical classification system, in cases of major alteration of excipients and major alteration or inclusion of production process, described in RDC Resolution 48/09, which provides for post-registration of medicines, and its subsequent changes.

 

CANDIDATE DRUGS FOR BIOISENTION (the list is constantly updated, check the ANVISA website

 

Candidate: shall meet the requirements of the full bioenvironmental test described in DRC 37.

 

·         Acetylsalicylic acid

·         Doxycycline hydrochloride

·         Levofloxacin

·         Caffeine

·         Dipyrone

·         Metoprolol

·         Capecitabine

·         Stavudine

·         Metronidazole

·         Propranolol hydrochloride

·         Fluconazole

·         Paracetamol

·         Memantine hydrochloride

·         Bisoprolol fumarate

·         Pregabalin

·         Venlafaxine hydrochloride

·         Rivastigmine hemitartrate

·         Temozolomide

·         Pramipexole dihydrochloride

·         Isoniazid

·         Sotalol

 

 

DRUGS THAT CAN BE BIO FREE

   Generic or similar drugs which are in certain pharmaceutical forms, such as: aqueous solutions and powders for reconstitution, provided that they contain the same drug in the same concentration and excipients having the same function as those present in the reference medicinal product, may be bio free; gases; topically applied medicinal products which do not have a systemic effect; parenteral oily solutions containing the same drug in the same concentration and the same oily carrier relative to the reference drug.

GENERAL

     I.        Immediate-release, delayed-release, and similarly pharmaceutical products produced by the same manufacturer may be exempted from bioequivalence studies.

   II.        The relative bioavailability/bioequivalence study(s) may be performed with the dosage form of higher or lower dosage, depending on the pharmacokinetic linearity or safety risk of the study participant volunteer.

 III.        The remaining dosages shall be exempt from the relative bioavailability / bioequivalence study provided that the dissolution profiles of the drugs, among all dosages, are similar.

 

OBS.: THE READING OF THE DRC AUGUST 31, 2011 ALLOWS GREATER CLARIFICATIONS

 

ANALYTICAL TECHNIQUES FOR BIO EXEMPTION

   BIO EXEMPTION STUDY: Only the ANVISA Authorized Pharmaceutical EQUIVALENCE laboratories can carry out this study. It is a comparative "iv" (in vitro) result between two formulations. The BIO EXEMPTION study is registered in the SINEB of ANVISA,

Study 1: It consists of analytical determinations such as: drug solubility in 250mL, drug stability, pH evaluation and dissolution profiles in the systemic media. All methods shall be indicative of stability and in accordance with Resolution RDC No. 166 of July 24, 2017.

 

Study 2: Bioi exemption is described in RDC 37 of ANVISA. In order to legitimize the study of Bio exemption it is necessary to study Pharmaceutical Equivalence. For the other concentrations, as long as you proportion, only the Pharmaceutical Equivalence studies and the Comparative Dissolution Profiles.

THE ANALYTICAL TECHNIQUES Used are based on the methodology applied to the active of the formulations.

     I.        DISSOLUTION: Dissolution must be carried out in a 900mL bowl (cylindrical open containers with a hemispherical bottom), any vat that differs from the one recommended must be authorized by ANVISA for conducting the tests. It must operate with apparatus 1 and 2.

   II.        The analyzes of solubility and content must be with method indicative of stability, validated according to RDC 166.

 III.        Instrumental: it will depend on the validated method and according to him T&E has several techniques:

 

 

HPLC:

·         High Performance Liquid Chromatography;

·         In its various detector: UV / DAD / Fluorescence / RID / MS etc;

·         Determination of peak purity using DAD;

 

CFG:

·         High efficiency gas chromatography;

In its various detectors:  FID / DCT / MS , etc.

 

ICP:

·         Induced plasma for analysis of metals / amethals and semi-metals;

 

AA:

·         Atomic Absorption Spectrum - Metal Analysis;

 

FC:

·         Flame photometry;

 

Pot:

·         Potentiometry to selective electrodes and complexiometry;


DISSOLUTION TEST: 

The Analytical T&E Center complies with RDC No. 37, dated August 3, 2011 in the two systems inserted in the RDC:

·         USP Apparatus 1 - Rotary Basket; 

·         USP Apparatus 2 - Blades; 

CUBAS

   Conventional vats are glass or polymeric, transparent or amber. The volume and shape of the vats are important for obtaining the results.

The normal tank of a dissolutor has a volume of 900mL, cylindrical open containers with hemispherical bottom.

 

·         Cuba of 900mL - hemispheric fund;

·         Cuba of 900mL cube (Peek Vessel) – internal pre-drilling bottom;

·         Cuba of 500mL cube - hemispheric fund;

 

Obs.: change of tank, as Peek Vessel should consult with ANVISA to conduct the tests, as it has a vortex of greater intensity.

 

 

The T&E CENTER OFFERS TO YOUR STUDY ALL THE TECHNIQUES AND DIRECTIONS NECESSARY

FOR THE BIOISENTION STUDY.