Ismael J. Hidalgo, Ph.D. Absorption Systems Panama (Clayton) Absorption Systems LP (Exton, PA) 2016 Absorption Systems

Transcripción

1 Ismael J. Hidalgo, Ph.D. Absorption Systems Panama (Clayton) Absorption Systems LP (Exton, PA) 1

2 Desafios Actuales Limitaciones de Metodologia Utilizada Metodos Alternativos Novedosos IDAS1 IDAS2 Monitoreo de la Calidad de los Medicamentos Conclusions 2

3 Registro de Bioequivalencia (BE) 1. Humanos Generico vs Medicamento de Referencia (MR) (AUC, C max ) 2. In Vitro Clasificacion del farmaco basada en BCS In vitro BE basada en los perfiles de disolucion 3

4 Bastante infraestructura Costosas Resultados inciertos Consideraciones eticas Falta de cumplimiento Fabricantes pequenos mas afectados Desabastecimiento Se aceptan datos dudosos, no se enforza la norma o se elimina 4

5 Number of BE studies per year: Typical number of subjects per study: 32 Typical cost per study: $220,000 J. Cook et al Mol. Pharm. 4: , 2010

6 Some Indian pharmaceutical companies are known for cutting corners, after the product gets approved, to make it cheaper Dr. Vinod Shah (A veteran of 3 decades at the US FDA)

7 Ranbaxy fabricated and falsified data to win approval of their products by the FDA. Forged own SOP s Most products applications filed in Brazil, MX, Russia, Asia, and Africa were based on totally fabricated data or data from different products of or different countries Of 163 products sold since 2000 only 8 were fully tested Used brand-name drugs as stand-ins for its own in BE studies On March 13, Ranbaxy pleased guilty to 7 federal counts of selling adulterated drugs and related charges and agreed to pay $500 millions in fines.

8 The US FDA has issued fours warnings against foreign drugmakers, citing reasons including problems with QC, a non-registered facility, and finished products that did not contain any of the labeled active ingredient. The Agency published a string of warning letters yesterday, following inspections which observed cgmp violations at facilities run by firms in the UK, The Netherlands, Switzerland and China. 8

9 Base cientifica solida Larga trayectoria en Estados Unidos Ventajosa en rapidez, costo yconfiabilidad No humanos Probablemente mejor para farmacos de alta variabilidad 9

10 Top 200 drugs Class 1 + Class 3 drugs ~ 63% J. Cook et al Mol. Pharm. 4: , 2010

11 Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy KS Amidon, P Langguth, H Lennernäs, L Yu, and GL Amidon Although in vivo studies in humans are extensively used to document BE, they should no longer be viewed as the only type of evidence that can be used to establish the BE of oral drug products. 11

12 Technicas utilizadas en el estudio de absorcion de farmacos Pruebas in vitro 12

13 Product Disintegration Drug Dissolution (Aqueous Solubility) Drug Intestinal Absorption

14

15

16

17 Analytical Paradigm Solubility, permeability and dissolution are measured independently, often under conditions that lack physiologic relevance. Consequences Poor linkage between in vitro drug product release characteristics and in vivo performance. Limited utility in formulation development and optimization. 17

18 % Dissolved % Dissolved % Dissolved 120 ph ph ph R T R T R T Minutes Minutes Minutes Test (T) Reference (R) T/R Cmax (ng/ml) * AUC 0-t (h*ng/ml) * *: Acceptance Criteria:

19 Falta de sensibilidad de las pruebas de control de calidad comunmente utilizadas para detectar diferencias entre diferentes productos 19

20 In-vitro Dissolution Absorption Systems IDAS1 IDAS2 20

21

22 22

23 Dissolution (%) Permeation (%) Dissolution Permeation of dosed of dissolved Minutes Minutes

24 Dissolution (%) Permeation (%) Dissolution Permeation of dosed of dissolved Minutes Minutes

25 Dissolution (%) Permeation (%) Dissolution Permeation of dosed of dissolved Time (min) Time (min)

26 Two marketed products with the same API Original formulation: 25 mg Capsule Improved formulation: 20 mg Capsule 26

27 USP Dissolution Test (ph 7.4) FDA Dissolution Test (ph 5.75) 140 Rapid dissolution NO DIFFERENCE % D i s s o l v e d Minutes

28 Donor conc (um) Receiver conc (um) Improved Reference 10 5 Improved Reference Minutes Minutes 28

29 Pruebas rutinarias de control de calidad no encontraron diferencias entre los productos de amlodipino de diferentes fabricantes 29

30 One-Step Receiver sampling Receiver sampling ph adj. Two-Step Donor sampling ph Receiver sampling Insert cell chamber, initiate permeation Permeation: FaSSIF (ph 6.5) 30

31 31

32 32

33 33

34 34

35 35

36 Comparative evaluation of dissolution and permeation rates for amlodipine products Product AUDC 2h (µm. min -1 ) % Permeation 2h FF ± ± 0.52 FF ± * 0.25 ± 0.13 * FF ± * 0.22 ±0.10 * FF ± * 0.55 ± 0.35 * FF ± ± 0.16 * *:P < 0.05 vs control (Panama RLD, FF15-025) 36

37 37

38 38

39

40 140 % D i s s o l v e d rpm 50 rpm 75 rpm Minutes

41 Conditions: 2 tabs/500 ml, 2 chambers/vessel, 50 RPM Low viscosity: SGF, ph 1.2 High viscosity: SGF + 1.4% Methocel E4M Class 1: Propranolol (80 mg) Class 2: Carbamazepine (200 mg) Class 3: Atenolol (100 mg) 41

42 Propranolol (80 mg) Carbamazepine (200 mg) Atenolol (100 mg)

43 Propranolol: 10 mg tablet (Barr Labs) Warfarin: 1 mg tablet (Qualitest Pharm.) P app = 161 ± 39 P app = 47.1 ± 5.2 P app Ate = 1.17 ± 0.31 Donor Chamber (Dissolution Medium): FaSSIF (3.75 mm NaTC, 0.75 mm Lecithin), ph 6.5 Receiver Chamber (IDAS-2): HBSS with 4.5% BSA, ph 7.4

44 % D i s s v 15 % P e r m 10 5 % Permeation v Dissolution % Dissolved % Permeation v Dose Minutes 44

45 IDAS1/IDAS2 can assess the impact of dissolution on permeability IDAS1/IDAS2 experiments consider GI volume physiologic phs and the role of blood/plasma in drug transport Apparatus design for IDAS2 is a modification of the current USP Dissolution apparatus compliant with the new FDA Guidance volume recommendation of 500 ml IDAS2 allows the use of an intact dosage form (e.g., tablet) to evaluate drug dissolution simultaneously with permeation through a relevant biological membrane 45

46 Evaluation of the impact of API solid state (polymorphs, hydrates/solvates, crystalline/amorphous, etc.) on dissolution and permeability Excipient selection and/or formulation optimization IDAS1 detected differences among different products of amlodipine (Most generics products differed from the innovator in Dissolution and all differed in Permeation) Evaluation of food effects to help determine appropriate powering in clinical studies IDAS2 offers potential for speedy prototype selection for pivotal clinical Bioavailability and BE studies 46

47 Verificando la bioequivalencia (BE) durante el registro Monitoreando la consistencia entre lotes de registro y lotes en el mercado 47

48 Base de Datos de Referencia 48

49 Identificacion de parametros relevantes Durante el registro Parametros rapidamente cuantificables (Ej., algunos analisis espectroscopicos son rapidos, no son destructivos, requieren muy poco material, y permiten analizar el espesor total de la tableta) 49

50

51 Phase II: Product Evaluation (New Lot) Is test lot comparable to reference lots? Yes No Low Risk: Acquire and add data point to Database Potential Risk: Do not acquire and Investigate and/or perform additional QC tests

52 Como profesionales de la salud tenemos una especial responsabilidad de velar por la salud de nuestra poblacion No se puede asumir que los fabricantes siempre van a hacer lo mejor por los pacientes La BE es importantes para garantizar la calidad de medicamentos Intentar implementar BE basandose en pruebas clinicas no es realista y puede conllevar a un abandono total de la iniciativa. In vitro BE parece ser la mejor opcion para la region; autoridades de la salud, los gobiernos, profesionales de la de salud, pacientes y fabricantes Existen metodos (p.ej. IDAS1/2) y estrategias (p.ej. base de datos) que pueden facilitar el monitoreo lote-a-lote de los medicamentos.

53 ASLP (Exton, PA) Jibin Li, Ph.D. Libin Li, Ph.D. Yuehua Huang, Ph.D. Nourdine Nessah, M.S. Svitlana Silchenko, Ph.D. ASP (Clayton) Lily Lau Manuel Grosso Nelson Rodriguez

54

55 One-Step Receiver sampling Receiver sampling ph adj. Two-Step Donor sampling ph Receiver sampling Insert cell chamber, initiate permeation Permeation: FaSSIF (ph 6.5) 55

56 % D i s s o l v e d P e r m e a t e d N o v a s c ( U S - R L D ) D i s s o l v e d % P e r m e a t e d M i n u t e s 56

57 % D i s s o l v e d P e r m e a t e d A m l o p i n D i s s o l v e d % P e r m e a t e d M i n u t e s 57

58 % D i s s o l v e d P e r m e a t e d C i n f a D i s s o l v e d % P e r m e a t e d M i n u t e s 58

59 % D i s s o l v e d P e r m e a t e d L a S a n t e D i s s o l v e d % P e r m e a t e d M i n u t e s 59

60 % D i s s o l v e d P e r m e a t e d A m l o p r e s s D i s s o l v e d % P e r m e a t e d M i n u t e s 60

61 % D i s s o l v e d P e r m e a t e d N o v a s c ( P a n - R L D ) D i s s o l v e d % P e r m e a t e d M i n u t e s 61