药物BCS分类系统.ppt

1、Pharmaceutical Development with Focus on Paediatric formulations,WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 2 May 2008,Biopharmaceutical Classification System (BCS),Presented by: Lembit Rgo MD, PhD Contact details: Dr Lembit Rgo Coordin

2、ator, Quality Assurance and Safety: Medicines Medicines Policy and Standards World Health Organization Geneva Switzerland E-Mail: ,Biopharmaceutical Classification System (BCS),Background What is a problem? What is WHO doing and planning to do? What resources are available? Conclusions,W

3、hat is the key for multisource (generic) pharmaceutical products?,New medicines applicant has to prove quality, safety and efficacy Multisource (generic) pharmaceutical products applicant has to prove quality, in case of safety and efficacy it refers to the originator product The key is THERAPEUTIC

4、INTERCHANGEABILITY It is assumed that if the concentration pattern in the blood is essentially the same then the safety and efficacy profile must be essentially the same,Therapeutic interchangeability: prerequisites,Constant and reproducible quality of MPPs Manufactured under GMP Compliance with all

5、 quality specifications Variations control No constant and reproducible quality, no need for proving interchangeability as it is meaningless (all batches different anyhow),Options to show therapeutic interchangeability of multisource pharmaceutical products (MPP),The in vitro approach refers to the

6、Biopharmaceutics Classification System (BCS),Drug substance classification according to the BCS. Active pharmaceutical ingredients (APIs) are classified into classes based on their aqueous solubility and permeability characteristics,In Vitro Approaches/Biowaiver options,The possibility of in vitro d

7、ocumentation of bioequivalence for certain medicines and dosage forms is specified in Section 9 of the WHO guidance document 1. If the drug substance in question is highly soluble and highly permeable (BCS class I) and is manufactured as an immediate release dosage form, exemption from an in vivo ph

8、armacokinetic bioequivalence study may be considered provided that relevant dissolution requirements are fulfilled.,Principles,The solubility is not meant to be the absolute solubility here. In contrast high solubility refers to the highest single unit dose to be completely soluble in 250 ml aqueous

9、 buffer medium within the pH range of 1.2 to 6.8 without any stability problems. As another related physicochemical characteristic high permeability should be demonstrated for the particular API demonstrating that the fraction dose absorbed amounts to at least 85 %. Accordingly, high permeability wo

10、uld stand for almost complete absorption of the compound in humans. Physicochemical measures needed for BCS classification purposes may be taken from sound literature. The WHO Model List of Essential Medicines has been reviewed based on the BCS concept and active compounds are classified accordingly

11、 in the appendix of respective WHO document 1.,A theoretical risk assessment is mandatory to minimize risk for falsely waiving a necessary in vivo study,Situations where BCS-based biowaivers are not applicable,Assessment of risks practical points,In practice some of the criteria listed in the table

12、for risk assessment are difficult to assess e.g., the meaning of critical use or bioavailability problems, and are probably not easy to be defined. However, published literature provides valuable examples of how to evaluate the applicability of the BCS based biowaiver approach (see biowaiver monogra

13、phs on the following slide).,Available resources: Biowaiver Monographs,Biowaiver monographs are worked out by group of well established scientists linked to FIP and published in Journal of Pharmaceutical Sciences These can be useful scientific material for manufacturers when considering applications

14、 for biowaiver based on BCS The monographs as such have no regulatory authority decisions will be made by regulators who may or may not accept biowaiver depending on their national legislation and requirements,Biowaiver monographs published,Stosik A.G., Junginger H.E., Kopp S., Midha K.K., Shah V.P.

15、, Stavchansky S., Dressman J.B., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: metoclopramide hydrochloride. J Pharm Sci Feb 12 (2008) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.: Biowaiver mon

16、ographs for immediate release solid oral dosage forms: Pyrazinamide. J Pharm Sci Feb 12 (2008) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochl

17、oride. J Pharm Sci Aug 21 (2007) Becker C., Dressman J.B., Amidon G.L, Junginger H.E., Kopp S., Midha K.K., Shah V.P., Stavchansky S., Barends D.M.:Biowaiver monographs for immediate release solid oral dosage forms: isoniazid. J Pharm Sci 96 (2007) 522-31,WHO Guidance (1),The in vitro dissolution in

18、vestigations including experimental conditions and characteristics are outlined in Section 9 of the WHO guideline 1. It is of utmost importance to note that it is not sufficient to demonstrate the in vitro dissolution characteristics for the particular multisource product, but to ensure the similari

19、ty of dissolution profiles between the test and comparator products 1.,WHO guidance (2),The WHO guidance in basic aspects is similar to the US FDA guidance on the biowaiver approach (August 2000) In addition, the current scientific discussions in terms of so called biowaiver extensions are also cons

20、idered. Accordingly, BCS based biowaivers may be acceptable for drugs containing BCS class 2 and 3 drug substances manufactured as immediate release dosage forms. As an example, a biowaiver may be possible for BCS class 3 drug products that are very rapidly (i.e. at least 85 % dissolution within 15

21、min in all required media) dissolving. The relevant dissolution criteria are outlined in section 9.2.1 of the WHO guideline 1.,Regulators guidance for industry,US FDA relevant to biowaiver guidelines: /cder/Guidance/3618fnl.pdf,Conclusions,Biowaiver concept is a developing concept and new

22、 guidance documents and scientific data are appearing Proper comparator products are also crucial for biowaiver Regulatory acceptance and practice of biowaivers needs to catch up the concept development WHO will soon issue more practical implementation guidelines for PQ programme WHO PQ programme st

23、arts accepting biowaivers, as appropriate,Some useful references,(1) Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report. Geneva, World Heal

24、th Organization, 2006, WHO Technical Report Series, No. 937, Annex 7: 347-390. (2) van Faassen F., Vromans H. et al. Biowaivers for oral immediate-release products: implications of linear pharmacokinetics. Clin Pharmacokinet 43 (2004) 1117. (3) Note to Applicants on the Choice of Comparator Products for the Prequalification Project. Located on the World Health Organization (WHO) Prequalification of Medicines web site, Guidance on selection of comparator product. Web page: /pq/ (4) Shah,