药物BCS分类系统

1、药物BCS分类系统Biopharmaceutical Classification System (BCS)Presented by: Lembit Rgo MD, PhDContact details:Dr Lembit RgoCoordinator,Quality Assurance and Safety: MedicinesMedicines Policy and StandardsWorld Health OrganizationGenevaSwitzerlandE-Mail: Biopharmaceutical Classification System (BCS)Backgroun

2、dWhat is a problem?What is WHO doing and planning to do?What resources are available?ConclusionsWhat is the key for multisource (generic) pharmaceutical products?New medicines applicant has to prove quality, safety and efficacyMultisource (generic) pharmaceutical products applicant has to prove qual

3、ity, in case of safety and efficacy it refers to the originator productThe key is THERAPEUTIC INTERCHANGEABILITYIt is assumed that if the concentration pattern in the blood is essentially the same then the safety and efficacy pro be essentially the same Therapeutic interchangeability: prerequisitesC

4、onstant and reproducible quality of MPPsManufactured under GMPCompliance with all quality specificationsVariations controlNo constant and reproducible quality, no need for proving interchangeability as it is meaningless (all batches different anyhow) Options to show therapeutic interchangeability of

5、 multisource pharmaceutical products (MPP)Sensitivity/useExperimental settingGenerally regarded as most sensitive Comparative pharmacokinetic studies in humans evaluation of systemic exposure by means of pharmacokinetic measures like e.g. AUC and Cmax (and Tmax) Prerequisites should be notedComparat

6、ive in vitro tests BCS-based biowaiverSensitivity may not be optimal, rarely usedComparative pharmacodynamic studies in humans evaluation of relevant pharmacodynamic endpoints like e.g., lowered blood pressure in mm HgRarely used for oral MPP formulations with systemic actionscomparative clinical tr

7、ials evaluation of e.g., non-inferiority trialsThe in vitro approach refers to the Biopharmaceutics Classification System (BCS) BCS classificationSolubilityPermeabilityBCS class IHighHighBCS class IILow HighBCS class IIIHighLowBCS class IVLowLowDrug substance classification according to the BCS. Act

8、ive 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 documentation of bioequivalence for certain medicines and dosage forms is specified in Section 9 of t

9、he 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 pharmacokinetic bioequivalence study may be considered provided that relevant dissolution requirements

10、 are fulfilled. PrinciplesThe 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 buffer medium within the pH range of 1.2 to 6.8 without any stability problems. As another related p

11、hysicochemical characteristic high permeability should be demonstrated for the particular API demonstrating that the fraction dose absorbed amounts to at least 85 %. Accordingly, high permeability would stand for almost complete absorption of the compound in humans. Physicochemical measures needed f

12、or 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 in the appendix of respective WHO document 1.A theoretical risk assessment is mandatory to minimize

13、risk for falsely waiving a necessary in vivo studyImmediate release dosage forms with intended systemic action Formulation related considerations- critical use medicines (e.g. hormones)- non-oral, non-parenteral products with systemic action (e.g. transdermal therapeutic systems (TTS), suppositories

14、, etc.)- narrow therapeutic range (steep dose-response curve) drugs- modified release products with systemic action- where there are documented evidence of bioavailability problems (or bio-inequivalence - fixed combination products with at least one API requiring an in vivo study i.e., this API is n

15、ot eligible for the BCS based biowaiver approach- polymorphs, certain excipients, or a manufacturing process which may have implications for bioavailability- non-solution products with non-systemic action (and without systemic absorption*), e.g., topical, locally acting emulsions Situations where BC

16、S-based biowaivers are not applicable Assessment of risks practical points In practice some of the criteria listed in the table 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 liter

17、ature provides valuable examples of how to evaluate the applicability of the BCS based biowaiver approach (see biowaiver monographs on the following slide).Available resources: Biowaiver MonographsBiowaiver monographs are worked out by group of well established scientists linked to FIP and published

18、 in Journal of Pharmaceutical Sciences These can be useful scientific material for manufacturers when considering applications for biowaiver based on BCSThe monographs as such have no regulatory authority decisions will be made by regulators who may or may not accept biowaiver depending on their nat

19、ional legislation and requirements Biowaiver monographs publishedStosik A.G., Junginger H.E., Kopp S., Midha K.K., Shah V.P., 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) Becke

20、r 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: 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

21、.P., Stavchansky S., Barends D.M.: Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride. 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 imm

22、ediate release solid oral dosage forms: isoniazid. J Pharm Sci 96 (2007) 522-31WHO Guidance (1) The in vitro dissolution investigations 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

23、 to demonstrate the in vitro dissolution characteristics for the particular multisource product, but to ensure the similarity 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 appr

24、oach (August 2000)In addition, the current scientific discussions in terms of so called biowaiver extensions are also considered. 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,

25、a biowaiver may be possible for BCS class 3 drug products that are very rapidly (i.e. at least 85 % dissolution within 15 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

26、 biowaiver guidelines:ConclusionsBiowaiver concept is a developing concept and new guidance documents and scientific data are appearingProper comparator products are also crucial for biowaiver Regulatory acceptance and practice of biowaivers needs to catch up the concept developmentWHO will soon iss

27、ue more practical implementation guidelines for PQ programme WHO PQ programme starts accepting biowaivers, as appropriate Some useful references(1) Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. In: WHO Expert Committee on Spec

28、ifications for Pharmaceutical Preparations, Fortieth Report. Geneva, World Health 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