1、 Draft Guidance Temp 05/04/15 Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comme
2、nts and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http:/www.regulations.gov. Submit written comments to the Division of Dockets Man
3、agement (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Mehul Me
4、hta 301-796-1573. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) May 2015 Biopharmaceutics Revision 1 Draft Guidance Temp 05/04/15 Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral D
5、osage Forms Based on a Biopharmaceutics Classification System Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4thFloor S
6、ilver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: druginfofda.hhs.gov http:/www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and
7、 Research (CDER) May 2015 Biopharmaceutics Revision 1Contains Nonbinding Recommendations Draft Not for Implementation Draft Guidance Temp 05/04/15 TABLE OF CONTENTS I. INTRODUCTION. 1 II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM . 2 A. Solubility . 3 B. Permeability . 3 C. Dissolution 3 III. RECOM
8、MENDED METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT . 3 A. Determining Drug Substance Solubility Class 3 B. Determining Drug Substance Permeability Class . 4 1. Pharmacokinetic Studies in Humans 4 2. Intestinal Permeability Method
9、s . 5 3. Instability in the Gastrointestinal Tract 7 C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity 7 IV. BIOWAIVERS BASED ON BCS 8 V. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER . 9 A. Excipients 9 B. Prodrugs . 9 C. Fixed Dose Combinations 10 D.
10、 Exceptions . 10 1. Narrow Therapeutic Range Drugs 10 2. Products Designed to be Absorbed in the Oral Cavity . 10 VI. REGULATORY APPLICATIONS OF THE BCS 11 A. INDs/NDASs . 11 B. ANDAs 11 C. Supplemental NDAs/ANDAs (Postapproval Changes) . 11 VII. DATA TO SUPPORT A REQUEST FOR BIOWAIVERS 12 A. Data S
11、upporting High Solubility 12 B. Data Supporting High Permeability . 12 C. Data Supporting Rapid, Very Rapid, and Similar Dissolution 13 D. Additional Information . 13 ATTACHMENT A . 14 Contains Nonbinding Recommendations Draft Not for Implementation Draft Guidance Temp 05/04/15 1 Waiver of In Vivo B
12、ioavailability and Bioequivalence Studies for 1 Immediate-Release Solid Oral Dosage Forms Based on a 2 Biopharmaceutics Classification System 3 Guidance for Industry14 5 6 This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) current 7 thinking on this topic. I
13、t does not create or confer any rights for or on any person and does not operate to 8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 1
14、0 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 11 the appropriate number listed on the title page of this guidance. 12 13 14 15 16 I. INTRODUCTION 17 18 This guidance provides recommendations for sponsors of investigational new drug applica
15、tions 19 (INDs), and applicants that submit new drug applications (NDAs), abbreviated new drug applications 20 (ANDAs), and supplements to these applications for immediate-release (IR) solid oral dosage forms, 21 and who wish to request a waiver of in vivo bioavailability (BA) and/or bioequivalence
16、(BE) studies. 22 These waivers are intended to apply to: (1) subsequent in vivo BA or BE studies of formulations 23 after the initial establishment of the in vivo BA of IR dosage forms during the IND period, and (2) in 24 vivo BE studies of IR dosage forms in ANDAs. 25 26 Regulations at 21 CFR part
17、320 address the requirements for BA and BE data for approval of drug 27 applications and supplemental applications. Provision for waivers of in vivo BA/BE studies 28 (biowaivers) under certain conditions is provided at 21 CFR 320.22.2This guidance updates the 29 guidance for industry on Waiver of In
18、 Vivo Bioavailability and Bioequivalence Studies for 30 Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System,331 published in August 2000, and explains when biowaivers can be requested for IR solid oral dosage 32 forms based on an approach termed the Biopharmac
19、eutics Classification System (BCS). This 33 1This guidance has been prepared by the Office of Pharmaceutical Quality and the Office of Translational Sciences in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. 2In addition to waiver of an in vivo BE requirement
20、 under 21 CFR 320.22, there are certain circumstances in which BE can be evaluated using in vitro approaches under 21 CFR 320.24(b)(6). The scientific principles described in this guidance regarding waiver of an in vivo requirement also apply to consideration of in vitro data under that regulation.
21、In such circumstances, an in vivo data requirement is not waived, but rather, FDA has determined that in vitro data is the most accurate, sensitive, and reproducible for a product, as required under 21 CFR 320.24(a). Nonetheless, for ease of the reader, in this guidance we will refer to either the d
22、ecision to waive an in vivo BE requirement under 21 CFR 320.22 or the decision to accept in vitro BE data in accordance with 21 CFR 320.24(a) as a “biowaiver.” 3We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA Drugs guidance Web page at htt
23、p:/www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Contains Nonbinding Recommendations Draft Not for Implementation Draft Guidance Temp 05/04/15 2 guidance includes biowaiver extension to BCS class 3 drug products, and additional modifications, 34 such as criteria fo
24、r high permeability and high solubility. 35 36 In general, FDAs guidance documents do not establish legally enforceable responsibilities. 37 Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 38 as recommendations, unless specific regulatory or statutory re
25、quirements are cited. The use of 39 the word should in Agency guidances means that something is suggested or recommended, but 40 not required. 41 42 43 II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM 44 45 The BCS is a scientific framework for classifying drug substances based on their aqueous solubi
26、lity 46 and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes 47 into account three major factors that govern the rate and extent of drug absorption from IR solid oral 48 dosage forms: (1) dissolution, (2) solubility, and (3) intestinal permeability.4Acco
27、rding to the BCS, 49 drug substances are classified as follows: 50 51 Class 1: High Solubility High Permeability 52 Class 2: Low Solubility High Permeability 53 Class 3: High Solubility Low Permeability 54 Class 4: Low Solubility Low Permeability 55 56 In addition, some IR solid oral dosage forms ar
28、e categorized as having rapid or very rapid557 dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug 58 development tool to help sponsors/applicants justify requests for biowaivers. 59 60 Observed in vivo differences in the rate and extent of absorption of
29、a drug from two 61 pharmaceutically equivalent solid oral products may be due to differences in drug dissolution in 62 vivo.6However, when the in vivo dissolution of an IR solid oral dosage form is rapid or very rapid 63 in relation to gastric emptying and the drug has high solubility, the rate and
30、extent of drug absorption 64 is unlikely to be dependent on drug dissolution and/or gastrointestinal (GI) transit time. Under such 65 circumstances, demonstration of in vivo BA or BE may not be necessary for drug products 66 containing class 1 and class 3 drug substances, as long as the inactive ing
31、redients used in the dosage 67 form do not significantly affect absorption of the active ingredients. 68 69 The BCS approach outlined in this guidance can be used to justify biowaivers for highly soluble and 70 highly permeable drug substances (i.e., class 1) as well as highly soluble and low permea
32、ble drug 71 substances (i.e., class 3) in IR solid oral dosage forms that exhibit rapid or very rapid in vitro 72 dissolution using the recommended test methods. The recommended methods for determining 73 solubility, permeability, and in vitro dissolution are discussed below. 74 75 4Amidon GL, Lenne
33、rns H, Shah VP, and Crison JR, 1995, A Theoretical Basis For a Biopharmaceutics Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res, 12: 413-420. 5Yu LX, Amidon GL, Polli JE, Zhao H, Mehta MU, Conner DP, et al, 2002, Biopharmaceutics class
34、ification system: The scientific basis for biowaiver extensions, Pharm Res, 19(7):921-5. 6See footnote 4. Contains Nonbinding Recommendations Draft Not for Implementation Draft Guidance Temp 05/04/15 3 A. Solubility 76 77 The solubility class boundary is based on the highest strength of an IR produc
35、t that is the subject of a 78 biowaiver request. A drug substance is considered highly soluble when the highest strength is 79 soluble in 250 mL or less of aqueous media over the pH range of 1-6.8. The volume estimate of 250 80 mL is derived from typical BE study protocols that prescribe administrat
36、ion of a drug product to 81 fasting human volunteers with a glass (about 8 ounces) of water. 82 83 B. Permeability 84 85 The permeability class boundary is based indirectly on the extent of absorption (fraction of dose 86 absorbed, not systemic BA) of a drug substance in humans, and directly on meas
37、urements of the rate 87 of mass transfer across human intestinal membrane. Alternatively, other systems capable of 88 predicting the extent of drug absorption in humans can be used (e.g., in situ animal, in vitro epithelial 89 cell culture methods). A drug substance is considered to be highly permea
38、ble when the extent of 90 absorption in humans is determined to be 85 percent or more of an administered dose based on a 91 mass balance determination (along with evidence showing stability of the drug in the GI tract) or in 92 comparison to an intravenous reference dose. 93 94 C. Dissolution 95 96
39、An IR drug product is considered rapidly dissolving when 85 percent or more of the labeled amount 97 of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) 98 Apparatus I at 100 rpm (or Apparatus II at 50 rpm or at 75 rpm when appropriately justified (see 99 sectio
40、n III.C.) in a volume of 500 mL or less in each of the following media: (1) 0.1 N HCl or 100 Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or 101 Simulated Intestinal Fluid USP without enzymes. 102 103 An IR product is considered very rapidly dissolving wh
41、en 85 percent or more of the labeled amount 104 of the drug substance dissolves within 15 minutes using the above mentioned conditions. 105 106 107 III. RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG 108 SUBSTANCE AND FOR DETERMINING THE DISSOLUTION 109 CHARACTERISTICS OF A DRUG PRODUCT 110 111 The
42、following approaches are recommended for classifying a drug substance and determining the 112 dissolution characteristics of an IR drug product according to the BCS. 113 114 A. Determining Drug Substance Solubility Class 115 116 An objective of the BCS approach is to determine the equilibrium solubi
43、lity of a drug substance 117 under physiological pH conditions. The pH-solubility profile of the test drug substance should be 118 determined at 37 1oC in aqueous media with a pH in the range of 1-6.8. A sufficient number of pH 119 conditions should be evaluated to accurately define the pH-solubilit
44、y profile within the pH range of 120 1-6.8. The number of pH conditions for a solubility determination can be based on the ionization 121 characteristics of the test drug substance to include pH = pKa, pH = pKa +1, pH = pKa-1, and at pH 122 = 1 and 6.8. A minimum of three replicate determinations of
45、 solubility in each pH condition is 123 Contains Nonbinding Recommendations Draft Not for Implementation Draft Guidance Temp 05/04/15 4 recommended. Depending on study variability, additional replication may be necessary to provide a 124 reliable estimate of solubility. Standard buffer solutions des
46、cribed in the USP are considered 125 appropriate for use in solubility studies. If these buffers are not suitable for physical or chemical 126 reasons, other buffer solutions can be used. Solution pH should be verified after addition of the drug 127 substance to a buffer. Methods other than the trad
47、itional shake-flask method, such as acid or base 128 titration methods, can also be used with justification to support the ability of such methods to predict 129 equilibrium solubility of the test drug substance. Concentration of the drug substance in selected 130 buffers (or pH conditions) should b
48、e determined using a validated stability-indicating assay that can 131 distinguish the drug substance from its degradation products.7If degradation of the drug substance 132 is observed as a function of buffer composition and/or pH, it should be reported. The solubility class 133 should be determine
49、d by calculating the volume of an aqueous medium sufficient to dissolve the 134 highest strength in the pH range of 1-6.8. A drug substance should be classified as highly soluble 135 when the highest strength is soluble in 2)8,9, using selected model drugs or chemicals at concentrations that do not saturate the 195 efflux system (e.g., digoxin, vinblastine, rhodamine 123). We recommend limiting the use of 196 animal or in vitro permeability test methods for drug substances that are transported by 197 passive mechanisms (efflux ratio of the test drug should be
