Impact of the US FDA âBiopharmaceutics Classification Systemâ (BCS

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Impact of the US FDA Biopharmaceutics Classification System (BCS) Guidance on Global Drug Development Mehul U. Mehta, Ramana S. Uppoor, Dale P. Conner, Paul Seo, Jayabharathi Vaidyanathan, Donna A. Volpe, Ethan Stier, Dakshina Chilukuri, Angelica Dorantes, Tapash Ghosh, Haritha Mandula, Kimberly Raines, Pariban Dhanormchitphong, Janet Woodcock, and Lawrence X. Yu Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.7b00687 • Publication Date (Web): 27 Oct 2017 Downloaded from http://pubs.acs.org on October 29, 2017

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Molecular Pharmaceutics

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IMPACT OF THE US FDA “BIOPHARMACEUTICS CLASSIFICATION SYSTEM” (BCS) GUIDANCE ON GLOBAL DRUG DEVELOPMENT AUTHORS: Mehul U. Mehta*, Ramana S. Uppoor, Dale P Conner, Paul Seo, Jayabharathi Vaidyanathan, Donna A. Volpe, Ethan Stier, Dakshina Chilukuri, Angelica Dorantes, Tapash Ghosh, Haritha Mandula, Kimberly Raines, Pariban Dhanormchitphong, Janet Woodcock, Lawrence X Yu. AUTHORS’ AFFILIATION: Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA *CORRESPONDING AUTHOR ADDRESS Mehul U. Mehta, Ph.D. Building 51, Room 2178, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA Phone: 301-796-1573 Fax: 301-796-9994 Email: [email protected]

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KEYWORDS Biopharmaceutics classification system (BCS), bioequivalence (BE), biowaiver, permeability, solubility, dissolution, BCS class 1


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ABSTRACT The FDA guidance on application of the Biopharmaceutics Classification System (BCS) for waiver of in-vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created world-wide interest amongst biopharmaceutical scientists in regulatory agencies, academia, and industry towards its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than one hundred sixty applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the CNS area. These findings indicate a robust utilization of the BCS approach towards reducing unnecessary in-vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA’s current thinking on areas of improvement of this guidance.



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INTRODUCTION Since the mid-1990s, scientists in FDA’s Center for Drug Evaluation and Research (CDER) and the academia were working to develop an approach that would avoid un-necessary bioequivalence (BE) studies in humans. After extensive research that was supported by FDA funding, the seminal paper proposing the use of fundamental drug substance properties (solubility and permeability) towards improved product quality was published by Amidon et al. in 19951. Thus, the BCS framework was first introduced in the FDA guidance “Dissolution Testing of Immediate Release Solid Oral Dosage Forms” published in 19972. The BCS framework was further developed towards BE assessment in the guidance entitled “Waiver of Invivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System", aka, the BCS guidance, under the direction of the Biopharmaceutics Coordinating Committee of CDER and was issued in August 2000. The guidance classified drug substances into 4 classes based on high/low solubility and high/low permeability and made the recommendation that for solid oral drug products that dissolved rapidly and had a drug substance that was highly soluble and highly permeable, the invivo BE study can be waived based on similar dissolution, over the physiologic pH range, between the two different formulations of that drug substance. Since its issuance, the guidance has sparked worldwide interest amongst scientists from academia, industry and the regulatory agencies. Nearly six hundred manuscripts have been published in the peer reviewed literature involving BCS and guidelines on BCS based biowaivers have been issued by agencies like European Medicines Agency (EMA), Health Canada (HC), World Health Organization (WHO), National Sanitary Surveillance Agency of Brazil (ANVISA); in May 2015, the FDA has issued an update of its guidance issued in year 20003.


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This article begins by providing a summary of the criteria defined in the BCS guidance that have to be met by a drug substance and the drug product (based on the BCS Guidance of year 2000 since the May 2015 guidance is still in the draft form) in order to be classified as BCS Class 1. This is followed by a detailed look at the implementation of the BCS guidance into review practice at the FDA. Highlights of the formation and functioning of the CDER BCS Committee, number of applications evaluated, BCS Class 1 approvals granted on the new drug side as well as the generic drug side are provided. Issues faced in permeability determination, a key criterion of BCS Class 1 requirement, are discussed, along with deficiencies commonly seen in these applications. The article next focuses on the impact created by this guidance on the drug development in USA as well as the rest of the world. Adoption of this guidance by other regulatory agencies in the world, including WHO, is summarized. Cost savings to industry are examined. Recently, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has selected the ‘BCS Based Biowaivers’ as a topic for harmonization and details posted on the ICH website on this topic are covered. Finally, revisions of this guidance being proposed by FDA are summarized. IMPLEMENTATION BCS Class 1 Criteria: The BCS guidance recommends that in order for the drug product to be classified as BCS Class 1, the drug substance has to be Highly Soluble (HS), Highly Permeable (HP), and the drug product has to be Rapidly Dissolving (RD). HP requirement is met when the absolute bioavailability, or the urinary recovery, of the drug is 90% or greater, or its permeability is greater than that of the reference compound(s) in in-vitro or in-situ assay systems. HS



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requirement is met when the solubility of the drug over the entire physiological pH range is greater than that of concentration obtained by dividing highest strength of the drug product by 250 ml. Finally, RD requirement is met when the drug product dissolution is 85% or greater in 30 minutes at pH 1, 4.5 and 6.8. BCS Class 1 based biowaiver recommendation is that the dissolution profile of the test and the reference products is similar at pH 1, 4.5, and 6.8; in case of dissolution being 85% or greater at 15 minutes, there is no need for profile comparison. The guidance also stipulates that the excipients used have to be known excipients and in normal quantity with respect to their intended function. Also, BCS based biowaiver consideration is not applicable for Narrow Therapeutic Index (NTI) products and also not for products intended for absorbption in the oral cavity. Finally, for prodrugs, where the conversion to the drug occurs is important. If it occurs in the gastrointestinal (GI) lumen, the drug moiety should be measured to assess permeability; if it occurs post GI wall permeation, then the prodrug moiety should be measured to assess permeability. Needless to say, this is not applicable in case of absolute bioavailability or mass balance study being used to assess permeability; for radioactivity based human mass balance study, it is assumed that the molecule is labeled in the stable region of the drug, and not in the portion utilized to create the prodrug. CDER BCS Committee: Even before the guidance was finalized, the need for consistent implementation of the guidance across all the therapeutic areas of CDER was clearly recognized and it was decided to centrally coordinate the implementation. The early version of the CDER BCS Committee, for centrally coordinated implementation of the guidance, was created right after the issuance of the guidance in 2000 and the committee was officially formed in March 2004. The objectives of the committee have been the following: a) provide expert advice on all


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BCS review (new drug application [NDA] and abbreviated new drug application [ANDA]) issues especially those where Class 1 claim is requested; b) serve as the point of contact for BCS related policy, questions, interactions and classification within FDA and with the external constituents, and; c) periodically evaluate if there is a need to consider updating the BCS guidance, based on internal and public information. The committee is made up of members from different offices within CDER that have the expertise in evaluating the BCS data package. It consists of two co-chairs plus ten additional voting members plus the Project Manager (PM). The key process aspect for successful implementation was to ensure that all BCS Class 1 requests, from the new and the generic drug sides, were submitted to the committee for evaluation. This was done by communicating to each relevant review division across CDER that in case of a sponsor asking for a BCS Class 1 request, the relevant data package should be summarized and submitted to the committee for evaluation. The committee members were key in communication and successful implementation of this policy across all review units. BCS Committee Process: When an application requesting BCS Class 1 status is received, the involved reviewers from the new / generic side put together the data package from the application and submit it to the PM. The PM, in consultations with the co-chairs, sets the deadline for the members to review the package and submit their vote; generally, the time given is 2-3 weeks and in case of emergencies, the members are requested to turn in their vote within a few days. The decision making on each application is by vote; the voting options are ‘yes’, ‘no’, or ‘insufficient information’. Each member has one vote and the decision is by majority. Official minutes of the vote are circulated and archived for subsequent review related requirements. On receiving all votes, a summary is prepared and finalized. It is subsequently sent to all the members, plus the consult originators, and also archived into the official records for subsequent



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need. In some cases, if the committee members could not make a clear determination because certain critical information was missing in the submission, the vote was ‘insufficient information’. The applicant was asked to submit the specific missing data, and once this data were submitted, the vote was revised to ‘yes’ or ‘no’ after further evaluation. RESULTS: BCS Classification Determination: The BCS committee database was created soon after the issuance of the guidance to capture details of the committee’s productivity and findings. The database consists of the drug name, application number, application type, dosage form, strength, information to support BCS classification, date of action, etc. Detailed results from this database are being published separately; the summary results presented below cover approval at the investigational new drug (IND) and NDA stages, as well as approvals and tentative approvals of ANDAs, over the period of years 2004 to first quarter of 2017. Figure 1. IND, NDA, and original ANDA number of applications received / year Figure 2. Number of follow-on ANDAs approved + tentatively approved / year. Figure 1 shows the rate at which BCS based applications were submitted to the FDA per year from 2004 to the first quarter of 2017. These include applications submitted at the IND, NDA, and ANDA stages. ANDAs included here are those that were asking for BCS Class 1 designation for the first time and that’s why they are referred to as ‘original ANDAs’. Once an ANDA was granted BCS Class 1, subsequent ANDAs did not come to the committee for evaluation and were directly acted upon - approval or tentative approval granted - by the Office of Generic Drugs. These are called ‘follow-on ANDAs’ and the rate of their approval / tentative approval by year is shown in Figure 2. As can be seen from Figure 1, the rate at which BCS applications were


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submitted varied considerably from year to year, with the lowest being only two in years 2013 and 2014 versus the maximum of twelve in 2005. Thus, there was no clear trend discernable in the uptake of the BCS based biowaivers over last 12 years; it is interesting to note that for the year 2017, four applications have already been submitted in the first quarter suggesting this to be a busy year. Figure 2 shows number of follow-on ANDAs approved / tentatively approved per year and here, there is a nice trend seen. In the beginning years, i.e., 2004 and 2005, there were no such actions taken and this was followed by a very slow pace till 2008. Since 2009, the rate of follow-on ANDAs grew many fold with the peak occurring in 2016 at twenty six follow-on ANDA approvals / tentative approvals. The grand total for these follow-on ANDA approvals / tentative approvals was one hundred and ten (110). Table 1. BCS Class 1 applications received and approved for new and generic drugs from 2004 to March 2017 Type of Application

New Drug

Generic Drug

# Applications

48

25

# Approved (% of

28 (58%)

23 (92%)

total) IND Stage

NDA Stage

# Applications

18

30

# Approved (% of

12 (67%)

16 (53%)

total)



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Next, Table 1 provides a summary of the number of applications submitted and approved over the period of 2004 to March 2017. These are broken down by the category of applications, i.e., IND, NDA, and ANDA. Seventy three products came up for evaluation in little over 12 years, giving an annual rate of 6 submissions / year. Of the 73 products received, 51 (70%) were classified as BCS Class 1. Forty eight products came from the new drug side and 28 of these (58%) were given BCS Class 1 designation. Eighteen products on the new drug side were submitted at the IND stage and nearly double that amount, i.e., 30 applications, were submitted at the NDA stage. Of the 18 submitted at the IND stage, 12 received BCS Class 1 designation and agreement on biowaivers; 4 were turned down and 2 had insufficient information. Of the 30 products at the NDA stage, 16 received BCS Class 1 designation and related regulatory relief; 10 were turned down and 4 had insufficient information. Twenty five products came from the generic side. Twenty three (92%) of the 25 products from the generic side were given BCS Class 1 designation and 2 had insufficient information. Most importantly, even though the number of drug products approved from the generic side was 23, the number of ANDAs approved / tentatively approved based on BCS (Class 1 designation) was 110 since there were more than one ANDA per drug for several of the 23 drug products. Specifically, the number ranged from 1 ANDA / drug product to 15 ANDAs / drug product. Thus, the total number of applications approved based on BCS (Class 1 designation) was 51 original approvals plus 110 follow-on approvals / tentative approvals, i.e., 161 applications, which would give nearly a 12 application approvals / year rate based on BCS for last 12.25 years. Figure 3. Follow-on approved / tentatively approved ANDAs by therapeutic class


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Therapeutic Areas of BCS Class I Drugs: Next, the follow-on ANDAs were further evaluated to see if there was any trend in terms of the different therapeutic areas they belonged to. Presenting these results by specific indications resulted in too many categories and therefore in order to create a meaningful comparison, we combined different specific indications into similar therapeutic areas. An additional reason was that in some cases, there was only one ANDA approved and citing this indication would potentially divulge the innovator product. Thus, Figure 3 shows the distribution of the follow-on ANDAs by broad therapeutic classes as Analgesics, Anti-Infectives, Cardiovascular, CNS (Central Nervous System), Endocrine / Metabolic, Oncology, Pulmonary / GI, Reproductive / Urology. It should be pointed out here that the vast majority of drugs in the CNS area came from the neuropharmacology and psychiatry indications. The results are very informative. CNS area claimed nearly 70% (69/110) of all the follow-on ANDAs approved, followed by Anti-Infectives (14), Oncology (14), and Pulmonary / GI (6); Analgesics, Cardiovascular and Endocrine / Metabolic each had only two follow-on ANDAs and the lowest was Reproductive / Urology area with only one follow-on ANDA. Even though the CNS group mainly contained a couple of sub areas, generic interest in invoking BCS based biowaivers in this area was evident by nearly 70% of the applications coming from this area. A further proof of this was that one of the products in this area had 16 follow-on ANDAs, which was the highest number of follow-on ANDAs in the entire cohort of 110. It should be further pointed out here that, on the lines of results seen with the follow-on ANDAs, nearly 50% of the moieties granted BCS class 1 status at the IND/NDA stage was from the CNS area. To ensure that these results are not biased, a spot analysis was done with the year 2016 data. Analysis of all NDAs submitted to the Agency for this year by specific therapeutic area showed that CNS NDAs formed only 7% of the total NDAs submitted to the Agency. These results are typical of 2004 –



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2017 time period, i.e., CNS applications have formed a minor fraction of all the applications submitted to the Agency during this time period. [https://www.fda.gov/aboutfda/reportsmanualsforms/reports/userfeereports/performancereports/u cm2007449.htm]

DISCUSSION The BCS guidance was one of the few early guidances that was developed based on extensive academic research. The BCS guidance was built on a sound scientific framework consisting of the fundamental properties of the drug substance and the drug product, namely solubility, permeability, and dissolution and based on extensive data. The FDA took the position in this guidance that for BCS Class 1 products, in-vivo BE studies can be waived for significant changes in formulation pre and post-approval for a new drug, as well as that for a generic to reference listed drug (RLD) comparison pre-approval and significant post-approval formulation changes. In addition to bringing out the guidance, another important step FDA took that contributed to the success of the guidance was the establishment of the BCS committee that led to a centralized and consistent evaluation of all BCS related applications. The overall success for BCS Class 1 designation was 70% indicating excellent work on the part of the industry in terms of generation and submission of quality data to meet the BCS Class 1 requirements. It is interesting to note that the success ratio was significantly higher on the generic drug side since 92% of the products submitted got BCS Class 1 designation, compared to 58% on the new drug side. A possible explanation is that the ANDA applications are likely to


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benefit from the knowledge gained and made available in the public domain about the BCS nature of the innovator products. It is very interesting and satisfying to see that BCS determination, and related regulatory relief, is attempted by innovators during the IND stage itself since nearly a third of the cases submitted on the new drug side were during the IND stage. It is also interesting to note that there were several cases without sufficient information. The two major areas of insufficient information were lack of proper method suitability data for the invitro Caco-2 permeability method and lack of data showing lumen stability of radioactive material. There were several other less frequent areas of concerns also which have been pointed out by some of the authors4, namely: a) Lack of multi-pH solubility profiles; b) Inappropriate method of solubility determination; c) Lack of dissolution data for all strengths; d) Missing standard operating procedures for analytical methods; e) Lack of data on efflux transporter(s) in the cell line used for in-vitro permeability, and; f) Lack of bidirectional in-vitro data on control model compounds. A detailed look at the results reveals some interesting trends. The first one of note is that it is clearly evident that the interest in the BCS based applications, and success in their approval, has increased considerably in the recent years, particularly when taking into account the follow-on generic applications. Prior to 2014, these approvals peaked in 2009 and were following a consistent downward trend, but since 2014, there is a clear increase in successive years, with 2016 showing more than a 100% increase compared to 2014. This indicates that the BCS principle has been firmly established and utilized well by the FDA and its regulated industry. It also seems that the maximal interest in the generic industry for BCS based biowaivers was clearly in the CNS area which dominated the follow-on approvals with nearly 70% of all such approvals; as mentioned earlier, this was clearly evident by the fact for one particular product,



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there were sixteen follow-on ANDAs approved. Even more importantly, it was noted that nearly 50% of the new drugs that were granted BCS Class 1 status at the IND/NDA stage were from the CNS area. This observation coincides well with the prediction of Benet5 who states that BDDCS (Biopharmaceutics Drug Disposition Classification System) Class 1 drugs (highly soluble, highly metabolized; very similar to BCS Class 1) will have significant brain distribution and CNS effects. Several additional major therapeutic areas also had a decent number of follow-on ANDAs approved indicating the broad based utility of the BCS approach. It is very satisfying to see that the Oncology area also had several follow-on ANDAs approved indicating that the BCS approach is beneficial in this critical therapeutic area also. The success of this guidance is indicated in several ways: a) just on cost, the guidance has saved the industry in excess of $100 million. This estimate is arrived at using the method utilized by Cook et al6 and using the number of approvals summarized in this article; b) several other agencies across the globe have issued their version of the BCS guidance. EMA formalized its position on BCS in 2010, ANVISA (Brazil) in 2011, and Health Canada has come out with their final position in 2014. Perhaps the greatest impact has been seen by the utilization of this approach by the WHO which has created its Essential Medicines list and several of these products are approved based on the BCS principles across many parts of the world where there is limited regulation, and; c) most importantly, a very large number of human subjects have been spared from being subjected to unnecessary BE trials. A special mention must be made of the recent formation of the multi-disciplinary topic M9 on ‘BCS based biowaivers’ at the ICH. This topic was endorsed by the ICH Management Committee in October 2016. As stated on the ICH website, when finalized this guideline will provide recommendations to support the biopharmaceutics classification of medicinal products and will provide recommendations to


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support the waiver of bioequivalence studies. This will result in the harmonization of current regional guidelines/guidance and support streamlined global drug development. The final Concept Paper, the business plan and the work plan of the working group is available at the ICH website [http://www.ich.org]. Finally, when the FDA took this position several years ago, it intentionally chose to be on the conservative side since this was a radical change being proposed, i.e., doing away with a human BE study and considering approval decision based on robust in-vitro results. In this context, it is gratifying to note that other agencies in the world followed later but with a more liberal position based on the experience and additional research7 done following the issuance of the BCS guidance, particularly in terms of considering BCS Class 3 also for biowaivers. These developments were monitored closely by the BCS committee and several years ago, it started putting together an internal database to gather the evidence for revision of the 2000 guidance. A database of more than 200 oral immediate release dosage form NDAs was created that contained all possible critical variables like the physicochemical properties of the drug substance, formulation details, pharmacokinetic characteristics, BE study results, etc. Using this database, and other relevant information in literature, several key issues were evaluated namely: a) can the 90% threshold for high permeability be lowered?; b) can the pH range for solubility be narrowed?; c) can biowaivers be extended to BCS Class 3 drug products?. A key finding was that for some BCS Class 3 drugs, there were in-vivo BE study failures but careful evaluation concluded that these were clearly due to study design or conduct issues and not attributable to the drugs in question. Based on these results (being published separately) and extensive discussions, the BCS committee made the following updates in the 2015 guidance: a) the 90% permeability threshold was lowered to 85%; b) the pH range was narrowed to 1.2 – 6.8; c) biowaivers were



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extended to BCS Class 3 drugs but with more stringent criterion for rapid dissolution and restrictions on excipients; simulations published by Yu et. al.8 contributed significantly for setting the criterion for very rapid dissolution. These changes have brought the FDA in greater harmonization with the other agencies in terms of requirements for BCS based biowaivers. The 2015 draft guidance also has the following additional changes worthy of note: a) greater clarity in terms of data needed for drug lumen stability; b) a separate section on BCS based biowaivers consideration for FDCs (Fixed Dose Combinations); c) a table defining what can be considered ‘quantitatively similar’ for excipient quantity differences, by providing the range of change for specific excipients, and; d) a revised list of reference compounds for the in-vitro or in-situ permeability study. In conclusion, it is really gratifying to see how a scientifically fundamental concept involving basic properties of the drug substance and drug product evolved into a regulatory guidance to benefit drug development that was then accepted worldwide and enhanced with further scientific thinking. By providing appropriate in-vitro methods to replace expensive, time consuming, and avoidable in-vivo BE studies, this guidance has facilitated availability of good quality drug products at reduced cost and at a faster pace for benefit of patients across the globe. It is also equally exciting to see ongoing ideas for possible further expansion of the BCS framework, e.g., BCS Class 2 a, 2b, 2c9, etc., and the FDA BCS Committee is looking forward to participate in these discussions with the goal of further enhancing the BCS guidance.


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REFERENCES: 1. Amidon, G.L.; Lennernas, H.; Shah, V.P.; Crison, J.R. A Theoretical Basis For a Biopharmaceutics Drug classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability. Pharm. Res. 1995, 12, 413-420. 2. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. 1997. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM070237.pdf 3. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. 2015. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid ances/UCM070246.pdf 4. Nair, A.K.; Anand, O.; Chun, N.; Conner, D.P.; Mehta, M.U.; Nhu, D.T.; Polli, J.E.; Yu, L.X.; Davit, B.M. Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA. AAPS J. 2012, DOI: 10.1208/s12248-0112-9384-z



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5. Benet, L.Z. The Role of BCS (Biopharmaceutics Classification System) and BDDCS (Biopharmaceutics Drug Disposition Classification System) in Drug Development. J. Pharm. Sci. 2013, 102(1), 34-42. 6. Cook, J.A.; Davit, B.M.; Polli, J.E. Impact of Biopharmaceutics Classification SystemBased Biowaivers. Mol. Pharm. 2010, 7, 15390-1544. 7. Yu, L.X.; Amidon, G.L.; Polli, J.E.; Zhao, H.; Mehta, M.U.; Conner, D.P.; Shah, V.P.; Lesko, L.J.; Chen, M.L.; Lee, V.H.; Hussain, A.S. Biopharmacuetics Classification System: the Scientific Basis for Biowaiver Extensions. Pharm Res. 2002, 19(7), 921-5. 8. Yu, L.X.; Ellison, C.D.; Conner, D.P.; Lesko, L.J.; Hussain, A.S. Influence of Drug Release Properties of Conventional Solid Dosage Forms on the Systemic Exposure of Highly Soluble Drugs. AAPS PharmSci. 2001, 3(3), E24. 9. Tsume Y.; Mudie D.M.; Langguth P.; Amidon G.E.; Amidon G.L. The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. Eur J Pharm Sci. 2014, 57, 152-63.


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Figure 1.



20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 2.


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Figure 3.



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254x190mm (96 x 96 DPI)


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