Agitation Rate and Time for Complete Dissolution in BCS Biowaivers

Article pubs.acs.org/molecularpharmaceutics

Agitation Rate and Time for Complete Dissolution in BCS Biowaivers Based on Investigation of a BCS Biowaiver for Dexketoprofen Tablets Alfredo Garcia-Arieta,*,† John Gordon,‡ Luther Gwaza,§ V. Mangas-Sanjuan,∥ Covadonga Á lvarez,⊥ and Juan J. Torrado⊥

Mol. Pharmaceutics 2015.12:3194-3201. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/02/18. For personal use only.

†

División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, 28022 Madrid, Spain ‡ Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada § Evaluations and Registration Division, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe ∥ Pharmacokinetics and Pharmaceutical Technology Area, Engineering Department, Miguel Hernández University, 03560 San Juan de Alicante, Spain ⊥ Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain ABSTRACT: The objective of the present work is to investigate the validity of the existing requirements for BCS biowaivers of immediate release products containing a class I drug in relation to the agitation rate (50 or 75 rpm in the paddle apparatus) and the time limit for complete dissolution (30 min) in the current biowaivers in vitro dissolution tests. Further, the possibility of extensions will be examined since it has been proposed that the time limit for complete dissolution should be revised to 60 min, and also, if cone formation occurs with apparatus 2 at 50 rpm, then a higher agitation rate is acceptable to eliminate it. The development of four generic dexketoprofen immediate release tablets is described. Dexketoprofen is the eutomer of ketoprofen. According to the BCS, dexketoprofen is a class I drug. Three out of the four products failed to show bioequivalence for Cmax in the initial bioequivalence study conducted with the product despite similar but nonrapid dissolution profiles at 50 rpm in the paddle apparatus, or similar and very rapid dissolution profiles at 75 rpm. In conclusion, these data indicate that BCS biowaivers for class I drugs should be granted only when dissolution with the paddle apparatus is complete in 30 min at 50 rpm. The time limit for complete dissolution should not be extended to 60 min. Furthermore, the agitation rate should not be increased to 75 rpm, even in the case of a coning effect. KEYWORDS: dexketoprofen, BCS class I, in vitro dissolution, bioequivalence, biowaiver

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INTRODUCTION In 1995 Amidon et al.1 proposed a biopharmaceutics classification system (BCS) that was taken into account by the US Food and Drug Administration (FDA) to define the requirements for scale-up and postapproval changes of immediate release solid oral dosage forms the same year.2 In 2000 the FDA issued its BCS biowaiver guideline3 that allows the use of in vitro dissolution data instead of in vivo studies to demonstrate bioequivalence for oral immediate release products containing class I drugs. Subsequently, the World Health Organization (WHO)4 and other regulatory agencies5,6 followed these recommendations to make bioequivalent products more affordable, especially in developing countries, since a biowaiver reduces significantly the cost of generic product development. Consequently, BCS-biowaivers have had a huge impact on the regulatory field. However, some minor differences exist between the recommendations of other jurisdictions because the FDA requirements were considered © 2015 American Chemical Society

too conservative by some (e.g., the FDA requirements were reduced with regard to the pH range where solubility needs to be investigated from 1.0−7.5 to 1.2−6.8, and the cutoff value for high permeability was reduced from 90% to 85%).4−6 However, in other cases the requirements have been increased in subsequent guidelines, e.g., the highest single therapeutic dose is used for the calculation of solubility instead of the highest strength, the amount of critical excipients should be identical even for class I drugs,5,6 and in the European Union (EU), only human permeability/absorption data has been considered acceptable.5 Also the limitation of BCS biowaivers to class I drugs only as indicated in the FDA guidance was considered too conservative and several extensions were Received: Revised: Accepted: Published: 3194

February 11, 2015 June 23, 2015 August 3, 2015 August 3, 2015 DOI: 10.1021/acs.molpharmaceut.5b00131 Mol. Pharmaceutics 2015, 12, 3194−3201

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Molecular Pharmaceutics proposed.7−9 Class III drugs were considered reasonable candidates for biowaivers,10 and presently the World Health Organization (WHO),4 the European Union,5 and Canada6 accept BCS biowaivers for class III drugs under stricter conditions on dissolution and excipient composition. Class II drugs that are highly soluble at pH 6.8 only (class IIa drugs) have been proposed also as candidates for BCS biowaivers,9 but only the WHO adopted this possibility.4 Later, it was demonstrated that the present dissolution methodology is not able to detect in vivo differences in rate of release/absorption for these drugs.11,12 Consequently, the WHO recommendations have been reviewed and the waiver for BCS class IIa drugs is no longer recommended.13 This illustrates that the review of failed bioequivalence studies can provide evidence for finetuning regulatory requirements that have been defined based on theoretical grounds. The objective of the present work is to investigate the validity of the existing requirements for BCS biowaivers of immediate release products containing a class I drug in relation to the agitation rate (50 or 75 rpm in the paddle apparatus) and the time limit for complete dissolution (30 min) in the current in vitro dissolution tests. Further, the possibility of extensions will be examined since it has been proposed that the time limit for complete dissolution should be revised to 60 min, and also, if cone formation occurs in apparatus 2 at 50 rpm, then a higher speed is acceptable to eliminate its formation.8 In fact, the WHO recommends the use of 75 rpm,4 instead of 50 rpm, with the paddle apparatus, and the EMA guideline5 is not clearly strict on this issue. To this end the experience gained with formulations that failed to show bioequivalence in the development of dexketoprofen generics is described.

Table 1. Qualitative Composition of the Reference Product and the Tablets That Failed to Show Bioequivalence dexketoprofen 25 mg film-coated tabletsa reference (enantyum)

product 1

product 2

product 3

qualitative composition of excipients core: microcrystalline cellulose, maize starch, glycerol distearate, sodium starch glycolate coating: hypromellose, titanium dioxide, polyethylene glycol (PEG) 600, and propylene glycol core: microcrystalline cellulose, maize starch, pregelatinized starch, hypromellose, colloidal silica, and magnesium stearate coating: hypromellose, titanium dioxide, and PEG 400 core: microcrystalline cellulose, maize starch, magnesium stearate, sodium starch glycolate, and colloidal silica coating: hypromellose, titanium dioxide, PEG 600, and talc core: microcrystalline cellulose, pregelatinized starch, magnesium stearate, and sodium starch glycolate coating: hypromellose, polydextrose, titanium dioxide, and PEG 4000

a

Products are identified differently in Tables 1 (numbers) and 2 (letters) for confidentiality reasons.

bioavailability; therefore, the differences in bioavailability, if any, have to be caused by differences in the in vivo dissolution. Similarly, the composition of the formulations that were shown to be bioequivalent to the reference product do not contain any critical excipients as can be verified in the Summary of Product Characteristics of the approved generics that is publicly available.17 Reagents were of analytical grade. Methods. In Vivo Bioequivalence Studies. Two-sequence two-period crossover bioequivalence studies were conducted in all cases. The sample size of the studies is given in Table 2. The sampling times of the eight bioequivalence studies were slightly different, but in all cases the concentration−time profile was adequately characterized and the failure to show bioequivalence was not related to an inadequate sampling schedule. The plasma concentrations were analyzed in all studies with an LC−MS/MS method that was validated according to the existing regulatory guidelines.18,19 In Vitro Studies. Dissolution studies were performed by the Applicants as part of the pharmaceutical development using apparatus 2 (paddle apparatus) at 50 and/or 75 rpm using 900 mL of various dissolution media at pH 1.2, 4.5, and 6.8. Buffers were prepared according to the European Pharmacopeia.20 All dissolution studies were performed at 37 ± 0.5 °C. Samples were filtered immediately and assayed by UV detection or HPLC-UV method. Dissolution profiles were compared with the f2 similarity factor, if necessary (i.e., where dissolution is not complete in 15 min). The similarity factor was calculated as required by the FDA (until both test and reference product reaches ≥85% dissolved)21 and the EMA method4 (until one of the products reaches ≥85% dissolved). Graphical analysis was performed using R software (http:// cran.r-project.org, version 3.1.0) and RStudio.

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EXPERIMENTAL SECTION Materials. Drug Substance. Dexketoprofen is the active enantiomer of ketoprofen, which has been developed as the trometamol salt to increase its dissolution rate.14 According to the BCS, dexketoprofen is a class I drug. Ketoprofen is classified as a class II drug, with a lowest solubility at pH 1.2 of 0.13 mg/mL.15 Assuming the same solubility for dexketoprofen trometamol, 32.5 mg of dexketoprofen could be solubilized in 250 mL of pH 1.2 buffered water at 37 °C. These results are consistent with data reported by some applicants (e.g., 0.26 mg/mL) of dexketoprofen products. Importantly, the maximum strength and maximum single dose of dexketoprofen is 25 mg,16 in contrast to the 100 mg of ketoprofen. Therefore, dexketoprofen can be considered as highly soluble and ketoprofen as having low solubility. The permeability of dexketoprofen, as in the case of ketoprofen, is considered high.14,15 Drug Products. Innovator dexketoprofen trometamol tablets (Enantyum 25 mg film-coated tablets) were authorized in April 1996, and 19 generic products have been approved in Spain as of 2013, although they are based only on four different developments. As a class I drug, demonstration of bioequivalence is supposed to be uncomplicated, especially since dexketoprofen is not a highly variable drug.14 However, the reference product does not exhibit rapid dissolution, and therefore, it does not behave like an oral solution. The qualitative composition of these dexketoprofen 25 mg film-coated tablets is described in Table 1. No critical excipients known to be able to affect bioavailability are included in the tablet core of these formulations, and the coatings are not considered to affect

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RESULTS The results of the bioequivalence studies conducted for the development of dexketoprofen generics in Spain are described in Table 2. The first company conducted two bioequivalence studies with the initial formulation, and both failed to show bioequivalence (A1 and A2). The company hypothesized that the first failed bioequivalence study might be a false negative 3195

DOI: 10.1021/acs.molpharmaceut.5b00131 Mol. Pharmaceutics 2015, 12, 3194−3201

Article

Molecular Pharmaceutics

Table 2. In Vivo Bioequivalence Studies Results of Dexketoprofen from Four Different Product Development Manufacturersa productb

study

batches

parameter

P.E.

90% CI

CV (%)

A

1 n = 29

test: D002 ref: 10063 test: D001 ref: 11016 test: E005 ref: 11080 test: 210/A ref: 10006 test: 311/A ref: 11043 test: 12024C ref: 11059 test: 12113C ref: 12095 test: SP078725 ref: 11022

Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC

79.71 99.59 69.87 97.74 103.36 99.07 116.45 101.37 99.08 107.99 112.24 101.91 98.91 100.49 101.26 99.61

69.73−90.43 95.65−103.69 62.54−78.05 95.42−100.11 94.69−112.81 97.01−101.17 102.65−132.10 98.78−104.02 90.46−108.51 104.29−111.82 100.36−125.53 99.16−104.74 91.51−106.91 98.64−102.37 89.80−114.18 96.32−103.01

29.68 9.04 30.84 6.54 25.38 6.00 24.61 4.97 20.55 7.80 27.75 6.67 22.73 5.36 30.35 8.31

2 n = 42 3 n = 46 B

1 n = 22 2 n = 29

C

1 n = 34 2 n = 47

D

1 n = 35

a

n: simple size. Test: generic product batch number. Ref: reference product batch number. P.E.: point estimate. 90% CI: 90% confidence interval. CV: coefficient of variation of the residual variability. Bold type is used to highlight the results outside of the acceptance range 80.00−125.00%. b Products are identified differently in Tables 1 (numbers) and 2 (letters) for confidentiality reasons.

Figure 1. In vitro dissolution profiles of dexketoprofen (Company A) from three different products (A1, A2, and A3) under different pH conditions. Red line represents reference product, and blue line represents test product. Gray dotted lines indicate 85% dissolved at 15 min.

dissolution. After formulation and manufacturing process changes, the product was shown to be bioequivalent (A3). The second and the third companies conducted an initial bioequivalence study (B1 and C1) that failed to show bioequivalence because the test products exhibited a quicker dissolution rate than the reference product. After some modifications in the manufacturing process, the generic products (B2 and C2) were able to show bioequivalence. The

study, and hence, the study was repeated with different test and reference batches with more similar dissolution profiles. As both test batches were taken from the three batches employed to validate the manufacturing process, and both batches are identical in composition, on one hand, and on the other hand, all batches of the reference product are assumed to have a similar bioavailability, it was confirmed that the test product exhibited a lower Cmax, which was caused by a slower in vivo 3196


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Figure 2. In vitro dissolution profiles of dexketoprofen (company B) from two different products (B1 and B2) under different pH conditions and agitation rates (50 and 75 rpm). Red line represents reference product, and blue line represents test product. Gray dotted lines indicate 85% dissolved at 15 min.

highly permeable,15 and it exhibits a short half-life (1.65 h),16 which makes its Cmax sensitive to changes in the in vivo dissolution rate.22 At the same time, the current in vitro methodology is not able to predict the in vivo dissolution when it is not rapid (i.e., 85% in 15 min) we would assume that dissolution occurs in the stomach, and gastric emptying would be the factor controlling the rate of absorption. However, in this case, the relatively low gastric dissolution rate seems to be slower than gastric emptying and some dexketoprofen is likely to exit the stomach undissolved. Most drugs exhibit a longer half-life or less permeability; consequently, a small difference in the fraction of dose dissolved at the time of gastric emptying is not reflected in Cmax, but for dexketoprofen the very high permeability and the short half-life increases the Cmax sensitivity. In contrast, AUC is consistently bioequivalent for dexketoprofen because sooner or later the whole dose is absorbed due to its very high permeability. In these three failed developments we can observe a first formulation (A1 and A2) that exhibited a slower in vivo dissolution rate that caused a point estimate 20% lower in the first bioequivalence study and 30% lower in the second bioequivalence study. In the second (B1) and the third (C1) failed generic developments the generics exhibited a quicker in

fourth company (D) was able to show bioequivalence in the first bioequivalence study conducted with the product. In order to investigate if these in vivo results can be predicted by the in vitro dissolution tests currently employed for a BCS biowaiver application, the dissolution profiles obtained by these sponsors were collected. The data submitted by these companies are shown in Figures 1−4. Some of these companies conducted studies at 75 rpm in addition to the usual 50 rpm because a coning effect was observed at 50 rpm. Moreover, although complete dissolution is obtained eventually, the sponsors expected a more rapid dissolution for a class I drug and the slow dissolution observed at 50 rpm was not desired, e.g., for quality control purposes.

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DISCUSSION The results described in this article show that immediate release products containing class I drugs are not always uncomplicated. In Spain, three out of four generic developments of dexketoprofen tablets were not successful in the first attempt/bioequivalence study (Table 2). Seventy-five percent with initial failures seems to be an unreasonably high proportion of failures if one were to anticipate that only gastric emptying were responsible for Cmax in statistically powered bioequivalence studies. In the case of the innovator dexketoprofen immediate release tablet, the release is not rapid, and this release seems to be difficult to mimic in vivo, in contrast to the cases where the tablets dissolve very rapidly and behave like oral solutions. These failures to show bioequivalence in Cmax (Table 2) seem to occur because dexketoprofen, like ketoprofen, is very 3197


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Figure 3. In vitro dissolution profiles of dexketoprofen (company C) from two different products (C1 and C2) under different pH conditions and agitation rates (50 and 75 rpm). Red line represents reference product, and blue line represents test product. Gray dotted lines indicate 85% dissolved at 15 min.

vivo dissolution rate and higher Cmax compared to the comparator product. In the second case it was 15% higher in the point estimate, and in the third, it was 10% higher. Generally, and as shown in all the three failed developments, a point estimate difference greater than 10% will result in failure to demonstrate bioequivalence as the sample size required is calculated under the assumption that the products are more similar (e.g., difference 85%) in 30 min in the paddle apparatus at 50 rpm in any of the buffer media for all companies despite some interlaboratory and interbatch differences. In addition, a large variability is observed, and this precludes the use of the f2 similarity factor for dissolution profile comparison. The companies argued that a coning effect caused this slow and incomplete dissolution. Notably, complete dissolution was reached at longer sampling times that are not shown. Consequently, the agitation rate was increased to 75 3198


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Figure 4. In vitro dissolution profiles of dexketoprofen (company D) from product (D1) under different pH conditions. Red line represents reference product, and blue line represents test product. Gray dotted lines indicate 85% dissolved at 15 min.

a class II drug at the only buffer media (pH 6.8) under assessment.24 Of course this should not normally be acceptable in variations or in BCS biowaivers. Furthermore, the omission of some of the last sampling times (e.g., at 20 and 25 min) would have also produced a f2 value above 50 with the FDA method. Therefore, it is essential to predefine the sampling times in a protocol and to verify that all appropriate sampling times are considered in the calculation of f2. In this case, dissolution was not complete in 30 min at pH 4.5 for the reference product. Otherwise, a BCS biowaiver would have been possible. Therefore, it seems clear that the dissolution time limit of 30 min should not be extended to 60 min as it has been proposed previously.8 Interestingly, at 75 rpm the f2 similarity factor was always below 50, suggesting that this agitation rate is more discriminative. However, at 75 rpm the reference product dissolved more quickly and the test product exhibited a higher Cmax. Therefore, at 75 rpm the dissolution profiles detected the differences in the wrong direction, and they are not predictive of the in vivo bioequivalence outcome. After this failure, the test product was modified to exhibit a much slower dissolution at 50 rpm. Interestingly, despite a much slower dissolution, the new product was bioequivalent in vivo. It cannot be claimed that the current dissolution tests are overdiscriminative because for the previous product (B1) it was hardly able to detect the existing in vivo difference. Therefore, it can be concluded that the current dissolution methodology of paddle apparatus at 50 rpm is not indicative of the in vivo bioequivalence for this immediate release product containing a class I drug with nonrapid dissolution. In the third failed generic development (Figure 3) the dissolution profiles were conducted at 50 and 75 rpm. At 75 rpm the dissolution profiles were complete in 15 min, and, therefore this product (C1) could have been waived based on a BCS biowaiver according to the WHO.4 However, the slight difference in the in vivo dissolution rate, which caused a 10% mean difference in Cmax and marginal failure in the 90% confidence interval of Cmax, cannot be detected at 75 rpm. Therefore, it cannot be claimed that in this case the in vitro dissolution profiles are more discriminatory or as discriminatory as the in vivo studies.25 In contrast, at 50 rpm a BCS biowaiver is not possible because dissolution is not complete in 30 min at pH 1.2, and the f2 value is below 50 at pH 6.8. After the failed bioequivalence study, some modifications were introduced to slow the release slightly, and the new product was found to be bioequivalent. Importantly, this company did not rely on the data at 50 rpm due to the coning

rpm by some of them (Figures 2 and 3). At 75 rpm dissolution was complete in 15 or 30 min. Consequently, a BCS biowaiver for dexketoprofen would not be possible if dissolution is required to be complete (>85%) in 30 min at 50 rpm, but it would be acceptable if the use of a 75 rpm agitation rate is allowed.4 A detailed assessment of the data of the first failed development shows that the batches of the first failed bioequivalence study (A1) exhibited similar dissolution profiles at 50 rpm (Figure 1). Therefore, the extension of the dissolution time from 30 to 60 min as it has been proposed8 is not appropriate. Otherwise, formulation A1 would have been waived from the in vivo study and the BCS biowaiver would have concluded bioequivalence for a product with a Cmax point estimate outside of the acceptance range 80−125%. In the batches tested in the second failed bioequivalence study (A2) the dissolution profiles were not similar at pH 1.2 because the reference batch behaved more slowly than expected. The test product behaved as expected because test batches D001 and D002 were exactly the same formulation, and these batches were two of the three batches manufactured for the validation of the manufacturing process. Thus, they can be considered almost identical. This illustrates that the dissolution tests can provide slightly different results if repeated with several batches of the reference or test product, and these differences could be lager if tested in different laboratories. In this case the dissolution profiles were complete at 30 min in buffer media at pH 4.5 and 6.8. It was only pH 1.2 that precluded obtaining a BCS biowaiver. Therefore, significant caution is necessary when dealing with BCS biowaivers because the core method of comparison is subject to the obvious risks associated with repeated testing since it is much easier to repeat than in vivo studies due to the higher cost and complexity of in vivo studies. Surprisingly, the dissolution profiles between the test batches of study A2 (D001) and A3 (E005) did not change notably, but the product became bioequivalent in study A3. This suggests that the current in vitro dissolution requirements at 50 rpm in the paddle apparatus are not discriminative between bioequivalent and nonbioequivalent formulations with nonrapid dissolution rate (85% in 30 min at pH 1.2. Although dissolution testing has been considered to be more discriminative than in vivo bioequivalence testing25 and the present BCS biowaiver criteria have been identified as extremely conservative,8 this is not always the case as illustrated by dexketoprofen immediate release tablets. Therefore, BCS biowaivers for class I drugs should be applied as required by the US-FDA3 or Health Canada6 with regard to agitation rate and time for complete dissolution.

effect and based the development in the data at 75 rpm. At 75 rpm, similarity between C1 and C2 is observed in the three pH buffers. On the contrary, at 50 rpm the difference between C1 and C2 observed at pH 1.2 is in the contrary direction of the in vivo Cmax difference, but it is in the same direction at pH 4.5 and 6.8. Regarding the comparison between test and reference, profiles at 75 rpm were similar again, which is not surprising since they have been shown to be nonpredictive previously with B1. At 50 rpm the profiles were similar for C2 and dissimilar at pH 6.8 for C1, which shows predictive power in contrast to the case of A1, but a BCS biowaiver would not have been granted for C2 if complete dissolution had been requested at 30 min because this requirement was not fulfilled at pH 1.2. In the fourth development (Figure 4) that succeeded in the first attempt, dissolution profiles were investigated only at 50 rpm and the profiles of the reference product were not complete in 30 min in all the three pHs, which precludes a BCS biowaiver presently. In this case the f2 similarity factor was more discriminative than the in vivo study25 because at pH 1.2 the f2 value was below 50 and the product was bioequivalent in vivo, as we would have expected also in the other cases. The present work has several limitations. First, it is a retrospective assessment of data submitted by the Applicants that reflects the real situations that regulators may face to make a decision on a BCS biowaiver. It could be argued that a prospective investigation in a single laboratory would be preferable to avoid bias; however, such types of studies are difficult to conduct because they are not profitable. Therefore, as regulators we need to obtain this information from failed generic developments. Second, in this case the dissolution profiles showed variability larger than acceptable for the use of the f2 similarity factor. However, f2 has been used because it is the simplest way to address similarity. Furthermore, even though in the United States the use of multivariate methods may be acceptable, they seem to be more permissive than f2 with the methodology recommended by the FDA.21 Therefore, it is expected that the use of a multivariate method would have concluded similarity in more cases than the f2, but not the contrary. In any case, the exact values are not critical since the objective is to show that complete dissolution in 30 min at 50 rpm in the paddle apparatus is essential to ensure bioequivalence and that in vivo trends are not always predicted by current in vitro dissolution tests (i.e., for A1 and A2 at 50 rpm and for B1 and C1 at 75 rpm) if dissolution is not rapid. Third, some of the profiles do not reach complete dissolution for both products, and a proper f2 calculation cannot be performed. These profiles were not conducted to obtain a BCS biowaiver, but simply as part of the pharmaceutical development. The Applicants did not consider longer sampling times to be necessary, and they are not available.

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AUTHOR INFORMATION

Corresponding Author

́ *Address: División de Farmacologiá y Evaluación Clinica, Departamento de Medicamentos de Uso Humano Agencia, Españ ola de Medicamentos y Productos, Sanitarios C/ Campezo 1, Edificio 8, Planta 2 Oeste, E-28022 Madrid, Spain. E-mail: [email protected]. Phone: +34 91 82 25 167. Fax: +34 91 82 25 161. Notes

This manuscript represents the personal opinion of the authors and does not necessarily represent the views or policy of their corresponding Regulatory Authorities. The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The pharmaceutical companies that allowed the anonymous publication of the data included in these generic pharmaceutical developments are acknowledged.

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REFERENCES

(1) Amidon, G. L.; Lennernas, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12 (3), 413−20. (2) FDA. Guidance for Industry Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation; 1995. (3) FDA. Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System; 2000. (4) WHO. Multisource (generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability, No. 937; 2006. (5) EMA. Guideline on the Investigation of Bioequivalence; 2010. (6) Health Canana. Release of Guidance Document: Biopharmaceutics Classification System Based Biowaiver2014 (7) Polli, J. E.; Abrahamsson, B. S.; Yu, L. X.; Amidon, G. L.; Baldoni, J. M.; Cook, J. A.; Fackler, P.; Hartauer, K.; Johnston, G.; Krill, S. L.; Lipper, R. A.; Malick, W. A.; Shah, V. P.; Sun, D.; Winkle, H. N.; Wu, Y.; Zhang, H. Summary workshop report: bioequivalence, biopharmaceutics classification system, and beyond. AAPS J. 2008, 10 (2), 373− 9. (8) Polli, J. E.; Yu, L. X.; Cook, J. A.; Amidon, G. L.; Borchardt, R. T.; Burnside, B. A.; Burton, P. S.; Chen, M. L.; Conner, D. P.; Faustino, P. J.; Hawi, A. A.; Hussain, A. S.; Joshi, H. N.; Kwei, G.; Lee, V. H.; Lesko, L. J.; Lipper, R. A.; Loper, A. E.; Nerurkar, S. G.; Polli, J. W.; Sanvordeker, D. R.; Taneja, R.; Uppoor, R. S.; Vattikonda, C. S.; Wilding, I.; Zhang, G. Summary workshop report: biopharmaceutics classification system–implementation challenges and extension opportunities. J. Pharm. Sci. 2004, 93 (6), 1375−81. (9) 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.;

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CONCLUSIONS In summary, these data indicate that for nonrapidly dissolving formulations where a paddle apparatus is used, BCS biowaivers should be granted only if complete dissolution (>85%) is obtained in all pH media in 30 min at 50 rpm. The limit of 30 min should not be extended to 60 min. Furthermore, BCS biowaivers should not be conducted at 75 rpm, even in the case of coning effect, as recommended by WHO4 or as potentially possible according to the EMA guideline,5 which simply says that the agitation speed to be employed is usually 50 rpm. BCS biowaivers for dexketoprofen tablets are not possible with the 3200


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Molecular Pharmaceutics Hussain, A. S. Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharm. Res. 2002, 19 (7), 921−5. (10) Blume, H. H.; Schug, B. S. The biopharmaceutics classification system (BCS): class III drugs - better candidates for BA/BE waiver? Eur. J. Pharm. Sci. 1999, 9 (2), 117−21. (11) Alvarez, C.; Nunez, I.; Torrado, J. J.; Gordon, J.; Potthast, H.; Garcia-Arieta, A. Investigation on the possibility of biowaivers for ibuprofen. J. Pharm. Sci. 2011, 100 (6), 2343−9. (12) Cristofoletti, R.; Chiann, C.; Dressman, J. B.; Storpirtis, S. A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: a crosssectional survey with 500 bioequivalence studies. J. Pharm. Sci. 2013, 102 (9), 3136−44. (13) WHO. Multisource (Generic) Pharmaceutical Products: Guidelines on Registration requirements to Establish Interchangeability. WHO Expert Committee on Specification for Pharmaceutical Preparations, 49th report. WHO Technical Report Series, No. 992; 2015. pp 131−184. (14) Barbanoj, M. J.; Antonijoan, R. M.; Gich, I. Clinical pharmacokinetics of dexketoprofen. Clin. Pharmacokinet. 2001, 40 (4), 245−62. (15) Shohin, I. E.; Kulinich, J. I.; Ramenskaya, G. V.; Abrahamsson, B.; Kopp, S.; Langguth, P.; Polli, J. E.; Shah, V. P.; Groot, D. W.; Barends, D. M.; Dressman, J. B. Biowaiver monographs for immediaterelease solid oral dosage forms: ketoprofen. J. Pharm. Sci. 2012, 101 (10), 3593−603. (16) Keral. https://www.medicines.org.uk/emc/medicine/17099. ( 17 ) AEM PS −CIM A. http://w ww.aemps.gob.es/cima/ fichasTecnicas.do?metodo=detalleForm. (18) EMA. Guideline on bioanalytical method validation; 2011. (19) FDA. Guidance for Industry Bioanalytical Method Validation; 2001. (20) European Pharmacopoeia. Buffer Solutions; 2001; pp 389−393. (21) FDA. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms; 1997−2000. (22) Kortejarvi, H.; Urtti, A.; Yliperttula, M. Pharmacokinetic simulation of biowaiver criteria: the effects of gastric emptying, dissolution, absorption and elimination rates. Eur. J. Pharm. Sci. 2007, 30 (2), 155−66. (23) Mudie, D. M.; Murray, K.; Hoad, C. L.; Pritchard, S. E.; Garnett, M. C.; Amidon, G. L.; Gowland, P. A.; Spiller, R. C.; Amidon, G. E.; Marciani, L. Quantification of gastrointestinal liquid volumes and distribution following a 240 mL dose of water in the fasted state. Mol. Pharmaceutics 2014, 11 (9), 3039−47. (24) Gupta, E.; Barends, D. M.; Yamashita, E.; Lentz, K. A.; Harmsze, A. M.; Shah, V. P.; Dressman, J. B.; Lipper, R. A. Review of global regulations concerning biowaivers for immediate release solid oral dosage forms. Eur. J. Pharm. Sci. 2006, 29 (3−4), 315−24. (25) Polli, J. E. In vitro studies are sometimes better than conventional human pharmacokinetic in vivo studies in assessing bioequivalence of immediate-release solid oral dosage forms. AAPS J. 2008, 10 (2), 289−99.

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Agitation Rate and Time for Complete Dissolution in BCS Biowaivers

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