Agitation Rate and Time for Complete Dissolution in BCS Biowaivers

Page 1 of 25

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

Molecular Pharmaceutics

Agitation rate and the time for complete dissolution in BCS biowaivers based on the investigation of a BCS biowaiver for dexketoprofen tablets

Alfredo Garcia-Arietaa,f,*, John Gordonb,f , Luther Gwazac,f, V. Mangas-Sanjuand, Covadonga Álvareze and Juan J. Torradoe a

División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios b

Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Canada c

Evaluations and Registration Division, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe

d

Engineering: Pharmacokinetics and Pharmaceutical Technology Area. Miguel Hernandez University. Spain

e

Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Spain.

f

This manuscript represents the personal opinion of the authors and does not necessarily represent the views or policy of their corresponding Regulatory Authorities.

*Corresponding author: Alfredo García-Arieta División de Farmacología y Evaluación Clínica Departamento de Medicamentos de Uso Humano Agencia Española 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

ACS Paragon Plus Environment


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

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 non-rapid 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 minutes at 50 rpm. The time limit for complete dissolution should not be extended to 60 minutes. 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


Page 2 of 25

Page 3 of 25

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


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 post-approval changes of immediate release solid oral dosage forms the same year2. 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 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 cut-off 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 acceptable5. 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 proposed7-9. Class III drugs were considered reasonable candidates for biowaivers10, and presently the World Health Organization (WHO)4,

the European Union5 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 biowaivers9, but only the WHO adopted this possibility4. Later, it was demonstrated that the present dissolution methodology is not able to detect in vivo differences in rate of release / absorption for these drugs11,

12

. Consequently, the WHO



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

recommendations have been reviewed and the waiver for BCS class IIa drugs is no longer recommended13. This illustrates that the review of failed bioequivalence studies can provide evidence for fine - tuning 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 rpm 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 formation8. In fact, the WHO recommends the use of 75 rpm4, 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.


Page 4 of 25

Page 5 of 25

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


EXPERIMENTAL SECTION Materials Drug substance: Dexketoprofen is the active enantiomer of ketoprofen, which has been developed as the trometamol salt to increase its dissolution rate14. 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/ml15. 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 37ºC. 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 mg16, in contrast to the 100 mg of ketoprofen. Therefore, dexketoprofen can be considered as highly soluble and ketoprofen as low solubility. The permeability of dexketoprofen, as in the case of ketoprofen, is considered high14, 15. Drug products: Innovator dexketoprofen trometamol tablets (Enantyum 25 mg film-coated tablets) were authorized in April 1996 and nineteen 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 drug14. However, the reference product does not exhibit rapid dissolution and, therefore, it does not behave as 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 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 available17. Reagents were of analytical grade.



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

Methods In vivo bioequivalence studies Two-sequence two-period cross-over 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 a LC-MS/MS method that was validated according to the existing regulatory guidelines18, 19. In vitro studies Dissolution 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 Pharmacopeia20.. All dissolution studies were performed at 37±0.5ºC. 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 minutes). 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®.


Page 6 of 25

Page 7 of 25

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


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 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 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 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.



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

DISCUSSION The results described in this paper 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 highly permeable15 and it exhibits a short half-life (1.65 h)16, which makes its Cmax sensitive to changes in the in vivo dissolution rate22. 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


Page 8 of 25

Page 9 of 25

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


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 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 < 5%). Importantly, in these four failed bioequivalence studies the 90% confidence interval (CI) of Cmax did not include the 100% value, which means that the difference is statistically significant at the significance level of the confidence interval, i.e. 10%. Therefore, an in vivo difference exists between products and it was detected with statistical significance. Furthermore, the studies did not fail because of insufficient statistical power, as the power was ≥80% in all studies, which was estimated based on the residual variability of the bioequivalence studies. Therefore, these examples represent products with a statistically significant difference in in vivo release rate that can be used to investigate whether the current dissolution methodology employed for BCS biowaivers are discriminative and predictive of the in vivo behavior, e.g. paddle apparatus at 50 rpm or 75 rpm. After the failed bioequivalence studies, these three pharmaceutical companies modified the formulation and/or the manufacturing process for their products and the second attempt (A3, B2 and C2) was able to demonstrate bioequivalence. In contrast, the fourth company (D) was able to demonstrate equivalence at the first attempt. In order to address whether the current in vitro dissolution methodology is discriminative and predictive of the in vivo bioequivalence outcome for cases of products containing class I drugs with non-rapid dissolution, figures 1-4 describe the dissolution profiles reported by these companies. Some of them were investigated at 50 and 75 rpm, but others were investigated only at one dissolution speed. Figures 1-4 show clearly that the dissolution profile of the reference product is not complete (>85%) in 30 min in the paddle apparatus at 50 rpm in any of the



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

buffer media for all companies despite some inter-laboratory and inter-batch 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 rpm by some of them (Figures 2-3). At 75 rpm dissolution was complete in 15 or 30 minutes. Consequently, a BCS biowaiver for dexketoprofen would not be possible if dissolution is required to be complete (>85%) in 30 minutes at 50 rpm, but it would be acceptable if the use of a 75 rpm agitation rate is allowed4. 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 min 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 batch 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.


Page 10 of 25

Page 11 of 25

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


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 non-bioequivalent formulations with non-rapid dissolution rate ( 85%) is obtained in all pH media in 30 minutes 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 case of coning effect, as recommended by WHO4 or as potentially possible according to the EMA



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

guideline5, which simply says that the agitation speed to be employed is usually 50 rpm. BCS biowaivers for dexketoprofen tablets are not possible with the paddle apparatus, even though it is a BCS class I drug, because the reference product does not dissolve >85% in 30 minutes 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 conservative8, 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.


Page 14 of 25

Page 15 of 25

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


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



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

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. Pharmaceutical research 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. Canada, H. Release of Guidance Document: Biopharmaceutics Classification System Based Biowaiver; 2014. 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. The AAPS journal 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. Journal of pharmaceutical sciences 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.; Hussain, A. S. Biopharmaceutics classification system: the scientific basis for biowaiver extensions. Pharmaceutical research 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? European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 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. Journal of pharmaceutical sciences 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 cross-sectional survey with 500 bioequivalence studies. Journal of pharmaceutical sciences 2013, 102, (9), 3136-44. 13. WHO Multisource (Generic) Pharmaceutical Products: Guidelines on Registration requirements to Establish Interchangeability. In: WHO Expert Committee on Specification for Pharmaceutical Preparations. Forty-ninth report. WHO Technical Report Series, No. 992, 2015. pp. 131-184. 14. Barbanoj, M. J.; Antonijoan, R. M.; Gich, I. Clinical pharmacokinetics of dexketoprofen. Clinical pharmacokinetics 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 immediate-release solid oral dosage forms: ketoprofen. Journal of pharmaceutical sciences 2012, 101, (10), 3593-603. 16. A.-Menarini-Farmaceutica-Internazionale-SRL Summary of Products Characteristics of Keral. https://www.medicines.org.uk/emc/medicine/17099


Page 16 of 25

Page 17 of 25

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


17. AEMPS–CIMA http://www.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. Pharmacopoeia, E. Buffer solutions; Strasbourg (France), 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. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 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. Molecular 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. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 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. The AAPS journal 2008, 10, (2), 289-99.



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 CAPTATIONS 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. Grey dotted lines indicate 85% dissolved at 15 minutes.

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 rpm and 75 rpm). Red line represents reference product and blue line represents test product. Grey dotted lines indicate 85% dissolved at 15 minutes.

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 rpm and 75 rpm). Red line represents reference product and blue line represents test product. Grey dotted lines indicate 85% dissolved at 15 minutes.

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. Grey dotted lines indicate 85% dissolved at 15 minutes.


Page 18 of 25

Page 19 of 25

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


TABLES Table 1. Qualitative composition of the reference product and the tablets that failed to show bioequivalence. Dexketoprofen 25 mg Qualitative composition of excipients film-coated tablets* Reference Core: microcrystalline cellulose, maize starch, glycerol (Enantyum) distearate, sodium starch glycolate. Coating: hypromellose, titanium dioxide, polyethylene glycol (PEG) 600 and propylene glycol Product 1 Core: microcrystalline cellulose, maize starch, pregelatinized starch, hypromellose, colloidal silica and magnesium stearate. Coating: hypromellose, titanium dioxide and PEG 400 Product 2 Core: microcrystalline cellulose, maize starch, magnesium stearate, sodium starch glycolate and colloidal silica. Coating: hypromellose, titanium dioxide, PEG 600 and talc. Product 3 Core: microcrystalline cellulose, pregelatinized starch, magnesium stearate and sodium starch glycolate Coating: hypromellose, polydextrose, titanium dioxide and PEG 4000 * Products are identified differently in table 1 (numbers) and 2 (letters) for confidentiality reasons.



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

Page 20 of 25

Table 2. In vivo bioequivalence studies results of dexketoprofen from four different product development manufacturers. 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% Product*

A

B

C D

Study 1 n=29 2 n=42 3 n=46 1 n=22 2 n=29 1 n=34 2 n=47 1 n=35

Batches 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

Parameter Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC Cmax AUC

P.E. 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

90% CI 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

CV (%) 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

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


Page 21 of 25

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


FIGURES

Figure 1.



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.


Page 22 of 25

Page 23 of 25

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 3.



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 4.


Page 24 of 25

Page 25 of 25

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


338x190mm (96 x 96 DPI)


Agitation Rate and Time for Complete Dissolution in BCS Biowaivers

Recommend Documents