Interactions between active pharmaceutical ingredients and excipients [PDF]

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European Journal of Pharmaceutical Sciences 65 (2014) 89–97

Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps

Commentary

Interactions between active pharmaceutical ingredients and excipients affecting bioavailability: Impact on bioequivalence q Alfredo García-Arieta ⇑ Head of Service on Pharmacokinetics and Generics, Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products, Madrid, Spain

a r t i c l e

i n f o

Article history: Received 23 June 2014 Received in revised form 4 September 2014 Accepted 4 September 2014 Available online 16 September 2014 Keywords: Excipient Drug–excipient interaction Bioavailability Biowaivers Regulatory requirements

a b s t r a c t The aim of the present paper is to illustrate the impact that excipients may have on the bioavailability of drugs and to review existing US-FDA, WHO and EMA regulatory guidelines on this topic. The first examples illustrate that small amounts of sorbitol (7, 50 or 60 mg) affect the bioavailability of risperidone, a class I drug, oral solution, in contrast to what is stated in the US-FDA guidance. Another example suggests, in contrast to what is stated in the US-FDA BCS biowaivers guideline, that a small amount of sodium lauryl sulphate (SLS) (3.64 mg) affects the bioavailability of risperidone tablets, although the reference product also includes SLS in an amount within the normal range for that type of dosage form. These factors are considered sufficient to ensure that excipients do not affect bioavailability according to the WHO guideline. The alternative criterion, defined in the WHO guideline and used in the FIP BCS biowaivers monographs, that asserts that excipients present in generic products of the ICH countries do not affect bioavailability if used in normal amounts, is shown to be incorrect with an example of alendronate (a class III drug) tablets, where 4 mg of SLS increases bioavailability more than 5-fold, although a generic product in the USA contains SLS. Finally, another example illustrates that a 2 mg difference in SLS may affect bioavailability of a generic product of a class II drug, even if SLS is contained in the comparator product, and in all cases its amount was within the normal range. Therefore, waivers of in vivo bioequivalence studies (e.g., BCS biowaivers, waivers of certain dosage forms in solution at the time of administration and variations in the excipient composition) should be assessed more cautiously. Ó 2014 Elsevier B.V. All rights reserved.

1. Introduction Most pharmaceutical excipients employed in immediate release oral dosage forms have been considered traditionally as ‘‘inert’’. Some of these excipients are employed simply to improve handling and dosing uniformity (e.g., fillers or diluents), to provide drug stability (e.g., antioxidants), good taste (e.g., sweetening agents and flavours), or appearance (e.g., colorant and coating components). Other excipients are essential to the manufacturing process (e.g., glidants, lubricants and binders), while some contribute to the release of the drug from the dosage form (e.g., disintegrants) so that drug availability is not impaired by the incorporation of q This commentary represents the author’s personal opinion and does not necessarily represent the policy or recommendations of the Spanish Agency for Medicines and Health Care Products. ⇑ Corresponding author at: Division of Pharmacology and Clinical Evaluation, Department of Human Use Medicines, Spanish Agency for Medicines and Health Care Products, C/Campezo 1, Edificio 8, Planta 2 A, 28022 Madrid, Spain. Tel.: +34 918225167; fax: +34 918225161. E-mail address: [email protected]

http://dx.doi.org/10.1016/j.ejps.2014.09.004 0928-0987/Ó 2014 Elsevier B.V. All rights reserved.

the drug into a solid dosage form. Other dosage forms (e.g., suspensions) require additional excipients (e.g., suspending agents) to avoid drug agglomeration, precipitation, and to facilitate drug dispersion with agitation. Traditionally, drugs with low solubility have required excipients like surfactants or wetting agents to facilitate or accelerate drug release and dissolution, which is the essential previous step for drug absorption. These excipients contribute ‘‘actively’’ to drug bioavailability of low solubility drugs. In addition, it has also been observed that some of these excipients are able to increase the permeability of low permeability drugs (i.e., absorption enhancers) and others are able to decrease absorption by affecting gastrointestinal physiology (e.g., motility). Recently, novel manufacturing technologies and excipients (e.g., micronisation to the nanoscale, solid dispersion and self-emulsifying systems) have been necessary to improve the release, dissolution and absorption of low solubility drug, which have become more frequent in the drug development pipeline. Comparative bioavailability/bioequivalence studies have played an essential role in the investigation of the impact of formulation

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changes on drug product bioavailability. However, these studies generate an ethical and economic cost that may limit the full investigation of the factors (e.g., manufacturing process or formulation/ excipients) affecting drug bioavailability and their underlying mechanisms. From a regulatory viewpoint, human bioequivalence studies are required only if necessary to ensure therapeutic equivalence. Therefore, a waiver of in vivo bioequivalence studies (which is called a ‘‘biowaiver’’) can be granted (Committee for Medicinal Products for Human Use, 2010) in four situations: (a) Additional strengths do not need to demonstrate bioequivalence if the most sensitive (if ethically acceptable) strength to detect bioavailability differences has shown bioequivalence with the corresponding strength of the reference product, providing that all strengths are manufactured with the same manufacturing process, certain conditions are met with respect to composition, and all strengths exhibit similar dissolution profiles. In the European Union (EU) the composition of the different strengths have to be qualitatively identical and the quantitative composition has to be (i) quantitatively proportional, (ii) constant where only the amount of drug changes if the amount of drug for all strengths is less than 5% of the tablet core weight, or (iii) constant like in the previous case, but the difference in amount of drug can be compensated by the diluent to obtain tablets of the same weight in all strengths. These three composition rules assume that excipients are ‘‘inert’’, but this may not be the case in solid dispersions, where the excipients dispersing the drug should not be kept constant, but proportional to the amount of drug. Furthermore, if an excipient is known to be able to affect the gastrointestinal physiology, the strength with the higher amount of this excipient should be tested according to common sense, although this may not be well defined in the regulatory guidelines (e.g., if mannitol used as filler, the lowest strength would contain the larger amount according to the rule (iii) above and the highest strength in case of rule (i) above). (b) Dosage forms where the drug is already released at the time of administration (e.g., oral solution, granule for oral solution, effervescent tablet, solution for injection, etc.) and the dosage form does not contain excipients that may affect bioavailability. In these cases, the absence of evidence with respect to the ability of an excipient to affect absorption is considered as evidence of absence. This is not methodologically correct, but regulations have assumed that traditional ‘‘inert’’ excipients have no effect of absorption until evidence of such an effect is shown. To the contrary, there are numerous examples of typical excipients affecting drug absorption. For example, carbohydrates (Kato et al., 1969; Mayersohn and Gibaldi, 1971) and phosphoric acid delay gastric emptying, due to their caloric content and pH, respectively, and affect the saturable absorption of riboflavin and the saturable biotransformation of salicylamide (Houston and Levy, 1975). As another example, bicarbonate accelerates gastric emptying and increases absorption rate of paracetamol (RostamiHodjegan et al., 2002a, 2002b; Kelly et al., 2003), and modifies the interaction of fluvastatin with membrane phospholipids (Larocque et al., 2010). Sodium acid pyrophosphate reduced small intestinal transit time by 43% and reduced ranitidine absorption from a effervescent tablet (Koch et al., 1993). To further complicate the issue, these effects can be drug and/or dose-dependent. Mannitol (2.264 g) reduced small intestine transit time by 23%, cimetidine AUC by 30% and Cmax by 50% when compared with sucrose (Adkin et al., 1995c), because sucrose does not alter small intestine transit (Adkin et al., 1995b). The magnitude of mannitol’s effect was shown to be dose-dependent in the range between 0.755 and 2.265 g (Adkin et al., 1995a). PEG 400, which stimulates gastrointestinal motility and accelerates small intestine transit (Basit et al., 2001; Schulze et al.,

2006), at a dose of 10 g reduced ranitidine bioavailability by 30% first (Basit et al., 2002), but later doses of 1 g proved to increase the bioavailability by 41%, whereas doses of 2.5 and 5 g decreased the bioavailability by 38% (Schulze et al., 2003). Subsequently, it was shown that PEG 400 enhanced the bioavailability of ranitidine in males, but in not in females (Ashiru et al., 2008), when used in a range between 0.5 and 5 g, with a maximum effect at 0.75 g (63% increase). PEG 400 showed a non-linear concentration dependence with a maxima at 1% (Ashiru-Oredope et al., 2011). The same mechanism of action has been described for other PEG and PEG derivatives (Wang et al., 2004; Shen et al., 2006). (c) Immediate release solid oral dosage forms containing certain type of drugs and with similar and sufficiently rapid dissolution profiles based on the biopharmaceutics classification system (BCS-based biowaiver). The BCS has significantly advanced pharmaceutical science by providing a quantitative methodology, based on drug solubility, drug permeability and drug product dissolution, to identify products with little risk of bioequivalence failure, if certain conditions are met. Its simplistic classification of drugs based on only 4 categories, depending on the dichotomous classification of high and low solubility and permeability, associated with conservative cut-off points, to avoid the approval of non-bioequivalent products, has facilitated its understanding and regulatory acceptance. However, the use of dissolution tests to compare test and reference products for the classes of drugs that can be waived is based on two assumptions: (i) that the current methodology of in vitro dissolution is indicative of in vivo dissolution (i.e., it is as or more discriminative as in vivo dissolution), which might be complicated by the presence of surfactants in any of the formulations and (ii) that differences in excipients do not affect permeability of the drugs. (d) Variations or post-approval changes (e.g., excipient composition, manufacturing process, etc.) may be accepted based on in vitro dissolution tests, without the need for an in vivo bioequivalence study, if the type and extent of the variation is not considered to affect the bioavailability of the product. The USFDA criteria for immediate release dosage forms are based on the drug BCS classification and the magnitude of the change. On the contrary, in the EU, the criteria are less clear and do not include any quantitative assessment of the change. In both regions, such a waiver assumes that, in the range of acceptable changes, excipients do not affect permeability or gastrointestinal physiology, and all their effects can be detected by in vitro dissolution tests. The aim of the present paper is to review existing US-FDA, WHO and EMA regulatory guidelines on bioequivalence and to illustrate, with the outcome of actual human bioequivalence studies, the impact that some excipients may have on the bioavailability of drugs and the impropriety of some of the regulatory guidelines. 2. US-FDA guidance for industry bioavailability and bioequivalence studies for orally administered drug products – general considerations This US-FDA guideline (U.S. Department of Health and Human Services, 2003) states: ‘‘Generally, in vivo BE studies are waived for solutions on the assumption that release of the drug substance from the drug product is self-evident and that the solutions do not contain any excipient that significantly affects drug absorption (21 CFR 320.22(b)(3)(iii)). However, there are certain excipients, such as sorbitol or mannitol, that can reduce the bioavailability of drugs with low intestinal permeability in amounts sometimes used in oral liquid dosage forms’’. Therefore, the position taken is that sorbitol and mannitol do not affect the bioavailability of highly permeable drugs.

A. García-Arieta / European Journal of Pharmaceutical Sciences 65 (2014) 89–97

This belief has been shown to be incorrect after the assessment of bioequivalence studies performed with oral solutions of risperidone containing a small amount of sorbitol in addition to the same qualitative and quantitative excipients included in the reference product (Risperdal 1 mg/ml oral solution). Risperidone can be considered a highly permeable drug since its absolute bioavailability in poor metabolisers is >85% and the absolute bioavailability is 100% for the active moiety (risperidone plus 9-hydroxy-risperidone) (Huang et al., 1993). A mass-balance study was not able to show complete absorption because all radioactivity is usually not recovered in this type of study, but it was able to recover 82% following an oral dose of 14C-risperidone (Mannens et al., 1993). Based on the BDDCS, risperidone has been classified as highly permeable based on its metabolic profile (Benet et al., 2011). Its classification as highly permeable is not unexpected since it has to be highly permeable to reach its site of action in the Central Nervous System. The innovator oral solution contains 1 mg/ml of risperidone with tartaric acid to improve its solubility through salt formation, benzoic acid as preservative and sodium hydroxide to adjust the pH and water. Due to the existence of a patent for an oral solution of risperidone without sorbitol (Francois and Dries, 1994), generic products have been developed with certain amounts of sorbitol. A manufacturer developed two possible formulations containing 10.00 mg or 71.43 mg of liquid sorbitol per millilitre (7 or 50 mg/ml), in addition to the same qualitative and quantitative excipients included in the reference product (Risperdal 1 mg/ml oral solution). Although the applicant justified that sorbitol should not affect bioavailability based on the FDA guideline and the literature where a large amount of sorbitol higher than 1 g was necessary to affect the bioavailability of ranitidine, a low permeability drug (Chen et al., 2006). The justification was not accepted because the effect of sorbitol might be drug-dependent. Therefore, a bioequivalence study was requested in order to gain marketing approval. It was agreed that if bioequivalence were shown for the 50 mg/ml sorbitol formulation, it could be assumed also for the 7 mg/ml formulation, since if 50 mg of sorbitol are shown not to affect risperidone bioavailability, a lower amount will also not affect it. Surprisingly, the study comparing test and reference product in 30 healthy volunteers was not able to show bioequivalence although the intra-subject variability of Risperisone is not high and the study was sufficiently powered. The 90% CI of T/R for Cmax (76.20–102.82%) was outside of the acceptance range, and the 90% CI of T/R for AUC (83.31–109.36%) was inside the acceptance limits. Then, the sponsor decided to perform a bioequivalence study for the formulation containing 7 mg/ml of sorbitol with the hope that a lower amount of sorbitol would not affect risperidone bioavailability. The new 2  2 study design was consistent with the previous study i.e., the same protocol and same number of subjects (n = 30), and the results were practically identical. The 90% CI of T/R for Cmax was 77.0–99.2% and the 90% T/R for AUC was 81.7–99.8. In this case the 90% confidence interval does not include the 100% value and, therefore, we can claim that there are statistically significant differences with a 10% significance level. These two studies demonstrate that a tiny amount of sorbitol might affect the bioavailability of a highly permeable drug in an oral solution. Importantly, the only difference between test and reference formulation is the amount of sorbitol and there is no manufacturing factor to explain the difference, as these are oral solutions. Furthermore, this observation in only one study could have been disputed as an accidental observation, but the results have been confirmed in a second study to eliminate doubt. It might be possible to argue that the centre where the studies were conducted is unable to perform correctly a bioequivalence study and consequently these two studies are biased. A simple literature search

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can identify a similar study that supports that these observations are not isolated observations due to the study centre. Dr. van Os et al. published a comparative bioavailability study (van Os et al., 2007) in 32 subjects where the test product was an oral solution containing sorbitol and the reference product was the oral tablet, the dosage form employed in phase III efficacy studies. In this study, not only Cmax (90% CI: 75.0–92.6), but also AUC (90% CI: 76.2–92.9) failed to show bioequivalence. In addition, statistically significant differences were detected in both parameters. In this paper the authors do not provide the sorbitol content, but they speculate that sorbitol might be the cause of the lower bioavailability of risperidone and propose the mechanism for such effect. After receiving permission from the sponsor, van Os has kindly informed the author that this solution contained only 60 mg/ml. Therefore, as the study investigated a dose of 1 mg, these study findings suggest that 60 mg of sorbitol may affect not only Cmax but also AUC, whereas Risperdal 1 mg/ml oral solution was shown bioequivalent with the Risperdal 1 mg tablets. In the first two studies the failure to show bioequivalence was due to a pair of subjects with low individual ratios that would be considered as outliers. If these subjects were excluded bioequivalence could be demonstrated. In the third study there were more outlier subjects. One of the subjects had a individual ratio of 0.32 for Cmax and 0.36 for AUC, according to the information provided by Dr. van Os. This ratio may be usual in highly variable drugs, but it is unexpected in a low variability drug like risperidone. Therefore, it is possible that just a few subjects in a population (e.g., 20% of the population based on the observations of these studies) may be sensitive to these low amounts of sorbitol and their intestinal transit times may be shorter without causing diarrhoea. Other risperidone oral solutions containing sorbitol may have been waived from the demonstration of bioequivalence based on the assumption that amounts larger than 1 g are necessary to affect bioavailability of low permeability drugs. Other risperidone oral solutions containing sorbitol may have been approved based on a bioequivalence study showing bioequivalence, if none of the recruited healthy volunteers were sensitive to sorbitol. These factors may mean that some approved products are not interchangeable, because, e.g., a reduction of 64% in AUC, as observed previously in an individual ratio, would be noticed by the schizophrenic patients. This would be a serious public health concern in those countries where generic products substitute for the reference product, but it is not a problem according to the EU legislation because it only deals with the authorisation of medicinal products to be prescribed and it does not deal with the interchangeability of medicinal products, which is a responsibility of the different member states (Committee for Medicinal Products for Human Use, 2010). In addition, the CHMP has been able to find a reason to deviate from the guideline recommendations in some cases (Committee for Medicinal Products for Human Use, 2011a, 2011b, 2013). In conclusion, certain excipients, such as sorbitol, can reduce the bioavailability of drugs in solution with high intestinal permeability, not only at large doses, but also at very low doses (e.g., 7, 50 or 60 mg). This effect may be drug dependent and thus it cannot be extrapolated between drugs or drug classes. More importantly, the effect appears to be subject-dependent since it seems to affect only sensitive patients. Bioequivalence studies that do not recruit this sensitive population may conclude equivalence, but this demonstration will not ensure than these generics are interchangeable in the whole patient population. Finally, the sorbitol contained in a drug product can also interact with other drugs administered simultaneously. Although the oral solution of lamivudine has shown to be bioequivalent to the oral tablet of the reference product in adult patients (Yuen et al., 1995), the exposure after the administration of the reference oral

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A. García-Arieta / European Journal of Pharmaceutical Sciences 65 (2014) 89–97

solution of lamivudine when administered with reference zidovudine and abacavir oral solutions was 45% lower than that observed with the corresponding reference tablets in children (Kasirye et al., 2012). Similarly, lamivudine AUC in a fixed dose combination containing stavudine, lamivudine and nevirapine was 30% higher compared with the corresponding oral solutions (Vanprapar et al., 2010) and a similar infra-bioavailability for lamivudine was demonstrated in a fixed dose combination tablet containing zidovudine, lamivudine and nevirapine compared to the corresponding innovator reference products (Chokephaibulkit et al., 2011). This difference in lamivudine was believed to be due to differences in behaviour between children and adults, but it is more likely caused by the presence of sorbitol in the reference oral solution of abacavir (340 mg/ml) and nevirapine (162 mg/ml).

3. US-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 This US-FDA guideline (U.S. Department of Health and Human Services, 2000) states: ‘‘In general, using excipients that are currently in FDA-approved IR solid oral dosage forms will not affect the rate or extent of absorption of a highly soluble and highly permeable drug substance that is formulated in a rapidly dissolving IR product. To support a biowaiver request, the quantity of excipients in the IR drug product should be consistent with the intended function (e.g., lubricant). Large quantities of certain excipients, such as surfactants (e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic’’. Consequently, it is implied that small amounts of these ‘‘active’’ excipients are not problematic. This belief is questionable given the revelation of the bioequivalence studies of some risperidone generics. Risperidone has been traditionally considered as a low solubility drug based on the pharmacopeial criterion. However, due to its low therapeutic dose or strength, it can be considered a highly soluble drug in terms of BCS classification. Risperidone solubility is enhanced by salt formation, therefore, its solubility in buffers is higher than in unbuffered water as can be seen in Table 1. Based on the worst solubility scenario at pH 8.0, 22 mg can be dissolved in 250 ml, and based on the solubility in unbuffered water 16 mg can be dissolved in 250 ml. As the highest therapeutic dose and strength is 6 mg, risperidone can be classified as highly soluble. As described in the previous section, risperidone is a highly permeable drug, so therefore, it can be classified as a BCS class I drug. This classification has also been granted based on the BDDCS (Benet et al., 2011). Interestingly, the reference risperidone tablet contains sodium lauryl sulphate in an amount that is considered to be within the normal range for that type of dosage form, according to the US-FDA database (U.S. Food and Drug Administration, 2014). A generic product containing 3.64 mg of sodium lauryl sulphate in the 1 mg tablet was not able to show bioequivalence in a conventional 2  2 design in 34 subjects because the 90% CI of Cmax was 70.01–86.80 and the 90% CI of AUC was 74.74–91.72. In both cases statistically significant differences can be detected as the point estimates indicate an approximate difference of 20%. Due to the presence of sodium lauryl sulphate in the reference product, the dissolution profiles in 500 ml with the paddle apparatus at 50 rpm is complete (>85%) in 10 min at pH 1.2 and 6.8. For the test product, dissolution was complete in 7.5 min. Data at pH 4.5 was not submitted with the documentation, but it can be speculated that the same results would have been expected at pH 4.5, since the lowest solubility of risperidone is at pH 6.8 (Table 1).

In conclusion, this example illustrates that a small amount of sodium lauryl sulphate (3.64 mg) is able to reduce the bioavailability of risperidone (even if sodium lauryl sulphate is used in the reference product) and this cannot be detected comparing the dissolution profiles. On the contrary, the surfactant facilitates the wetting and dissolution of risperidone and makes dissolution very rapid. Sodium lauryl sulphate can be used to improve dissolution and permeability, but its deleterious effect on permeability/ absorption has also been described (Buch et al., 2010; Miller et al., 2011). Importantly, a BCS biowaiver might have been applied for this risperidone tablet because it could have been classified as a class I drug and the dissolution profiles of the test and reference product would have shown complete dissolution in 15 min. Therefore, the only way to protect the patients from non-bioequivalent products is pay attention to critical excipients, even if they are in minute amounts. The above was not an isolated case since another generic product containing 1.5 mg SLS in the 1 mg strength failed to show bioequivalence with a 90% CI for Cmax of 77.9–95.0 and a 90% CI for AUC of 80.7–98.1 (please note that bioequivalence studies of risperidone are usually performed with the 1 mg strength for safety reasons). In this case, the lower bioavailability is also statistically significant since the 90% CI does not include the 100% value. The regulatory experience has shown that risperidone generic tablets without sodium lauryl sulphate were able to show bioequivalence, generic tablets containing a small amount of sodium lauryl sulphate were also able to show bioequivalence and even a generic containing 9 mg of sodium lauryl sulphate was able to show bioequivalence with the reference product. Therefore, it is not only the amount of sodium lauryl sulphate that negatively affects the bioavailability, but the interaction with other excipients may block the action of sodium lauryl sulphate (e.g., by absorption or adsorption). The mechanism responsible for this reduced bioavailability of risperidone is unclear. It could be a reduction of permeability (Miller et al., 2011, 2012; Dahan and Miller, 2012), entrapment of the drug in micelles where the drug is not available for absorption (Buch et al., 2010) or simply that the sodium lauryl sulphate included in the formulation decreases the discriminatory power of the dissolution test to detect differences that have in vivo relevance and hence these differences are not being seen.

4. WHO guideline: multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability This guideline (World Health Organization, 2006) recommends BCS-based biowaivers for class I drugs (as does the US-FDA), class III drugs (as does the EMA along with class I), and also class II drugs that are weak acids and highly soluble at pH 6.8. This third type of BCS-based biowaiver is not the only regulatory innovation for this guideline, since some recommendations are also given on how to assess whether the excipients have an impact on bioavailability.

Table 1 Solubility of risperidone in different buffered media and unbuffered water. Media and pH

Solubility (g/100 ml)

HCl 0.1 N HCl 0.01 N Citrate-phosphate buffer pH 2.2 Citrate-phosphate buffer pH 4.0 Citrate-phosphate buffer pH 6.0 Citrate-phosphate buffer pH 8.0 Borate – NaOH buffer pH 9.0 Unbuffered water

4.1 0.41 8.7 2.6 0.18 0.0088 0.0040 0.0064

A. García-Arieta / European Journal of Pharmaceutical Sciences 65 (2014) 89–97

This WHO guideline states that: ‘‘evidence that each excipient present in the multisource product is well established and does not affect gastrointestinal motility or other processes affecting absorption, can be documented using the following information: (i) The excipient is present in the comparator product, or the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the International Committee on Harmonisation (ICH) or associated countries; and (ii) The excipient is present in the multisource product in an amount similar to that in the comparator, or the excipient is present in the multisource drug product in an amount typically used for that type of dosage form.’’ Therefore, the first option of bullet point (i) allows the use of an excipient (e.g., sodium lauryl sulphate) that is present in the comparator product (e.g., Risperdal), if used in an amount typically used for that type of dosage form (e.g., tablet), but we have seen in the previous example that this is not able to guarantee bioequivalence of multisource products. Furthermore, the alternative of bullet point (ii) to decide if the amount is similar to that in the comparator product is not defined. In absolute terms, we could consider that this small amount of sodium lauryl sulphate are similar, and even in relative terms (as percentage over the whole tablet core) the small amount may represent less that 1% of the tablet core and be considered as insignificant. Therefore, this criterion seems to be vague and insufficient for the purpose. The second option of bullet point (i) allows the use of excipients different to those used in the reference product if the excipient is present in a number of other products which contain the same API as the multisource drug product and which have marketing authorizations in countries participating in the International Committee on Harmonisation (ICH) or associated countries. This criterion is inadequate based on the following case. Alendronate is a class III drug that can be biowaived according to the WHO guideline. The excipients in the 10 mg reference tablet (Fosamax 10 mg tablet) are as follows: microcrystalline cellulose, lactose anhydrous, sodium croscarmellose, magnesium stearate and carnauba wax as coating. A generic product was developed with the following excipient composition: mannitol 60: 60 mg, Pearlitol SD200 (mannitol): 118.95 mg, crospovidone: 2.00 mg, sodium lauryl sulphate: 4.00 mg, magnesium stearate: 2.00 mg and Coating Sepifilm 002. Most of the excipients are not considered to be critical. Only mannitol (178.95 mg) and SLS (4 mg) can be considered critical, but their amounts are within the normal range for tablets. Therefore, if generics products were marketed in the ICH region this product could be biowaived based on dissolution profiles. An internet search can identify that mannitol is included as excipient in an alendronate generic product approved in the EU: alendronate Ranbaxy (Summary of Product Characteristics of Alendratol 10 mg, Tabletten) and SLS is included in an alendronate generic product approved in the United States: alendronate Mylan tablet (Labelling of Alendronate Sodium Tablet, Mylan Institutional Inc.). Therefore, this product could have been waived based on the excipient criterion defined in the WHO guideline because both the reference product and the test product dissolved in less than 15 min at pH 1.2, 4.5 and 6.8 in the paddle apparatus at 50 rpm. However, a bioequivalence study was initiated with a sequential design because alendronate is a highly variable drug that requires a huge sample size, but the study was stopped in the interim analysis because of futility. The 90% CI for Rmax was: 460.0–733.7% and the 90% CI for Ae0 36 h was 445.6–746.1%. The presence of SLS in the generic formulation was able to increase 5–6-fold the

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bioavailability of alendronate because alendronate exhibit an extremely low bioavailability (0.7%) (MSD, 2013) and SLS is able to break the intestinal membrane to enhance drug absorption (Narkar et al., 2008). In conclusion, the excipients may affect bioavailability even if they are present: (a) In the multisource product approved in an ICH country. (b) In an amount typically used for that type of dosage form. In order to be sure that excipients do not affect bioavailability of low permeable drugs, the excipient has to be in the reference product and its amount should be very similar to that in the reference product.

5. FIP’s BCS biowaiver monographs It was mentioned above that there is no criterion in the WHO guideline for determining if two products contain a ‘‘similar amount’’ of a certain excipient. The same concerns arise with the concept of ‘‘amount typically used for that type of dosage form’’. FIP’s BCS biowaiver monographs (International Pharmaceutical Federation, 2014) state that a ‘typical amount’ is defined by the range of the amounts present in dosage forms with a marketing authorisation in the USA, which can be obtained from the U.S. FDA Inactive Ingredients Database. This claim is questionable because the amount described for sodium lauryl sulphate is 51.69 mg. Therefore, according to the WHO guideline we should conclude that amounts up to 51.96 mg of sodium lauryl sulphate do not affect risperidone absorption. In conclusion, it is not possible to define a typical amount without an associated effect in the case of critical excipients and the latter may be drug-dependent and formulation-dependent. In addition, this concept is not used consistently in FIP monographs. In the Ibuprofen BCS monograph (Potthast et al., 2005) it was stated that a biowaiver for immediate release ibuprofen solid oral dosage form is scientifically justified, provided that the test product contains only the excipients shown in Table 2 of that monograph, in amounts that are usual for IR solid oral dosage forms. In that table, sodium lauryl sulphate is included because it can be found in some ibuprofen products in the Netherlands and Finland. However, it is not stated that its use is mandatory if present in the reference product. It is simply stated that its presence or its absence does not affect ibuprofen bioavailability. Alvarez et al. (2011) showed that BCS-based biowaivers for ibuprofen, as a model drug for class II weak acid drugs that are highly soluble at pH 6.8, are inappropriate because existing dissolution test requirements are not sufficiently discriminative to distinguish between bioequivalent and non-bioequivalent products containing this type of drugs. This failure to show bioequivalence between two ibuprofen generic products and the reference product, although the generics showed similar dissolution profiles to those of the reference product, have been justified in the ketoprofen BCS Biowaiver monograph (Shohin et al., 2012) based on 3 possible causes: (a) The reference product contains sodium lauryl sulphate, whereas the test product in development did not. In their opinion ‘‘this difference in excipient composition would preclude application of the biowaivers to the test product as per the recent EMA guidance and probably the WHO Guidance’’. It is difficult to understand why previously in the Ibuprofen BCS monograph the presence of SLS in the generic products was irrelevant and now in the ketoprofen BCS monograph the presence of SLS in the ibuprofen reference product is critical, although the presence of SLS in ketoprofen generics is accepted even though SLS is not present

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in the reference ketoprofen product. It is certain that the EMA guideline (Committee for Medicinal Products for Human Use, 2010) would not allow these BCS biowaivers because class II drugs cannot be waived and critical excipients have to be quantitatively identical. However, based on the wording of the WHO guideline (World Health Organization, 2006) described above, it is questionable that those countries following this guideline would reject an application for ibuprofen tablets based on the WHO guideline and FIP’s BCS monographs. In addition, it is essential to clarify that the reference product in Spain contains SLS now, as these authors claimed, but it did not contain SLS at the time these studies were started, when the reference product belonged to Knoll and it was manufactured in Spain. Later, in the middle of this generic development, knoll was sold by BASF to Abbott and the reference product is no longer manufactured in Spain. This change in manufacturing site and formulation can explain why the second study showed a worse result compared with the first one. It can be speculated that the reference product increased slightly in Cmax after the changes took place and the generic did not improve between formulation 1 and 2. (b) The f2 similarity factors were not provided by Alvarez et al. (2011), but these are not necessary because at 75 rpm, as required by the WHO guideline, the dissolution is complete at pH 6.8 after 15 min and a visual inspection of the plots at pH 1.2 and 4.5 do not show a difference larger than 10% in the amount dissolved at any sampling time point and therefore f2 cannot be lower than 50. At 50 rpm dissolution f2 values were not given for brevity. Dissolution was not complete in 15 min, but at 20 min for both test and reference products. A visual inspection of the plots at pH 1.2 and 4.5 did not show a difference larger than 10% in the amount dissolved at any sampling time point. At pH 6.8 the differences are smaller than 10%, except in one sampling time where the difference is 11.8%, the f2 similarity factor in that comparison is 57.18 and the quickest dissolution is observed with the test product, which exhibits a lower Cmax, which reinforces that dissolution tests for ibuprofen at pH 6.8 are meaningless. (c) The two failed bioequivalence studies were underpowered, which is evidently incorrect, because intra-subject variability was never higher than 17%. With that variability only 10 subjects are necessary to obtain a power of 80%, if no difference between products is assumed, and 12 subjects are necessary for a power of 80%, if a 5% difference between test and reference product is assumed. It is evident that the failure of Cmax 90% CI is a problem related to product differences because the Cmax 90% CIs of the first and second formulation that failed to show equivalence do not include the 100% value and in the second failed bioequivalence study the point estimate was outside of the acceptance range. With that difference it is impossible to show equivalence at any sample size. When the third formulation, which is bioequivalent, was tested in a pilot study, bioequivalence was shown with only ten subjects, although the point estimate was 10% lower.

6. EMA guideline on the investigation of bioequivalence After considering the above examples, it is easier to understand the strict requirements (Committee for Medicinal Products for Human Use, 2010) concerning excipient composition in order to obtain a biowaiver. Annex III on BCS-based biowaivers requires the same qualitative and quantitative composition for those excipients that might affect bioavailability. For the other excipients the requirements depend on the BCS class of the drug. For class I drugs, the excipients may differ qualitatively and, of course, quantitatively, although the use of the same excipients in similar amounts is encouraged. For class III drugs, the composition of these non-critical excipients must be qualitatively identical and

quantitatively similar, because even conventional excipients may have effects on permeability, although these might have been unknown at the time the guideline was written. This position has been reinforced by published evidence that sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, povidone (K29/32), povidone (K90), magnesium stearate, glyceryl monostearate, soft anhydrous silicic acid, ethyl cellulose, and methylcellulose affected the membrane permeation of 5(6)-carboxyfluorescein, as a model water soluble compound, in the in vitro sac method in rat jejunum and ileum (Takizawa et al., 2013). Further, it has been noted that carboxymethylcellulose calcium and microcrystalline cellulose were able to increase methyprednisolone absorption by modulating P-gp (Oda et al., 2004). Carrageenan (Kalitsky-Szirtes et al., 2004), ascorbic acid (El-Masry and bou-Donia, 2003) and EDTA (Li et al., 2006) may also enhance the absorption of drugs. Annex II of the guideline defines the requirements for oral solutions, where critical excipients are defined. It is stated: ‘‘If the test product is an aqueous oral solution at time of administration and contains an active substance in the same concentration as an approved oral solution, bioequivalence studies may be waived. However, if the excipients may affect gastrointestinal transit (e.g., sorbitol, mannitol, etc.), absorption (e.g., surfactants or excipients that may affect transport proteins), in vivo solubility (e.g., co-solvents) or in vivo stability of the active substance, a bioequivalence study should be conducted, unless the differences in the amounts of these excipients can be adequately justified by reference to other data. The same requirements for similarity in excipients apply for oral solutions as for biowaivers (see Appendix III, Section IV.2 Excipients). This text could be considered ambiguous because a justification by reference to other data seems possible, whereas the strict requirements for BCS-based biowaivers seem to be applicable, with no justification acceptable, as explained above. This ambiguity, or the fact that this is only a guideline that the Applicants can deviate from if justified, has encouraged generic companies to continuously try justifying the differences between test and reference products in terms of their critical excipients, mainly in sorbitol, based on Chen et al.’s paper (Chen et al., 2006). As the EU is composed of 28 countries presently (plus three additional European Economic Area countries) it is easy to find a country able to accept the differences, whereas others prefer to follow the guideline. Consequently, many arbitration cases end up at the CHMP. The CHMP has accepted Applicants’ justifications on this issue, despite the recommendations of the guideline on the investigation of bioequivalence and a specific question and answer document from the pharmacokinetic working party on the effect of sorbitol on the pharmacokinetics of highly permeable drug substances. This Q&A document states that ‘‘strict compliance with the BE Guideline is recommended to be followed in the development and assessment of generic applications’’ because the effect of sorbitol is not limited to the osmotic effect, accelerating intestinal transit and increasing intestinal water content, caused by large quantities (>1.25 g in class II drugs and 5 g in class I drugs), but also in a significant subpopulation (P2 subjects in some studies recruiting around 30 subjects) to an intolerance effect that can follow the administration of just a few milligrams of the excipient.

7. Literature data Fassihi et al. showed in only 5 subjects that theophylline tmax was affected (1.30 h vs. 2.10 h) by 10 g of sorbitol (Fassihi et al., 1991). Although the authors considered this outcome as evidence of altered absorption, it has been used to claim that even large

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quantities do not affect bioavailability (Cmax and AUC) of class I drugs. Among the literature data available, the paper by Chen et al. (2006) is the most relevant because most studies have been conducted in animals or with a limited number of subjects. Chen et al. (2006) investigated the effect of 5 g of sorbitol on metoprolol (class I) and ranitidine (class III) bioavailability in comparison with sucrose. These authors employed sucrose as control because it does not alter intestinal transit, but sucrose may have other effects, e.g., delaying gastric emptying and on fluid uptake (Fassihi et al., 1991) and a simple water solution should have been the control. In Chen et al.’s paper the dose-dependent effect of sorbitol on ranitidine, a class III drug, was investigated. Ranitidine solutions containing 2.5 and 5 g of sorbitol were neither bioequivalent in Cmax nor AUC. The point estimate of the 1.25 g solution was 7% lower in AUC and Cmax. In addition, two replicate bioequivalence studies were conducted with ranitidine, (a class III drug) and metoprolol (a class I drug) solutions containing 5 g of sorbitol. These studies demonstrated a higher effect of sorbitol on ranitidine compared to metoprolol. Ranitidine Cmax and AUC decreased by 50% and 45%, respectively, whereas metoprolol Cmax and AUC only decreased by 23% and 7%, respectively. As the effect of 5 g of sorbitol on ranitidine absorption was larger than that on metoprolol absorption and a ranitidine oral solution containing 1.25 g of sorbitol was shown to be bioequivalent to an oral solution containing sucrose, it has been generalised that amounts of sorbitol lower than 1.25 g will not affect absorption of class I drugs. Interestingly, as two of these studies had a replicate cross-over design it was possible to address the subject-by-formulation interaction. Fig. 2 of this paper includes a stick plot for individual AUC values of ranitidine where the sorbitol effect can be observed. The sucrose solution exhibits a significant inter-subject variability, but the sorbitol solution makes all subjects more similar. All of them become poor absorbers of ranitidine, with AUC levels similar to those of the worst absorbers of ranitidine in the sucrose solution. This effect is different to that observed previously where a small amount of sorbitol was used with risperidone. In those cases only a few groups of subjects became poor absorbers.

8. Variations in low solubility drugs Surfactants are used to increase wettability and dissolution rate of low solubility drugs, which is the previous and essential step for drug absorption. Therefore, it is evident that surfactants are critical excipients able to modify the rate and/or extent of absorption of low solubility drugs. Several surfactants have been shown to affect permeability: Sodium lauryl sulphate (Rege et al., 2001), Tween 80 (Jamali and Axelson, 1978; Cornaire et al., 2000; Wagner et al., 2001), Tween 20 (Yamagata et al., 2007a, 2007b), Pluronic P85 (Batrakova et al., 2004), Pluronic L61 (Krylova and Pohl, 2004), docusate sodium (Rege et al., 2001), Cremophor EL (Cornaire et al., 2000; Wagner et al., 2001), Cremophor RH40 (Tayrouz et al., 2003), d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) (Chang et al., 1996), self-emulsifying systems (Constantinides, 1995), phospholipids like lecithin and sterols, sodium taurocholate (Goole et al., 2010). Other excipients with similar effects are cyclodextrines (Rajewski and Stella, 1996), like 2,6-di-O-methyl-b-cyclodextrin (Arima et al., 2001), chitosans (Bernkop-Schnurch and Dunnhaupt, 2012), cosolents like ethanol (Wagner et al., 2001) and polymers like polyacrilates (Goole et al., 2010). A class II drug was formulated originally with Poloxamer 188 by the innovator, but later this excipient was removed. Bioequiva-

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lence was demonstrated between these two innovator formulations. A generic company developed a formulation containing Poloxamer (4 mg) to match the same qualitative composition as the initial reference product. This formulation failed to show bioequivalence for Cmax (90% CI: 112–127%) in a study with 60 subjects. After reducing Poloxamer to 2 mg, the new formulation was bioequivalent with the reference product in a study with 23 subjects (90% CI: 94–113%). This example illustrates that even minute changes (2 mg) in the surfactant, a critical excipient, may affect bioavailability. And this occurs even if they are present in the comparator product in an amount typically used for that type of dosage form. Therefore, it should not be possible to obtain approval for a class II drug variation based only on in vitro dissolution profile comparisons, where the amount of surfactant is doubled or halved. The existing EU guidelines (European Commission, 2010) are not sufficiently clear to avoid the lenient interpretation of the guidelines. It is not clear how to decide whether such variation is a qualitative or quantitative change in one or more excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product. Even when it is felt that a change may affect bioavailability, no official requirements are explicitly defined. It is simply stated that: ‘‘specific supporting data for Type IB and Type II variations will depend on the specific nature of the change. In some cases, reference is made to specific scientific guidelines’’. In this regard the guideline on the investigation of bioequivalence establishes in section 4.4 on variation applications that: ‘‘If a product has been reformulated from the formulation initially approved or the manufacturing method has been modified in ways that may impact on the bioavailability, an in vivo bioequivalence study is required, unless otherwise justified. Any justification presented should be based upon general considerations, e.g., as per Appendix III, or on whether an acceptable level A in vitro/in vivo correlation has been established (see CPMP/QWP/604/96)’’. Therefore, the strict interpretation for BCS-based biowaivers should be applied and bioequivalence studies should be required for all variations of low solubility drugs if they are classified as potentially affecting the bioavailability. The SUPAC IR guidance of the US-FDA (U.S. Department of Health and Human Services, 1995) does not mention the surfactants, but the SUPAC IR: questions and answers (U.S. Department of Health and Human Services, 1997) clarifies that wetting agents are not covered by the guideline. Only components included in categories spelled out in the guidance qualify as SUPAC-IR changes. Therefore, any change in surfactants requires an in vivo study. 9. Conclusion The effect that a certain excipient may have on the absorption of drugs cannot be generalised for all the drugs within a BCS class. The effect of the excipient and the magnitude of the effect is not only dose-dependent, it is drug-dependent (since an effect has been detected with some class I drugs), formulation-dependent (since other ‘‘inert’’ excipients may modulate the effect of the ‘‘active’’ excipient) and subject-dependent (since small amounts can affect absorption in a subpopulation of patients), which questions the inter-changeability of these generic products in the whole patient population. Acknowledgements Sandra van Os (Synthon) and other anonymous companies that shared the data of failed studies and allowed publication of the data. John Gordon (Health Canada) and Mike Robertson for their comments on the manuscript.

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