Pharmaceutical excipients — quality, regulatory and biopharmaceutical considerations

    Pharmaceutical excipients — quality, regulatory and biopharmaceutical considerations David P. Elder, Martin Kuentz, Ren´e Holm PII: DOI: Reference:

S0928-0987(15)30092-0 doi: 10.1016/j.ejps.2015.12.018 PHASCI 3435

To appear in: Received date: Revised date: Accepted date:

5 August 2015 25 November 2015 11 December 2015

Please cite this article as: Elder, David P., Kuentz, Martin, Holm, Ren´e, Pharmaceutical excipients — quality, regulatory and biopharmaceutical considerations, (2015), doi: 10.1016/j.ejps.2015.12.018

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ACCEPTED MANUSCRIPT Pharmaceutical excipients – quality, regulatory and

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biopharmaceutical considerations

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David P. Elder1,*, Martin Kuentz2 and René Holm3

GlaxoSmithKline, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom.

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University of Applied Sciences and Arts Northwestern Switzerland, Institute of

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H.Lundbeck A/S, Biologics and Pharmaceutical Science, Ottiliavej 9, 2500 Valby,

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Pharmaceutical Technology, Gründenstr. 40, CH-4132 Muttenz, Switzerland.

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Denmark.

* To whom correspondence should be addressed: Dr. David P. Elder, GlaxoSmithKline Pharmaceuticals, Park Road, Ware, Hertfordshire, SG12 0DP, UK. E-mail: [email protected]

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ACCEPTED MANUSCRIPT Abstract Practically all medications contain excipients, which are added for the purpose of production

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enhancement, patient acceptability, improving stability, controlling release etc. Typically

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excipients are the major components of a drug product, with the active molecule only present

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in relative small amounts. Historically, excipients were termed inactive components. However, as highlighted in the present paper; excipients can have an impact on the

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absorption, distribution, metabolism and elimination (ADME) processes of the coadministered drug, which is important information when selecting excipients for any new

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formulation. Further, this review also provides a description of the regulatory processes to get new excipients approved in different regions and a discussion of the recent regulatory

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initiatives, e.g. excipients for paediatric formulations, thereby providing points to consider for

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the pharmaceutical scientist when selecting excipients for a new drug formulation.

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Keywords: excipients, safety, quality, IPEC, ICH, FDA, SUPAC, pharmacopoeial

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considerations, biowaiver

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ACCEPTED MANUSCRIPT 1. Introduction Most medicinal products contain excipients. They are added for a number of reasons and can

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enhance product performance, e.g. enabling formulations, patient acceptability and

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compliance as modified release formulation or taste masked syrups for children or provide a

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more efficient and safe medication. The latter may be achieved e.g. by ensuring that peak plasma concentrations are kept below adverse effect or even toxic levels. Excipients are

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historically viewed as pharmacologically inactive materials (however, this view is almost certainly outdated - see section 6) and are derived from different sources, e.g., biological,

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minerals, chemical synthesis-based, etc. Excipients often contain concomitant (production related) components, processing aids, as well as impurities. The amount of excipient(s) used

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in the dosage form can often be significantly higher than API (active pharmaceutical

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ingredient), and there is some guidance on appropriate levels in different formulations (Rowe

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et al., 2005). As excipients are an important component of all pharmaceutical formulations it is crucial for the pharmaceutical scientist to understand the different types/grades of excipients that are available. It is further critical to recognise whether a new excipient will be

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required (understanding the cost, availability, biopharmaceutical and project related risks) within the formulation and how these new excipients can gain regulatory approval. There are roughly 8000 nonactive ingredients being used in food, cosmetics, and pharmaceuticals (De Jong, 1999). In 1996, approximately 800 different excipients were used in marketed pharmaceutical products in the United States (De Jong, 1999). Excipient manufacturers usually supply their material to different end users, i.e. pharmaceuticals, food, cosmetic, etc. Hence, suppliers of excipients do not necessarily know the final use of their products, i.e. it is often difficult helping end users select appropriate grades and grades are often not interchangeable (Hebestreit, 2009). However, as excipients for pharmaceutical use may need

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ACCEPTED MANUSCRIPT additional quality, functionality, and safety requirements. The focus on grade and supplier is

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important for the end-user.

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Excipients typically have multiple uses within a formulation and for example

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microcrystalline cellulose can be a filler/diluent, binder or disintegrant in a solid dosage form. Excipients can be added to a formulation to improve powder flow or compression and thereby enhance manufacturability, e.g., diluents/fillers, lubricants, glidants, etc. Moreover,

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excipients are used to enhance drug stability, e.g., low moisture grades of common fillers (in

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the case of hydrolytic instability) or antioxidants (in the case of oxidative instability); to enhance disintegration and thereby dissolution, e.g., disintegrants; to improve palatability,

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e.g., sweeteners, flavourants. The appearance of the finished dosage form can be improved by

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additives e.g., aqueous film coating components. Finally, excipients can also be used to enhance oral bioavailability by affecting drug solubility or permeability. The purpose of the

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present work is therefore to provide an overview of the regulatory process related to excipients and highlight that excipients are often not „inert‟ from a biopharmaceutical

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perspective. Moreover, industrially relevant work is discussed that employed modern in silico or high-throughput methods for the selection of pharmaceutical excipients.

2. Selection of excipients and supplier 2.1.Quality Excipients are low-value, high-volume products that may be used by several industries. The pharmaceutical industry, in general, is not the major customer of excipients in terms of volume supplied. It is not uncommon for the supplier to change its manufacturing process to make production more efficient, often without informing their customers. Therefore, having a contract or a quality agreement that prevents the supplier from making any changes in the Page 4

ACCEPTED MANUSCRIPT process/quality of the material, without informing their customers, is advantageous. These changes may force the pharmaceutical company to choose another supplier, which can‟t be

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done without prior approval from the appropriate regulatory agencies. It is important for the

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contract partners to evaluate and define timelines that are required for any potential changes

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so as to not run into stock-out issues with the risk of not being able to supply the required medicine to the patients. The pharmaceutical industry operates under the quality directives outlined in the current good manufacturing guidelines (cGMP) and at all times it‟s the

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company‟s duty to ensure that it fulfils the intentions stated in the current guidelines. It is the

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responsibility of the marketing authorisation holder (MAH) to ensure that the pharmaceutical product delivers the quality promised to the user, which also includes appropriate quality of the raw materials, i.e. the excipients. This led to the publishing of “Good Manufacturing

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Practice Guide for Bulk Pharmaceutical Excipients” (USP, <1078>). This guideline forms an acceptable framework that can be used by the excipient suppliers in the development of a

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quality system. Further, it facilitates a harmonised across the major regulatory regions, i.e. United States, Europe and Japan. The guideline uses an ISO 9000 format, which is different

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from many other guidelines within the pharmaceutical setting. It not only provides a way to assess whatever systems are in place and to evaluate how effective they are, but it also provides guidance on how to conduct an audit of an excipient supplier.

Many pharmaceutical companies will also assess the supply chains of those critical excipients, i.e. release controlling excipients (SUPAC MR, 1997) or structure forming excipients (SUPAC SS, 1997). This often involves initiating a „dual-supply‟ strategy so that these critical excipients can be obtained from more than one source in the case of unanticipated interruptions to the pharmaceutical manufacturing supply chain. Some of these „interruptions‟ include input raw material shortages, changes in distribution processes, natural

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ACCEPTED MANUSCRIPT disasters, regulatory issues (including changes in regulatory guidance), manufacturing challenges and finally decisions by companies to discontinue specific materials/grades A good example of this issue was the explosion at Shin-Etsu‟s

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(PhRMA, 2011).

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methycellulose manufacturing plant in Japan in 2007 that affected worldwide supplies of

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HPMC (Reuters, 2007).

Many companies were faced with stock-out of this excipient from Shin-Etsu and were forced

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to either stock-pile existing supplies or assess different suppliers/grades of HPMC, e.g. Dow

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HPMC. However, Dow supplies of HPMC was also severely rationed and in addition customer‟s found that the „equivalent‟ grades from Dow were not necessarily inter-

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changeable as the resulting drug product could not be guaranteed to meet registered in vitro

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dissolution specifications of the MR product.

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Another, aspect of excipient quality has been introduced with the ICH Q8(R2) guideline, that described the identification of critical material attributes (CMAs) for the drug substance and

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excipients. Variations in excipient, e.g. particle size, have therefore become an integral part of the quality by design (QbD) principles. A number of excipient vendors therefore offer to supply „special packages‟, i.e. batches of a designated excipient with differing physicochemical properties, but which still meet the pharmacopoeial specification,

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design of experiments studies (DoE). E.g. FMC Biopolymer offers a range of special services including process data, special samples and technical service to accommodate the design space (FMC, 2015). The variability is assessed using statistical tools. Therefore, the quality of excipients will likely have an even higher impact on pharmaceutical development in the foreseeable future.

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ACCEPTED MANUSCRIPT During the development of a new formulation, the pharmaceutical scientist selects excipients that will provide a stable, efficacious, and functional product. The choice should be

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appropriate for the intended purpose and according to the ICH Q8 (R2) guideline “at

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minimum those aspects of drug substances, excipients, container closure systems, and

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manufacturing processes that are critical to product quality should be determined and control strategies justified”, where critical is defined as where variation may have an impact on the drug product quality. For the selected excipients, their concentration and their potential

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influence on manufacturing and product performance (e.g. ascorbic acid to improve oxidative

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stability or a preservative systems‟ ability to inhibit microbiological growth) should be discussed relative to their intended function. Further, the excipients‟ ability to maintain their

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function throughout the products‟ shelf-life should be demonstrated, e.g. antioxidants and

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disintegrants. Finally, the compatibility between different excipients and between excipients and the drug substance should be evaluated. Selection of excipients following compatibility

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investigation is the obvious first step in any rational drug development process and it is well known that unfavourable combinations of drugs and excipients can alter both the stability and

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the bioavailability of the drug in the formulation (Serajuddin et al., 1999; Verma and Garg, 2005). However, there are no general well defined principles for selection of the most appropriate excipient or the most appropriate supplier. A good example for oral solid dosage forms is microcrystalline cellulose (MCC) for which several suppliers exist, e.g. FMC Biopolymer (avicel) or JRS Pharma (vivapur). A range of grades are available and commonly used, are for example, a relatively coarser grade coded “102” (e.g. avicel PH 102; vivapur 102) and the finer grade “101”. However, for a hydrolytically unstable drug, a low moisture, directly compressible grade of microcrystalline cellulose may be required, e.g. avicel PH 112; vivapur 112; whereas, for a cohesive, poorly flowing drug, a co-processed grade of

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ACCEPTED MANUSCRIPT microcrystalline cellulose with mannitol (avicel HFE-102) or with colloidal silicon dioxide

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(prosolv SMCC 50) may be appropriate (FMC, 2015).

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Ironically, „dual-sourcing‟ of key excipients also introduces issues with drug development. It

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is well precedented that the use of different suppliers of the same excipient is likely to introduce increased variability into excipient/product performance (Dave et al., 2015). The comparative compression behaviours of „similar grades‟ of MCC from different suppliers

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(avicel 101from FMC Bio-polymer and vivapur 101 from JRS Pharma) were assessed using

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multi-variate analysis. The data showed significant inter-supplier variability (Haware et al., 2010). Prednisone tablets which were manufactured using direct compression, with MCC

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from various sources, were assessed and they demonstrated significant differences in the

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dissolution rates of the resultant product (Landin et al., 1992). This part of the development often applies in-house methodology, but eventually the final judgment is made based on the

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formal stability studies as described in the ICH guideline on the topic (ICH, 2003). ICH Q8 (R2) guideline also states that excipient ranges needs to be justified and relevant in vitro and

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in vivo studies should be discussed relative to the formulation in order to link clinical to commercial formulation, thereby clearly defining excipients as potentially critical, components of the formulation. In addition to excipient compatibility with the drug, the impact of the manufacturing process on formulation selection, i.e. direct compression versus wet granulation excipient grades and the packaging system also needs to be considered. For instance, there may be preservatives within the formulation that will adsorb onto the container/closure system and that will impact on the choice and levels of these excipients. Special precautions related to the route of administration need to be understood, i.e. the maximum allowable concentrations of certain preservations for parenteral use. Similar considerations are germane for the choice of certain preservations for paediatric use.

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ACCEPTED MANUSCRIPT Additionally, other important elements relevant to excipients are; does a dossier or drug master file (DMF) exist; has the excipient previously been used for this route of delivery

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(FDA Inactive Ingredient Database, 2013a); the cost and availability (including dual-sourcing

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consideration, if appropriate); does the excipient vendor follow IPEC GMP guideline or is it

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ISO 9000 certified; does the excipient meet the designated pharmacopoeial requirements (USP, Ph.Eur and JP); and have the excipient vendor(s) previously been audited by the appropriate regulatory agencies? Some of these questions may seem less relevant during early

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development when creating the first prototype formulation, however, should the formulation

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perform appropriately in man then it‟s worthwhile paying attention to these kind of questions.

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3. IPEC classification of excipients

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The International Pharmaceutical Excipeint Council (IPEC) classified excipients into four classes based upon available safety information (IPEC, 1998): New chemical excipients

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Existing chemical excipients – first use in humans

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Existing chemical excipients

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New modifications or combinations of existing excipients These four classes will be described in the following section.

3.1. New chemical excipients If there is no historical precedence for use in an existing drug product, then the material is to be considered a new excipient and a pre-clinical safety assessment should be performed to demonstrate the safety of the material in its intended pharmaceutical application, at the desired level. The USP-NF Excipient Biological Safety Evaluation Guidelines <1074> provides substantive guidance on performing a safety assessment of a novel excipient (USP, Page 9

ACCEPTED MANUSCRIPT 2015). The estimated cost of safety studies for new chemical excipients has been reported to be approximately $35 million over 4-5 years (Nema et al., 2013). However, this is highly

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dependent upon use as different requirements are defined for excipients for short term oral

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use versus chronic parenteral use. The „inert‟ nature of excipients, have historically made

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safety testing difficult; however, developments in permeation enhancers have changed this perception significantly. Also there is currently a lot of scientific focus on the potential use of monoclonal antibodies in delivery systems (Gabathuler, 2014; Elvin et al., 2013), and should

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a company get this principle to the market it will provide yet more diversity in the

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pharmaceutical excipients.

3.2. Established excipients

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Established excipients include, i) existing chemical excipients – first use in humans; ii)

excipients.

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existing chemical excipients and iii) new modifications or combinations of existing

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3.2.1. Existing chemical excipients – first in humans These are a class of excipients where animal safety data does exist, as data may have been used in another regulatory application. Additional safety information may have to be collected to justify the use in humans dependent upon route and duration of use (see Table 1 and 2).

3.2.2. Existing chemical excipients These are excipients that have been used in man, but for another route of administration, higher dose etc., and hence additional safety data may be required. Importantly, just because

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ACCEPTED MANUSCRIPT an excipient is listed as GRAS does not mean that it can be used for all pharmaceutical

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purposes - as most GRAS classified excipients are for oral use.

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The safety of established excipients, particularly for paediatric use, has come under

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significant focus over the last decade. It is well established that although all excipients to be used in medicinal products for human use need to have either GRAS or FAP (Food Additive Petition) status (Hebestreit, 2009), most of this supporting data was generated in adults (both

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clinically and pre-clinically). Indeed, many excipients that are viewed benignly and are

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commonly used in adult medicinal products have been linked to safety concerns in paediatrics. Unfortunately, this information is both sparse in nature and difficult to access.

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There are several well documented cases of severe adverse reactions in children to common

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excipients (Fabiano et al. 2011; Ernest et al., 2007). To address these concerns, the European and United States Paediatric Formulation Initiative (PFI) have collaboratively created the

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Safety and Toxicity of Excipients for Paediatrics (STEP) database (Salunke et al., 2012). The purpose of this database is to serve as a free and accessible database for safety data and

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supporting toxicity studies for excipients. The objectives are to: facilitate the rapid identification of potential safety concerns during the screening and selection phase of formulation development. 

identify, whether there are any causal relationships between exposure and clinically relevant toxicity of excipients, in paediatric patients.

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identify, differences in the types or patterns of toxicity in paediatrics compared to the adult population.

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identify, whether there are any requirement for any additional safety data, to support the use of excipients within the paediatric population (juvenile toxicity studies, bridging studies, etc.).

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support, ongoing regulatory filings by providing „open access‟ to any underpinning safety data. support and facilitate research activities by providing a platform to share proprietary

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data from large companies and to any share unpublished data.

In parallel, the European Study of Neonatal Exposure to Excipients (ENSEE) aims to generate „denominator based estimates of excipient exposure and indicate opportunities for

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substitution‟ (Turner et al., 2013). In addition, pharmacokinetic data for some common

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excipients, e.g. parabens, ethanol, etc., in neonates is being generated on an opportunistic basis (Turner at al, 2013b; Hubbard et al., 2013). The group‟s intention is to provide

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information as monographs available to prescribers, nurses, pharmacists, etc. Each

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monograph will summarise neonate data for particular excipients, thereby allowing practitioners to develop individualised risk management plans for neonates, based on

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exposure to different excipients in different approved medicines.

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3.2.3. New modifications of existing excipients The last class of established excipients are the new modifications or combinations, which would not require safety evaluation (Russell, 2004). They are often termed co-processed excipients and comprise of mixtures of different types of excipient. For example, silicified microcrystalline cellulose is a mixture of the established diluent/filler, microcrystalline cellulose and the established glidant, colloidal silicon dioxide. The latter is difficult to handle (very low bulk density) in a manufacturing environment and airborne particles of colloidal silicon dioxide do constitute a worker safety hazard.

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ACCEPTED MANUSCRIPT Therefore, co-processing the two excipients prior to use produces a single excipient that addressing handling and safety concerns and exhibits excellent properties in terms of powder

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flow, blending properties, enhanced lubrification and compactibility.

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4. Regulatory guidance on excipients

Whilst there is a defined strategy for getting new excipients to the market, there are still a

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number of other cases where the use of excipients may be linked to regulatory requirements, or pharmacopeal considerations or ongoing discussions to align the pharmacopeial

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monographs for some excipients. Some of these recent guidelines and initiatives are

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discussed in the present section.

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4.1. Recent EU guidance on excipients

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The European Commission (EC) has decided to revise the guideline on „Excipients in the label and package leaflet of medicinal products for human use‟ (EU, 2003). This guidance

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provides useful perspectives around current regulatory thinking on several key excipients. A multi-disciplinary sub-group (CHMP Excipients drafting group (ExcpDG)) was set up during 2011. ExcpDG consists of the Safety Working Party (SWP), the Quality Working Party (QWP), and the Paediatric Committee (PDCO), the Pharmacovigilance Risk Assessment Committee (PRAC), the Coordination Group for Mutual Recognition and Decentralised Procedures - Human CMD(h), the Vaccines Working Party (VWP), the Biologics Working Party (BWP) and the Blood Products Working Party (BPWP). Other working parties or groups, such as the Patients' and Consumers' Working Party (PCWP), the Healthcare Professionals' Working Party (HCWP), the Working Group on Quality Review of Documents

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ACCEPTED MANUSCRIPT (QRD) or the Committee on Herbal Medicinal Products (HMPC) have also been consulted

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during the revision process.

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The primary objective of the ExcpDG is to update the labelling of selected excipients within

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the aforementioned guideline, as well as to add any new excipients to the list, as discussed in a supporting concept paper (CPMP, 2012). The ExcpDG prepares a series of questions-andanswers (Q&As) document for each excipient under review, containing the updated

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information for the labelling and package leaflet, in addition to a background scientific report

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where considered relevant. Thus far Q&A documents have been prepared on seven excipients; three preservatives (benzyl alcohol (EMA, 2014a), benzoic acid/benzoates (EMA,

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2014b) and benzalkonium chloride (EMA, 2014c)), two cosolvents ((ethanol (EMA, 2014d)

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and propylene glycol/esters (EMA, 2014e)), one diluent/filler (wheat starch (EMA, 2014f)) and one solubilising excipient (cyclodextrin (EMA, 2014g)). The Q&A‟s documents are

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progressively released for public consultation. In addition, three background papers have been published on propylene glycol (EMA, 2013), parabens (EMA, 2014h) and cyclodextrins

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(EMA, 2014i). Further, the EMA has issued general guidance on antioxidants/antimicrobial preservatives (EMA, 1997), and EMA has a general regulatory guidance on excipients (EMA, 2007).

4.2. Recent FDA guidance on excipients According to FDA‟s 21 CFR 210.3(b)(8) guidance, an excipient or inactive ingredient is any component of a drug product other than the active ingredient. The FDA‟s Inactive Ingredient Database (2013a), which was initiated in 2009 provides information on excipients that are present in FDA-approved drug products. The information in this database can be used by industry as an aid in developing drug products. For the purposes of new drug development,

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ACCEPTED MANUSCRIPT once an excipient has appeared in an approved drug product for a particular route of administration, i.e. oral, then the excipient is no longer considered „new‟ and may require a

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less extensive regulatory review for any subsequent times it is included in new drug products.

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For example, if a particular excipient has been approved in a certain dosage form at a certain

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level, a sponsor could consider it safe for use in a similar manner for a similar type of

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Pharmacopoeia requirements

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product.

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21 CFR 211.84(d) indicates that, „Each component shall be tested for conformity to all written specifications for purity strength and quality’. The USP in turn indicates that for an

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excipient, that‟ Every compendia article in commerce shall be so constituted that when

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examined in accordance with these assay and test procedures, it meets all of the requirements

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in the monograph defining it’. The JP and Ph. Eur. have similar perspectives. Therefore, an excipient monograph provides a list of quality attributes, i.e. a specification, which is meant to define the desired performance of the excipient. These monographs include universal tests and

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may include specific tests as required; the latter typically only when they have an „impact on the quality of the excipient for release and/or compendial testing and/or when needed to allow the differentiation of the available commercial physical grades of the excipient‟. Optional tests may be included to fully describe/control the quality of a specific excipient. Thus, functionality-related tests may be included, but this should be assessed on a case-by-case basis. Functionality tests for an excipient relate to any desirable properties, e.g. flow, compression, etc., that facilitate the manufacturing process and thereby enhance the quality and performance of the drug product. Therefore, the requirement for any functionality tests, procedures, and related acceptance criteria in a general excipient monograph is typically limited, as they tend to be dosage form related. Thus, any meaningful and reliable evaluation of the overall functionality related properties is only

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ACCEPTED MANUSCRIPT possible within the context of the specific formulation and any process technology that is utilized in its manufacture. Whilst functionality related tests could be viewed as relevant for quality

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attributes of the drug product formulation, they are nevertheless still important for any excipient

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monograph. The harmonization of selected excipient monographs (as well as pharmacopoeial

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general chapters/procedures) across the three main pharmacopoeias (Ph. Eur., JP and USP) was seen as a critical activity underpinning the successful implementation of the ICH initiatives. It was considered important to avoid unnecessary testing by industry brought

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about through differences between these regional pharmacopoeias. Moore (2014) exemplified the issue using the carboxymethylcellulose calcium monograph as a case study. Prior to ICH,

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a total of 37 tests (USP = 13, JP = 13, Ph. Eur. = 11 tests) would be required for full compendial release in all three regions, compared to a mere 10 tests in a post ICH world.

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Although some progress has been made towards harmonization of the excipient monographs there are still significant challenges. Most pharmacopoeial excipient monographs are

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harmonized by attributes. Thus for example, mannitol, a common excipient in tablet products is harmonized by attributes, apart from heavy metals test. Local requirements are for second

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identification (Ph. Eur.), absence of Salmonella (Ph. Eur.), and functionality related characteristics. JP does not stipulate microbial contamination or bacterial endotoxins. The principal impediment to total harmonization of excipient monographs across the three main pharmacopoeias still appears to be the heavy metal test (linked with ICH Q3D – see above). Some parts of the microbial general chapters (microbial enumeration tests USP <61>) and tests for specified microorganisms USP <62>) are also influencing ongoing harmonization of some excipients of natural origins, e.g. starch.

4.4. Regulatory filing process for new excipients

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ACCEPTED MANUSCRIPT European Union (EU) directive 75/318/EEC states that new chemical excipients will be dealt with in an identical fashion to new APIs. Consequently, there is a requirement for a

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regulatory dossier within the EU region for any new excipient(s), i.e. extensive safety testing

generally recognized as safe (GRAS) determination pursuant to 21 CFR 182, 184 and

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is required. In the United States the approval mechanisms for new excipients include:

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approval of food additive petition under 21 CFR 171

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as contained within a new drug application (NDA) approval for a specific drug

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product and for a particular function or use within that dosage form

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This will require a DMF to be registered with the FDA and this will open the excipients use

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in other products and ultimately will see its inclusion within the National Formulary. These

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different regulations impose different evaluation schemes and as most pharmaceutical products are intended for worldwide registration, these differences should be kept in mind when selecting any new excipient. Different guidelines have therefore been suggested by

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IPEC-Americans (Steinberg et al., 1996) and IPEC-Europe (De Jong, 1999); see Table 1 and 2, respectively.

In addition to the physicochemical data that define the quality attributes of the excipient, the additional safety data defined in Table 1 and/or 2 needs to be included within the file (all safety studies should meet the current good laboratory practice (cGLP) guidelines). One of the unique aspects of the IPEC approach is that not all of the safety tests outlined in Tables 1 and 2 are required. Some of the safety tests are conditional upon findings in other tests and different tests are defined as a function of the intended route of delivery and exposure duration. This means that the basic data is generated for all excipients and any additional tests Page 17

ACCEPTED MANUSCRIPT are conducted as a reflection of exposure duration and administration route. The guidelines are not to be used as a checklist, but as an „aide memoire‟ for qualified professionals to make

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the necessary judgements concerning the conditional tests, e.g. when to conduct the

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carcinogenicity test in rodents.

4.5. Regulatory filing process for new excipients (case study)

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Hebestreit (2009) recently reported on his company‟s experience with the regulatory approval of a new coating excipient (Kollicoat IR). The safety expert report was accepted by the 14

C-radiolabelled material at

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regulatory agency. There was no absorption observed using

concentrations of up to 1000 mg/kg. Oral bioavailability was well below 1 %, with no

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accumulation in any organs or tissues. The marketing authorisation holder‟s (MAH)

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conclusions that the slightly different compositions of this excipient will have no impact on the observed bioavailability (90 % confidence intervals of the ratios for AUC 0-last and Cmax

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were within the accepted ratios of 0.80 and 1.25) were accepted. No deaths or treatmentrelated clinical observations were seen in either the single or repeat dose studies,

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mutagenicity was not observed, and there were no effects in reproduction toxicity studies. Taken together, no toxicological issues were observed relating to the use of Kollicoat IR as tablet coating agent for oral use. All three ICH regions (US, EU, Japan) required formal registrations, i.e. CMC (chemistry manufacturing and controls) and safety data (safety expert report). In the US, the CMC data was included in a type IV DMF, non-clinical data was included in a type V DMF. In the EU, no EMF (European Master File) procedure is currently available, i.e. all data for the new excipient has to be included in the dossier for MA (marketing authorisation) of a medicinal product (EMA, 2007). After successful worldwide registration, the company initiated preparation of pharmacopoeial monographs within the

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ACCEPTED MANUSCRIPT various ICH region(s). Ph. Eur. monograph for this excipient was first published in 2009

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(Macrogol poly(vinylalcohol) grafted copolymer (2523).

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5. Regulatory guidance on excipients affecting drug product approval

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The previous section described the regulatory process for getting regulatory approval for established/new excipients; however, as excipients are important components in

5.1.

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pharmaceutical product they are a part of.

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pharmaceutical products they may also influence the regulatory approval of the

SUPAC (scale-up and post approval changes) and biowaiverimplications

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The various FDA scale-up and post-approval changes (SUPAC) guidance documents were

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first issued during 1995-1997 (SUPAC IR, 1995; SUPAC SS 1997; SUPAC MR 1997). These guidance documents identify information that should be provided to FDA to assure

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continuing product quality and performance characteristics of an immediate release solid oral dose formulation for specified post-approval changes. The guidance defines 1) the levels of

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change; 2) the recommended CMC tests for each level of change; 3) the in vitro dissolution tests and/or in vivo bioequivalence tests for each level of change, and 4) the documentation that should support the change. Specifically, the SUPAC guidance assessed the impact of changes to the type or amount (components and composition) of excipients within the formulation. These changes were termed level 1 („unlikely to have any detectable impact on formulation quality and performance‟), level 2 („could have a significant impact on formulation quality and performance. Tests and filing documentation for a Level 2 change vary depending on three factors: therapeutic range, solubility, and permeability’) or level 3 (‘likely to have a significant impact on formulation quality and performance. Tests and filing vary depending on therapeutic range, solubility, and permeability’) changes. Page 19

ACCEPTED MANUSCRIPT The SUPAC guidance also defines two further categories of excipients. For modified release solid oral dosage forms (SUPAC MR), consideration should be given as to whether or not the is

critical

to

drug

release,

i.e.

release

controlling

excipients,

e.g.

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excipient

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hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol (PVA), polylactic acid (PL),

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alginates, etc. A recent article from Casas et al. (2015) attempts to introduce the concept of excipient efficiency for controlled release products. This parameter is specific for a given drug to excipient ratio and is defined via the matrix porosity divided by the obtained

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Higuchi‟s release rate constant. Different corrections were proposed to account for particle

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size and solubility of the active compound.The determination of excipient efficiency is straight forward using newly derived or pre-existing data from matrix systems.

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Secondly, the semi-solid guidance (SUPAC SS) defines structure forming excipients. These

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are excipients which are involved in the formation of the matrix that structures an ointment, cream or gel etc., to define its semisolid character. These include gel forming polymers,

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petrolatum, certain colloidal inorganic solids, waxy solids (e.g., cetyl alcohol, stearic acid)

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and emulsifiers, etc.

5.2. BCS and biowaiver implications The SUPAC initiatives were an obvious precursor to the development of the biopharmaceutics classification system (BCS) (Amidon et al., 1995), with the objective of granting bio-waivers for SUPAC type activities.

The BCS system entered regulatory

thinking during early 2000 and the bio-waiver concept was extended beyond SUPAC considerations to allow for the approval of BCS class I generic products (FDA, 2000). One of the opportunities offered by the BCS approach was a process to justify a waiver for in vivo bioequivalence, often termed a „bio-waiver‟. For a BCS-based bio-waiver the drug needs to be BCS class 1 (highly soluble/highly permeable), that is rapidly dissolving, i.e. > 85%

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ACCEPTED MANUSCRIPT dissolution within 30 minutes. It is further most important that the excipients used in the dosage form should previously have been used in an FDA drug product (now enshrined in

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FDA‟s Inactive Ingredient Database) and the quantity of these excipients needs to be

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consistent with their intended function(s). EMA (2010, 2011) gives similar guidance, but is

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slightly more proscriptive with respect to allowable formulation changes, i.e., „the composition of the strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths’.

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In addition, the guidance does provide some added flexibility, if, ‘i. the amount of the active

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substance(s) is less than 5 % of the tablet core weight, the weight of the capsule content; ii. the amounts of the different core excipients or capsule content are the same for the concerned

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strengths and only the amount of active substance is changed; iii. the amount of a filler is

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changed to account for the change in amount of active substance. The amounts of other core excipients or capsule content should be the same for the concerned strengths’. WHO (2006)

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loosened the criteria for bio-waiver consideration by re-defining high solubility using a dose/solubility ratio of 250ml over physiologically relevant pH‟s (1.2-6.8), re-defining the

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dose, which should be the highest dose indicated in WHO‟s Model List of Essential Medicine‟s (EML), and re-defining the permeability criteria, which now includes some class III drugs, i.e. paracetamol, acetylsalicylic acid, allopurinol, lamivudine and promethazine. Finally, the guidance further allows pharmaceutical products containing BCS class II drugs, „that are weak acids which have a dose: solubility ratio of 250 ml or less at pH 6.8 to be eligible for the biowaiver procedure, provided that they dissolve rapidly at pH 6.8 and similarly to the comparator product at pH 1.2 and 4.5’.

There has been considerable debate about extending the BCS bio-waiver process to BCS class 3 compounds (highly soluble/poorly permeable), and application of this approach would

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ACCEPTED MANUSCRIPT necessitate that excipients do not affect either permeability or intestinal residence time (Rege et al., 2001). Recently, FDA has re-issued their guidance for bio-waivers (FDA, 2015) and it

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now extends to BCS class III compounds. The standard warning for BCS class I products is

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still retained within the guidance, „Large quantities of certain excipients, such as surfactants

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(e.g., polysorbate 80) and sweeteners (e.g., mannitol or sorbitol) may be problematic, and sponsors are encouraged to contact the review division when this is a factor‟. However, in addition, there is specific commentary regarding BCS class III compounds, „Unlike for BCS

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class 1 products, for a biowaiver to be scientifically justified, BCS class 3 test drug product

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must contain the same excipients as the reference product. This is due to the concern that excipients can have a greater impact on absorption of low permeability drugs. The composition of the test product must be qualitatively the same and should be quantitatively

New regulatory guidance with potential for impact on control of excipients

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5.3.

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very similar to the reference product’.

Two of the most recent ICH quality guidelines (ICH M7 (2014) and ICH Q3D (2014) have

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the potential to impact on excipients and subsequent product control strategies. The recent guideline on mutagenic impurities (ICH M7, 2014) specifically excludes established excipients, stating, „Assessment of the mutagenic potential of impurities as described in this guideline is not intended for excipients used in existing marketed products, flavoring agents, colorants, and perfumes’. However, the guideline also states that for new excipients that, „The safety risk assessment principles of this guideline can be used if warranted for impurities in excipients that are used for the first time in a drug product and are chemically synthesized‟.

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ACCEPTED MANUSCRIPT The recent guideline on elemental impurities (ICH Q3D) applies to human drug products, but not to the components of the drug product, i.e. API, excipients, container/closures, etc.

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However, the supporting risk assessment will almost certainly involve assessing the relative

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importance of inputs from the various sources, e.g., API, excipients, container closure,

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manufacturing equipment, utilities, etc. The risk of excipients meaningfully contributing to the overall elemental impurities risk is typically determined by the source/manufacturing process. Therefore mined excipients, e.g. talc pose the greatest risk, followed by those

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synthesized using metal catalyst(s), e.g. mannitol, those that are of plant origin, e.g. cellulose

MA

derivatives, those that are of animal origin, e.g. lactose and gelatine and those posing the least risk are those synthesized without metal catalysts, e.g. colloidal silicon dioxide (Schoneker,

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2015). Additionally, there is little evidence that excipients meaningfully contribute to the

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overall levels of residual metals (Schoneker, 2015). By far and away the biggest contributor to the overall total are residual catalysts (class IIb elements, e.g. Pt, Pd, etc.) in APIs and

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because of the earlier guidance (EMA, 2007) these are well controlled in both API and drug products. Both USP and Ph. Eur. will remove all heavy metal tests from existing

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pharmacopoeial monographs when they introduce the harmonized ICH Q3D requirements. JP will eventually harmonize their monographs with ICH Q3D, but the timings are unclear and at this stage there is no clarity as to whether they will remove heavy metals testing from their excipient monographs. Ph. Eur. will harmonize their elemental impurity requirements for excipients with ICH Q3D and this will be implemented in December 2017. USP will implement its requirements in January 2018 and importantly, it will harmonize its new general chapters (<232> and <233>) with ICH Q3D (Schonecker, 2015).

5.4. Excipients as coformers

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ACCEPTED MANUSCRIPT Both the FDA (2013b and EMA (2014,j) have recently issued guidances for cocrystals. These are defined as, „solids that are crystalline materials composed of two or more molecules in the

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same crystal lattice‟ (FDA, 2013b). Cocrystals are comprised of the API (active

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pharmaceutical ingredient) and a conformer, which is typically an excipient (Elder et al.,

SC R

2014). Indeed, the FDA defines cocrystals as dissociable „API-excipient‟ molecular complexes that are to be treated as drug product intermediates (DPI) (FDA, 2013b). In contrast, EMA (2014j) views cocrystals in the same way as solvates and hydrates and

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therefore an API variant rather than a DPI. Not unsurprisingly, FDA‟s views have met with

MA

sustained criticism from the scientific community (Elder et al, 2014; Aitipamula et al., 2012). The very large number of approvable excipients (GRAS listed) that can be used as coformers

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has seen a significant increase in the incidence of cocrystals usage (Elder et al, 2014). For

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instance, more than 50 cocrystals of piroxicam and carbamazepine have been reported in the

2007).

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literature, the former using 23 different excipient coformers (Childs et al., 2009; Childs et al.,

For drugs that are susceptible to degradation, the formation of cocrystals with stabilizing

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excipient coformers offers an elegant strategy for enhancing stability (Trask et al., 2006; Gao et al., 2012; Elder et al., 2014). Adefovir dipivoxil degrades via hydrolysis and the rate is pH dependent (pH 7.2 > pH 2). Therefore, it would be expected that stabilisation will occur with acid coformers, e.g. saccharin and destabilisation will occur with basic coformers, e.g. nicotinamide, and this indeed was found (Gao et al., 2012).

6. Influence of excipients on solubility, permeability, absorption and presystemic metabolism of the API Although there is a plethora of safety data supporting the use of GRAS excipients, there is a surprisingly limited amounts of information regarding the impact of excipients on solubility, Page 24

ACCEPTED MANUSCRIPT permeability and absorption (particularly the efflux and transporter mechanisms) and hence their effect on the absorption, distribution, metabolism, elimination and toxicity properties of

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most drugs (Goole et al., 2010).

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6.1.Solubility

The increased number of APIs with lowered aqueous solubility arising from high throughput

NU

screening (Lipinski et al., 2001) has had a significant impact on excipient selection. As a consequence, there has been increased usage of solubilising excipients, e.g. cosolvents,

MA

surfactants, cyclodextrins, phospholipids, polymers, etc., during drug development (Strickley, 2004). The challenge for the formulator is to select the best combination of excipients that

D

will address concerns relating to adequate bioavailability, good stability and good

TE

manufacturability. Oftentimes, compromises need to be made, for instance adding excipients to enhance bioavailability that will adversely impact on the stability of the dosage form. In

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these cases, control strategies need to be implemented that address these concerns.

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The evaluation of the additive effects on a drug candidate‟s solubility and dissolution is a central part of early pharmaceutical development. It is possible to employ miniaturized automated screening assays (Alsenz et al., 2007) to generate drug solubility data in the presence of a broad range of excipients. A particular advancement for such miniaturized tests is the parallel screening capability of the excess drug solid remaining after equilibrium solubility assessments using x-ray diffractometry (Wyttenbach et al., 2007). This provided insights into the likely mechanisms of how excipients can influence solubility because these additives can impact on solvent-mediated polymorphic or solvate transitions. For better understanding of drug-excipient effects, it is an option to use real-time analytics during a solubility or drug dissolution assay (Kuentz, 2014). Excipient effects on solubility are often Page 25

ACCEPTED MANUSCRIPT not simple and it is essential for ionizable drugs to evaluate a range of different pH values. Based on such data, Avdeef et al. (2008a) proposed solubility-excipient classification

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gradient maps that were helpful in ranking excipients for given compounds. Interestingly,

IP

drug aggregation was often encountered. Some drugs exhibited drug aggregation at pH values

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for which the compound was uncharged (case 1), while other APIs formed charged, anionic or cationic molecular aggregates (case 2). Finally, some APIs showed a mixed drug aggregation across a broad pH range (case 3). The various excipients assessed were shown to

NU

differently perturb such drug aggregates, demonstrating that excipient effects on drug

MA

solubility are essentially complex.

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The complexity of additive effects makes prediction of drug solubility rather challenging.

TE

Whilst many in silico methods can be used to predict the aqueous solubility of the drug alone (Elder and Holm, 2013), the modelling of additive effects is often sub-divided into separate

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excipients categories, for example, cosolvents (Jouyban, 2008). A general drug solubility prediction with different kinds of excipients is possible by calculating the solid-liquid

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equilibrium using a thermodynamic model. The classical Scatchard-Hildebrand approach has often been used in pharmaceutics and it was extended for better predictions in polar solvents (Adjei et al., 1980; Bustamante et al., 1993). Solubility parameters are further typically employed for in silico screening of excipients affecting miscibility and solubility (Forster and Rades, 2001). More recently, a Conductor-like Screening Model for Real Solvents (COSMORS) (Klamt, 1995) has been tried for excipient selection in early formulation development (Pozarska, et al., 2013). The latter approach is based on quantum-mechanical calculations that require minimal information based on chemical structure. This is different from groupcontribution methods used to predict drug solubility in excipients and water. Such group contribution methods are typically require large datasets and different estimation versions

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ACCEPTED MANUSCRIPT were compared regarding actual solubility data of „representative‟ pharmaceuticals (Diedrichs and Gmehling, 2011). Amongst the different thermodynamic approaches, the

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pertubated-chain statistical associating fluid theory (PC-SAFT) (Gross and Sadowski, 2001)

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method has been applied in the pharmaceutical field (Cassens et al., 2010; Spyriouni et al.,

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2011; Prudic et al., 2014). Apart from these solubility predictions, the PC-SAFT theory has been tried for non-equilibrium modelling of drug dissolution (Ji et al., 2015). Paus et al. (2015) used this theoretical approach to study the influence of excipients on solubility and

NU

dissolution of pharmaceutical products. They measured the solubility of two model anionic

MA

APIs (naproxen and indomethacin) in the presence of polyethylene glycols (PEG), polyvinylpyrrolidone (PVP) and mannitol. The authors reported that enhanced solubilisation

D

was possible in the presence of these common excipients and the outcome was also predicted

TE

by means of the PC-SAFT theory. Interestingly, although the solubilities of the two APIs were increased by the presence of excipients, the dissolution rates were sometimes decreased

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(for example, with PEGs, which was related to the molecular weight of the PEG). The authors attributed these differences to the combination of molecular interactions between the

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polymers and the influence of the excipients on the kinetics of the reaction, i.e., a combination of the rate constants of the surface reaction and the diffusion of the API.

This example shows that modern thermodynamic modelling can lead to a better understanding of excipient effects on drug solubility and dissolution. Whilst the nonequilibrium modelling of drug dissolution is still rather academic, some pharmaceutical companies have started to use modern thermodynamic methods for a rational excipient selection. Companies have to decide, in which theoretical and experimental methods they are willing to invest. It is expected that thermodynamic modelling and high-throughput solubility testing will become increasingly important in the pharmaceutical industry.

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Industrial high-throughput testing generally includes drug solubility in bio-relevant media

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such as fasted state simulated intestinal fluid (FaSSIF) (Galia et al., 1998; Vertzoni et al.,

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2004; Kloefer et al., 2010; Fuchs et al., 2015; ). The presence of bile salts and phospholipids

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in these media can interact with excipients resulting in a net drug solubilization that should be assessed by parallel or off-line testing. Another important aspect to consider is drug supersaturation and precipitation in presence of these excipients. Several drug delivery

NU

systems provide drug supersaturation after aqueous dilution. The resultant high drug

MA

concentrations obtained within the gastrointestinal tract would then promote a high absortive flux. Excellent reviews have been published on drug supersaturation and on how

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pharmaceutical excipients affect kinetic drug concentrations (Brouwers et al., 2009, Warren

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et al., 2010; Kawakami, 2012; Bevernage et al., 2013). Pharmaceutical companies should evaluate such excipient effects on kinetic and equilibrium solubilization early on in

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this knowledge.

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development so that preclinical as well as clinical formulation development can benefit from

6.2.Permeability

The more complex drug permeability models such as the Ussing diffusion chamber or in situ perfusion studies are labour intensive and less suited for an industrial study of excipient effects. Therefore, permeability screening in the pharmaceutical industry makes use of the parallel artificial membrane permeability assay (PAMPA) and other similar approaches (Kansy et al., 1998). Different PAMPA versions are widespread in the pharmaceutical industry and permeability results can be correlated with human absorption data (Kansy et al., 2003; Sugano et al., 2001). However, membrane permeability can of course only test passive diffusion and it is still openly debated as to how important this contribution is for the majority

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ACCEPTED MANUSCRIPT of pharmaceutical compounds (Kell et al., 2011). In order to assess the impact of active drug transport, cell-based assays (e.g. Caco-2, MDCK) have been used and high-throughput

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arrangements do exist within some pharmaceutical companies (Alsenz and Hänel, 2003).

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These rather elaborate resource intensive assays generally do not replace, but complement the

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simpler and more robust screening tests based on artificial membrane permeability.

Bendels et al. (2007) evaluated several excipients with respect to how they affect passive

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membrane permeability and maps were constructed for a better overview. This work was

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continued with a study of how pH and aqueous boundary layers could affect solubility and permeability of specified drugs (Avdeef et al., 2008b). In particular, they assessed the impact

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of several key excipients (e.g., sodium taurocholate, hydroxypropyl-β-cyclodextrin potassium

TE

chloride, propylene glycol, methylpyrrolidone and polyethylene glycol 400) on these parameters, and the results were visualized as classification gradient maps. They found that

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excipients typically lowered permeability, but often not in an absolutely reciprocal manner to the increases in observed solubility. The APIs studied showed differences in „absorption

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potential‟ (facilitated by these excipients), in the order: clotrimazole > griseofulvin > progesterone > dipyridample > glibenclamide > mefanamic acid > butacaine > astemizole. Interestingly, the data for albendazole and glibenclamide with hydroxypropyl-β-cyclodextrin appeared to be aligned with in vivo cmax data.

Several other studies in the literature have reported excipient effects in cell-based permeability assays that consider active transport mechanisms. Without aiming for a comprehensive review of this field, some examples will be provided. Thus, many surfactants were shown to have an effect on permeability: tween 20 (Yamagata, 2007), tween 80 (Wagner et al., 2001), cremophor EL (Wagner et al., 2001), cremophor RH40 (Tayrouz et al.,

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ACCEPTED MANUSCRIPT 2003), pluronic P85 (Batrokova et al., 2004) pluronic L61 (Krylova and Pohl, 2004), sodium lauryl sulphate (Rege et al., 2001), sodium docusate (Rege et al., 2001), sodium taurocholate

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(Goole et al, 2010) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (Chang et

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al., 1996). In addition, other excipients showing an effect on permeability are cyclodextrins

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(Rajeski and Stella, 1996), chitosans (Bernkop-Scnurch and Dunnhaupt, 2012), polymers (Goole et al., 2010), and ethanol (Wagner et al., 2001).

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The different excipients show rather diverse effects with respect to the underlying

MA

mechanisms. These mechanisms are based on physicochemical interactions and in many cases they show the influence of drug transporters. The view of excipients as being “inert”, is

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in those cases certainly questionable and the biological effects are not limited to drug

TE

absorption. Due to the abundance of drug transporters in the body and their dynamic interplay with metabolizing enzymes, excipients affecting transporters are prone to influence

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practically all ADMET (absorption, distribution, metabolism, elimination and toxicology) processes. However, this review is focussed primarily on the absorption step, which includes

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consideration of gastrointestinal solubility, permeability, transporter function and metabolism.

6.3.Metabolising enzymes (cytochrome P450) and efflux transporters Several common solubilising excipient, e.g. PEGs and cremophor EL (CrEL) have been shown to inhibit metabolising enzymes (cytochrome P450) and efflux transporters, e.g. Pglycoprotein (Pgp) ABCB1, and multidrug resistant associated protein 2 (ABCC2) (Stegemann et al., 2007; Buggins et al., 2007). Engel et al. (2012) recently reported on the influence of four common solubilising excipents (PEG 400, CrEL, solutol HS (SOL) and hydroxypropyl-β-cyclodextrin (HPCD)) on a wider range of organic anion transporting

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ACCEPTED MANUSCRIPT protein systems (OATP). The two surfactants (SOL and CrEL) were strong inhibitors of all of these pathways, with the strongest effect on OATP1A2, OATP1B3 and OATP2B1. HPCD

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inhibited all transport proteins, but only for „substrates containing a sterane-backbone‟.

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Finally, PEG 400 is a selective and potent inhibitor of OATP1A2. The authors cautioned that

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inclusion of these excipients could reduce the oral bioavailability of many drugs, including quinolones by blocking intestinal absorption via OATP1A2 (cf: fruit juices) and lowering the therapeutic effect of these antibiotics. Similarly, they could affect the hepatic reuptake of

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statins by OATP1B1 and OATP1B3, reducing the lipid-lower activity of these drugs.

A similar study on the impact of common excipients on in vivo cytochrome P450 (CYP450)

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activity was recently published (Martin et al., 2013). The authors looked at the effect of 23

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common excipients (13 surfactants and 10 polymers) on seven common CYP450 enzymes. These excipients were found to have an effect on at least 57% of the enzymes studied. More

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concerningly, a majority of the excipients studied could either inhibit or increase activity of several different CYP450 enzymes. Typically, this required concentrations (>100µM), which

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were higher than those typically achievable therapeutically (<100µM), but 20% were seen at concentrations below this level (<100µM), and hence could modify the pharmacokinetics of vulnerable substrates (i.e. sub-therapeutic exposure or enhanced toxicological risks). These findings were very similar to an earlier study by Ren et al. (2008) who looked at 22 common excipients and found that over two-thirds of these compounds could inhibit the activity of CYP3A4 by more than 50% in vitro (these findings were particularly true of the surfactants and polymers).

6.4.Oral absorption

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ACCEPTED MANUSCRIPT Depending on the given drug properties, the extent and variability of oral absorption may depend on drug solubility, dissolution, permeability (and active transporters), and optional

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metabolism in the gastrointestinal tract. Absorption is hence the outcome of several

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individual processes that can each be influenced by pharmaceutical excipients. It is common

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in major pharmaceutical companies to use the acquired in vitro data from solubility and permeability experiments to estimate oral drug absorption using physiologically-based

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pharmacokinetic (PBPK) modelling (Kostewicz et al., 2014).

MA

Parameter sensitivity analysis is valuable to reveal which factors will likely affect oral absorption of a compound at a given dose (Kuentz, 2008). A scenario is that absorption

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concerns with a BCS class II drug are caused by preclinical animal PK data at comparatively

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high doses. Parameter sensitivity analysis can here estimate oral drug absorption in humans at clinically relevant doses to find a suitable formulation strategy for clinical development.

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Moreover, a possible dissolution limitation can be differentiated from a true solubility limitation (i.e., DCS class IIa versus DCS class IIb), which is of critical importance for

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formulation development (Butler and Dressman, 2010).Excipients are typically thought to have no effect on the absorption of BCS class I compounds (high solubility and permeability) and limited effect on BCS class III compounds (high solubility, low permeability), particularly those anionic drugs that are substrates for transporter mediated absorption, e.g. atenolol. Alternatively, for, BCS class II and IV compounds, excipients are likely to have a significant effect. However, Garcia-Arieta (2014) has recently challenged this proposition indicating that a given excipient effect can be dose dependent, drug dependent, formulation dependent and subject dependent. Garcia-Arieta (2014) emphasised for example different bioequivalence studies of the drug risperidone (a highly permeable drug based on its metabolic profile, i.e. BCS class I). Interestingly, different bioequivalence studies with

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ACCEPTED MANUSCRIPT alternative levels of sorbitol did not demonstrate bioequivalence. The results were not attributable to high variability or inadequate statistical power of the clinical studies. However,

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these findings cannot be viewed as ultimate proof of a sorbitol effect on oral bioavailability

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of risperidone, but there is some likelihood of such an effect. It is important to be aware of

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excipient effects as they are not easily detected by in vitro tests. For example, bicarbonate was shown to accelerate gastric emptying and increased absorption rate of paracetamol (Rostami-Hodjegan et al., 2002a, 2002b). Another example is the effect of mannitol on small

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intestinal transit times in cimetidine formulations, which was found to be dose-dependent

MA

(Adkin et al., 1995a). It was recently argued by Kubbinga et al. (2014) that retrospective analysis of approved generic products is an alternative “top down approach” as compared to

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the “bottom-up approach” that is the standard approach in pharmaceutics to gain knowledge

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from in vitro and in vivo animal studies. The authors used such retrospective analysis to study potential lactose effects in solid oral dosage forms, for drugs of different BCS classes. Such

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excipient effects.

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retrospective analyses may spark future mechanistic studies as well as modelling to clarify

It seems fair to state that the effect of excipients on drug absorption is often not fully understood. Goole et al. (2010) felt that this issue shouldn‟t be addressed by re-classifying excipients as active agents, as this would have a significant impact on overall healthcare costs without materially improving patient safety and drug efficacy. Indeed, food contains many similar types of substances (natural surfactants, bio-polymers, etc.), so food would be anticipated to affect the ADMET properties of drugs to a significantly greater effect than drugs. Additionally, gut microflora can also metabolically transform drugs in a similar way to excipients. The gut micro-biota can activate or deactivate drugs, alter drug permeability and metabolism via direct and in-direct mechanisms (Deweerdt, 2015).

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6.5. The influence of excipients on biowaiver extensions

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The BCS system has been widely used to support the use of biowaivers, particularly for BCS

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class I compounds (FDA, 2015). However, current guidance cautions against the affect that

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certain excipients can have on the rate and extent of bioavailability. This is particularly important for surfactants, e.g. polysorbate 80 and certain sweeteners, e.g. mannitol or sorbitol. This is viewed as being particularly important for BCS class III compounds and the

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current regulatory view is that generic products should contain the same excipients at similar

MA

levels as the reference product (FDA, 2015). Several authors have provided in vitro data to demonstrate that certain common excipients do not influence the permeability of certain BCS

7. Conclusions

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class III compounds (Parr et al., 2015).

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Excipients are a very important component of most pharmaceutical products. Historically, excipients have been seen as inactive components within the formulation. However,

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excipients may have a number of biopharmaceutical implications for the drug product. The selection of excipients should therefore focus on biopharmaceutical, as well as pharmaceutical processing and stabilising perspectives.. This means that regulators need to find a balance between over-regulating drug product approvals and avoiding granting unnecessary biowavers , based on these potential biopharmaceutical differences introduced by certain excipients.

Excipient grades/quality can typically vary over a pharmaceutical product‟s life time. Excipients should be selected carefully with focus on supply security, particularly for less common excipients, i.e. stockpiling. Introduction of second supplier of certain key excipients, Page 34

ACCEPTED MANUSCRIPT within the new drug application (NDA) could be a way to mitigate this risk. The introduction of quality by design (QbD) may make the selection excipients, with respect to variability,

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understood and controlled, from the development phase onwards.

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easier over the product life time as the impact of the excipients on the product should be well

The regulatory aspects of novel excipients vary significantly across the three major markets, e.g. FDA will assess a new excipient in conjunction with a NDA, whereas in Europe it is

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treated as a new drug application. There also exists disagreement on the contents of the

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regional pharmacopoeial monographs. In parallel, there is also constant regulatory focus on this area. This topic should be constantly reviewed to ensure that the best scientific and

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regulatory practice is reflected during the formulation development and subsequent

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8. References

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pharmaceutical production.

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Table 1. Summary of IPEC-America safety testing guidelines (modified from Steinberg et al., 1996). R is required tests C is conditional

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T

dependent upon the results from the others, see main text.

Oral

Mucosal

Parenteral

Acute oral toxicity

R

Acute dermal toxicity

Topical/

Inhalation/int

transdermal

ranasal

Ocular

R

R

R

R

R

TE D

Baseline toxicity data

MA N

US

Test

CR

Routes of administration in humans a)

R

R

R

R

R

R

C

C

C

C

R

C

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

Acute parenteral toxicity

-

-

R

-

-

-

Application site evaluation

-

R

R

R

R

-

Pulmonary sensitization

-

-

-

-

R

-

Phototoxicity/photoallergy

-

-

-

R

-

-

Skin irritation Skin sensitization

AC

Eye irritation

CE P

Acute inhalation toxicity

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R

R

R

R

R

R

Chromosomal damage

R

R

R

R

R

R

ADME – intended route

R

R

R

R

R

R

28-days toxicity (2 species) intended route

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

C

C

C

C

C

R

R

R

R

R

R

C

C

C

C

R

R

R

R

R

R

Photocarcinogenicity

-

-

-

R

-

-

Carcinogenicity

C

C

C

C

C

C

R

Teratology (rat and/or rabbit)

R

Additional assays b)

C

C

C

1st generation reproduction

CE P

Chronic toxicity (rodent, nonrodent)

AC

Additional data: long- or chronic use

IP CR

US

90-days toxicity (most appropriate species)

TE D

MA N

Additional data: short- or intermediate repeated use

Genotoxicity assays

T

AMES test

a) Extent of testing is dependent upon conditions and duration of exposure. Basis for less than 2 weeks, short or intermediate for 2 to 6 weeks and long term is more than 6 weeks.

b) Additional assay are dependent on the judgement of the data evaluator. They may include, but are not limited to screening for endocrine modulators or tests to determine if findings in animals are relevant to humans

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Table 2. Summary of IPEC-European safety testing guidelines (modified from De Jong, 1999). R is required tests C is conditional dependent

IP

T

upon the results from the others, see main text.

Oral

Mucosal

Parenteral

ADME

R

Step 1, basic data

TE D

Step 0

MA N

US

Test

CR

Routes of administration in humans a) Topical/

Inhalation/int

transdermal

ranasal

Ocular

R

R

R

R

R

R

R

R

R

R

-

R

R

R

R

R

-

R

R

R

R

R

R

R

R

R

R

R

Acute parenteral toxicity

-

-

R

-

-

-

Application site evaluation

-

R

R

R

-

-

Pulmonary sensitization

-

-

-

-

C

-

Phototoxicity/photoallergy

-

-

-

C

-

-

Skin irritation Skin sensitization

AC

Eye irritation

R

CE P

Acute oral toxicity

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R

R

R

R

R

R

Chromosomal damage

R

R

R

R

R

R

Micronucleus

R

R

R

R

R

R

28-days toxicity (2 species) intended route

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

R

C

C

C

C

R

R

R

R

R

R

C

C

C

C

C

C

Photocarcinogenicity

-

-

-

C

-

-

Carcinogenicity

C

C

C

C

C

C

R

Teratology (rat and rabbit)

R

Genotoxicity assays

R

C

C

R

Segment III

CE P

Segment I

AC

6-9 month chronic toxicity (rodent, nonrodent)

IP CR

US

90-days toxicity (most appropriate species)

TE D

MA N

Additional data: short- or intermediate repeated use

Additional data: long- or chronic use

T

AMES test

a) Extent of testing is dependent upon conditions and duration of exposure. Basis for less than 2 weeks, short or intermediate for 2 to 6 weeks and long term is more than 6 weeks.

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AC

CE P

TE D

MA N

US

CR

IP

T

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Graphical abstract

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