The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan

Regulatory Toxicology and Pharmacology 73 (2015) 947e952

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The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan Lin-Chau Chang a, Jaw-Jou Kang b, Churn-Shiouh Gau a, * a b

Center for Drug Evaluation, 3F, No.465, Sec.6, Zhongxiao E. Rd., Taipei 11557, Taiwan Institute of Toxicology, College of Medicine, National Taiwan University, No.1, Sec.1, Jen Ai Rd., Taipei 10051, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 2 September 2015 Received in revised form 14 September 2015 Accepted 15 September 2015 Available online 24 September 2015

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed. © 2015 Elsevier Inc. All rights reserved.

Keywords: Excipient Quality Safety Regulatory

1. Introduction In the past, excipients were considered to be inert components of the drug products. However, because of the development in science and technology together with the enhanced use and more understanding of the excipients, excipients nowadays are known to influence the characteristics of the drug products such as the quality, stability, functionality, safety, solubility of the drug substance(s), and acceptance of patients (Abdellah et al., 2015). In addition to the important role of excipients, the safety issues related to the excipients, such as the contamination with diethylene glycol (DEG) (Brent, 2014), and the impact of globalization have also led to vigorous discussion and more stringent regulatory requirements (Mullin, 2015). Moreover, the design or use of novel/ new excipients (Baldrick, 2010; Kohli et al., 2014) has brought another challenge to regulatory authorities regarding the amount and extent of safety data required.

* Corresponding author. E-mail addresses: [email protected] (L.-C. Chang), [email protected] (J.-J. Kang), [email protected] (C.-S. Gau). http://dx.doi.org/10.1016/j.yrtph.2015.09.020 0273-2300/© 2015 Elsevier Inc. All rights reserved.

In response to the above-mentioned issues, regulatory authorities have taken measures to increase the assurance of the quality and safety of the excipients and also to assure the functions of the excipients. For example, considering the contamination with diethylene glycol, the United States Food and Drug Administration (US FDA) has published a guidance (US FDA, 2007) which emphasized the importance of the current good manufacturing practice (CGMP) and test procedures distinguishing glycerin from DEG to avoid the use of DEG-contaminated glycerin. Recently, the European Union (EU) has issued a guideline on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use (EU, 2015). In the guideline, the manufacturing authorisation holder is responsible for ensuring the suitability of the excipient used and for the determination of the appropriate good manufacturing practice applied which is based on the type and use of excipients. The concept of quality risk management pointed out in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q9 (ICH, 2005) is incorporated in the guideline. Moreover, regarding the safety issues of excipients, the labeling requirements regarding

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excipients such as warning statements are stated in the US Code of Federal Regulations Title 21 (21 CFR Part 201). Regarding the warning statements of excipients, the European Commission (EC) has published a guideline (EC, 2003) entitled “Excipients in the label and package leaflet of medicinal products for human use” encompassing the warning statements of around 50 categories of excipients. The European Medicines Agency (EMA) has recently announced a series of draft documents for public consultation which include proposals for new or updated information for the labelling and package leaflet about certain excipients of concern, such as benzoic acid and benzoates (EMA, 2014a), benzyl alcohol (EMA, 2014b), ethanol (EMA, 2014c), benzalkonium chloride (EMA, 2014d), wheat starch (EMA, 2014e), cyclodextrins (EMA, 2014f, 2014g), and propylene glycol (EMA, 2014h, 2014i). For novel/new excipients, the US FDA has issued a guidance to describe the safety data required to support use of new excipients (US FDA, 2005) and has adopted the definition of novel excipients in ICH guideline (US FDA, 2001). The EMA has also published a guideline to discuss the overall requirements for excipients in the dossier submitted which includes the regulatory considerations for the safety data for novel excipients (EMA, 2007). About the functions of excipients, the EMA has pointed out that preservatives, antioxidants, permeation enhancers must be demonstrated effective and the level should be controlled in the specification (EMA, 2007). The US FDA has also depicted the close relationships between lipid excipients and liposomes so that the chemistry, manufacturing, and controls (CMC) requirements for the lipid components should be provided at the same level of detail expected for a drug substance (US FDA, 2002). The aim of the present paper was to compare the regulatory framework of Taiwan with that of the stringent regulatory authorities, mainly the EMA and the US FDA in order to reflect on the strengths and weaknesses of the current status. Meanwhile, the strategies, evolution, and challenges for international harmonization of the regulations regarding excipients in Taiwan were discussed. The main concepts of the draft proposal submitted to the Taiwan Food and Drug Administration (TFDA) and the future perspectives for the regulations of excipients were also presented. 2. Current situation in Taiwan in comparison with the EU and the US While many countries in the world realize the need for the enhancement of the regulatory supervision on excipients (Abdellah et al., 2015; Mullin, 2015; Xiao and Liu, 2014), Taiwan is no exception. In Taiwan, the regulatory requirements of excipients are mainly stated in Regulations for registration of medicinal products (Ministry of Health and Welfare, Taiwan, 2015b) and the guide published by the Pharmaceutical Inspection Convention (PIC) and Pharmaceutical Inspection Co-operation Scheme (PIC Scheme) (PIC/S, 2014) while some considerations are mentioned in the Guidelines on the drug stability study (Ministry of Health and Welfare, Taiwan, 2005). No specific and detailed guidance for the definition of excipients and novel excipients, CMC documentation or safety data requirements for excipients exists as those published by the EMA or the US FDA as mentioned above, although these considerations and ICH guidelines are generally adopted (Ministry of Health and Welfare, Taiwan, 2014). As for the review process, the review and the dossier of excipients are incorporated into that for the application for registration as those in the EU. In the US, although the review of excipients is also accomplished together with the application, the detailed information of excipients, especially those for novel/new excipients could be referred to corresponding drug master files. Regarding national standards, around 130 items for excipients

are listed in the Taiwan Pharmacopoeia which contains 2120 items/ monographs. Some of the excipients may also be used as an active pharmaceutical ingredient such as calcium carbonate, magnesium carbonate, dioctyl sodium sulfosuccinate, etc. Although the amount of the excipients listed is much less than those listed in the European Pharmacopoeia (EP) or the United States Pharmacopeia and the National Formulary (USPeNF), the pharmacopoeia officially accepted is not limited to the Taiwan Pharmacopoeia. Pharmacopoeias published by the 10 countries listed in the Regulations for registration of medicinal products, or pharmacopoeias approved by the central health competent authority are also accepted if the cited edition is published within the last 5 years (Ministry of Health and Welfare, Taiwan, 2015b). Nonetheless, there are other importance considerations in addition to the basic requirements stated in the monograph of the pharmacopoeia (Carlin, 2015). As the concept of Quality-by-Design has been proven more and more important nowadays (Carlin, 2015; Kushner et al., 2014), the characteristic of the excipient is known to be one of the key factors which could have huge impact on the quality of drug products (ICH, 2009; Kushner et al., 2014; Sugita et al., 2014). Therefore, the extensive discussion regarding excipient performance or functionality-related characteristics of excipients is incorporated into the general information/general texts section of the pharmacopoeias, such as <1059> Excipient performance in the USP, <5.15> Functionality-related characteristics of excipients in the EP. The guideline published by the EMA has also pointed out the considerations on the inclusion of additional tests and acceptance criteria depending on the intended use of the excipient, i.e., functionality-related characteristics (EMA, 2007). However, the above-mentioned concerns have not yet been described in detail in the Taiwan pharmacopoeia or other guidelines. Besides, the functions of antimicrobial preservatives and antioxidants are due to their inherent properties which might be associated with certain risks for human use (EMA, 2007). While the use and the concentrations selected require justification and the efficacy should be assessed, the EMA has also pointed out that an identification test and a content determination test should be included in the release specification (EMA, 2007). The limits for antimicrobial preservatives should also be included in the shelf-life specification (EMA, 2007). Similar concepts have also been mentioned in USP <341> Antimicrobial agents-content. In Taiwan, monitoring of the antimicrobial properties and effectiveness has been pointed out in the Guidelines on the drug stability study (Ministry of Health and Welfare, Taiwan, 2005). In addition, in USP <467> Residual solvents and EP <5.4> Residual solvents, the limits and controls are stressed not only for drug substances, products, but also for excipients. However, there are no general chapters regarding the controls of residual solvents in the Taiwan pharmacopoeia. In the guideline published by the EMA, it is mentioned that the bioburden and, where relevant, the endotoxin limits for excipients used in the manufacture of sterile medicinal products shall be stated (EMA, 2007). However, regulatory requirements regarding the controls of residual solvents and bioburden in excipients are not described in the regulations or guidelines in Taiwan. Similar situations have been observed in China (Xiao and Liu, 2014). The considerations regarding excipients largely depended on the requirements and concepts depicted in PIC/S GMP (PIC/S, 2014). Moreover, some excipients are not listed in any pharmacopoeia, which might be the mixture of the pharmacopoeial excipients or not related to those included in the pharmacopoeia. There is a need to specify the requirements of the specification for nonpharmacopoeial excipients. The issue is also closely related to the definition of novel excipients since the extent of the information

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required depends on the novelty and the risk of the use of the excipient (EMA, 2007; US FDA, 2005). In the guideline published by the EMA (EMA, 2007), the test items which should be considered while establishing the specification include physical characteristics, identification tests, purity tests, assay or limit tests and other relevant tests. Some international specifications are pointed out as a potential reference in the guideline as well (EMA, 2007). In Taiwan, neither the definition of novel excipients or regulatory requirements for non-pharmacopoeial excipients are specified currently. Although the concepts mentioned in the guidelines published by the EMA and the US FDA are generally adopted, there is a need to elucidate the current thinking of regulatory authorities so as to facilitate the transparency of the review process. For example, lipid-based formulations are one of the dosage forms of interests. While there are various designs of the lipid for the improvement of drug delivery (Kohli et al., 2014), the regulatory concerns become challenging. As lipid components are an essential excipient which largely influence the performance of liposome drug products, the US FDA has stressed the importance of the quality and purity of the lipid components in the guidance published (US FDA, 2002). Moreover, information concerning the chemistry, manufacturing, and controls of the lipid components is expected to be provided at the same level of detail as that for a drug substance. Regarding the specification, the assessment for impurities is pointed out as a major concern. While the establishment of an appropriate specification is fundamental, reliance solely on specification could be problematic (Carlin, 2015). The complexity of some excipients, such as those which are multicomponent, polymeric, and polydispersed, the reliability of the supply chain, together with the excipient-related problems in production make it necessary to consider the issues beyond specification (Carlin, 2015). The EU has recently published a guideline (EU, 2015) to further elucidate and emphasize the risk assessment approach for the evaluation of the GMP status of the excipients according to related Directives. The assessment is based on the type and use of the excipients, the risk profile of the excipient manufacturer, as well as the ongoing risk review (EU, 2015). The supervision of the supply chain is also enhanced in the US with the US Food and Drug Administration Safety and Innovation Act (FDASIA, US, 2012), which requires manufacturers who register to include, as part of a drug listing, the name, address and unique facility identifiers (UFIs) of associated excipient manufacturers. In Taiwan, PIC/S GMP has been implemented. The requirements included in PIC/S GMP are applied. However, there is no detailed guidance on the GMP requirements for the manufacturers of excipients as those in the EU or the US. Besides, the information of the suppliers of excipients is not required for registration. Regarding the labelling requirements, the information of excipients on the label is important for both healthcare professionals and patients. While certain excipients may cause risks or concerns for a particular population, such as aspartame containing a source of phenylalanine which may be harmful for people with phenylketonuria, special attention is required. While the name of the excipient used is required to be listed in the package leaflet/labelling with some additional requirements on specific dosage forms with higher risk (Table 1), the listing of the name of the excipient on the package leaflet was not a requirement in Taiwan until very recently. The listing of the name of the excipients should be completed before 31st December, 2015 in Taiwan (Ministry of Health and Welfare, Taiwan, 2015a). Moreover, warning statements for some excipients of concern are collectively announced in the guideline published by the EC (EC, 2003) while those are listed mainly in the Code of Federal Regulations in the US. (US 21 CFR 201) While there are only a few announcement which are associated

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with the warning statement of the excipient in Taiwan, an assessment for the proposal of warning statements is currently in progress. The comparison of the regulatory framework/requirements for excipients in the European Union (EU), Taiwan, and the United States (US) is summarized in Table 1. 3. Proposal for the international harmonization of the regulatory requirements Realizing the need for the establishment of a sound regulatory framework harmonized with international regulations, the Taiwan Food and Drug Administration (TFDA) has initiated a series of projects of which the regulation of excipients is one of the main focuses. The Center for Drug Evaluation (CDE) was assigned to conduct the sub-project and to investigate the regulatory framework of excipients worldwide, especially the system established in advanced countries so as to improve the efficiency of the management and administration. During the execution of the project, various recommendations were made and some of them have been adopted by the TFDA. For example, the submission of specification and the certificate of analysis of the excipients for the manufacturing of the domestic drug products were not required in the past. Generally, the information was only available during inspection if the item and usage of the excipients have already been approved in Taiwan. After the adoption of the suggestions regarding the importance of the review of relevant documentation in the application for marketing approval by the TFDA, the documents are now required for the submission, which were announced on 7th May, 2015 (Ministry of Health and Welfare, Taiwan, 2015b). Furthermore, the listing of the name of the excipient on the package leaflet is going to be completed before 31st December, 2015 as mentioned above (Ministry of Health and Welfare, Taiwan, 2015a). Nonetheless, a detailed guidance for excipients which elucidates the regulatory considerations is necessary for the communication and also the transparency of the regulatory requirements. In order to draft a suitable proposal of the guideline for regulatory requirements of excipients, an expert committee was formed. The committee members included professors from universities, representatives from pharmaceutical associations, and scientists with related expertise. Meetings chaired by the executive director of the Center for Drug Evaluation, Taiwan were held to exchange ideas and to discuss the draft guideline proposed. The TFDA also sent representatives to participate in the meetings. In addition, experts including the expert pharmaceutical assessor from the Medicines and Healthcare products Regulatory Agency (MHRA), former officer in the US FDA, scientists from international and domestic pharmaceutical companies were invited to deliver speeches to familiarize the audience with the international standards and/or perspectives from the domestic pharmaceutical company. The feedback from the audience was also a source for further discussion in the expert committee. The seminar not only served as a platform for the exchange of information but also made the related professionals aware of the importance of excipients. The main points of the proposal for international harmonization of the regulatory requirements regarding excipients are described as follows. 3.1. The definition of excipients Currently, there is no official definition of excipients in the regulation in Taiwan. The definition of excipients proposed in the guideline is harmonized with those used internationally (EMA, 2007; US FDA, 2005) since it is not only accepted worldwide but

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Table 1 The comparison of the regulatory framework/requirements for excipients in the European Union (EU), Taiwan, the United States (US). Country/ Regulatory framework/requirements for excipients region Novel/new excipient Specification

Public database

EU

CMC documentation and safety data are required.a The definition and/or detailed requirements are specified.a The review is incorporated in that for the whole application.a

Current edition of the EP or the Not available pharmacopoeia of an EU Member State and other necessary tests and acceptance criteria such as functionality-related characteristicsa If an excipient is not listed in the pharmacopoeias mentioned above, justification is required in addition to the specification provided.a

Taiwan

CMC documentation and safety data are required. The definition and/or requirements are not specified. The review is incorporated in that for the whole application.

US

CMC documentation and safety data are required.h,i The definition and/or requirements are specified.i The review is incorporated in that for the whole application, but the data can be placed either in the application or in a drug master file (DMF).i

The Taiwan Pharmacopoeia, pharmacopoeias published by the 10 countries listed in the Regulations for Registration of Medicinal Products, or pharmacopoeias approved by the central health competent authority published within the last 5 yearse The detailed requirements for the excipients not listed in the pharmacopoeias mentioned above are not specified. USP-NF An appropriate specification with justificationj

Name and ingredient code of the excipient included in the approved drug product

Inactive Ingredient Database (IID) Generally Recognized as Safe (GRAS) Substances (SCOGS) Database

Label/package leaflet

GMP

All excipients need to be declared on the labelling of an injectable or a topical, or an eye preparation.b For products other than the preparations mentioned above, excipients known to have a recognised action or effect, and included in the guidelines published by the Commission pursuant to Article 65, need to be declared on the labelling.b A full statement of excipients, warning statements for certain excipients on the package leafletb The name of the excipients should be listed on the package leaflet for all drug products.f

The drug product manufacturer is responsible for the compliance of GMP.c The manufacturing authorisation holder should ensure that the excipients are manufactured with appropriate GMP and should incorporate the excipient risk assessment/risk management procedure in the pharmaceutical quality system.d

A list of the inactive ingredients; warning statements for certain inactive ingredientsk For parenteral injection: the quantity or proportion of all inactive ingredients, except that ingredients added to adjust the pH or to make the drug isotonic may be declared by name and a statement of their effect; and if the vehicle is water for injection it need not be named.k

The manufacture, processing, packing, or holding of a drug should meet CGMP requirements.l,m Excipient manufacture should be carried out in accordance with the GMP concepts (USP <1078> Good manufacturing practices for bulk pharmaceutical excipients).

The drug product manufacturer is responsible for the compliance of GMP (PIC/S GMP).g

CGMP: Current good manufacturing practice; CMC: Chemistry, manufacturing, and controls; EP: European Pharmacopoeia; EU: European Union; SCOGS: Select Committee on GRAS Substances; PIC/S: Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme; US: United States; USP-NF: United States Pharmacopeia and the National Formulary. a EMA, 2007. b EC, 2003. c EC, 2010. d EU, 2015. e Ministry of Health and Welfare, Taiwan, 2015b. f Ministry of Health and Welfare, Taiwan, 2015a. g Ministry of Health and Welfare, Taiwan, 2009. h US FDA, 2001. i US FDA, 2005. j US FDA, 2002. k 21 CFR Part 201. l 21 CFR 210. m 21 CFR 211.

also a concept generally accepted in Taiwan. The excipients are defined as the components of a pharmaceutical dosage form apart from the active substance(s). 3.2. The definition and the requirements for novel excipients Currently, there is no official definition of novel excipients in the regulation in Taiwan. Considering the emerging of the development and use of novel excipients, the definition is drafted and extensively discussed in the expert committee. The major concerns and the challenges are associated with the scope of the experience acknowledged and the extent of the information required. According to the ICH (ICH, 2002), novel excipients are defined as excipients used for the first time in a drug product or by a new route

of administration. In the guideline published by the EMA (EMA, 2007), the definition is the same as that stated by the ICH. The EMA further explained that a novel excipient may be a new chemical entity or a well-established one which has not yet been used for human administration and/or for a particular human administration pathway in the EU and/or outside the EU. The US FDA has adopted the ICH guideline (US FDA, 2001). In addition, in the guidance issued by the US FDA (US FDA, 2005) for the discussion of safety profiles required, another term, new excipients, was mentioned. The phrase, new excipients, means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) the US FDA believes are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control

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release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration. Considering the opinions gathered in the expert committee and the seminars held, the definition of novel excipients proposed and revised after the discussion of the expert committee is as follows. Novel excipients are excipients which have not been used in a drug product, or are used beyond the level approved or by a new route of administration in Taiwan or 10 countries listed in Regulations for registration of medicinal products. If the excipient is the component of common food or food additives, used by a same administration route with a dose below intake amount of food or the limit of the food additive, and with complete supportive data, the excipient could be exempted from being considered as a novel excipient. The level approved is generally referred to the amount used in the drug product with the same administration route in Taiwan. In addition, information gathered from the US FDA Inactive Ingredient Database, Handbook of Pharmaceutical Excipients (Rowe et al., 2009), the US FDA Generally Recognized as Safe (GRAS) Substances (SCOGS) Database could be used as a reference. If the above-mentioned references could not be used, other evidence should be provided by the applicant for justification. For novel excipients, complete information regarding chemistry, manufacturing, and controls should be provided. The data should be presented in the format as those for drug master files for the drug substances. In addition, safety data should be provided. The applicant is encouraged to provide references which could be relevant to and support the intended use. Discussion with regulatory authorities as soon as possible is also highly recommended. 3.3. Considerations for specification For all the excipients, general considerations for residual solvents should be applied while bioburden and, where relevant, the endotoxin limits for excipients used in the manufacture of sterile medicinal products should be stated. For the excipients listed in the Taiwan pharmacopoeia or those of 10 countries listed in Regulations for registration of medicinal products (Ministry of Health and Welfare, Taiwan, 2015b), the specification in the pharmacopoeia should be followed together with the functionality-related characteristics. For the excipients not listed in the Taiwan pharmacopoeia or those of ten countries listed in Regulations for registration of medicinal products (Ministry of Health and Welfare, Taiwan, 2015b), the regulatory considerations are mentioned in the proposal which is harmonized with the requirements stated in the guideline issued by the EMA (EMA, 2007). Mainly, a suitable specification for the excipient should be established and properly justified. The test items should include the tests for physical characteristics, identification, impurities, assay, and other necessary tests for the parameters related to the performance of the dosage form. The applicants should also provide the evidence and information to justify that the excipients are not novel. Herein, the challenges encountered mostly involve the evidence of precedented use as discussed above and for justification of the specification. Therefore, the completeness of the data and the evidence are essential for proper judgement based on scientific rationale. In the proposed guideline, the importance of the controls on antioxidants, antimicrobial preservatives is also stressed. The requirements are harmonized with those stated in the guidelines published by the EMA and the ICH, respectively. Regarding antioxidants, an identification test and a content determination test should be included in release specifications. The acceptance criteria should be based on the results from batch analysis. The omission of the related tests in release specifications should be justified. If appropriate, antioxidant levels are monitored periodically

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throughout the shelf life. The main concern is to ensure the maintenance of the function of the antioxidants throughout the shelf life. For antimicrobial preservatives, the level used and maintained should be safe and effective at the same time. Antimicrobial effectiveness testing should be performed. While an identification test and a content determination test for antimicrobial preservatives should be included in release specifications, the content of antimicrobial preservatives should be assessed throughout the shelf life. Moreover, the effectiveness should be ensured throughout the in-use period for non-solid drug products packaged in multidose containers. While the testing of antimicrobial preservatives is widely accepted, the challenges lie in the necessity of monitoring the level of antioxidants. Similarly, the basis for the omission would depend on the appropriateness of justification. 3.4. The format and other requirements In order to streamline the application of the format of common technical document (CTD) for the registration of the drug products, the TFDA has assigned the CDE to hold a series of training courses and seminars for the applicants. The implementation of the CTD format on the applications of new chemical entities has started on 1st November, 2012 (Ministry of Health and Welfare, Taiwan, 2012) while that for the rest of the applications has begun on 1st July, 2014 (Ministry of Health and Welfare, Taiwan, 2013a, 2013b). Since the data required currently should be presented using the CTD format, the format of the proposal for the guideline is also displayed according to the structure of the CTD, which is similar to the guideline published by the EMA (EMA, 2007) so as to facilitate the application of the CTD as well. The description of the documentation suggested for module 3 sections P.1, P.2, P.4, P.5, P.8 and A.3 is elucidated sequentially, which also incorporates the requirements stated in the ICH guideline (ICH, 2002), such as the detailed description of the grade or composition of excipients, the choice of the excipients during pharmaceutical development. As for the warning statements for the excipients, the applicants must refer to the announcements published by the TFDA. 4. Conclusions As the understanding of the manufacturing of the drug products becomes more profound, the importance of the quality and selection of excipients is more apparent. Moreover, the development of novel excipients has brought about issues of safety concerns in addition to new possibilities of drug delivery and therapeutic advancement. The rapid globalization has also added the complexity of the quality controls and the GMP requirements. These events and trend have led to the extensive discussion among the stakeholders and the publications of various guidelines by the regulatory authorities to communicate their current thinking and consensus. Taiwan, as a member of the PIC/S, is active in the participation of the ICH activities and the international harmonization of regulatory requirements. The proposal of the regulatory requirements on excipients in the present study was based on the investigations on the requirements of stringent regulatory authorities, reviewed by the expert committee, and finally sent to the TFDA for jurisdiction. The comparison of the regulatory requirements between Taiwan and the stringent regulatory authorities served as a starting point for the reflection on the major issues. Although some issues, such as the detailed GMP requirements, more comprehensive warning statements, and the revision and expansion of the pharmacopoeia remain to be discussed, the present proposal which mainly focuses on the quality requirements could be the fundamental step toward international harmonization.

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