Journal of Pharmaceutical Sciences xxx (2016) 1e8
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Review
An Overview of Pharmaceutical Excipients: Safe or Not Safe? tia G. Abrantes 1, Dinah Duarte 1, Catarina P. Reis 1, 2, 3, * Ca fona de Humanidades e Tecnologias, Lisboa, Portugal School of Sciences and Health Technologies, Universidade Luso fona de Humanidades e Tecnologias, Lisboa, Portugal CBIOS - Research Center for Biosciences and Health Technologies, Universidade Luso 3 IBEB, Biophysics and Biomedical Engineering, Faculty of Sciences, Universidade de Lisboa, Lisboa, Portugal 1 2
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 December 2015 Revised 1 March 2016 Accepted 15 March 2016
A medicine consists of 2 fundamental parts: the active pharmaceutical ingredient and the excipient. Most, if not all, medicines could not be made without the use of excipients. In the early times, the safety of excipients was overlooked and no specific safety tests were generally conducted. This fact has been changed over times and is currently being recognized that the excipient’s toxicity is not negligible, because its direct interaction with the active pharmaceutical ingredient or between other excipients may occur, leading to a potential change in the relationship between effectiveness and toxicity. This review is intended to address the general status of the pharmaceutical excipients and to describe the safety assessment. As a summary, this review suggests the interest of simplifying the formulations as much as possible and the interest of reducing the number of excipients necessary to strictly meet the required functions. The risk/benefit ratio of an excipient should be always evaluated on the basis of not only its production/quality but also of its safety. Further research according to Good Manufacturing Practices, Guiding Principles in Toxicology Assessment, Good Laboratory Practices, and Good Distribution Practices requirements are needed and are fundamental for health safety, contributing to a comprehensive picture of this matter. © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Keywords: excipients toxicology drug interactions pre-formulation stability solid dosage form
Introduction A pharmaceutical excipient is by definition a substance or a group of substances that completes a volume of agglomerating a mixture, which serves as a vehicle and incorporates active pharmaceutical ingredients (APIs); the word itself is defined in some of the features of a pharmaceutical excipient. Examples of excipients include absorption enhancers, coloring agents, emulsifiers, extenders, diluents, fillers, flavors, preservatives, wetting agents, solvents, and sustained release matrices. An ideal excipient is one that provides the volume, the uniformity, and the dose of the API in the medicine throughout the production process to the administration by the patient. At the beginning of time, specifically at the beginning of the production and handling of medicines, excipients have been described as inert substances that were added to the API only to achieve the required consistency to the formulation. Therefore, several natural products were used in formulating medicines, such as honey as well as other simple substances, which are still used today, such as lactose.1,2
* Correspondence to: Catarina P. Reis (Telephone: þ351-217-515-550; Fax: þ3512175-155-98). E-mail address:
[email protected] (C.P. Reis).
Over the years, the use of excipients was considered as the addition of simple vehicles (e.g., syrups). Nowadays, pharmaceutical excipients are more than just simple substances added to complete a total volume formulation; these substances require numerous guarantees to the safety and efficacy of the medicine, such as ensure stability throughout the formulation process to the administration of the medicine by the patient. They also may guarantee that the dose is administered and delivered with the same precision and accuracy that is established for that API in particular, thus making the medicine administration more adequate and reflecting positive results in terms of patient adherence to therapy. The progress of pharmaceutical technology has made possible the assessment of the excipients from its origin, estimating their behavior in a mixture with other excipients and APIs, where it is possible to check their status. This fact results in a formulation which has the ability to improve the bioavailability and efficacy of the API, whenever necessary.3-6 With the advancement of pharmaceutical technology, new drug delivery systems evolved to provide better results: sustained release systems, liposome formulations, and mixtures of various excipients are some examples. The addition of excipients to the API provides the final product with a wide range of functions for the formulation. Excipients must be added appropriately to a dosage
http://dx.doi.org/10.1016/j.xphs.2016.03.019 0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
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form so that it can conveniently be administered enterally, parenterally, or topically.1,2,7-12 Pharmaceutical excipients perform multiple functions, such as to complete the volume of the formulation, ensure stability by protecting the API, improve the precision and API dose accuracy in the product, improve bioavailability, facilitate the API administration by both improving the organoleptic characteristics or produce a final pharmaceutical form more pleasant, and, finally, to improve the acceptance of the treatment by the patient. It should be noted that the safety and effectiveness of excipients depends on these functions mentioned above. The most important function of any excipient is to ensure the safety and efficacy of the medicine throughout the formulation, the storage period, and during and after its administration.13-26 The toxicity of excipients (intrinsic or specific toxicity) is not a simple issue for several reasons: first, the large number of excipients and their diversity of chemical profiles or sources or technological functions and, second the presence or probability of occurrence of secondary products and contaminants. Excipients are no longer considered inert substances because they can interact with the API, lowering their titer. They also can generate undesirable impurities or alter the absorption, distribution, metabolism and excretion (ADME) and, ultimately, reduce the bioavailability of the API. They are assessed as functional and essential substances added to a modern pharmaceutical formulation. However, there is still no common and equitable order in the world for the safety of the excipients used in the pharmaceutical industry. Those problems may be overcome by adopting and carefully adhering to good manufacturing practices (GMPs) similar to those for active principles. The methods used to guide the safety assessment and regulations are still different in Europe, the United States, and Japan. The purpose of this review is to describe the safety standards for excipients used in the formulation of the medicine. It is generally recognized that existing human data for some excipients can substitute for certain nonclinical safety data, and an excipient with documented prior human exposure under circumstances relevant to the proposed use may not require evaluation in the full battery of toxicology studies outlined in literature, but it should be analyzed case-by-case. Safety Assessment Excipients constitute about 90% of the total volume of a medicine, and as such the probability of changing API’s molecular structure is very high if the manufacturing or transport conditions are not appropriate. Thus, global regulatory agencies require routine testing of pharmaceutical excipientsdto ascertain and verify the identity, purity, traceability of batches at any moment, resistance, and qualitydwhich have become essential for the production of safer and more effective medicines.27 The manufacturer must evaluate the safety of excipients before their access to the pharmaceutical market.28 Fortunately, the intrinsic toxicity of excipients is becoming much rare because they are usually chosen from among the materials noted for being very nearly pharmaco-toxicologically inert. This review will describe the excipient safety guidelines from 3 regulatory agencies: the US Food and Drug Administration (FDA), the European Medicines Agency, and the Japanese Ministry of Health, Labour, and Welfare. Those agencies operate under different rules for a common goal: the safety of excipients used by the pharmaceutical industry.29-47 Pharmaceutical Excipients Safety Assessment The use of an excipient in a pharmaceutical formulation begins by relying on the precedence of use. The safety assessment is done
through 2 options: the excipient has precedence of use or the excipient has no precedence of use.48-50 Excipient With Precedence of Use The excipient has already been used in a pharmaceutical product, a food additive, or any product with human exposure, that is, where previously safety tests were carried out. These excipients are already registered in a pharmaceutical product and usually are included in the pharmacopoeias. Excipient With No Precedence of Use The excipient has never been used in any product and therefore safety tests are required. Each regulatory authority has its own way of acting.38,39,42,51,52 Food and Drug Administration FDA has an excipient database for consultation, Inactive Ingredient Database, where it is possible to consult the excipient’s historical precedence of use.32,33,53 European Medicines Agency There is no list of ingredients for quick consultation. A review of excipients with the precedence of use is generally made by a drug compendium in each country. For example, in France there is the “Dictionnaire Vidal,” in Germany the “Die Rote Liste,” or in UK “The Electronic Medicines Compendium.”29,54 Japanese Ministry of Health, Labour, and Welfare In Japan, there is a precedence of use dictionary for consultationdthe Japanese Pharmaceutical Excipients Dictionary. FDA and Japanese Ministry of Health, Labour, and Welfare list excipients that have been previously used in drug formulations, with the description of its characteristics, and the maximum dose used in diverse routes of administration.29 International Pharmaceutical Excipients Council (IPEC) recommends that the GMP principles follow the “IPEC-PQG Excipient Guide” for all excipients. If the excipient to be used does not have precedence of use, this material is considered as a new excipient. New Excipients A new excipient is considered as a material to be used in a drug product for the first time or it will be used by a new route of administration according to ICH Guideline M4. In other words, a new excipient is a substance that is not present in the Inactive Ingredient Database, United States Pharmacopeia-National Formulary (USP-NF), European Pharmacopoeia (Ph. Eur), Japanese Pharmacopoeia (JP), “Handbook of Pharmaceutical Excipients,” or “Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete.” An excipient with previous chemical changeehowever smalleis considered as a new excipient by the industry. When there is an excipient that has never been used in any pharmaceutical formulation, there are several guidelines imposed by the regulatory authorities to allow its use. FDA has the “Nonclinical Studies for Development of Pharmaceutical Excipients” and the USP-NF 26 General Chapter “Excipient Biological Safety Evaluation Guidelines,” while IPEC has the “New Excipient Evaluation Guidelines” and “The Proposed Guidelines for the Safety Evaluation of New Excipients.” It is important to consult these documents to assess the safety of a chemical agent to be used as an excipient.
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The excipient manufacturer must develop safety information recommended in the guidelines, according to their future use, in a particular pharmaceutical form. As an example, all potential new excipients be appropriately evaluated for pharmacological activity using a battery of standard tests (ICH guidance S7A). Requirements for New Excipients To commercialize an excipient there is no regulatory requirement to indicate that there should be a monograph of this substance. However, if there is an excipient monograph in a pharmacopoeia, the excipient should be complemented with the monograph because the regulatory authorities require conformity. For the supplier, it is always preferable to present an excipient with a monograph or a complementary document about it that is relevant, because it means that this excipient has quality for pharmaceutical use. National pharmacopoeias delineate quality requirements for pharmaceutical excipients and these receive precedence over the 3 major pharmacopoeias (USP-NF, Ph. Eur., and JP). The Excipient Is Described in One or More Monographs If the excipient is present in several compendiums, the manufacturer is advised to ensure the excipient’s conformity for all monograph requirements, present in all pharmacopoeias, before its commercialization to the global market. The manufacturer must list all the monograph tests required for all pharmacopoeias or compendiums, with a brief description of the used analysis method. This description is necessary because sometimes there is a test with the same name designation but the test method is completely different. Finally, the manufacturer demonstrates that the method is valid and provides assurance that the excipient, when tested by this method in every monographs, conforms to all requirements. The Excipient Is Not Described in a Monograph When the excipient is not present in any pharmacopoeia or other monograph in a compendium, the manufacturer can establish its own specification, based on a similar monograph present in the pharmacopoeia. If there is not an available similar monograph, the specification can be based on their own experience and in the chemical and physical properties of the excipient according to the intended use of administration. The commercial relevance of an excipient and subsequently the use of an approved drug is a prerequisite for inclusion in a monograph in the USP-NF, Ph. Eur, or JP/Japanese Pharmaceutical Excipients. Both users and excipient suppliers can request the national pharmacopoeia to develop a new monograph, once the excipient has been used in an approved drug. An excipient that is not written in any pharmacopoeia can be used in a drug product, even if there is no monograph on the same. The regulatory authorities require a detailed evaluation of the excipient’s safety and toxicity. Once the regulatory authority has approved the application of the drug product containing the excipient, this excipient is considered acceptable for the same route of administration and for the same level of use by providing the same specifications as those previously used in the approved drug.38,39,42,52
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Once these steps are all set, a document with all information is accomplished and it is confidential and not available to the user, nominated Drug Master File (DMF), or European Certificates of Suitability (CEP). This document provides all the technical information such as specifications and test methods for raw materials, in-process testing, the finished excipient product, a complete description of the manufacturing process, safety date, packaging details, and content label. In the United States, the supplier submits the DMF to FDA to keep this excipient confidential information in its database. In Europe, the DMF only exists for APIs and is not available for excipients. CEPs are used for pharmaceutical excipients, which may be treated in 2 different ways: CEPs to excipients existing in Ph. Eur. and CEPs to APIs and excipients that are not present in the Ph. Eur. In the first case, CEP is obtained by excipient manufacturers submitting the Common Technical Document of the excipient described in Ph. Eur. to the European Directorate for the Quality of Medicines in Strasbourg. The information contained in the CEP is not shared with the excipient user, like the DMF in the United States. The second type of CEP is used for APIs and excipients that are not reported in Ph. Eur., which do not have the potential to develop Transmissible Spongiform Encephalopathy and Bovine Spongiform Encephalopathy. When exists, the risk of Transmissible Spongiform Encephalopathy transmission to humans through the product drug is low or none. In Japan, the DMF is submitted to regulatory authorities by the pharmaceutical industry that contains the details of the excipient. This system is made for individual excipients and not for excipient mixtures.55-57 The excipient supplier must have knowledge and control of the origin of raw materials, the degradation products of the excipient, the presence of catalyst residue, decomposition or degradation products, as well as the addition of additives and processing aids. The manufacturer should assess the effect of excipients as part of the regulatory assessment of medicinal products. The introduction of the new excipient on the market depends on the conclusion of the evaluation, which must demonstrate that the excipient can be produced properly for their intended use. The excipient's quality on all batches is guaranteed by the process validation study, which aims to confirm and assure the efficacy of the process. All procedures of pharmaceutical excipients manufacture, including packaging, distribution, and labeling, should be performed in accordance with the GMP and Good Distribution Practice requirements. In excipient labeling, the Certificate of Analysis and Bill of Lading are required.49 Excipient’s Quality When there are several monographs published for a particular excipient, all test methods described must be carried out and the results should be in accordance with what is described in these compendiums, to guarantee excipient quality. When there are no monographs, the manufacturer must perform test methods that are similar to other monographs, and obtain comparable results. In this last case, test methods should always be validated, according to ICH Q2 Validation Guidance, and must confirm with the existing compendiums.58-61 Excipient Development
New Excipient’s Introduction into the Market The first step to introduce a new excipient in the market is the determination of its functionality, route of administration, identification, and stability of the intended API for a drug formulation.
The user sets the excipient formulation design for a new API for the redesign of an existing formulation, such as formulation with an API that is already known but in a different administration route, or the development of a generic drug.
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Once the aim of this new project is defined, it identifies the route of administration, dosage form, and the target population. The excipients are chosen according to the required functions to be performed in the formulation, and according to the compatibility with the API being used in the new drug product. The excipient is considered acceptable for use in the formulation by a regulatory excipient expertise, which confirms that the excipient may be used in the intended route of administration, for the dosage form defined for the new drug product.15,49,62-64 Excipient Biological Evaluation Guidelines The excipient biological evaluation guidelines for assessing the safety of excipients and APIs are different because pharmaceutical excipients and APIs are substances that are classified differently, with singular functions and mechanisms of action. Therefore, the biological activity and the risk-benefit ratio in use will consequently differ.53,65-68 When a new excipient is introduced in the pharmaceutical market, this is subject to safety test methods that are required and mandatory for each regulatory agency.27,49 Both experts and agencies use test methods, where the priority lies with the methods already validated with reliable safety results, which can be used as an alternative to pre-clinical in vivo assays. In all cases, the excipient’s safety test methods should respect the Guiding Principles on the Use of Animals in Toxicology as well as the Good Laboratory Practice.29,42,51,69 The information of the pharmaceutical excipient’s safety is determined through analysis of the existing databases and literature. To create a database with specific information for each excipient used in the pharmaceutical industry, the collection of all information about the same is required, both chemical and toxicological specifying the possible routes of administration, the dose, and exposure time. In general, safety information must include the physical and chemical properties of the substance, in which production processes can be used, routes of administration, the dosage form, and the target population. Toxicity limits as well as the presence of impurities and interactions with APIs and exposure conditions for the excipient are also assessed. Also, the ADME and pharmacokinetic studies are decisive factors in the selection of the excipient.70-75 In addition, there are 2 age groupsdthe neonatal/ pediatrics and geriatricsdwhich require more attention in the preparation of the pharmaceutical form, which must be tailored to their needs and ability to administer the drug (solutions and suspensions preferably). Furthermore, in these patients the excipients may be potentially more toxic than in other populations, because altered metabolism or excretion could lead to toxic effects. The main difficulties are generally associated with microbiological control and thus the stability and potency of the formulation. It is also necessary to keep in mind the influence of the volume of the dose used in solutions and suspensions dosage forms that will have on patient acceptability, tolerability, or palatability problems. The critical points to consider in formulating the suspensions include the physical and chemical characteristics, which emphasize the particle size and viscosity, as well as the potential for foaming, air trapping, sedimentation, and adhesion of the API to the primary container and the measurement equipment. It is noted that for oral suspensions the importance of uniformity comes from the potential for segregation during production and storage of the product. The microbiological control in the solutions and oral suspensions can be done through the application of temperature during the manufacturing process. Temperature is also used for the purpose of checking and ensuring the dissolution of the product.
Subsequent storage is done at a controlled temperature, avoiding the formation of degradation products. Some oral solutions may present microbiological contamination with significant risk to health and for these cases there are specific limits for each microbiological test, such as the testing of raw materials, with particular attention to the purified water. Validation of oral solutions is made, for example, by ensuring the dissolution of the API and preservatives, which evaluate the parameters of temperature and time. For oral suspensions, additional specifications include the drug particle size in suspension, the pH, the dissolution, and viscosity associated with bioequivalence.76-84 The Excipient Biological Evaluation Guidelines provide the necessary information to create a reliable database for novel excipients (Table 1). Tests that are required (R) by the guidelines are different from those conditionally recommended (C). However, the basic information and toxicity profile for each substance are sufficient as a safety measure when its use is made in the short term or as a diagnostic agent.27,68,85-87 Additional tests are required for all new excipients, which have a long-term use.39,42,52,88,89 API/Excipient Incompatibilities and Interactions Pre-formulation At the pre-formulation stage, interactions between all substances may occur and compatibility studies between excipients and between excipients and API are strongly required. During the pre-formulation for the production of a particular pharmaceutical form, several interactions may occur and the analysis of the results where interactions can be beneficial or harmful may have a strong effect on the stability, the bioavailability of the API, and, especially, the effectiveness and safety of the medicine.90-97 There are some cases described in the literature in which the interaction between the excipients and APIs had positive effects on the final pharmaceutical form. On the other hand, it is very common that the interaction of the excipients with the API has a negative effect, resulting in the degradation of the API, decreasing the effectiveness of therapy, and, therefore, can lead to harmful damage to the patient health.73,90,98-106 Interactions Assessment Interactions, chemical or physical types, occur more frequently between excipient and API than between excipients. The physical type of interaction can modify as exemple the rate of dissolution or the uniformity of the dosage and, ultimately, bioavailability. The chemical type of interaction can lead to the degradation of the API and/or the occurrence of impurities. The most frequent chemical reaction is hydrolysis, mainly because the water is the preferred solvent in liquid formulations. Less frequent but other possible reactions are isomerization, photolysis, and polymerization. These reactions can lower the title of the API and lead to dangerous impurities. As well, ionizable API may react with ionized soluble excipients giving rise to the formation of insoluble products. Computational Method The computational method is the most economic method of evaluating interactions between substances, in which the compatibility between the excipient and API is predicted in a database. Database consists of detailed information about the excipient, the presence of impurities, and some reactive functional groups. The safety analysis of excipients performed by a computing
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Table 1 Toxicological Tests Performed for Each Route of Administrationa Assay
Toxicity database Acute oral toxicity Acute dermal toxicity Acute inhalation toxicity Eye irritation Skin irritation Skin sensitization Injectable acute toxicity Local evaluation of application Pulmonary sensitization Phototoxicity/photoallergy Genotoxicity testing ADME-PK/route of administration Toxicity 28 days (2 species): route of administration Additional data: repeated use in short or medium term 90 days toxicity (appropriate species) Embryo-fetal toxicity Additional trials Genotoxicity assays Immunosuppression assays Additional data: intermittent long-term or chronic use Chronic toxicity (rodent, non-rodent) Reproductive toxicity Photo carcinogenicity Carcinogenicity
Exposure Routes for Humans Oral
Mucous
Dermal/Topical/Transdermal
Injectableb
Inhalation/Intranasal
Ocular
R R C R R R e e e R R R R
R R C R R R e e e e R R R
R R C R R R R R e R R R R
R R C R R R R R e R R R R
R R R R R R e e C R R R R
R R C R R R e e e e R R R
R R C R R
R R C R C
R R C R C
R R C R R
R R C R C
R R C R C
C R C C
C R e C
C R C C
C R C C
C R C C
C R e C
R, required; C, conditional. a Intravenous, intramuscular, intrathecal, and so on. b Pharmacopeia, U.S. Excipient Biological Safety Evaluation Guidelines.51
method is very quick and generally does not require large amounts of sample. However, the major disadvantage is generally related to the lack of predictability.90
where there is the need to have a more accurate result, HPLC or High Resolution Mass Spectrometry with Liquid Chromatography can be also used.109,112,113
Binary Mixing and High Performance Liquid Chromatography Detection, Isothermal Stress Testing, and Differential Scanning Calorimetry
International Conference of Harmonization (ICH) ICH is a council that develops the global requirements of various technical points of medicines registration, containing new excipients. They have published several guidelines on pharmaceutical excipients and their impact on the market but the main objective is generally related the API and the dosage form.29
The use of binary mixing is a very common method. In binary mixtures, there is an excipient mixture with an appropriate proportion of API, which can be taken with or without the addition of water, where the dosage form is subject to Isothermal Stress Testing (IST) conditions. The compatibility analysis is implemented after the mixture has been subjected to those conditions and it can be analyzed by high performance liquid chromatography (HPLC). Differential scanning calorimetry (DSC) and thermogravimetric analysis can also be used to evaluate it.90,107,108 DSC is one of the chosen method to evaluate the interactions of pharmaceutical excipients because it allows a rapid screening of incompatibility arising from the appearance of deviations from normal state, the absence of peaks and variations in the corresponding DH, using minimum sample size (around 2-5 mg) when compared to the other methods. The IST should always confirm DSC data but this last analysis is generally a time-consuming technique and involves a subsequent quantitative analysis, which can resort to HPLC.90,109-111 Isothermal Microcalorimetry The isothermal microcalorimetry is used as a change detection method using the heat flow. Thus, in a mixture of API with excipients in the solid state it is possible to identify any change that influences the formulation stability. After change identification with the isothermal microcalorimetry, a combination of techniques such as Hot Stage Microscopy or Scanning Electron Microscopy can be performed, identifying the causality of the problem. In cases
ICH Q3A, Impurities in New Medicine Substances This guideline was created in order to assess the presence of impurities in the formulation, present in excipients or in API and their limits. Impurities can be found in the raw materials during the production process or after preparation. In all cases, it is required that the impurity should always be identified after any change in the formulation.29,114,115 ICH Q3C(R5), Impurities: Guideline for Residual Solvents The guideline for residual solvents defines 4 distinct classes of organic solvents used as pharmaceutical excipients: solvents to avoid, solvents to be limited, solvents with low toxic potential, and solvents without toxicological evidence. Each of these classes has specific limits and maximum levels that can be used and observed in the finished dosage form but the use of residual solvents, regardless of the chosen class, must be avoided when possible.114 Stability Assessment The stability of the excipients is directly dependent of the type of excipient, its chemical and physical properties, and if it is used alone or simultaneously with other excipients.116 A classification of the excipients according to the degree of stability was made and excipients are distinguished from very stable, stable, or limited
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stability.59 This classification depends on the period of time for which the excipients proved always stable when packaged in a specific container. The stability evaluation includes both physical and chemical properties evaluation where excipient can be classified as very stable when there are no changes during the production and excipients remain unchanged with the same property for at least 60 months at a particular package.117,118 Meanwhile, stable excipients are stable in a range between 24 and 60 months for reassessment and impurities are easily detected. Finally, there are excipients with limited stability mainly due to the reassessment interval or an expiration date less than 24 months. Those excipients do not follow specifications because they are generally sensitive to hydrolysis, moisture absorption or degradation by light, change in viscosity, oxidation, or otherwise they are adversely affected by environmental conditions. When these excipients are hygroscopic, losses during drying or determining the moisture content can be used as indicators of stability testing.119,120 In this case, additional tests to assess the originated reaction products and establish a long-term stability program are essential. In all cases, a summary report with the procedures and results of the stability studies is required for the 3 excipients stability classes. It is necessary to ensure the excipient stability throughout the production process, because the guarantee of the excipient protection in packaging and storage is applied to ensure the excipient protection, to avoid the degradation products formation and consequent toxicity.44,121,122 Each excipient can also be attributed one or more classifications of stability. This fact is directly dependent on packing and must always be justified.39,42,59,114,123-127 Conclusion In the manufacture of medicines, 2 major key elements should be considered in developing the pharmaceutical dosage form: the API and the excipient. The ideal excipient must be able to ensure the adequate API dose, should have high stability, with simple and predictable release, and, ultimately, be able to contribute to the quality and safety of the medicine. The physical and chemical characteristics of each excipient must be beneficial and profitable that optimizes the performance of the formulation, both during the manufacture and during and after the administration to the patient. For many years the quality, efficacy, and safety of the API were the most important parts of the medicine assessment but currently the need to study not only the excipient quality but also its safety is a reality. Today, any new chemical entity, whose effects on humans are still unknown, should be subjected to all toxicological tests planned for the API before it can be accepted as an excipient. In addition, not only the excipient safety must be taken into account, but also possible interactions that may occur in the final mixture. The best rule to follow should be as follows: simplify formulations as much as possible as well as reduce the number of excipients to those strictly necessary to fulfill the required functions of the medicinal product. It is important to perform risk-benefit assessments on proposed new excipients in medicines and to establish permissible and safe limits for these substances. References 1. Pifferi G, Restani P. The safety of pharmaceutical excipients. Farmacognosia. 2003;58(8):541-550. 2. Chaudhari SP, Patil PS. Pharmaceutical excipients: a review. Int J Adv Pharm Biol Chem. 2012;1:21-34. 3. Morton. The Nurse Dictionary. 24th ed. London: Faber & Faber; 1957. 4. Saunders WB, ed. Dorland’s Medical Dictionary. 25th ed. Philadelphia, PA: W.B. Saunders; 1974. 5. Winek CL. History of excipient safety and toxicity. Drugs PharmSci. 2000;103:59. 6. Pifferi G. Eccipienti ieri e oggi. Rapp GSIRS. 1996:96-97.
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