From Inactive Ingredients to Pharmaceutical …

1 62 Pharmaceutical TechnologyJULY the past three decades, the Pharmaceutical industry has seenthe development of drugs that actually cure disease ratherthan just offer symptomatic relief. During these years, theconcepts of improving efficacy and good manufacturing prac-tices (GMPs) have grown in importance. In addition, towardthe end of the last quarter of the previous century, many newconcepts and terms had come into common usage. For exam-ple, the concept that a dosage form must act to release the ac-tive ingredient has become generally accepted. Words like dis-integration,dissolution, and bioavailabilityalso have gainedprominence and meaning. Accompanying these terms and con-cepts was the realization that Inactive Ingredients frequentlyare critical to ensure storage stability, safety, and efficacy of drugdosage forms. The transition from excipients being perceivedas Inactive , inert Ingredients to the present status of pharma-ceutical excipients was well on its Pharmaceutical Technologywas a new magazine 25years ago, most tableting and encapsulation largely were per-formed using common foods, food additives, and salts onlythe first polymers were then in use (1).

2 For the most part, usershad to refine the materials for Pharmaceutical use and had toconduct any necessary performance industry became more interested in faster and lower-costdrug production, new processes such as direct compression,fluidized-bed granulation, automatic capsule filling, and filmcoating were introduced (2). Therefore, new and improved ex-cipients were required to make this progress technology was advancing, significant changes also wereoccurring on the business side of the Pharmaceutical in part to the introduction of new national regulationsand the influence of regulators, companies in the industry grewas national entities. Companies with headquarters in one coun-try and subsidiaries in other countries tended to operate each ofthe subsidiaries as national businesses. It wasn t until the devel-opment of the European Union (EU) that many recognized theadvantages of an EU regional industry rather than a country-by-country approach to marketing.

3 In addition, acquisitions, merg-ers, and business growth fostered a growing realization that thepharmaceutical industry, like other large industries, truly wasglobal in its reach. With this expanded view came an increasedrecognition of the need for global standardization of that end, first came the trade name excipients , which weremarketed in as many venues as possible. The United States Phar-Marshall Steinberg, PhD,is thechairman and president of InternationalPharmaceutical excipients Auditing, Inc.,and the past-chairman of IPEC-Americas,1655 North Fort Myer Dr., Suite 700,Arlington, VA 22209, tel. , fax , e-mail Blecheris the founding chairman ofIPEC-Americas. Alan Mercillis thesecretary/treasurer of IPEC-Americas.*To whom all correspondence should be Inactive Ingredients to Pharmaceutical ExcipientsMarshall Steinberg,* Lou Blecher, and Alan MercillIIn this article, the authorstrace the evolution of theindustry s opinions anddevelopments that have led to the current perceptionand use of excipients .

4 Fromtheir initial use as inertingredients to the presentpractice of using them to aid the release of activeingredients, high-purityexcipients now areconsidered to have moreimportance in the TechnologyJULY , through its National Formulary(USP/NF), containeda compilation of excipient standards. In the EU, the EuropeanPharmacopoeiabecame the standard, supplanting more than20 national pharmacopeias. In the same time period, the firstedition of the handbook of Pharmaceutical excipients (1986)was the excipient and Pharmaceutical industries came to re-alize that materials such as crystalline cellulose, spray-dried lac-tose, anhydrous lactose, cocrystallized sugar, povidone, crospovi-done, sodium starch glycolate, various cellulose compounds,acrylates, and others had different monographs in different phar-macopeias. Each major geographic area s governing body haddeveloped its own regulations and guides, and each reflected itsown cultural characteristics and local idiosyncrasies.

5 Thus, mul-tiple products and/or multiple standards and tests were requiredfor international distribution (3).Recognizing that something had to be done, the three primarypharmacopeias formed the Pharmaceutical Discussion Group(PDG) in the late 1980s and began a program to harmonizemonographs. It soon became apparent that the PDG needed out-side help, and at a USP open meeting in late October 1990, theconcept of an international industry association composed ofboth users and manufacturers of excipients first evening, after a paper was read reviewing the lack ofregulation and guidance for the safety evaluation of a candidateexcipient, several dozen representatives of excipient user andproducer companies agreed to form what became the Interna-tional Pharmaceutical excipients Council of the Americas (IPEC-Americas), which was officially implemented in April 1991 inWashington, DC.

6 Other IPECs eventually were formed in Eu-rope and Japan ( , IPEC Europe and JPEC). The need for geo-graphical separation was necessary because of the practicalitiesimposed by distance and differing regional practices and na-tional regulations. One should note, however, that IPEC has spo-ken and will speak with one harmonized voice when the needarises. The organization also has demonstrated, through the har-monized guidelines it has published, that it is an important voicefor international users and producers of accomplish its goals, IPEC formed working committees,composed of representatives of producer and user companies,to address safety evaluation, excipient GMPs, monograph har-monization, assistance for new drug chemistry reviewers, andother issues that surfaced. IPEC also made provision for assist-ing regulatory and international governing bodies when theywere faced with new and unusual challenges.

7 Some examplesof this assistance involved the Centers for Disease Control, theWorld Health Organization (WHO), and the Pan AmericanHealth Organization in its reviews of the Haiti cough syrupissue. IPEC also is partnering with the PDG to harmonize ex-cipient unfortunate occurrence in Haiti in 1996, which involvedthe mislabeling of a product that was used in a cough syrup thatultimately killed more than 90 people, highlighted the need toaddress the quality and control of excipients . The incident drewattention to several weaknesses in the entire process of manu-facturing, shipping, handling, and labeling excipients . Some ofthese problem areas are aggravated by inexact requirements forcertificates of analysis, a lack of GMPs followed by developingcountry manufacturers and distributors of excipients , a grow-ing necessity to audit suppliers and distributors, and the needfor development of impurity profiles to name just a responded to the need for industry guidanceand developed several guidelines such as thelGMP Guide for Bulk Pharmaceutical ExcipientslGMP Audit Guide for Distributors of Bulk PharmaceuticalExcipientslGMP Audit Guide for Suppliers of Bulk Pharmaceutical Ex-cipientslIPEC Significant Change Guide for Bulk Pharmaceutical Ex-cipientslNew excipients Safety Evaluation Guidance (4)

8 LIPEC Guide for Development of an Impurity ProfilelFormat and Content of a Certificate of first three have been harmonized with IPEC has incorporated the IPEC GMP Guide for Bulk Phar-maceutical excipients into its guidances offered to nationalmember states, and USP has published in USP 24/NF19boththe IPEC GMP guide and a slightly modified version of theIPEC-Americas safety evaluation guidance as general infor-mation chapters. In addition, as an aid to manufacturers andusers of excipients , IPEC-Americas recently developed a third-party auditing program. A subsidiary of IPEC-Americas calledInternational Pharmaceutical excipients Auditing, Inc. (IPEA)was formed late last year. This organization, through use ofIPEA-trained international auditors, will be able to audit facil-ities in Europe, Asia, Australia, and North and South Americafollowing IPEC and International Organization for Standard-ization guidance standards.

9 As a result, international auditingcosts are expected to be substantially lower for companies thatno longer will need to send their own auditors on long over-seas increased sophistication in functionality associated withsome of the newer excipients is consistent with the shift fromthe concept of excipients as Inactive , inert Ingredients to beingmaterials that help deliver the active ingredient to target organsor body areas. Some of the sophistication stems from productsproduced through biotechnology, and these requirements willundoubtedly expand IPEC s future Shangraw, Pharmaceutical excipients : Characterization, Func-tionality and Harmonization, presented at Land-o-Lakes Conference,Merrimac, WI, June Shangraw and Demarest, A Survey of Current IndustrialPractices in the Formulation and Manufacture of Tablets and Cap-sules, Pharm.

10 (1), 32 44 (1993). Moreton, New excipients From Idea to Market, Eur. (3), September (1997). Steinberg, et al., A New Approach to the Safety Assessment of Phar-maceutical excipients , Regul. Toxicol. and (2), October(1996).PT