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EPT Excipients Safety Testing

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  E   x   c  i       p i      e n  t      s  – E   x    p i     r    a  t     i      o n  Excipients: Safety Testing Marshall Steinberg International Pharmaceuticals Council, Kennett Square,Pennsylvania, U.S.A. Florence K. Kinoshita Hercules Incorporated, Wilmington, Delaware, U.S.A. INTRODUCTION The safety issues concerning pharmaceutical excipientscanbeclassifiedintothreecategories:quality,toxicology,and improper use. [1] Various regulatory directivesaddress the quality category. In addition, the Inter-national Pharmaceutical Excipient Council’s (IPEC)guideline publications address this issue by followingthe Organization of International Standardization(ISO) 9000 structure. IPEC is an industry associationwith worldwide membership that includes over 200pharmaceutical, chemical, and food processing firmsthat develop, manufacture, sell, and use pharmaceuticalexcipients. IPEC comprises three regional organizationslocated in the United States, Europe, and Japan eachwith the same objectives. Quality The aforementioned IPEC guidelines that addressquality include:   Good Manufacturing Guide for Bulk Pharmaceuti-cal Excipients.   Good Manufacturing Practices (GMP) AuditGuideline for Distributors of Bulk PharmaceuticalExcipients.   IPEC-Americas Significant Change Guide for BulkPharmaceutical Excipients.   GMP Audit Guideline for Suppliers of BulkPharmaceutical Excipients.   New Excipient Safety Evaluation Guidance.   IPEC-Americas Guide for the Development of anImpurity Profile.   Format and Required Content of Certificates of Analyses.The IPEC-Americas Safety Guidelines (modified)are presented as an information chapter in UnitedStates Pharmacopoeia (USP) 24/NF 19. [2] The GoodManufacturing Guide or Practices for Bulk Pharma-ceutical Excipients also has been published as an infor-mation chapter in USP 24/NF 19. The guideline alsoserves as a basis for the World Health Organization(WHO) guidance to its national members. [3] Theintention of IPEC is to ensure that these guidelinesreflect the concerns and intentions of responsible par-ties in the United States, the European Union (EU),and Japan. In other words, the guidelines areharmonized so that excipients that meet the require-ments of a harmonized monograph can be sold andused in these three areas of the world. The use of theseand other national guidelines ensure the quality of excipients.These guidelines, using an ISO 9000 format, notonly provide a way to assess whether systems are inplace, but provide a means for evaluating the effective-ness of the systems. They also provide guidance onhow to conduct an audit of a manufacturing operationthat produces excipients [4] and in turn, give guidelineson auditing their distribution and repackaging. [5] International Conference on HarmonizationResidual Solvent Guidance Excipient impurity profiles and how to evaluate thisimportant aspect of excipient manufacture, parti-cularly in light of the International Conference onHarmonization (ICH) guidance published in 1999, [6] also are addressed. Care must also be taken thatresidual solvent levels do not exceed those prescribedin the ICH Guidance for Residual Solvents publishedin 1999. Solvents are divided into three classes:1.  Class 1 solvents: Solvents to be avoided . Theseinclude known human carcinogens, stronglysuspected human carcinogens, and environmen-tal hazards.2.  Class 2 solvents: Solvents to be limited . Theseinclude non-genotoxic animal carcinogens orpossible causative agents of other irreversibletoxicity, such as neurotoxicity or teratogenicityand solvents suspected of other significant butreversible toxicities.3.  Class 3 solvents: Solvents with low toxic poten-tial . These include solvents with low toxic Encyclopedia of Pharmaceutical Technology  DOI: 10.1081/E-EPT-100001052Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved. 1656          E      x      c         i      p          i      e       n        t       s     –         E      x      p          i      r      a         t         i      o       n potential to man; no health-based exposurelimit is needed. Class 3 solvents have permitteddaily exposures of 50mg or more per day. IPEC Significant Change Guidance Two areas of concern to excipient makers and usershave been those of significant change and certificatesof analyses. Any change by the manufacturer of anexcipient that alters an excipient’s physical or chemicalproperty from the norm or that is likely to alter theexcipient’s performance in the dosage form is con-sidered significant. [7] Regardless of whether there is aregulatory requirement to notify the local regulatoryauthority, the manufacturer has an obligation to notifyits customers of significant change so that the customercan evaluate the change on the customer’s products.The Significant Change Guidance establishes uniformconsiderations for evaluating significant changesinvolving the manufacture of bulk excipients. Thetypes of changes that might be considered include:   Site   Scale   Equipment   Process   Packaging   SpecificationsThe requirement for evaluating the impact of change on the excipient begins at the processing stepfrom which GMP compliance begins, as noted inthe IPEC Good Manufacturing Guide or PracticesGuide for Bulk Pharmaceutical Excipients, or later inthe process.The evaluation criteria in the guideline include:1. Changes in the chemical properties of the excipi-ent owing to the change.2. Changes in the physical properties of the excipi-ent owing to the change.3. Changes in the impurity profile of the excipientowing to the change.4. Changes in the functionality of the excipientowing to the change.5. Changes in the moisture level of the excipientowing to the change.6. Changes in the bioburden of the excipient owingto the change.The guideline also provides for consideration of objective criteria when considering changes to theimpurity profile of an excipient as a result of anychange. IPEC-Americas has developed a guide forthe preparation of an impurity profile for excipients.The profile addresses the following:1. All specified organic impurities.2. Unidentified organic impurities at or above0.1 %  whether specified or not, unless theimpurity has an established pharmacologicaleffect or is known to be unsafe at a lower level.3. Residual solvents.4. Inorganic impurities.5. Toxic impurities.The content of the impurity profile varies with thenature of the excipient, the raw materials used in itsmanufacture, and its chemical composition. Changesare considered significant whenever a new impurity isintroduced at or above the 0.1 %  concentration orwhen an impurity previously present at or above0.1 %  disappears. IPEC Certificate of Analysis Guidance The second issue involves the certificate of analysis thatthe manufacturer must provide to the formulator whenshipping the excipient. Most often, a certificate of analysis does not contain information developed as aresult of analysis of the specific batch of material beingdelivered. The analysis may have either been conduc-ted on previous individual batches or on a mixture of aliquots of previous batches. No guidelines regardingexactly what should be found in the certificate andhow it should be presented have been established. Thisis addressed in the guideline. [8] At the time of this writ-ing, the frequency of sampling has not been resolvedwith the U.S. Food and Drug Administration (FDA).Some believe that in the face of no significant changesit should not be necessary to sample each manufac-tured batch, but that there is a need only for sufficientsampling to ensure that statistical significance of sampling results can be met. What to do if the manu-facturing process is continuous rather than a batchprocess would fall under the same criteria except thatthe sampling frequency would probably be based ontime/volume rather than batches. EXCIPIENT USAGE There are roughly 8000 ‘‘nonactive’’ ingredients beingused in food, cosmetics, and pharmaceuticals world-wide. [1] In 1996, approximately 800 excipients wereused in marketed pharmaceutical products in theUnited States. [1] Although the FDA maintains a ‘‘list’’of inactive ingredients, the EU and other European Excipients: Safety Testing 1657  E   x   c  i       p i      e n  t      s  – E   x    p i     r    a  t     i      o n  countries do not have official published lists, althoughsteps are being taken to rectify this situation.Few excipients are manufactured specifically forpharmaceutical use. Many are manufactured for otherpurposes (e.g., food, cosmetics, paint thickeners, con-struction, etc.). For their use in pharmaceuticals,additional quality, functionality, and safety require-ments must be met. Improper Use of Excipients The improper use of excipients is addressed, to a cer-tain extent, by the package inserts found in the formu-lated products. The challenge is to educate consumersand health providers to read and comply with theinformation contained in these inserts. DEFINITION OF AN EXCIPIENT For toxicological purposes, it may be inappropriate todefine excipients as inert ingredients. It may be moreappropriate to define an excipient [9] as ‘‘Any substanceother than the active drug or pro-drug which has beenappropriately evaluated for safety and is included in adrug delivery system to either:1. Aid processing of the system during manufac-ture.2. Protect, support, or enhance stability, bioavail-ability.3. Assist in product identification.4. Enhance any other attribute of the overall safetyand effectiveness of the drug product duringstorage and use.’’As the fourth definition indicates, excipients includea multiplicity of activities from mold releasers toabsorption enhancers, and more recently include sub-stances that permit large molecule (e.g., proteins) tobe absorbed from the gastrointestinal tract withoutdegradation. Most actions by an excipient are mechan-ical rather than pharmacological. APPROVAL MECHANISMSFOR EXCIPIENTS Currently, regulatory agencies have not establishedsafety-testing guidelines specifically for excipients. [10–13,17] Under U.S. law, a new pharmaceutical excipient,unlike an active drug, has no regulatory status unlessit can be qualified through one or more of the approvalmechanisms available for components used in finisheddrug dosage forms. These approval mechanics include:   Generally Recognized As Safe (GRAS) determi-nation pursuant to 21 Code of Federal Regulations(CFR) 182, 184, and 186.   Approval of a food additive petition under 21CFR 171.   As contained in a New Drug Application (NDA)approval for a specific drug product and for aparticular function or use in that dosage form.Within the EU there is a directive that makes it clearthat new chemical excipients will be treated in the sameway as new actives. [14] TOXICITY TESTING The very nature of excipients, for the most part, repre-sents unique problems in testing for toxicity. Theactions sought for many excipients are mechanicalrather than physiological. Exceptions to this are fla-vors. [12,21] A most desirable description of some excipi-ents would include being pharmacologically inert andmechanically functional. An alternative would be onewhere the toxic dose was so high as to be meaninglesswhile still retaining functionality requirements througha range of high and low doses. The acceptable risk fora traditional excipient, when compared to an activeprinciple in a formulation, is generally several ordersof magnitude different. Unless an excipient has somevery unique properties, it is unlikely that a new excipi-ent would be developed that did not have a large safetyfactorfortoxicityandsideeffectsunderconditionsofuse.As excipients become more complex and are requiredto perform functions not required in the past, it is con-ceivable that a distinction will have to be made betweenexcipients and what might be termed ‘‘co-drugs.’’The use of monoclonal antibodies to deliver an activeprinciple to a specific tissue site might be considered anexample of this diversity.In 1994, as part of the IPEC-Americas program toobtain stand-alone status for excipients, a safety com-mittee was formed. The committee was composed of men and women from a variety of medical and chem-istry disciplines who were directed to develop safety-testing guidelines for new excipients. These guidelineswere published in 1996. [12] At that time, regulationsin most developed countries did not address regis-tration of an excipient as a separate entity. Forexample, the drug master file for an excipient in theUnited States is reviewed only as part of the NDA pro-cess. Inherent to the current process is the assumptionthat the use of an excipient in an approved drug dosageform ensures its acceptance in other dosage forms and 1658 Excipients: Safety Testing          E      x      c         i      p          i      e       n        t       s     –         E      x      p          i      r      a         t         i      o       n its ultimate inclusion in the National Formulary (NF).The NF monographs provide standards/ specificationsfor identity, purity, and analysis. Priority for inclusionis given to formulations with approved NDAs andthose approved for use in foods. The FDA favorsthe use of commercially established excipients, suchas food additives and substances that have beendesignated GRAS.The guidelines developed by IPEC-Americas [12] provide for a tier approach to required testing. Thetests to be conducted are based upon the route of application of the formulated drug and the durationof use. A base set of data is required for all candidateexcipients. The guidelines require a review of thechemical and physical properties of the excipient anda review of the scientific literature, exposure conditions(including dose, duration, frequency, route, and userpopulation), and absence or presence of pharmacologi-cal activity.Alternatives to the use of living animals are encour-aged wherever these procedures have been validated.The information will provide sufficient informationupon which to base a safety judgment and the data willbe acceptable to a regulatory agency. The studiesshould also follow the appropriate legal and pro-fessional codes [15] in the conduct of all tests and shouldmeet the Good Laboratory Practices of the agency-(ies) to which the data will be submitted.The base set of data is designed to provide funda-mental information regarding acute toxicity by the oralroute and/or intended dose route (Table 1). Skin andeye irritation testing should be conducted irrespectiveof the route of use of the candidate excipient. Thesedata are intended to protect researchers during theresearch and production life of the material.Absorption/distribution/metabolism/excretion/pharmacodynamics are considered fundamental data,as are mutagenicity tests (e.g., Ames test, in vivo Table 1  Summary IPEC-America safety testing guidelines Routes of exposure for humansTests OralMucosal transdermal/injectable topicalInhalation/intranasal Ocular Baseline toxicity data Acute oral toxicity R R R R R RAcute dermal tox. R R R R R RAcute inhalation tox. C C C C R CEye irritation R R R R R RSkin irritation R R R R R RSkin sensitization R R R R R RAcute parenteral tox. — — — R — —Application site eval. — R R R R —Pulmonary sensitization — — — — R —Phototoxicity/allergy — — R — — —Bacterial gene mutation R R R R R RChromosomal damage R R R R R RADME—intended route R R R R R R28-day toxicity (2 species) intended route R R R R R R Additional data: Short- or intermediate-termrepeated use 90-day toxicity (most appropriate species) R R R R R REmbryo-fetal toxicity R R R R R RAdditional assays a C C C C C CGenotoxicity R R R R R RImmunosupression [3] R C C R R R Additional data: Intermittent long-term or chronic use Chronic toxicity (rodent, non-rodent) C C C C C C1-generation reproduction R R R R R RPhotocarcinogenicity — — C — — —Carcinogenicity C C C C C C R, required; C, conditional. a Additional assays are dependent on the judgment of the data evaluator. They may include, but are not limited to screening for endocrine mod-ulators or tests to determine if findings in animals are relevant to humans.(From Ref. [12] , p. 53.) Excipients: Safety Testing 1659
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