98 Pharmaceutical Technology MARCH 2005 www.pharmtech.com

n the October 2000 issue of this magazine, I de-scribed the recently issued International Phar-maceutical Excipients Council of the Americas

(IPEC-Americas) Significant Change Guide forBulk Pharmaceutical Excipients. Now, IPEC-Amer-icas has completed a major update to the guide-line to address current concerns about bovinespongiform encephalopathy, genetically modifiedorganisms, and allergens. The updated guide alsocontains a new section to assist manufacturers indeveloping an impurity profile.

Overview of the original guidelineThe significant change guideline was developed tohelp excipient manufacturers evaluate the signif-icance of manufacturing changes and to assess therisk that those changes will affect drug productsthat contain the excipient. The guideline also ex-plained which changes should prompt communi-cation with drug manufacturers.

The guideline began with a working definitionof significant change as one that alters a chemicalor physical property of an excipient from its normal range or one that alters an excipient’s per-formance.

The next section of the guide discussed the cri-teria for evaluating changes in excipient manu-facture and how to apply those criteria to deter-mine whether the change could significantly affecta drug manufacturer’s use of the excipient. Thissection introduced the concept of three levels ofrisk that a change may be significant, rising froma Level 1 change, which was defined as a minorchange, to a Level 2 change, which may be signif-icant, and ending with a Level 3 change, whichwould be considered significant. The section con-cluded with a discussion of significant change pro-tocol design and supporting data.

The section that followed contained an exten-sive discussion of the types of changes that canlead to a significant change in the excipient. Theguide provided examples of changes of each type listed in the first section (site, equipment,process, etc.) and the recommended change level classification.

The last section explained the relationship be-tween the change level and the need to commu-nicate changes to a drug manufacturer. The guidenoted that Level 1 changes do not need to be com-municated to a drug manufacturer. Level 2changes, however, should be discussed with thedrug manufacturer so that the manufacturer maydecide if it should review the effect of the excip-ient manufacturing change on its drug product(s).Level 3 changes are of sufficient significance thatthe excipient manufacturer should discuss thechange with the drug manufacturer before thechange is implemented. For Level 3 changes, thedrug manufacturer may want to carefully evalu-ate the effect of the change on products that con-tain the excipient ingredient.

The IPEC-Americas guide concluded with sev-eral appendices, including one that presented illustrative examples of changes to excipient man-ufacture that fall within each of the three levels ofrisk. The final appendix presented a decision treethat further illustrated the risk levels for typicalchanges.

Current issuesRecent developments in the business climate havenecessitated an update to the significant changeguide. Since the guide was first published in 2000,the pharmaceutical industry has faced concernsabout ingredients derived from genetically mod-ified organisms (GMOs) and allergenic material,the risk of transmitting bovine spongiform en-cephalopathy/transmissible spongiform en-cephalopathy (BSE/TSE), and the potential forterrorists and counterfeiters to tamper with thedrug supply.

Consumers and regulators are concerned aboutthe potential for excipients and drug products tocontain materials from bovine byproducts con-taminated with BSE/TSE. Such contaminationwould create a finite risk that a patient could de-velop “mad cow” disease from the contaminateddrug product. Therefore, drug manufacturersshould be made aware of any changes to excipi-ent composition that could introduce these ma-

IPEC-Americas’ Updated Significant Change Guide for BulkPharmaceutical ExcipientsIrwin Silverstein

I

Irwin Silverstein,PhD, is the principal ofIBS Consulting in QualityLLC in Piscataway, NewJersey, irwin.s@att.net.He is a consultant tothree IPEC-Americascommittees and serveson the Board of Directorsof IPEA, the excipientGMP auditing subsidiarycorporation of IPEC-Americas.

EXCIPIENT INSIDER

IPEC-Americashas justcompleted amajor update toits significantchange guidelineto addresscurrent issues inthe manufactureof excipientingredients andto assistmanufacturers indeveloping animpurity profile.

100 Pharmaceutical Technology MARCH 2005 www.pharmtech.com

terials into a drug product. Also, suchchanges can result in noncompliance ofthe drug product with relevant BSE/TSEregulations (1–2).

Concerns about pharmaceutical ingre-dients produced from genetically modi-fied plants are expressed primarily by con-sumers. In contrast to concerns about madcow disease, however, consumers’ fearsabout genetically modified organisms arenot linked to any specific illness. Patientsare concerned about genetically modifiedorganisms because they believe that sci-ence has not clearly established that phar-maceuticals produced with ingredients de-rived from these materials are safe.

Lastly, IPEC recognized that for mineral-based excipients, a change in geological for-mation can lead to a significant change inthe composition of inorganic excipient ingredients.

The seventh criterion for evaluating change.In response to these concerns, the signif-icant change guide has been updated toinclude a seventh criterion for evaluatingchange. This criterion calls on the manu-facturer to answer the question,“Has therebeen a change in the origin of any raw ma-terials or contact packaging?”

If a source has been changed, the newsource must be reviewed carefully. The ex-cipient manufacturer must contact thenew supplier and request a list of the rawmaterials used to produce the raw mate-rial or contact packaging. The source (syn-thetic, animal, or vegetable) of all raw ma-terials should be identified.

If the raw material’s source is animal, itis important to establish the risk that theraw material or contact packaging con-tains BSE/TSE-risk material. For example,if the raw material is sourced from bovinematerials, the country of origin of the cat-tle should be known. If BSE/TSE has beendetected in that country’s herds, the ex-cipient manufacturer should notify itsdrug manufacturing customers.

If the source is vegetable, the excipientmanufacturer should find out whetherthere has been a change from one plantspecies to another or from a natural plantspecies to one grown from geneticallymodified seed. Drug manufacturersshould be notified of such changes becausesome manufacturers are sensitive to con-sumer concern about GMO-sourced ingredients.

Drug manufacturers are also concernedabout the potential for introducing aller-genic material into drug products from anexcipient whose source of raw materialshas changed to one that can elicit an al-lergenic response in sensitive individuals.For instance, it is well known that somepeople are very sensitive to peanuts andtheir derivatives. Therefore, a switch fromnon–peanut sourced raw material to apeanut-derived raw material is importantto a drug manufacturer.

Mineral-derived excipient ingredientspresent a somewhat different reason forsignificant-change notification. Variationsin geological formations can significantlychange the composition of inorganic ex-cipient ingredients. Therefore, if the min-ing site of a mineral ingredient haschanged, the drug manufacturer shouldbe informed. Not all such changes, how-ever, will be readily apparent to the excip-ient manufacturer.

Impurity profileThe other major change to the IPEC-Americas Significant Change Guide forBulk Pharmaceutical Excipients is the ad-dition of an appendix that describes thedevelopment of an impurity profile. Ex-cipient manufacturers must realize that achange in an excipient’s impurity profilemay change the impurity profile of thedrug product. A change in the impurityprofile of a drug product would have seri-ous regulatory ramifications to the drug

manufacturer. Therefore, comparing anexcipient’s impurity profile after a manu-facturing change with the impurity pro-file before the change is the third criterionfor evaluating change that is described inthe guideline.

An impurity profile is defined as the ma-terials, other than concomitant compo-nents and foreign substances, that are pres-ent along with the intended excipientchemical. A concomitant component is asubstance found in an excipient that is notthe intended chemical entity but that maybe necessary for ensuring the proper per-formance of the excipient in its intendeduse. Because concomitant components canalter the performance characteristics of anexcipient in a drug formulation, the quan-tities of these components should be mon-itored but not reduced.

By contrast, a foreign substance is a com-ponent present in an excipient but not in-troduced as a consequence of the excipi-ent’s synthesis or purification and whichis not necessary to achieve the requiredexcipient functionality. Foreign substancesthus differ from impurities because thelatter are introduced into the excipient asa consequence of excipient synthesis orpurification. Foreign substances must beremoved from the excipient, whereas im-purities must be monitored through theimpurity profile.

The guide classifies impurities into or-ganic impurities, inorganic impurities,and residual solvents. The guide defines aresidual solvent as any organic or inorganicliquid used in the manufacture of the ex-cipient that remains unchanged by pro-cessing. A pharmaceutical manufacturerneeds to know about residual solvents tocomply with the requirements containedin the International Conference on Har-monization’s Q3C guidance on residualsolvents (3).

The significant change guideline sug-gests that an excipient manufacturer at-tempt to account for 100% of the excipi-ent composition. However, if excipientpurity cannot be directly measured, mak-ing it impossible or impractical to accountfor 100% of the composition, the guidesuggests that the supplier be prepared toaccount for as much of the excipient com-position as can be measured.

In the pharmaceutical industry, bothdrug manufacturers and regulatory au-

Excipient Insider

The pharmaceutical

industry faces concerns

about ingredients

derived from genetically

modified organisms and

allergenic material, the

risk of transmitting

BSE/TSE, and the

potential for tampering

with the drug supply.

102 Pharmaceutical Technology MARCH 2005 www.pharmtech.com

Excipient Insider

thorities expect all activities related togood manufacturing practices to be doc-umented. Therefore, the impurity profileappendix concludes with the suggestedcontent of documentation to support thedevelopment of the impurity profile. Thedocumentation should describe the sam-pling plan and test methods, the processused to identify impurities, and the ex-tent of the excipient composition quan-tified. This documentation can be com-piled in various ways by the supplier suchthat it can be retrieved to support the im-purity profile.

An excipient’s impurity profile can re-veal details of a proprietary manufactur-ing process. As a result, drug manufactur-ers should understand that excipientmanufacturers will not always be willingto disclose an impurity profile in detail. Ifan excipient manufacturer treats the im-purity profile as confidential information,then the drug manufacturer should merelyconfirm that a reference impurity profilehas been established and is being properlyused to evaluate the change.

Terrorism and counterfeitingAlthough the significant change guidelinefocuses on whether a change to an excip-ient’s manufacture warrants notificationto a drug manufacturer, the guide servesa secondary purpose as well. A change inan excipient’s impurity profile can alertthe excipient manufacturer or its customer

to the presence of a foreign substance.Such substances can be the result of pur-poseful tampering with the excipient withthe intent to introduce the foreign sub-stance into the drug supply by way of theexcipient. This not only would have reg-

ulatory consequences but could jeopard-ize the quality of the drug supply and putpatients at risk.

In addition, developing an excipient im-purity profile can help identify counter-feit excipients. If a question arises from adrug manufacturer concerning the au-thenticity of an excipient, the excipientimpurity profile can be an important toolin establishing the excipient’s authentic-ity. The profile also can alert the drugmanufacturer of an unauthorized changearising at an approved excipient source.

SummaryThe enhancements to the IPEC-AmericasSignificant Change Guide for Bulk Phar-maceutical Excipients bring the guidelineup to current industry expectations. Theserevisions establish new excipient industrypractices to meet changing drug productmanufacturer requirements to addressnew consumer and regulatory concerns.

References1. General Text 5.2.8, “Minimizing the Risk of

Transmitting Animal Spongiform En-cephalopathy Agents via Medicinal Products,”European Pharmacopoeia 5.0 (European Di-rectorate for the Quality of Medicines, Stras-bourg, France, 2005), 463–471.

2. US Department of Agriculture, Animal andPlant Health Inspection Service (APHIS),“9CFR Parts 93, 94, and 95, Bovine SpongiformEncephalopathy; Minimal Risk Regions andImportation of Commodities (ProposedRules),” Federal Register 68 (213), 62,386–62,405 (4 November 2003).

3. International Conference on Harmonization,ICH Q3C, Impurities: Guidelines for Resid-ual Solvents (ICH, Geneva, Switzerland,1997). PT

A change in an

excipient’s impurity

profile can alert the

excipient manufacturer

to the presence of a

foreign substance.

The Hydraulic Institute (Parsippany, NJ, www.pumplearning.org), under the approval of theAmerican National Standards Institute (ANSI), isseeking individuals to participate in the review of anewly completed standard for the definition,application, installation, operation, andmaintenance of controlled volume metering pumps.

The new standard is limited to positive-displacement metering pumps such as hydrauliccoupled disc diaphragm, hydraulic coupled tubulardiaphragm, mechanical coupled disc diaphragm,electromagnetic drive, reciprocating air drive,packed plunger, and piston pumps.

For more information, contact Joseph Latta atjlatta@pumps.org or 973.267.9700 ext. 15.

Call for reviewers