Health authorities increasingly recognize the role excipients play as essential constituents of medicinal products. Pharmaceutical excipients contribute unique functionalities to formulations, thereby largely determining the drug product's quality and influencing its safety and efficacy. Changes and variations of excipients in licensed products are, therefore, placed under strict regulatory control. In this paper three levels of excipient change with potentially increasing impact on the performance of the pharmaceutical formulation are distinguished. The regulatory implications further depend on the function of the particular excipient in its specific formulation. The first change level relates to the quality variations that may result when changing excipient manufacturer. Such variations are generally larger and of higher regulatory impact than the usual batch-to-batch quality variations occurring for excipients obtained from one single manufacturer. However, when an excipient manufacturer changes its manufacturing site, its equipment, or its specifications the change in excipient quality may also have significant influence on its functionality in the drug formulation. The second change level relates to a change of excipient grade or in excipient concentration. The third change level relates to substitution of an excipient by another excipient of the same or similar functionality.
SamAPFokkensJGThe drug delivery system: adding therapeutic and economic value to pharmacotherapy. Pharma Tech Europe.1997; Part I, 9(5): 36–40, & 1997;Part II, 9(6):58–66.
2.
LangerR.Drug delivery and targeting. Nature.1998;392: Supp. 5–10.
3.
EU Guideline: Excipients in the dossier for application for marketing authorization of a medicinal product (3AQ9A). In: The Rules Governing Medicinal Products in the European Union.Luxembourg; EudraLex, Office for Official Publications of the European Union: 1988;Volume 3A, 67–74.
4.
Notice to Applicants, The Rules Governing Medicinal Products in the European Union, Vol. 3A, Guidelines for Medicinal products for human use, Quality and biotechnology.Luxembourg; EudraLex, Office of Official Publications of the European Union: 1998.
5.
JonesTMThe influence of physical characteristics of excipients on the design and preparation of tablets and excipients. Pharm Ind.1977;39(5):469–476.
6.
EU Guideline: Excipients in the label and package leaflet of medicinal products for human use (3BC7A). In: The Rules Governing Medicinal Products in the European Union.Luxembourg; EudraLex, Office of Official Publications of the European Union: 1998;Volume 3B:223–232.
7.
ICH Guideline: Stability testing of new drug substances and products (topic Q1A(R). Step 2. Geneva, Switzerland: International Conference on Harmonization; Oct. 1999.
8.
ICH Guideline: Specifications and acceptance criteria for new drug substances and new drug products: chemical substances (topic Q6A). Geneva, Switzerland: International Conference on Harmonization; Oct. 6, 1999.
9.
HellerJ.Drug delivery in the plastics age. In: Innovations in drug delivery—Impact on Pharmacotherapy.SamAPFokkensJG, eds. The Netherlands: Anselmus Foundation; 1996.
10.
Commission Regulations (EC) No. 541/95 and 542/95 as amended by Commission Regulation (EC) 1146/98 and 1069/98. Further clarified by: A guideline on Dossier Requirements for Type I Variations. Brussels, Belgium: EC Commission; Nov. 1999.
11.
FDA Guidance for Industry: SUPAC-IR: Immediate Release Solid Oral Dosage Forms; Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence. Federal Register. Nov 1995;60(230/30).
12.
FDA Guidance for Industry: SUPAC-MR: Modified Release Solid Oral Dosage Forms, CMC, In Vitro dissolution testing, In Vivo Bioequivalence Documentation.Rockville, MD: U.S. Food and Drug Administration; September 1997.
13.
TicehurstMDYorkPRoweRCDwivediSKCharacterisation of the surface properties of α-lactose monohydrate with inverse gas chromatography, used to detect batch variation. Int J Pharm.1996;141: 93–99.
14.
di MartinoPMartelliSGuyot-HermannA-MGuyotJCConfiantP.The batch-to-batch non-reproducibility of the compression ability of lactose. Reasons and detection. S.T.P. Pharma Sciences.1993;3(6):436–441.
15.
de HaanPKroonCSamAPDecomposition and stabilization of the tablet excipient calcium hydrogenphosphate dihydrate. Drug Dev Ind Pharm.1990;16(13):2031–2055.
16.
LandinMRoweRCYorkP.Particle size effects on the dehydration of dicalcium phosphate dihydrate powders. Int J Pharm.1994;104:271–275.
17.
LandinMMartinez-PachecoRGomez-AmozaJLSoutoCConcheiroARoweRCEffect of batch variation and source of pulp on the properties of microcrystalline cellulose. Int J Pharm.1993;91: 133–141.
18.
DunnRLEnglishJPStrobelJDCowsarDRTiceTRPreparation and evaluation of lactide/glycolide copolymers for drug delivery. In: Polymers in Medicine III.Migliaresi, eds. The Netherlands: Elsevier; 1988:149–160.
19.
Pérez-MarcosBMarinez-PachecoRGomez-AmozaJLSoutoCConcheiroARoweRCInterlot variability of carbomer 943. Int J Pharm.1993;100: 207–212.
20.
IPEC-Americas guideline: Significant change guide for bulk pharmaceutical excipients. Rosslyn: International Pharmaceutical Excipients Council; February 2000.
21.
FDA Guidance for Industry: BACPAC I: Intermediates in Drug Substance Synthesis—Bulk Actives Postapproval Changes: Chemistry, Manufacturing, and Controls Documentation.Rockville, MD: U.S. Food and Drug Administration; November 1998.
22.
WottonPKWadeGMoretonRCExcipients. In: International Pharmaceutical Product Registration—Aspects Of Quality, Efficacy And Safety.CartwrightACMatthewsBR, eds. Chicester, England: Ellis Horwood;1994.
23.
MrozC.Problems arising in connection with change of suppliers. In: Excipients In Pharmaceutical Formulations—Regulatory And Scientific Requirements, Proceedings of the Arbeitsgemeinschaft für Pharmazeutische Verfahrens Technik. Mainz, Germany, Symposium. February 1997.
24.
Code of Federal Regulations (Food & Drugs) 21 314.50 (d)(1)(ii), rev. April 1, 1997.
25.
HoelzerAWAn investigation of batch to batch variation of commercial magnesium stearates. Proceedings 3rd Congress Technology and Pharmacy. Paris, France, 1983;4:72–80.
26.
BillanyMRRichardsJHBatch variation of magnesium stearate and its effect on the dissolution rate of salicylic acid from solid dosage forms. Drug Dev Ind Pharm.1982:8(4): 497–511.
27.
ParkerMDRoweRCSource variation in the wet massing (granulation) of some microcrystalline celluloses. Powder Tech.1991;65:273–281.
28.
LandinMMartinez-PachecoRGomez-AmozaJLSoutoCConcheiroARoweRCInfluence of microcrystalline cellulose source and batch variation on the tabletting behaviour and stability of prednisone formulations. Int J Pharm.1993;91:143–149.
29.
RoweRCMcKillopAGBrayD.The effect of batch and source variation on the crystallinity of microcrystalline cellulose. Int J Pharm.1994;101: 169–172.
30.
O'LaughlinRSachsCBrittainHCohenETimminsPVariaS.Effects of variations in physico-chemical properties of glyceryl monostearate on the stability of an oil-in-water cream. J Soc Cosmet Chem.1989;40:215–229.
31.
ShahABrittenNJOlanoffLSBadalamentiJNGel-matrix systems exhibiting bimodal controlled release for oral drug delivery. J Control Release.1989;9:169–175.
32.
BolhuisGArends-ScholteAWStuutGJde VriesJADisintegration efficiency of sodium starch glycolates, prepared from different native starches. Eur J Pharm Biopharm.1994;40:(5)317–320.
HussainASLeskoLJLoKYShahVPVolpeDWilliamsRLThe Biopharmaceutics Classification System: Highlights of the FDA's draft guidance. Diss Techn.1999:6(2):5–9.
35.
WhitemanMYarwoodRJThe evaluation of six lactose-based materials as direct compression tablet excipients. Drug Dev Ind Pharm.1988;14(8):1023–1040.
36.
Type II Complex Variation Definitions, Appendix 3 to Special MAIL“New system for additional category of variations,” (Medicines Act Leaflet) London, UK: April 1995.
37.
FDA Draft guidance for industry: Food-Effect Bioavailability and Bioequivalence Studies.Rockville, MD: U.S. Food and Drug Administration, Center for Drug Evaluation and Research; October 1997.
38.
KuiphuisTArends-ScholteAWGruben-RutgersKLFiller/binders in wet granulation, AVEBE Pharmaflash. Veendam, The Netherlands.
39.
ThwaitesPMMashadiABMooreWDAn investigation on the effect of high speed mixing on the mechanical and physical properties of direct compression lactose. Drug Dev Ind Pharm.1991;17(4): 503–517.
40.
HussainA. In (transcript): Meeting of the Advisory Committee for Pharmaceutical Science, FDA, CDER. 13–23, December 11, 1997.
41.
SteinbergMBorzellecaJFEntersEKKinoshitaFKLoperAMitchellDBTamulinasCBWeinerMLA new approach to the safety assessment of pharmaceutical excipients. Reg Toxicol Pharmacol.1996;24:149–154.
42.
LutzJAugustinAJBrandiD.Acute toxicity and depression of the phagocytosis in vivo by liposomes: influence of lysophosphotidylcholine. Life Sci.1995;56:99–106.
43.
UchegbuIFFlorenceATAdverse events related to dosage forms and delivery systems. Drug Safety.1996;14:39–67.
44.
Commision Directive 1999/82/EC of 8 September 1999 amending the Annex to Council Directive 75/318/EEC on the approximation of the laws of the Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. Official Journal of the European Communities, number L 243, 15.9.1999;7–8.
45.
Committee for Proprietary Medicinal Products. Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products. CPMP/BWP/1230/98. London: Committee for Proprietary Medicinal Products; April 21, 1999.
46.
Council of Europe. Public Health Committee (Partial Agreement). Resolution AP-CSP (99) 5. Strasbourg, France: December 10, 1999.
47.
The European Agency for the Evaluation of Medicinal Products. Implementing the amendment to the Annex of Council Directive 75/318/EEC: Demonstration of compliance with the CPMP-TSE guideline. Briefing Document. EMEA/CPMP/BWP/2962/99. London: European Agency for the Evaluation of Medicinal Products: November 1999.
48.
Council of Europe. Public Health Committee (Partial Agreement). Resolution AP-CSP (99) 4. Certification of suitability to the monographs of the European Pharmacopoeia (revised version). Strasbourg, France: December 22, 1999.
49.
U.S. Food and Drug Administration.FDA Guidance for Industry: Changes to an approved NDA or ANDA.Rockville, MD: U.S. Food and Drug Administration; Nov. 1, 1999.
