Safety of Pharmaceutical Excipients and Regulatory Issues

Author(s): Kanteti V.R.N.S. Ramesh*, Hemant Yadav, Omar Sarheed

Journal Name: Applied Clinical Research, Clinical Trials and Regulatory Affairs
Continued as Applied Drug Research, Clinical Trials and Regulatory Affairs

Volume 6 , Issue 2 , 2019

Graphical Abstract:


Background: Pharmaceutical excipients are critical in the formulation of any dosage form. Not many additives employed in the drug product manufacture have properties, which meet the desired qualities that the finished product must have. Therefore, it is mandatory to mix the drug substance with other substances to overcome the deficiencies. As a result, almost all pharmaceutical products are mixtures of active pharmaceutical ingredient and additives. So, there is a compelling need of these substances and normally they occupy the major part of any drug product. Excipients are of different chemical categories that have varying physicochemical properties like solubility, miscibility and the nature and source of these materials vary. With growing number of pharmaceutical excipients and polymers, the question of evaluating their toxicity is becoming a complex issue. Many polymers and novel excipients are now available in the market and with their diverse chemical nature and different sources and presence of impurities and their adverse effects will further complicate the safety profiling of these excipients.

Conclusion: This review article will discuss the unwanted biological activities of some commonly used excipients and issues of the supply of the pharmaceutical excipients that need to be highly regulated and monitored to ensure availability of quality and pure excipient compounds.

Keywords: Excipients, pharmaceutical product, safety, efficacy, biological effects, regulation, stability.

USP 38- NF 33 (United States Pharmacopeial Convention) General Information Chapter, Good Manufacturing Practices for Bulk Pharmaceutical Excipients. Rockville, MD: USP 2015.
Giorgio P, Patrizia R. The safety of pharmaceutical excipients. Farmaco 2003; 58(8): 541-50.
Baldrick P. Pharmaceutical excipient development: The need for clinical guidance. Regul Toxicol Pharmacol 2000; 32(2): 210-8.
Fathima N, Mamatha T, Qureshi HK, Anitha N, Rao JV. Drug-excipient interaction and its importance in dosage form development. J Appl Pharm Sci 2011; 1(6): 66-71.
Cavatur R, Vemuri NM, Chrzan Z. Use of isothermal microcalorimetry in pharmaceutical preformulation studies. Part III. Evaluation of excipient compatibility of a new chemical entity. J Therm Anal Calorimetry 2004; 78(1): 63-72.
Moreton RC. Excipient development for pharmaceutical, biotechnology and drug delivery systems. New York: CRC Press 2006; pp. 93-108.
Steele DF, Edge S, Tobyn MJ, Moreton RC, Staniforth JN. Adsorption of amine drug onto microcrystalline cellulose and silicified microcrystalline cellulose samples. Drug Dev Ind Pharm 2003; 29(4): 475-87.
Mackay KM, Michael R, Richards E, Xing JZ. Excipients interaction with Cetylpyridinium chloride activity in tablet based lozenges. Pharm Res 1996; 13(8): 1258-64.
Dawoodbhai SS, Chueh HR, Rhodes CT. Glidants and lubricant properties of several types of talcs. Drug Dev Ind Pharm 1987; 13(13): 2441-67.
Pleurisy. [Cited: 6 June 2018]. Available from:
Aelony Y. Talc pleurodesis and acute respiratory distress syndrome. Lancet 2007; 369(9572): 1494-6.
Bouchama A, Chastre J, Gaudichet A, Soler P, Gilbert C. Acute pneumonitis with bilateral pleural effusion after talc pleurodesis. Chest 1984; 86(5): 795-7.
Milanez JR, Werebe EC, Vargas FS. Respiratory failure due to insufflated talc. Lancet 1997; 349(9047): 251-2.
Ferrer J, Villarino MA, Tura JM. Talc preparations used for pleurodesis vary markedly from one preparation to another. Chest 2001; 119(6): 1901-5.
Kennedy L, Rusch VW, Strange C. Pleurodesis using talc slurry. Chest 1994; 106(2): 342-6.
Todd TRJ, Delarue NC, Ilves R, Pearson FG, Cooper JD. Talc poudrage for malignant pleural effusion. Chest 1980; 78: 542-3.
Rehse DH, Aye RW, Florence MG. Respiratory failure following talc pleurodesis. Am J Surg 1999; 177(5): 437-40.
Lin SY, Kawashima Y. The influence of three poly (oxtethylene) poly (oxypropylene), surface-active block copolymers on the solubility behavior of indomethacin. Pharm Acta Helv 1985; 60(12): 339-44.
Tadros TF. Viscoelastic properties of sterically stabilized emulsions and their stability. Adv Colloid Interface Sci 2015; 222: 692-708.
Andrew MB, Paschalis A. Formulation of poloxamers for drug delivery. J Funct Biomater 2018; 9(11): 1-24.
Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res 2006; 23(12): 2709-28.
Jonathan K, Armstrong H, Timothy C, Fisher N. Inhibition of red blood cell-induced platelet aggregation in whole blood by a nonionic surfactant, poloxamer 188 (Rheothrx® Injection). Thromb Res 1995; 79(5-6): 437-50.
Safety assessment of poloxamers. [Cited: 6 June 2018]. Available from
Lee RC. Pipe Dream or paradigm shiftUniversity of Chicago Magazine 2006; 98(3) [Cited: 14 June 2018]. Available from:.
Orringer EP, James FC, Kenneth IA, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease. JAMA 2001; 286(17): 2099-106.
Monograph on polyethylene glycol. In: Rowe RC, Sheskey PJ, Quinn ME, Eds Handbook of Pharmaceutical Excipients. 6th ed. London: Pharmaceutical Press 2010; pp. 517-22.
Dohsi DH, Ravis WR, Betageri GV. Carbamazepine and polyethylene glycol solid dispersions: Preparation, in vitro dissolution, and characterization. Drug Dev Ind Phar 1997; 23(12): 1167-76.
Jithan AV, Krishna MC, Vimaladevi M. Development and evaluation of a chloramphenicol hypertonic ophthalmic solution. Indian J Pharm Sci 2008; 70(1): 66-70.
Chatterjee A, Mohan S. Formulation and in vitro characterization of zaltoprofen suppositories using bases and different concentration of plasticizer RJPBCS. 2014; 5(4): 359-70.
Erickson BA, Austin JC, Cooper CS, Boyt MA. Polyethylene glycol 3350 for constipation in children with dysfunctional elimination. J Urol 2003; 170(4 pt 2): 1518-20.
Michail S, Gendy E, Preud HG, Mezoff A. Polyethylene glycol for constipation in children younger than eighteen months old. J Pediatr Gastrontrol Nutr 2004; 39(2): 197-9.
Salvatore S, Barberi S, Borrelli O, Castellazzi A, Di Mauro D, Di Mauro G. Pharmacological interventions on early functional gastrointestinal disorders. Ital J Pediatr 2016; 42(1): 68-76.
Loening-Baucke V. Polyethylene glycol without electrolytes for children with constipation and encopresis. J Pediatr Gastrontrol Nutr 2002; 34(4): 372-7.
Seen C, Adam C, Ran DG. Polyethylene glycol 3350 without electrolytes for treatment of childhood constipation. Can Fam Physician J 2009; 55(5): 481-2.
De Muynck C, Cuvelier C. Rectal mucosa damage in rabbits after subchronical application of suppository bases. Pharm Res 1991; 8(7): 945-50.
Kjellin M, Johansson I. Surfactants from renewable resources. Hoboken, NJ, USA: John Wiley & Sons 2010; p. 65.
Corrigan OI, Healy AM. Surfactants in pharmaceutical products and systems. In: Encyclopedia of pharmaceutical technology. 3rd ed. Taylor and Francis 2006; pp. 3583-96.
Rayman C, Sheskey PJ, Quinn ME. Handbook of Pharmaceutical Excipients. 6th ed. UK: Pharmaceutical Press 2010; p. 550.
Shelly WB. Polysorbate 80 hypersensitivity.[letter] Lancet 1995; 345(8960): 1312-3.
Alade SL, Brown RE, Paquet A. Polysorbate 80 and E-Ferol toxicity. Pediatrics 1986; 77(4): 593-7.
Balistreei WF, Farrell MK, Bove KE. Lessons from the E-Ferol tragedy. Pediatrics 1986; 78(3): 503-6.
FAO/WHO Toxicological evaluation of certain food additives with a review of general principles and of specifications, Seventeenth report of the joint FAO/WHO expert committee on food additives. World Health Organ Tech Rep SER 1974; No. 539; Geneva, Switzerland. Available from:
Johnson R, Steer R. Methyl paraben monograph. In: Rowe RC, Sheskey PJ, Weller PJ, Eds. Handbook of Pharmaceutical Excipients. 5th ed. London: Pharmaceutical Press 2006; pp. 466-70.
Johnson R, Steer R. Methyl paraben monograph. In: Rowe RC, Sheskey PJ, Weller PJ, Eds. Handbook of Pharmaceutical Excipients. 5th ed. London: Pharmaceutical Press 2006; pp. 629-32.
Johnson R, Steer R. Methyl paraben monograph. In: Rowe RC, Sheskey PJ, Weller PJ, Eds. Handbook of Pharmaceutical Excipients. 5th ed. London: Pharmaceutical Press 2006; pp. 83-5.
Fransway F. The problem of preservation in the 1990s: III agents with preservation function independent of formaldehyde release. Am J Cont Derm 1991; 2: 145-74.
EMA. Reflection paper on the use of methyl- and propylparaben as excipients in human medicinal products for oral use. EMA/CHMP/SWP/272921/ 2012. 2015; Available from:.
Hetherington NJ, Dookey MJ. Potential for patient harm from intrathecal administration of preserved solution. Med J Aust 2000; 173(3): 141-3.
EMA. Questions and answers on benzyl alcohol in the context of the revision of the guideline on ‘Excipients in the label and package leaflet of medicinal products for human use’ (CPMP/463/00). EMA/CHMP/508188/2013. 2014; Available from:.
Evens RP. Toxicity of intravenous benzyl alcohol. Drug Intell Clin Pharm 1975; 9(3): 154-5.
Hahn AF, Feasby TE, Gilbert JJ. Paraperesis following intrathecal chemotherapy. Neurology 1983; 33(8): 1032-8.
WHO expert committee on biological standardization. Thirty-seventh report. World Health Organ Tech Rep Ser 1987; 760: 1-203.
US Food and Drug Administration. Pneumovax 23. 2018; [Cited: 14 June 2018]. Available from: .
Brancato DJ. Recognizing potential toxicity of phenol. Vet Hum Toxicol 1982; 24(1): 29-30.
Fransway AF. The problem of preservation in the 1990s: III agents with preservation function independent of formaldehyde release. Am J Cont Derm 1991; 2(3): 145-74.
Lohr L. Mercury controversy heats up. Am J Pharm 1978; 18: 23.
Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following intrathecal chemotherapy. Neurology 1983; 33(8): 1032-8.
Lahti A, Pylvänen V, Hannuksela M. Immediate irritant reactions to benzoic acid are enhanced in washed skin areas. Contact Dermatitis 1996; 35(1): 51.
Tabor E. Corneal damage due to eye contact with chlorhexidine gluconate. J Am Med Assoc 1989; 261(4): 557-8.
Bowler GM, Galloway DW, Meiklejohn BH, Macintyre CC. Sharp fall in blood pressure after injection of heparin containing chlorbutol. Lancet 1986; 1(8485): 848-9.
Zandlo M. Final report to the safety assessment of p-chloro-m-cresol. Int J Toxicol 1997; 16(3): 235-68.
Malakar S, Panda S. Post inflammatory depigmentation following allergic contact dermatitis to chloroxylenol. Br J Dermatol 2001; 144(6): 1275-6.
Boyer Y. Irritation by eye drops containing 2- phenylethyl alcohol. Pharm Weekbl Sci 1981; 3: 826-7.
Kligman AM. The identification of contact allergens by human assay: III. The maximization test: A procedure for screening and rating contact sensitizers. J Invest Dermatol 1966; 47(5): 393-409.
Nair B. Final report to the safety assessment of benzyl alcohol, benzoic acid sodium benzoate. Int J Toxicol 2001; 20(Suppl. 3): 23-50.
Hebestreit P. Addressing specific regulatory excipient requirements in the marketing authorizationPharm- SciFair Nice 2009; [Cited: 14 June 2018] Available from: uploads/attachments/Specific_regulatory_requ_PH.pdf?t=1407175233
Hertrampf A, Müller H, Menezes JC, Herdling T. Advanced qualification of pharmaceutical excipient suppliers by multiple analytics and multivariate analysis combined. Int J Pharm 2015; 495(1): 447-58.
Singh J. International conference on harmonization of technical requirements for registration of pharmaceuticals for human use. J Pharmacol Pharmacother 2015; 6(3): 185-7.
Abrantes CG, Dinah D, Reis CP. An overview of pharmaceutical excipients: Safe or not safe? J Pharm Sci 2016; 105(7): 2019-26.
Swarbrick J. Excipients: Safety testing. 3rd ed. Encyclopedia of Pharmaceutical Technology . New York, NY: Informa Health Care 2007; pp. 1658-60.
Shuren J. Guidance for industry on nonclinical study for the safety evaluation of pharmaceutical excipients2005 [Cited: 20 June 2018] Available from:
Uchiyama M. Regulatory status of excipients in Japan. Drug Inf J 1999; 33(1): 27-32.
Pharmaceutical administration and regulations in Japan. [Cited: 15 October 2018]. Available from: http://
Demerlis CC, Smith A, Schoneker DR. Regulatory information for excipients Pharmaceutical excipients: Properties, functionality and applications in research and industry. Hoboken: John Wiley and Sons 2017; pp. 241-68.
Kashappa GD, Hirokazu O, James DC, Douglas PN. Japan-specific key regulatory aspects for development of new biopharmaceutical drug products. J Pharm Sci 2018; 107(7): 1773-86.
Self-imposed good manufacturing practices for pharmaceutical excipients and its explanation. [Cited: 16 October 2018]. Available from: http://www.jpec.grjp/gmp/doc/gmp_e_web.pdf.
Gilbert SB, Rhodes CT. Modern Pharmaceutics. 4th ed. New York: Informa Healthcare 2010; pp. 651-2.
Guideline on excipients in the dossier for application for marketing authorization of a medicinal Product. [Cited: 15 October 2018]. Available from:
IPEC Europe The IPEC Excipient Stability Program Guide The International Pharmaceutical Excipients Council, 2010; [Cited: 18 June 2018] Available from: UPLOADS/100311_ IPECStabilityGuide-Final.pdf
Lesney MS. More than just the sugar in the pillToday’s Chemist at Work 2001; 10(1): 30-6 Available from: i01/html/01lesney.html
Pifferi G, Mannucci A. Drug impurities: Problems and regulations. Boll Chim Farm 1999; 138(10): 500-7.

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Article Details

Year: 2019
Published on: 02 July, 2019
Page: [86 - 98]
Pages: 13
DOI: 10.2174/2213476X05666181105123750

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