674 ⟨1066⟩ Physical Environments / General Information USP 36

human factors and ergonomics (3rd ed., pp. 384–427). 53. Womack, JP. Jones, DT. Lean Thinking. Simon &New York: Wiley.) Schuster: New York. 1996.

32. MayoClinic.com. Presbyopia. http://www.mayoclinic. 54. Yerkes, RM. Dodson, JD. 1908. The relation ofcom/health/presbyopia/DS00589/ DSECTION=1 strength of stimulus to rapidity of habit-formation.(Accessed 10/30/2007). Journal of Comparative Neurology and Psychology

33. Megaw, ED. Bellamy, LJ. Illumination at work. 18:459–482.Oborne, DJ. Gruneberg, MM. editor. The PhysicalEnvironment at Work. New York: John Wiley & Sons;1983. p. 109–141.

34. Murdoch, Joseph B. Illumination Engineering FromEdison’s Lamp to the Laser, Second edition, VisionsComm., 1994.

35. Noy, YI. Karwowski, W (eds.). Handbook of Human ⟨1072⟩ DISINFECTANTS ANDFactors in Litigation. 2004. Section 11–6.

36. Oborne, DJ. Gruneberg, MM. The environment and ANTISEPTICSproductivity: An introduction. In: Oborne, DJ.Gruneberg, MM. editor. The Physical Environment atWork. New York: John Wiley & Sons; 1983. p. 1–9.

37. Page, A. ed. 2004. Institute of Medicine: KeepingPatients Safe: Transforming the Work Environment of INTRODUCTIONNurses (2004). The National Academy of Sciences, allrights reserved, 2001. A sound cleaning and sanitization program is needed for38. Pape, TM. Guerra, DM. Muzquiz, M. et al.: Innovative controlled environments used in the manufacture of Phar-approaches to reducing nurses’ distractions during macopeial articles to prevent the microbial contamination ofmedication administration. Journal of Continuing these articles. Sterile drug products may be contaminatedEducation in Nursing 2005; 36(3):108–16; quiz 141–2. via their pharmaceutical ingredients, process water, packag-39. Poulton, EC. A new look at the effects of noise: A ing components, manufacturing environment, processingrejoinder. Psychological Bulletin. 85; 1978. 1068–79. equipment, and manufacturing operators. Current Good40. Poulton, EC. 1979. Composite model for human Manufacturing Practices (cGMPs) emphasize the size, de-performance in continuous noise. Psychological sign, construction, and location of buildings and construc-Review. 86; 361–75. tion materials, and the appropriate material flow to facilitate41. Roth, E. et al 2006, Evolvable work-centered support cleaning, maintenance, and proper operations for the manu-systems for command and control, Ergonomics, 49 facture of drug products. When disinfectants are used in a(7), 688–705 manufacturing environment, care should be taken to pre-42. Rothschild, JM. Keohane, CA. Cook, EF. et al.: A vent the drug product from becoming contaminated withcontrolled trial of smart infusion pumps to improve chemical disinfectants as a result of the inherent toxicity ofmedication safety in critically ill patients. [see the disinfectants. The requirements for aseptic processing in-comment]. clude readily cleanable floors, walls, and ceilings that haveCritical Care Medicine 2005; 33(3):533–40. smooth and nonporous surfaces; particulate, temperature,43. Sanders, MS. McCormick, EJ. Human factors and and humidity controls; and cleaning and disinfecting proce-systems. Human Factors in Engineering and Design. dures to produce and maintain aseptic conditions. TheNew York: McGraw-Hill; 1987. p. 5. cleaning and sanitization program should achieve specified44. Sanders, MS. McCormick, EJ. Illumination. Human cleanliness standards, control microbial contamination ofFactors in Engineering and Design. New York: McGraw- products, and be designed to prevent the chemical contam-Hill; 1987. p. 408. ination of pharmaceutical ingredients, product-contact sur-45. Sanders, MS. McCormick, EJ. Human Factors in faces and/or equipment, packaging materials, and ultimatelyEngineering and Design. New York: McGraw-Hill; the drug products. These principles also apply to nonsterile1993. dosage forms where the microbial contamination is con-46. Simmons, D. Phillips, MS. et al. Error-avoidance trolled by the selection of appropriate pharmaceutical ingre-recommendations for tubing misconnections when dients, utilities, manufacturing environments, sound equip-using luer-tip connectors: a statement by the USP ment cleaning procedures, products especially formulated toSafe Medication Use Expert Committee. The Joint control water activity, inclusion of suitable preservatives, andCommission Journal May 2008; 34(5):293–296. product packaging design.47. Smith, M.J. and Carayon-Sainfort, P. A balance theory In addition to disinfectants, antiseptics are used to decon-of job design for stress reduction. International Journal taminate human skin and exposed tissue and may be usedof Industrial Ergonomics, 1989, vol. 4, pp. 67–79. by personnel prior to entering the manufacturing area.48. Spath, P. 2000. Reducing errors through work system Chemical sterilants may be used to decontaminate surfacesimprovements. In: Spath P, ed. Error Reduction in in manufacturing and sterility testing areas. Furthermore,Healthcare. San Francisco, CA: Jossey Bass. pp. sterilants may be used for the sterilization of Pharmacopeial199–234. articles, and UV irradiation may be used as a surface49. The Center for Health Design. 2003b. Pebble Project: sanitizer.Selected Preliminary Data. http://www.pebbleproject. This general information chapter will discuss the selectionorg/pebble_data.php. of suitable chemical disinfectants and antiseptics; the dem-50. Ulrich, R. Zimring, C. The role of the physical onstration of their bactericidal, fungicidal, and sporicidal ef-environment in the hospital of the 21st Century: A ficacy; the application of disinfectants in the sterile pharma-once-in-a-lifetime opportunity. Concord, CA; 2004 ceutical manufacturing area; and regulation and safetySeptember. considerations. Biofilm formation and its relationship to dis-51. Wakefield, B. Wakefield, D. Uden-Holman, T. Blegen, infectants are outside the scope of this chapter. AdditionalM. 1998. Nurses’ perceptions of why medicationadministration errors occur. MEDSURG Nursing7(1):39–44.

52. Walters, J. 1992. Nurses’ perceptions of reportablemedication errors and factors that contribute to theiroccurrence. Applied Nursing Research 5(2):86–88.

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USP 36 General Information / ⟨1072⟩ Disinfectants and Antiseptics 675

information not covered in the chapter may be obtained Table 2. General Classification of Antiseptics, Disinfectants, andfrom standard texts on disinfectants and antiseptics.1 Sporicidal Agents

Chemical Entity Classification ExampleAldehydes Sporicidal agent 2% GlutaraldehydeDEFINITIONSAlcohols General purpose dis- 70% Isopropyl alcohol,

Antiseptic—An agent that inhibits or destroys microor- infectant, antisep- 70% alcoholganisms on living tissue including skin, oral cavities, and tic, antiviral agentopen wounds. Chlorine and sodi- Sporicidal agent 0.5% Sodium hypo-

Chemical Disinfectant—A chemical agent used on inani- um hypochlorite chloritemate surfaces and objects to destroy infectious fungi, vi- Phenolics General purpose dis- 500 µg per gruses, and bacteria, but not necessarily their spores. infectant Chlorocresol, 500 µgSporicidal and antiviral agents may be considered a special per g chloroxylenolclass of disinfectants. Disinfectants are often categorized as

Ozone Sporicidal agent 8% Gas by weighthigh-level, intermediate-level, and low-level by medically ori-Hydrogen perox- Vapor phase steri- 4 µg per g H2O2 va-ented groups based upon their efficacy against variouside lant, liquid por, 10%–25% solu-microorganisms.

sporicidal agent, tion, 3% solutionCleaning Agent—An agent for the removal from facilityantisepticand equipment surfaces of product residues that may inacti-

Substituted digua- Antiseptic agent 0.5% Chlorhexidinevate sanitizing agents or harbor microorganisms.nides gluconateDecontamination—The removal of microorganisms by

disinfection or sterilization. Peracetic acid Liquid sterilant, va- 0.2% Peracetic acid, 1Disinfectant—A chemical or physical agent that destroys por phase sterilant µg per g peracetic

or removes vegetative forms of harmful microorganisms acidwhen applied to a surface. Ethylene oxide Vapor-phase steri- 600 µg per g Ethylene

Sanitizing Agent—An agent for reducing, on inanimate lant oxidesurfaces, the number of all forms of microbial life including Quaternary am- General purpose dis- Concentration depen-fungi, viruses, and bacteria. monium com- infectant, antiseptic dent on application,

Sporicidal Agent—An agent that destroys bacterial and pounds Benzalkonium chlo-fungal spores when used in sufficient concentration for a ridespecified contact time. It is expected to kill all vegetative β-Propiolactone Sporicidal agent 100 µg per g β-Propi-microorganisms.

olactoneSterilant—An agent that destroys all forms of microbiallife including fungi, viruses, and all forms of bacteria and The effectiveness of a disinfectant depends on its intrinsictheir spores. Sterilants are liquid or vapor-phase agents. biocidal activity, the concentration of the disinfectant, the

Microorganisms differ greatly in their resistance to disin- contact time, the nature of the surface disinfected, the hard-fection agents. The order of resistance of clinically significant ness of water used to dilute the disinfectant, the amount ofmicroorganisms to chemical disinfectants from most to least organic materials present on the surface, and the type andresistant is listed in Table 1. the number of microorganisms present. Under the Federal

Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Envi-Table 1. The Resistance of Some Clinically Important Microor- ronmental Protection Agency (EPA) registers chemical disin-

ganisms to Chemical Disinfectants (Listed in Order of fectants marketed in the United States and requires manu-Decreasing Resistance) facturers to supply product information on the use dilution,

type of microorganisms killed, and the necessary contact Type of time. Certain liquid chemical sterilizers intended for use onMicroorganisms Examples critical or semicritical medical devices are defined and regu-Bacterial spores Bacillus subtilis and Clostridium lated by the U.S. Food and Drug Administration (FDA).

sporogenesMycobacteria Mycobacterium tuberculosis

SELECTION OF AN ANTISEPTIC FOR HANDNonlipid-coated viruses Poliovirus and rhinovirusAND SURGICAL SITE DISINFECTIONFungal spores and vegeta- Trichophyton, Cryptococcus, and

tive molds and yeast Candida spp.Hands and surgical sites are disinfected in a hospital set-Vegetative bacteria Pseudomonas aeruginosa, Staphylococcus

ting to reduce the resident flora and to remove transientaureus, and Salmonella spp.flora (e.g., Streptococcus pyogenes) and methicillin-resistantLipid-coated viruses Herpes simplex virus, hepatitis B virus, S. aureus and P. aeruginosa that have been implicated inand human immunodeficiency virus hospital-associated infection. Use of antiseptics to disinfecthands has been shown to be more effective than soap andwater in reducing the counts of bacteria on the skin; re-peated antiseptic use further reduces these counts. TheseCLASSIFICATION OF DISINFECTANTSprinciples may be applied to clean-room operators in thepharmaceutical industry.Chemical disinfectants are classified by their chemical

Common antiseptics include 4% chlorhexidine, 10%type. This includes aldehydes, alcohols, halogens, peroxides,povidone–iodine, 3% hexachlorophene, 70% isopropyl alco-quaternary ammonium compounds, and phenolic com-hol, and 0.5% chlorhexidine in 95% alcohol.pounds (see Table 2).

1Ascenzi, J.M., Ed. Handbook of Disinfectants and Antiseptics, 5th ed.; MarcelDekker: New York, 1995; Block, S.S., Ed. Disinfection, Sterilization, and Preser- SELECTION OF A DISINFECTANT FOR USE INvation, 5th ed.; Lippincott Williams & Wilkins Publishers: Philadelphia, 2000.Russell, A.D.; Hugo, W.B.; Ayliffe, G.A.J., Eds. Principles and Practices of Disin- A PHARMACEUTICAL MANUFACTURINGfection, Preservation and Sterilization, 3rd ed.; Blackwell Science Inc.: London, ENVIRONMENT1999.

When selecting a disinfectant for use in a pharmaceuticalmanufacturing area, the following points should be consid-ered: the number and types of microorganisms to be con-

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676 ⟨1072⟩ Disinfectants and Antiseptics / General Information USP 36

trolled; the spectrum of activity of commercially available 31 (or by one-third), while phenol with a concentration ex-disinfectants; the claims as a sterilant; the disinfectant or ponent of 6 will have a 36 (or a 729-fold) reduction in disin-sanitizer supported by the EPA registrations; the concentra- fectant activity. Disinfectants with a larger concentration ex-tion, application method, and contact time of the disinfec- ponent or dilution coefficient rapidly lose activity whentant; the nature of the surface material being disinfected diluted. The concentration exponents for some disinfectantsand its compatibility with the disinfectant; the amount of are listed in Table 3.organic compounds on the surface that may inactivate adisinfectant; the possible need to maintain a residual bacte- Table 3. Concentration Exponents of Common Antiseptics, Dis-ricidal activity of the disinfectant on the surface; the corro- infectants, and Sterilantssiveness of the disinfectant to equipment with repeated ap-

Concentrationplication; the safety considerations for operators applying Disinfectant Exponentsthe disinfectant; the compatibility of the disinfectant with

Hydrogen peroxide 0.5cleaning agents and other disinfectants; the planned disin-fectant rotation; and the steps that need to be taken to Sodium hypochlorite 0.5avoid the contamination of pharmaceutical products by a Mercuric chloride 1disinfectant.2 Chlorhexidine 2

Formaldehyde 1THEORETICAL DISCUSSION OF Alcohol 9

Phenol 6DISINFECTANT ACTIVITYQuaternary ammonium compounds 0.8 to 2.5

Plots of the log of the number of microorganisms per mL Aliphatic alcohols 6.0 to 12.7surviving in a disinfectant solution indicate that first-order Phenolic compounds 4 to 9.9kinetics can be applied as a gross approximation to the re-duction in microbial count with respect to time. In practice, Another important consideration may be the pH of thethe plots show a more sigmoid curve with a slower initial disinfectant. Many disinfectants are more active in the ion-reduction in numbers followed by an increasing rate with ized form, while others are more active in the nonionizedrespect to time. form. The degree of ionization will depend on the pKa of

The rate constant, K, for the disinfection process can be the agent and the pH of the disinfection environment. Forcalculated by the formula: example, phenol, with a pKa of 10, will be more effective at

a pH below 7 where it is nonionized. (1/t)(log N0/N)

in which t is the time, in minutes, for the microbial count to MECHANISM OF DISINFECTANT ACTIVITYbe reduced from N0 to N; N0 is the initial number of organ-isms, in cfu per mL; and N is the final number, in cfu per Table 4 lists the sites and modes of action of some repre-mL, of organisms. sentative disinfectants.

As with a first-order chemical reaction, the same concen-tration of disinfectant reduces the number of organisms

Table 4. Mechanism of Disinfectant Activity Againstmore rapidly at elevated temperatures. This can be ex-Microbial Cellspressed as a temperature, T, coefficient per 10° rise in tem-

Target Disinfectantperature, Q10, calculated by the formula:Cell wall Formaldehyde, hypochlorite, and

Time to decontamination at T°/Time to decontamination at glutaraldehydeT Cytoplasmic membrane, ac- Anilides and hexachlorophene

tion on membrane potentialin which T is T° – 10.

Membrane enzymes, action HexachloropheneFurther evidence that a first-order reaction is an inade-on electron-transport chainquate description of disinfection is that the Q10 values for

Action on ATP Chlorhexidine and ethylene oxidechemical and enzyme reactions are 2 to 3, while the com-Action on enzymes with −SH Ethylene oxide, glutaraldehyde, hy-mon disinfectants phenol and alcohol have a Q10 of 4 andgroups drogen peroxide, hypochlorite,45, respectively.

and iodineCritical to the successful employment of disinfectants is anunderstanding of the effect of disinfectant concentration on Action on general membrane Alcohols, chlorhexidine, and quater-microbial reduction. A plot of the log of the time to reduce permeability nary ammonium compoundsthe microbial population in a standard inoculum to zero Cell contents, general coagu- Chlorhexidine, aldehydes, and qua-against the log of the disinfectant concentration is a straight lation ternary ammonium compoundsline with the slope of the line termed the concentration ex- Ribosomes Hydrogen peroxideponent, n. The relationship can be expressed as follows:

Nucleic acids HypochloritesThiol groups Ethylene oxide, glutaraldehyde, hy- n = (log of the kill time at concentration C2) – (log of the

drogen peroxide, and hypochloritekill time at concentration C1)/(log C1 – log C2)Amino groups Ethylene oxide, glutaraldehyde, and

in which C1 and C2 are the higher and lower disinfectant hypochloriteconcentrations, respectively. General oxidation Hypochlorite

The wide differences in concentration exponents, n, havepractical consequences in picking the use dilution of differ-ent disinfectants and in using dilution to neutralize a disin-

MICROBIAL RESISTANCE TO DISINFECTANTSfectant in disinfectant-effectiveness testing and routine mi-crobial monitoring of the manufacturing environment. For

The development of microbial resistance to antibiotics is aexample, mercuric chloride has a concentration exponent ofwell-described phenomenon. The development of microbial1, so a 3-fold dilution will reduce the disinfectant activity byresistance to disinfectants is less likely to occur at significant

2Denny, V.F.; Marsik, F.J. Current Practices in the Use of Disinfectants within levels, as disinfectants are more powerful biocidal agentsthe Pharmaceutical Industry. PDA J. of Pharmaceutical Sci. and Tech., 1997, 51, than antibiotics. In addition, they are normally applied in(6), 227–228.

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USP 36 General Information / ⟨1072⟩ Disinfectants and Antiseptics 677

high concentrations against low populations of microorgan- croorganisms used in laboratory challenge tests than theyisms usually not growing actively, so the selective pressure are against the numbers that are found in clean rooms (seefor the development of resistance is less profound. However, Microbiological Control and Monitoring of Aseptic Processingthe most frequently isolated microorganisms from an envi- Environments ⟨1116⟩); that inocula from the log growthronmental monitoring program may be periodically sub- phase that are typically employed in laboratory tests arejected to use-dilution testing with the agents used in the more resistant, with the exception of spores formed duringdisinfection program to confirm their susceptibility, as there the static phase, than those from a static or dying culture orare real differences among different species in resistance to stressed organisms in the environment; and that microor-the lethal effects of different sanitizers. ganisms may be physically removed during actual disinfec-

tant application in the manufacturing area.Although not all inclusive, typical challenge organisms

DISINFECTANT CHALLENGE TESTING that may be employed are listed in Table 5.

Under FIFRA, the EPA requires companies that registerTable 5. Typical Challenge Organismspublic health antimicrobial pesticide products including dis-

infectants, sanitization agents, sporicidal agents, and steri- AOAC Challenge Typical Environmentallants to ensure the safety and effectiveness of their products Organisms Isolatesbefore they are sold or distributed. Companies registering Bactericide: E. coli, ATCC 11229; Bactericide: M. luteus, S.these products must address the chemical composition of S. aureus, ATCC 6538; epidermidis, Coynebacteriumtheir product, include toxicology data to document that P. aeruginosa, ATCC 15442 jeikeium, P. vesicularistheir product is safe if used as directed on the label, include Fungicide: C. albicans, ATCC 10231 Fungicide: P. chrysogenum,efficacy data to document their claims of effectiveness or 2091; Penicillium chrysogenum, A. brasiliensisagainst specific organisms and to support the directions for ATCC 11709; A. brasiliensis, ATCCuse provided in the labeling, and provide labeling that re- 16404flects the required elements for safe and effective use. While

Sporicide: B. subtilis, ATCC 19659 Sporicide: B. sphaericus, B.these directions provide valuable information, they may notthuringiensisbe helpful in terms of the products’ use as disinfectants in a

manufacturing environment. Because a wide range of different materials of construc-In the United States, the official disinfectant testing meth- tion are used in clean rooms and other controlled areas,

ods are published by AOAC International3 and include the each material needs to be evaluated separately to validatePhenol-Coefficient Test, Use-Dilution Method Test, Hard Sur- the efficacy of a given disinfectant. Table 6 contains a list offace Carrier Method, and Sporicidal Carrier Test. A scientific common materials used in clean room construction.study submitted for EPA review in support of disinfectantregistration must be conducted at a laboratory facility that

Table 6. Typical Surfaces to be Decontaminated by Disinfec-follows the Good Laboratory Practices (GLP) regulations (21tants in a Pharmaceutical Manufacturing Area CFR 58). To demonstrate the efficacy of a disinfectant within

a pharmaceutical manufacturing environment, it may be Material Applicationdeemed necessary to conduct the following tests: (1) use- Stainless steel 304L and 316L Work surfaces, filling equipment,dilution tests (screening disinfectants for their efficacy at va- grades and tanksrious concentrations and contact times against a wide range Glass Windows and vesselsof standard test organisms and environmental isolates); (2)

Plastic, vinyl Curtainssurface challenge tests (using standard test microorganismsPlastic, polycarbonate Insulation coatingand microorganisms that are typical environmental isolates,Lexan (plexiglass) Shieldsapplying disinfectants to surfaces at the selected use con-

centration with a specified contact time, and determining Epoxyl-coated gypsum Walls and ceilingsthe log reduction of the challenge microorganisms); and (3) Fiberglass-reinforced plastic Wall panelinga statistical comparison of the frequency of isolation and Tyvek Equipment wrapsnumbers of microorganisms isolated prior to and after the

Terrazzo tiles Floorsimplementation of a new disinfectant. This is considerednecessary because critical process steps like disinfection ofaseptic processing areas, as required by GMP regulations,need to be validated, and the EPA registration requirements DISINFECTANTS IN A CLEANING ANDdo not address how disinfectants are used in the pharma- SANITIZATION PROGRAMceutical, biotechnological, and medical device industries. Forthe surface challenge tests, the test organisms are enumer- The selection of suitable disinfectants and the verificationated using swabs, surface rinse, or contact plate methods. of their effectiveness in surface challenge testing is critical inNeutralizers that inactivate the disinfectants should be in- the development of a cleaning and sanitization program.cluded in either the diluent or microbiological media used Issues associated with the successful implementation offor microbial enumeration or both. Information on disinfec- such a program are the development of written procedures,tant neutralization may be found in Validation of Microbial staff training, decisions on disinfectant rotation, institutionRecovery from Pharmacopeial Articles ⟨1227⟩. of application methods and contact times, environmentalThe disinfectant efficacy test must have realistic accep- monitoring to demonstrate efficacy, and personnel safety.tance criteria. In practice, sufficient organisms need to be The cGMP 21 CFR 211.67, Equipment Cleaning and Main-inoculated on a 2-inch × 2-inch square of the surface being tenance, details the requirements for written procedures fordecontaminated, i.e., a coupon, to demonstrate at least a 2 cleaning, maintenance, and sanitization of pharmaceutical(for bacterial spores) to 3 (for vegetative bacteria) log reduc- manufacturing equipment. These procedures should addresstion during a predetermined contact time (i.e., 10 minutes the assignment of responsibility, establishment of schedules,over and above the recovery observed with a control disin- details of cleaning operations, protection of clean equip-fectant application). The efficacy of the neutralizers and ment prior to use, inspection for cleanliness immediatelytheir ability to recover inoculated microorganisms from the prior to use, and maintenance of cleaning and sanitizationmaterial should be demonstrated during the use-dilution or records.surface-challenge studies. Points to remember are that disin- Staff involved in disinfection require training in microbi-fectants are less effective against the higher numbers of mi- ology, industry practices for cleaning and sanitization, safe3AOAC International Official Methods of Analysis, 15th, 16th, and 17th edi- handling of concentrated disinfectants, the preparation andtions. Arlington, VA.

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678 ⟨1072⟩ Disinfectants and Antiseptics / General Information USP 36

disposal of disinfectants, and appropriate application meth- assessments of excipients and active drug substances willods. It should be emphasized that the preparation of the differ. Therefore, it is important to note that the guidelinescorrect dilutions is critical because many disinfectant failures presented in this informational chapter apply only to thecan be attributed to use of disinfectant solutions that are safety assessment of excipients, not to the safety assessmenttoo dilute. Typically disinfectants used in aseptic processing of active drug substances.and filling areas are diluted with Sterile Purified Water, and These testing guidelines are informational in nature andare prepared aseptically. Alternately, the disinfectant may be are intended to be used by professionals having a knowl-diluted with Purified Water, and then sterile filtered to elimi- edge of toxicology and associated sciences. It is also in-nate microorganisms that may potentially persist in a disin- tended that the applicable safety test method requirementsfectant. Diluted disinfectants must have an assigned expira- of the receiving regulatory authority would be used in ation dating justified by effectiveness studies. proposal for market entry. For example, if a proposal is to

The rotation of an effective disinfectant with a sporicide is be submitted to the U.S. Food and Drug Administration,encouraged. It is prudent to augment the daily use of a that agency’s safety test requirements would have to bebactericidal disinfectant with weekly (or monthly) use of a met. These guidelines do not provide specific details regard-sporicidal agent. The daily application of sporicidal agents is ing test methodology and data interpretation. Test proce-not generally favored because of their tendency to corrode dures that are generally recognized by experts and by theequipment and because of the potential safety issues with regulatory agencies should be used. Alternatives to the usechronic operator exposure. Other disinfection rotation of living animals are encouraged wherever these alternativeschemes may be supported on the basis of a review of the procedures have been validated for the intended purposehistorical environmental monitoring data. Disinfectants ap- and where it is known that the alternative procedure willplied on potential product contact surfaces are typically re- provide sufficient data upon which to base a safety judg-moved with 70% alcohol wipes. The removal of residual dis- ment. It is recommended that the Guiding Principles on theinfectants should be monitored for effectiveness as a Use of Animals in Toxicology of the Society of Toxicologyprecaution against the possibility of product contamination. (1996) and, in other countries, the appropriate legal and

The greatest safety concerns are in the handling of con- professional codes, be adhered to in the conduct of all testcentrated disinfectants and the mixing of incompatible dis- procedures. All studies must meet the requirements of theinfectants. For example, concentrated sodium hypochlorite appropriate national good laboratory practice guidelines insolutions (at a concentration of more than 5%) are strong effect in the country where the studies are beingoxidants and will decompose on heating, on contact with conducted.acids, and under the influence of light, producing toxic and In cases of extensive human experience based upon foodcorrosive gases including chlorine. In contrast, dilute solu- use, there may be sufficient information to fulfill the require-tions (at a concentration of less than 0.5%) are not consid- ments of the guidelines for orally-ingested excipients only.ered as hazardous. Under no circumstances should disinfec- In addition, there may be animal-based data, which was de-tants of different concentrations be mixed. Material Safety veloped for other purposes, that may be used to fulfill theData Sheets for all the disinfectants used in a manufacturing testing guidelines requirements. If the data requirementsarea should be available to personnel handling these agents. have been met through prior human use experience andAppropriate safety equipment such as face shields, safety pertinent human data have been collected in a scientificallyglasses, gloves, and uniforms must be issued to personnel sound manner, there is no need to provide animal data forhandling the disinfectant preparation, and personnel must those endpoints evaluated by prior clinical experience.be trained in the proper use of this equipment. Safety show- Some dosage routes offer unique toxicological challenges,ers and eye wash stations must be situated in the work area and the guidelines include provisions for these routes (e.g.,where disinfectant solutions are prepared. inhalation). Also, further explanation is provided regarding

numbers of species and other basic information (e.g., twospecies, one rodent and one nonrodent).

The extent of information required to define a set of base-line data, which constitute a toxicological and chemicaldatabase, is dependent upon the intended use of, and dura-tion of, dosing of the candidate excipient material. It is criti-cal that a thorough review of background information be⟨1074⟩ EXCIPIENT BIOLOGICALconducted before embarking on a testing regimen. In addi-tion to literature database reviews, information should beSAFETY EVALUATION GUIDELINESobtained regarding the physical and chemical properties ofthe compound; its manufacturing process (or processes);and product specifications including limits of impurities, po-tential for pharmacological activity, exposure conditions(i.e., dose, duration, frequency of use, dosage formulation,INTRODUCTION and route of administration), and potential user population.Also, base toxicity information covering the topics is funda-This informational chapter presents a scientifically-based mental. Particular attention should be addressed to the ab-approach for the safety assessment of new pharmaceutical sorption/distribution/metabolism/excretion/pharmacokineticsexcipients (i.e., those excipients that have not been previ- (ADME/PK) studies because much of the later decision pro-ously used or permitted for use in a pharmaceutical prepara- cess will be dependent upon these data.tion). The guidelines presented herein provide a protocol for These guidelines provide a mechanism for obtaining setsdeveloping an adequate database upon which to establish of baseline data for all candidate excipient materials. Theconditions for the safe use of a new excipient intended for background information and baseline toxicity informationuse in products administered by various dosage routes. alone may support the use of the candidate excipient either[NOTE—The final section of this chapter, Definition of Terms, in a short half-life product that is not administered in a fre-lists some terms referred to in this chapter.] quency that results in a residual excipient build-up in bodyAn excipient may perform a variety of functionality roles tissue or in a product used only once or twice in a lifetime,in a pharmaceutical product; but, unlike pharmacologically such as a diagnostic agent. Additional tests, listed underactive drug entities, the excipient displays either no pharma- Step 4 of the Safety Assessment Guidelines, are necessary forcological activity or very limited and directed activity. Be- candidate excipient material that is to be used in a mannercause of these differences between excipients and active that will result in short- or intermediate-term repeated expo-drug substances in terms of risk and benefit relationships sure in humans—that is, a pharmaceutical product that willand expected biological activities, the approaches for safety be administered for less than 10 days or for 30 to 90 con-

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