sures. The areas of critical concern are the immediate micro-bial environment where these presterilized components areexposed during assembly to produce the finished dosageform and the aseptic filling operation.

The requirements for a properly designed, validated, andmaintained filling or other aseptic processing facility aremainly directed to (1) an air environment that is suitablycontrolled with respect to viable and nonviable particulates,of a proper design to permit effective maintenance of airsupply units, and (2) the provision of trained operating per-sonnel who are adequately equipped and gowned. The de-sired environment may be achieved through the high levelof air filtration technology now available, which contributesto the delivery of air of the requisite microbiological quality.3The facilities include both primary (in the vicinity of the ex-posed article) and secondary (where the aseptic processingis carried out) barrier systems.

For a properly designed aseptic processing facility or asep-tic filling area, consideration should be given to such fea-tures as nonporous and smooth surfaces, including wallsand ceilings that can withstand routine decontamination;gowning rooms with adequate space for personnel and stor-age of sterile garments; adequate separation of preparatoryrooms for personnel from final aseptic processing rooms,with the availability, if necessary, of devices such as airlocksand air showers; proper pressure differentials betweenrooms, the most positive pressure being in the aseptic pro-cessing rooms or areas; the employment of unidirectionalairflow in the immediate vicinity of exposed product orcomponents, and filtered air exposure thereto, with ade-quate air change frequency; appropriate humidity and tem-perature environmental controls; and a documented sani-tization program. Proper training of personnel in hygienicand gowning techniques should be undertaken so that, forexample, gowns, gloves, and other body coverings substan-tially cover exposed skin surfaces.

Certification and validation of the aseptic process and fa-cility are achieved by establishing the efficiency of the filtra-tion systems, by employing microbiological environmentalmonitoring procedures, and by processing of sterile culturemedium as simulated product.

Monitoring of the aseptic facility should include periodicHEPA filter evaluation and testing, as well as routine particu-late and microbiological environmental monitoring. Periodicmedia-fill or process-simulation testing should also be per-formed.

STERILITY TESTING OF LOTS

It should be recognized that the referee sterility test mightnot detect microbial contamination if present in only a smallpercentage of the finished articles in the lot because thespecified number of units to be taken imposes a significantstatistical limitation on the utility of the test results. This in-herent limitation, however, has to be accepted, because

3 Available published standards for such controlled work areas include thefollowing: (1) ISO 14464 1-7 Cleanrooms and Associated Controlled Environ-ments. (2) NASA Standard for Clean Room and Work Stations for MicrobiallyControlled Environment, publication NHB5340.2, Aug. 1967. (3) Contamina-tion Control of Aerospace Facilities, U.S. Air Force, T.O. 00-25-203, 1 Dec.1972, change 1-1, Oct. 1974.

current knowledge offers no nondestructive alternatives forascertaining the microbiological quality of every finished ar-ticle in the lot, and it is not a feasible option to increase thenumber of specimens significantly. For information regard-ing the conduct of the sterility test please see Sterility Tests71.

1216 TABLET FRIABILITYThis general information chapter has been harmonized

with the corresponding texts of the European Pharmacopoeiaand the Japanese Pharmacopoeia. The harmonized texts ofthese three pharmacopeias are therefore interchangeable,and the methods of the European Pharmacopoeia and/or theJapanese Pharmacopoeia may be used for demonstration ofcompliance instead of the present United States Pharmaco-peia general information chapter method. These pharmaco-peias have undertaken not to make any unilateral change tothis harmonized chapter.

This chapter provides guidelines for the friability determi-nation of compressed, uncoated tablets. The test procedurepresented in this chapter is generally applicable to mostcompressed tablets. Measurement of tablet friability supple-ments other physical strength measurements, such as tabletbreaking force.

Use a drum,* with an internal diameter between 283 and291 mm and a depth between 36 and 40 mm, of transpar-ent synthetic polymer with polished internal surfaces, andsubject to minimum static build-up (see figure for a typicalapparatus). One side of the drum is removable. The tabletsare tumbled at each turn of the drum by a curved projectionwith an inside radius between 75.5 and 85.5 mm that ex-tends from the middle of the drum to the outer wall. Theouter diameter of the central ring is between 24.5 and 25.5mm. The drum is attached to the horizontal axis of a devicethat rotates at 25 1 rpm. Thus, at each turn the tablets rollor slide and fall onto the drum wall or onto each other.

* The apparatus meeting these specifications is available from laboratory sup-ply houses such as VanKel Technology Group, 13000 Weston Parkway, Cary,NC 27513, or from Erweka Instruments, Inc., 56 Quirk Road, Milford, CT06460.

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Tablet Friability Apparatus

For tablets with a unit weight equal to or less than 650mg, take a sample of whole tablets corresponding as near aspossible to 6.5 g. For tablets with a unit weight of morethan 650 mg, take a sample of 10 whole tablets. The tabletsshould be carefully dedusted prior to testing. Accuratelyweigh the tablet sample, and place the tablets in the drum.Rotate the drum 100 times, and remove the tablets. Removeany loose dust from the tablets as before, and accuratelyweigh.

Generally, the test is run once. If obviously cracked,cleaved, or broken tablets are present in the tablet sampleafter tumbling, the sample fails the test. If the results are dif-ficult to interpret or if the weight loss is greater than the tar-geted value, the test should be repeated twice and themean of the three tests determined. A maximum meanweight loss from the three samples of not more than 1.0%is considered acceptable for most products.

If tablet size or shape causes irregular tumbling, adjust thedrum base so that the base forms an angle of about 10with the horizontal and the tablets no longer bind togetherwhen lying next to each other, which prevents them fromfalling freely.

Effervescent tablets and chewable tablets may have differ-ent specifications as far as friability is concerned. In the caseof hygroscopic tablets, an appropriate humidity-controlledenvironment is required for testing.

Drums with dual scooping projections, or an apparatuswith more than one drum, for the running of multiple sam-ples at one time, are also permitted.

1217 TABLET BREAKINGFORCE

INTRODUCTION

There are a variety of presentations for tablets as deliverysystems for pharmaceutical agents, such as rapidly disinte-grating, slowly disintegrating, eroding, chewable, and loz-enge. Each of these presentations places a certain demand

on the bonding, structure, and integrity of the compressedmatrix. Tablets must be able to withstand the rigors of han-dling and transportation experienced in the manufacturingplant, in the drug distribution system, and in the field at thehands of the end users (patients/consumers). Manufacturingprocesses such as coating, packaging, and printing can in-volve considerable stresses, which the tablets must be ableto withstand. For these reasons, the mechanical strength oftablets is of considerable importance and is routinely meas-ured. Tablet strength serves both as a criterion by which toguide product development and as a quality control specifi-cation.

One commonly employed test of the ability of tablets towithstand mechanical stresses determines their resistance tochipping and surface abrasion by tumbling them in a rotat-ing cylinder. The percentage weight loss after tumbling isreferred to as the friability of the tablets. Standardized meth-ods and equipment for testing friability have been providedin general chapter Tablet Friability 1216.

Another measure of the mechanical integrity of tablets istheir breaking force, which is the force required to causethem to fail (i.e., break) in a specific plane. The tablets aregenerally placed between two platens, one of which movesto apply sufficient force to the tablet to cause fracture. Forconventional, round (circular cross-section) tablets, loadingoccurs across their diameter (sometimes referred to as dia-metral loading), and fracture occurs in that plane.

The breaking force of tablets is commonly called hardnessin the pharmaceutical literature; however, the use of thisterm is misleading. In material science, the term hardness re-fers to the resistance of a surface to penetration or indenta-tion by a small probe. The term crushing strength is also fre-quently used to describe the resistance of tablets to the ap-plication of a compressive load. Although this term de-scribes the true nature of the test more accurately than doeshardness, it implies that tablets are actually crushed duringthe test, which often is not the case. Moreover, the termstrength in this application can be questioned, because inthe physical sciences that term is often used to describe astress (e.g., tensile strength). Thus, the term breaking force ispreferred and will be used in the present discussion.

TABLET BREAKING FORCEDETERMINATIONS

Early measuring devices were typically hand operated. Forexample, the Monsanto (or Stokes) hardness tester wasbased on compressing tablets between two jaws via a springgauge and screw. In the Pfizer hardness tester, the verticallymounted tablet was squeezed in a device that resembled apair of pliers. In the Strong Cobb hardness tester, the break-ing load was applied through the action of a small hydraulicpump that was first operated manually but was later motor-ized. Problems associated with these devices were related tooperator variability in rates of loading and difficulties inproper setup and calibration. Modern testers employ me-chanical drives, strain gaugebased load cells for forcemeasurements, and electronic signal processing, and there-fore are preferred. However, several important issues mustbe considered when using them for the analytical determi-nation of breaking force; these are discussed below.

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Official from December 1, 2014Copyright (c) 2015 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 10.6.1.10 by ProIndi7 on Thu Jan 15 07:27:11 EST 2015