Document vyYDK4pZ1oM0oV37w76Mv4R4b

CS-I The C o m i ssi cner Through: The Deputy Cernissicner ________ ' UG i 0 2373 Acting Director Bureau of Drugs Prelini nary Peoort: "Special Survey on Asbestos Particles in Parenteral Drugs" - INTOPPATI ON NE'TPATTTT . PURPOSE In our Information btenorandun to the Ccmissicner dated January 24, 1972, concern was expressed in the potential radical hazards posed by the presence of asbestos particles especially in parenteral drugs. In order to obtain information to assess this potential, a Special Survey was instituted which entailed the inspection (with the collection of approcciate samples) of fourteen parerveerai drug manufacturers. The objective of this study was to determine the extent of use of asbestoscontaining filters and filter aids in the manufacture of drugs, and also to analyze samples for the presence of asbestos particles by appropriate nethodologies, namely, light microscopy and electron microscopy. TEXT OF INFOPJiATIOH The Special Survey Program, dated July 16, 1972 was preoared by theOffice of Compliance in collaboration with the Bureau Project Officer for Asbestos It contained methodologies for botn light and electron nicrosccny to be used by our hew York Laboratory and Bureau of Biologies, ressectively, since they possessed the facilities, capabilities and requisite expertise to carry then out. The field inspection reports of the fourteen firms (Tab A) indicated the following usage of asbestos filters: a . Seven firms do not use asbestos in any form. b. Four firms use asbestos filters but the drugs are final filtered through nenbrane filters. q $ P `D ( o l /VS- Page 2 Tr.e Commissioner One of these firms uses asbestos filters to filter its rinse water without final filtration. c. Two firrs only use asbestos filters for filtering their rinse water but wit-scut final filtration. d. One firm. uses asbestos filters in all its filtrations without final filtration. The proposed methodology for Light ?!icrosccny was modified (Tab B) by our }j. y. Laboratory analyst because of severe problems encountered in the filtration process ana in the preparation of the nerorane filter for observation of the eifferent samples. They were ex-fined at 4CO-5:OX using tomarski-Ir.terfere-nce, Phase Contrast and Polarized Light .`'icroscony. Seventeen sarpies collected in the Survey were subjected to the prcceoure and the results (Tab A) shoved 11 positive for presence of asbestos, 1 ouestionable positive, 1 negative and 4 could not bo satisfactorily corpleted because of preparation problems. . The proposed methodology for Electron Microscopy likewise was rodified (Tab C) bv our Gurcau of Biologies analyst because of problem encountered in preparing and analyzing the sarnies. They were examined by Scanning and Transmission Electron Microscopy following preparation of sfoles either by ashing, filtration or centrifugation using asbestos-free reagents and clean room techniques ; Identification was based on norpholcgy and 1n some cases by electron diffraction. This phase of the analysis presented the extremely difficult problem of quantitation. The use of a ccrouter is presently being utilized to sursnount this difficulty. Since this study is still ongoing, the results can only be stated in qualitative terms. The seventeen samples analyzed (Tab A.) showed 12 positive and 5 have not been satisfactorily completed because of preparation problems. 0. Richard Crout, H.D. Enclosures Tab A - Preliminary Results of Special Survey '. Tab B - Licht Microscopy Tab C - Transmission Electron Microscopy and Scanning Electron Microscopy Prepared by: BD-140, ARCasola, S/9/73, X33418 cc: . -0C=J BD-1 BD-2/MJFinkel BD-100 BD-140/Files 0C-2 BD-140/ARCasola:abc/S/9/73 BO-lCS/JKLanar SI-430/PMcGrath  ! Page 3 The Ccmissicner Preliminary P.esults cf Special Survey - Asbestos Particles in Pare n t e r a l brums (C? 7322.11) Below, in tabular f e m , Is listed the pertinent Information obtiined from field inspections of fourteen firms with regard to the use of asbestos filters, and of analytical results by ligr.t and electron microscopy obtained on tna seventeen samples procured frexn these firms by our inspectors. It cannot be stressed strongly enough that each rug product, when subjected to the analytical procedures, presented its own individual problem(s) of preparation due to its distinctive chemical and pnysical properties and mode cf preparation. Therefore, it nay be necessary to utilize a different and possibly unique procedure, rather than a Standard one, in order to render each sample amenable for analysis. I t should be noted that one firm (flO) was not manufacturing at the tira of inspection. Thus, no samele was.available for the study. Incioently i t was the sole firm, using asbestos filters in production without the use of a final membrane filter. Two samples were obtained fron three firms (i? 1, 2, 3) 1n an attemot to correlate, to some extent, the effect cn the asbestos content by the_ elimination, or reduction, in the use of asbestos filters in production. Ho inattempt has been made this preliminary report to describe the fibers, found by light microscopy, according to size categories. This will be done in the final report. Page 4 The Comal ssloner RESULTS OF SPECIAL SURVEY Firm Use of Asbestos filter Use of Membrane Filter (or Final Filter) Sample Amount L1ght Mcroscopy . 400-600 X Fl bers as chrysotlle and/or amphibole Electron Microscopy Presence of Asbestos Fibers 1 no yes a O ) : 1 ml b(2): 1 ml 3 11 Positive Positive 2 yes yes a(3): 1 ml (only for rinse water) b ^ : 10 ml 8 9 Posltiva Positive 3 yes yos a(5): 1 g. prparation problem preparation problem b ^ : 1 g. 4 yes yes 1000 ml v\ 5 no yes 10 ml 6 no yes 30`ml 7 yes yes (not for a: 500 mg (only for rinse v/ater) rinse water) b: 500 mg 0 yes ($ot for rlnso water) i g. 7 7 prparation problem 0 27 5 Positive Positive preparation problem preparation problem Positive V Positive Page 5 The Commissioner Finn 9 Use of Asbestos filter no RESULTS OF SPECIAL SURVEY COMT'D Use of Membrane Filter (or Final Filter) Sample Amount Light Microscopy . 400-500 X Fibers as chrysotHo and/or amphlbole Electron Microscopy Presence of Asbestos Fibers yes 40 g. . preparation problem preparation problem yes no no sample available - m 11 no yes 1000 ml 1 Positive 12 13 t 14 no yes no yes 5'00 ml yes (not for rinse water) 30 ml ' yes 1 'ml 25 (questionably positive, identity rot assured) 4 1 Positive Positive Positive NOTES: ' (1) drug produced using asbestos filter before 1t was eliminated by firm' h ) same drug produced using only final membrane filter (3) t (4) those are different drugs produced by the firm (5) S (G) same drug; respectively before and after partial elimination of asbestos filters 1n the manufacture ' Page 6 The Ccnn1ss1oner Light liicrcscopy: Using clean room technicoes a given amount of sample, as suspension or solution, is filtered onto a 0.22 micron nillioore filter, 12 -n in diameter, in a S.nr.nex colder using y actor~. It is rir.sc-d with 100 ml. of ultra-clean distilled wafer, followed by a rinse v/ith 5 rl. ultra clean isstjtyi alcor.ol. Allow the filter to dry in holder using vacuum.. Remove the filter and piece it on a glass slide - cover the sample end allow it to dry for 1 hour at 100-150C on a hot plate. Piece the cried filter in a plastic cetri dish fcr storece. To examine, mount the dried filter cn a clean slide witn a 1 to 1 solution of dietryl oxalate and dimethyl phthalats (refractive index 1.455 to 1.470). Cover with a pre cleaned cover glass and examine in the light microscope using phase contrast, polarized light and Homerski interference microscopy. Page 7 The Commissioner Transmission Electron !'.icrcsccov: (A) A given amount of a sa-ole is suspended 1n filtered distilled water (filter pore size 0.22 micron) to aive 40 nl. It is centrifuged at 22,003 rpm for 1 hour in a number 25 rotor c.n a model L 1 Bec>~an centrifuge. The supernatant fluid is poured off and the pellet resus pended. "l'he sample is centrifuged again for 1 hour at 22,000 rrm. The supernatant is poured off ar.d the pellet suspended in 0.1 nl. of filtered ondistilled water. A five nicroliter drop of tois preparation is placed an electron microscope crio cr.d exar.ir.ed at 20,000 mamnificeticn. Asbestos particles are identified by m.orpnology and electron detraction. (B) A given amount of a sample is oushed through a 0.22 nicron membrane filter and rinsed with filtered distilled water, dried and ashed in a low temperature asner. The ash is resuspended in 0.1 n l . of filtered distilled water and dispersed using an ultrasonic generator or placed directly cn the electron microscope grid and examined at 20,000 magnification. Scanning Electron Microscopy: " A agiven amount .of sample 1s pushed through 0.22 nicron membrane filter end rinsed with filtered distilled water. The filter id either coated with Gold-Palladium and examined in the Scanning Microscope, or ashed and the 1nash is examined the Scanning Electron Microscope after being coated with Gold-Palladium. Energy Dispersive X-ray Analysis is done on fibers and a count of Kagnesiim and Silicon peaks is used to determine the presence of asbestos. MEMORANDUM# DEPARTMENT OF H E A L T lJfc D U C A T I ON, AND W ELFARE PUBLIC H ^ p T H SERVICE FO'OD AND D R U G A D M IN IS T R A T IO N TO : DGrr.ouApr,mB$nDd-54Casola - Chairman, A sbestos Work DATE: July 10, 1973 THRU: DPar.thBoelongnye,tt BLoB. E lisb erg , D irector, D iv isio n o f^f^* J f r o m : MDri.v isPiho nilipo fMPcaGtrhaothlo, gDy,irBeocBtor, E lectron Microscopy Branch subject: anidecAtrfotnerMFiiclrtorsactoipoinc EThxraomuignhataionnAosfbeastoSsusFpeilntseiorn Poadf 7RF02 A sbestos Before Od1fl0inaa0emskmgertlauemorsifnosgdft eil7rsaRitblFiilo0zl2reiandatgoswbryaeasstvbteoarecs.sutuofmrTsohmwfiisilttthhseeuraspJpnoehanedngsisaoitnnMivtoaewnaavps irlfteliiesblstuuCerlroae.etdewodaf sthaErpsroupluesrnpgomhexneidmayeead6rtecilnym. 2egof0ilfrelitcdtsrtoasarmote2pina5olcenhminp.icwechrreoeregsscroopidpfreepmanagedrrreicddauslrlfyorw.woemirneCgtahprebri otenpsaatmoarne'pdddlrebyfobyreimnfpovlraaaerccinfcloigolsateatrdead5tpim3oe0tni0rcirmaondeldsiihsteharcf. otepdrFproeivpre - saThnhodewffeidivbeervieglrsry.id gs(Prpirdrienpstqasure#ad1reafrncodomve#rt2he)de aalsmb eossttoscosmupspleetneslyionwibthefoarseb efsitlotsr aftiiboenr s To21fh0ef ifgbirvirdei l sgsq,ruidoansreeps crlweupemarpreedpsuefrrrvoeemyveedrthyea3t 0f i2l0gt,rr0iad0t0esmqsuahaogrwnesifainccoaoutcinoctnaed.si.on(Palrinsmt a#l3l )colvuemrp Fucdosptdsihatuaseferismeeplpmratdweftacrpahoclatcalfcndrietitcefuest.iiyeditrrdorloueetanouTtfcrsethfihttsirnroltteuhyohgnltaaurhfeileobngffliiwruhyilsofollgirrtumhledtcacrthsldteaauetoaeutvmlrtrhnrcliiacey.sppionaetsanebgsfpdobTsootr.orxotoefhhrcesthwwrefetToiedhefhbiedsiauatetlheuvursttrmfoiebecseniseueeelrgbttfsttoheutsteheewooatlrhnedennstaneeyseapawslsomnamtftseardicooaledoodtytutanhdfenetwhteocitmrasmiatfadmhovseoehbeafdinindnseyetsdacas.vtoarndtsrimobubmatcenSeeteevpeoefnt.sidloanmfctiernnore.opgdesttImlhhaiodeerub5iyind0tesehrrnceleeaetalimaeovbulbvlefgusaeieeroi1trdlvds0rktee0wataenhaftbaroomssilerrslya .iJ m J M X* . 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' c. ;j - , ,^ * ` '' i l>Sfe J < ^ ; . hVcL ^ ^ '* a V Z5,i \ ' V . v - 'J V V _<? -\ . * V V, A * *' r1 3' i, X :Wf'i, V .... ^t- ai ItiliiillMfci^litoiiiiMiiAili i n l^ lM iiiitt n .......... , , . , i a 4 ^ 8 ^ ^ '. i k a , . ^ i..||i',i.r | j ^ | | ti(t|)||>)|| <| ^ ^ 1|1-..,-i,i... j Suspension 7FR02 before filtration