•

----

Pharmacopueia as a pharmaceutical code

for public health authoritieJO

G. H. !IIARI~I-BETTOJ.U Formn Pn.>side111 Europ~au Pharmm:opoPifl Cammis;·,..-.r.

Tlw contro! of drug.~ in dw variou~ countrie,; of the world d'~lwnd­

largely on tl11· e:xistence of regulations estahlishing t11e charactcri."tic~ and ~peciJications of tl1e products to h e controlled and the manner in which ~uclJ contro! i,.. to br t>fl"ected, Tbesc rules acquirC' juridical value \fhen a SJW<~ifìc legislatiH· or normatin~ regulation on thc part of tl1e State e.xists or \\-lwn au agrecment is in forc(' hetween State~ whenen:r these regulations appl~­to se\·eral couutries.

Thi~ concepL l!'yntheticaJiy CXJir!"ssed in moden1 term~. it< alread~: to ht> found in thf' {'arliest documento; of tlw Western world, in which thf' duti1·.~ anrl limits of thl' medicai and pharmaceutical professiou.~ are estaLiislwd for tlu· first tinlf', i. e., iu thf' Constitutions of Melfi (1231) writtf'n undN Frederick Il Holwnstaufen (l). Th1•s(' regulations ar1· n·ry pn•cisf' ldth re~ard tu tlJt> training of physiciaw;. They even gu so far a:, to specify what text.~ the dor.tl)r is required to study and tu hold tlu· Statt' rcsponsihle for supenising his professional qualification. They are less prec.is(' with regard to tht· compulsory rules for preparing drugs, but t'\'en bere tl1ey insist tbat this must be dont' juxta formam coustitutiones, quod omnes confrr:lione.~ sua.~ serundum predìctam fortrnlm Jacient sirte frauàf' (1).

Whether tbe « form » was onc of the Antidotaries or El('(·tuarit>'" in me a t tl1at tim1• in thc Kingdom of tln· Two Sidlies and in Salerno is of nu consequence. Undouhtedly from that timc on - once the pharmaceutical profession had heen defined - there had to be a rule to Le followed by tht• mcmbers ofthis profession in order tu protect thc consumer. i. e. tht> patif'nt, and to ensure effective controJ.

W e must also remt'mh!•r that since Graeco-Roman times there existe1l texts on the preparation of drugs which, a .. Ar~tidotaria, Electuaria, etc., -were passed on to the Middle East and into tl1e Arab world (2). These text.<: listed the methods of preparation of medicine.s and sometimes indica t ed the characteristies of the raw materia! s. especially when they were of a vegetahlf'

OC!glll.

l

l l l

l

:!IAl:UNt-BETTOr..O 255

The need felt in the Western world at the dose of tbe tenth century for a contro! of the preparation - not yet the production - and of the -ale of medicines, transformed the Antidotaria and Electuaria into technical tcxts nf a normative character which were then adopted by varioue ('ities.

The Ricettario Fiorentino, a collection of prescriptions printed in the famons city of Flort'lnce at the request of tbe heads of the University of the Apothecaries had, already in H98, a juridical value, which was later stated in the 1573 edition, whicb also reported tbe order, provision, chapters, datutes and supplements concerning pbysicians and pharmacists.

Here it is stated that in the future medicai compounds, that is lloctor's pn~scriptions, are to be well prepared, clean, durable, free from any fraud or blemish, in accordance with the order and manner established by the Rin·trario Fiorentino (J,,f.).

During the 17th century, compendiums for the preparation of medi­cines - which had assumed the name « pharmacopoeia » and had acquired a national character since ahout 1500 - gained generai recognition. On the tirst page of the text of these compendiums the King's decisione wcre often printed, conferring legai value to the particular pbarmacopoeia and making it compulsory in the preparation of medicines. In this connection we may mention tbe foreword by James Il to the Pharmacopoeia LondiMnsis of 1618: «In the time to come, the manner and form by the said book (Pharma­mpoeia Londinensis) should he generally and solely practised by apothecaries for the common good of our subjects" (5).

The politica! evolution from city-State to national States resulted iu the uni6cation of pharmacopoeias especially in GtJrmany, Belgium and Italy, but this did not change their juridical value, which ali States re­<:ognized either tlirectly or indirectly (6). An examination of these early tcxts, clearly reveals that for at least 800 years the pharmacopoeias bave been normative technical codes. At present, there are ahout 3.') pharmacopo­,.ias for more than 140 countries. This means that some countries use ano­ther country's code as a basis for contro! or else a<lopt the international pharmacopoeia of the World Health Organisation. W e may mention bere that beside the national pharmacopoeias of Great Britain, France, Germany, Jtaly, Belgium, The Netherlands, Hungary, Czccboslovakia, USSR, I.;SA, Japan, Brazil. Venezuela and Argentina, there are codes adopted hy several States, such as the European Pharmacopoeia, the Northern Pharmacopoeia ~tnd the rcccnt East European Common ,\[arket (COMECON) Code. These are legally valid not merely in their owu States but also in1lirectly in many countries that bave adopted them: for example, the t'nitcs States Pharmaco­POJ~ia (USP) adopted (in its Spanish Pdition) in many Latin-American Hrpublics; the British Pharmacopoeia (BP) used in the English-speaking

PllAR-"l.ACliPOEIA~ A'lò!O <)hi.Lln LO~TIWJ. i>t J/Rt o.~

l'ountrii·~ of Afriea. A~<ia

and the }'rench l:ode of Africa.

and ( h~i·ania enforced m

~tartm:: wilh AuHr:dia alltl lJJtha: man> }'reudJ-spl'akin/;: l'uuutrit··

Thus all countries eithu directly or indi.rectly recuJ!uÌzt· a phanuaeopoci<o a." a tedmical standard for drug fJUality. \\e may stiil add·thal iu priYak transactions hctween firm~, the quality of drug-- Ì~< specifil'd in aecordant·• with a pharmacopoeia 011 which tht• partif'~ t'<>Hr.t~rned ho.~ 1 e agrt~et.i.

Uu clo~;er analysis it may ahu Le noted that thes•· code~ are usuall_1 drawn up Ly 'l'echnical Commission"' appointed by tlu· States arul un hehall' of tbc Stal•·· Such il' tht• case, for instane!', in Frauee. Germauy, Ital~··

Bclgium, the 1\etherlauds, SwedeJJ . .-le. lu some ollrer Ctluntries, thl' Com­mission cmerged frolli an unofhcial hut fully-recognizcd institutit>n. a, for instancc in Grcat Brhain, where it was appointed by the Generai Mr­dical Council, and in thl' lìnited Statt•s, where the USP Commission wa~ set up by a privatt• enterprisl'.

I Lave used the past tense in referriug to the:w (;ommissions, becaus•· in recent years th(' Brìtish Commission has heen made official and is now under the jurisdiction of the Ministry of Health, whilt~ iu the United State~ the Commission is now heing integrated intn the Health Education anù Welfarc Department (HE~') and has been transferred to "W1ashington so that it can keep in closc touch with Fcde.ral contro! bodies such as thtl Fo{)(l and Drug Administration. In hoth cases the technical regulations published in the BP and in the VSP had previously enjoyed an indirect de facto recogni­

tiou by the Britisl1 :Ministry of Health and thf" FDA respectively, as wcll as recognition by a number of foreign countries as alrcady mentioned.

In the field of supernational pharmacopoeias, we havf". thf' :!nd edition of the Pharmacopoeia lnternationalis, now bearing tht· titlf' "Speci6cation" for the Quality Contro! of Pha.rmaceutical Preparations ", ami the regional pharmacopoeias.

From the technieal point of view these pharmatopoeias can undouht­edly be consìdered similar to the national codes, although frum the normative point of ·vie\\· they contain some inno\'ations. The lnternational PharmacojH>­eias, as drawn up and published Ly WHO, collect~:> tln· specifications conccrn­ing thc most widely-used medinines and the methods to be used for their contro!. Unlikt' the national codes, these spccifications bave no legai valw· hut are merely recommendation>- addressed tn tht~ variou~ member States. The latter art• free to adopt them eithcr totally or partially by a specili•· law of thell· own or by som•• other rcgulation. In tbc caM~ of partial adoption. the national code~ may include in their own tcxts thc monographs and methods recommended by the lnternational Pharmacopoeia.

Thf' rcgional pharmacopoeia~. iuspired by the need for uniformity in the rcgulations in order to facilitate tlw excbangc of drug~ whithin tlu·

:WARlNI·BETTOLO 257

frame of a unified marked, are the result of the collaboration between techni­cians of the various States concerned. Througb inttirnational treaties and agreements, the specifications are adopted and included among tbe technical regulations established by each of tbe contracting countries.

The European Pharmacopoeia, the Northern Pbarmacopoeia and tbe r:vmpendium .\fedicammtorum (7, 8) are examples in point.

From tbe preceding consideratios it emerges that in all countries the public bealtb authorities want to guarantee the quality of tbe droga, eithe~ by establishing their own specifications or else by adopting the com­p~ndium of regulations best suited to the country's needs. Finally, it may be said that in each State the control of drugs is or can be carried out according to a methodology established by a pharmacopoeia. On the basis of the specifications reported for each suhstance it is possible to verify the quality an d purity of the drugs thus fulfilling the demands of the health authorities for the protection of the consumer. Consequenùy, is quite obvious that any type of drug control by the health authorities is based on the existence of ,pecifications, in other words of a pbarmacopoeia.

At this point I should like to introduce into our survcy two questions which seem to me to be of a great interest: on the one band the establishment of precise limita witb regard to drug control and, on the other, the validity uf the pharmacopoeia as a means of control. The question of drug control is much more complicated tban it appears at first. A medicine is in reality not always a well-<lefined cbemical compound, such as i. e. acetylsalicylic acid, but may also be a biologica! preparation such as a vaccine. In these two cases, control requirements will be quite diffe.rent, not only from the methodological point of view, but alao because of the possihle need, in the case o-f the vaccine, for control not only of the finisbed product, but also during the manufacturing process.

:Moreover, despite the improvement in analytical methods and instru­mental analysis, it may be difficult to discover with certainty and accuracy in many associations of chemical products an error which could bave occurred (luring the manufacturing process. For this .reason, the quality control is necessary during the whole process of manufacture, as evidenced by the WHO rPgulations co-ncerning good manufacturing practices (9).

This, however, is nothing new: if we consider the .regulations of the Venetian Hepublic conceming the preparation of Theriac and Mitridate, we tind that in order to ~arantee that ali requested ingredients be used, the Pntire manufactnring process had to take piace in the presence of the Public )fagistrate and the College of Physicians and Apothecaries (3).

Furthf'rmore, control may be carried out on the raw materia}. during t be manuf8.cturin~ procegs, aud on the finished product in its pharmaceutical form (tablets, \·ials, et~.). In this case we deal with a simple medicine,

251-: PHARMACOPOJ:IA>; ANI> Ql-'A!.ITY CO~TiiOL 111' Df<l'\,~

consisting of a sin!!'k component, hul pharmaceutwal preparation~ maY <'uu­sist also of nuxtun·~- sometimes quitc compii':>.. rcsultiug in compuund drug~. "'ht•u th,-. formulat· uf thetie mixture~ reft•r t o typical eompositiou.~ e~tahh­sht•d by the ~late or h~- other hodies, we- ha ve tht• ~o--calle-(! <dnrmulate-d >> ur ((gal,:uira\ prodnct~»- lustrati. wheu they rcfcr to mixtures pruposed hy imli­vidual product>r.~ an1l authorizcd hy tht~ Statt:>. tht·y an• calleJ specialtit·~­

The lattr-r may t:ven cunsist of a singk compuiielll \\<ltt>u parttcular care i~

required tu pn:pare them, or, when tlwy are prt~l<ented in a particular form In view of its pre"cut structun• as a compcndium of specification~ fnr

ccrtain ~:>uhslances used in the prcparation of mPdicint·~- the pharmacopm·1a can lw most useful for controlling tbc purity ami quali t~- of th•· raw materia!~ and of the mediein1· in its various phannaeruti(·al forms. bring rt"strictl'tl huwt'V!'f to the suhstauccs llll'ntioned in it (Hl).

Tht' seetion of thP pharmacopneia dealing with tiH' so-called galt>n.ieal prot.lucts can be equally useful: il will help asccrtaiu their cmnpositiou in accordanee with the formulac givt"u in tlw text itsclf.

In tht' case of specialtie~ madt· up of mon• tha11 one componenL dtt· technieal rcgulations of the pharmacopoeia can pron· useful - once tlw various ingredients haYe becn separated -- for purposed of identificatiou and assay in mixtures. In this case. of course. it will Le difficult to ascertain thl' impurities of the various raw materials.

As legally valid technieal rules, tbc pharmacopueias an• ohviously iil­rlispensahll' for the contro! of medicines. but al this point wc may well a~;k ourselves if they are adequatt' even for this purpos•·.

I can stati.' at once that this is not the ca~;e, fur they do not includ•· all the actiYe principles on the market: ht>nce substances which are perhaps more dangerous and le~;s well-known can escap1· a rigorous contro!; wherea~ it would be necessary prceisely for the former suhstances to undergo a more thorough contro! than those used in medicai practicr fur some timt', and of which the methods of prcparation and possible adverse reactions in tbc human body are well known.

During this Meeting the probll'ms concerning tbe choicf' of mono­graphs were discussed and tbeir complexity reHaled (1 l). I should like tu point out tbat, at tbc present timc, pharrnacopneias (except for thc sectirm dealing with the so---called gal('nical formulaf') do noi contain any longer prescriptions in.nructin!! the pharmacist on how to preparf' a given medicine. HenCl', strietl~· speakinlo!:- these modf'm publieations art• no longer pharma· copoeias in the ethymological scnsr- of tbc word, that is a collection indi· cating how to preparf' drugs, but they are essentially an analytical code which enahles one to estahlish thP identity and purity only of" a certain numher of suhstances" used in the preparation of medicines. This code, as said hefore, doe~ not merely establish thc charactcristics of compound~.

259

but it also 1lescribes the methods by which they are analyzed. These methods are compulsory in the case of controversia! opinions.

Such a code, which has become mainly a book of standards, is there­fore intended chiefly for the contxolling bodies: these are generally the health authorities, but could also be financial authorities such as custolll8 officers, <"te. Tbe code is also intended for producers, usuaUy the pharmaceutical firms: nowadays, prescriptions are less and less frequently filled in a pharmacy and therefore there is less need to test the raw materiale and the finished proùuct at the pharmacist's level: anyway ìt would now be often impossible t o perform t be necessary tests with the means available in a pharmacy.

'rhe fact that a pharmacopoeia fails to include ali tbe monographs rdating to the products used in tbe pi"t"paration of the authorized drugs is, to my mind, the cause of a serious defi.ciency in the control system.

The system whereby new substances are included and others cancelled rcsults in an unreliable contro!. Tbc cancellation of a product from the list does not mean that its use as a drug is prohibited: it merely meana that it is excluded from the pharmacopoeia. In tbis case, however, the controller is left without up-to-date meana for controlling such products although they continue to be in use.

In order to overcome these difficulties some countries bave adopted the 8o-called rlouble code. When a substance is cancelled from the pbar­macopoeia it is automa.tically registered in a code or formulary, a normative­informative book existing in some countries, such as Great Britain and the United States.

The criteria for the inclusion of new substances in the pharmacopoeia varies considerably in different countries. As a rule, the fact that the rf'gistra­tion Commission authorizes a new drug-that is to say, a new and originai .~uhstance-and that it is lawfully employed in the preparation of ~pecialties, is not sufficient to cnsure its inclusion in the pharmaeopoeia.

Before any suhstance can be registered in the pharmacopoeia, it is usually necessary to wait until it has been unequivocalJy proven to be safe and effective, and until it has gained a certain commerciai suceess.

From this point of view tbe pharmaeopoeia~ whieh is today intende!~ to protect the citizen or patient by ensuring the quality of drugs, protects him merely in the case of those drugs which ha ve already shown to be safe. The pharmacopoeia becomes a kind of Debrett of medicine, based especially "n the trinomial safety-quality-effieaey, while it fails to take iuto t:on­_,;,feration a nnmber of .whstances which can a iso invade the market and for which the controllers bave no easily availahle specifications. _\.t the most, !ht•sf: may be transmitted to the health authorities. From this point of ·vicw, mndern pharmacopneia n~present a very incomplete ami imperfect instru­uwnt for drug control. Data regarding various pharmacopot'ias recorded in

PltAHA-lM:OI'IU:U~ A'il! Qt:ALITY CO'iTRO), Ot IJRI <,~

}'1g. l E-how tlw numlwr nf tlru!!~ cane!"'JleJ aml the numht•r of IWW drug~

addcJ iu reeeut year~.

'fhe period 19-JIJ tu 19;);). in v.hieh tht• g-reat thcrapt~utie rcvolution of the century took piace, is e_,.cJuded horn tlu~ anah·~i~. Thc yeab }9j.l

to 1970 present what v.e ma) cali norma! value~.

,, '" <Qo:

)OOJ

loo·

' '"'Liii '" " 1940

,.

,.,

MONOGRAPHIES

.,., ••ll

•'" ,.,

'" VIii

1965 197~

ITALIA

HOO

''" ~"JiL

Ph Fr VII! IX

1965 1972

FRANCE

1 "' o

i·~_t.Jrl11 8"\Ph ~(,J>!, V; USPo XVI XVII

1963 1972 1970

GREAT BRITAIN SUISSE

1960 1965 197G

UNITED STATES

Fig. L • Drug• cancelled and new dru~" added in t h{' Pharmacopoeia in r~CI'Ill yeoro in SOllll' conntrie,.

Ohviously, the numLer of cancellations is compensated by the numhl"r of new drugs included, although in ali nationat pharmacoporias wc invariahly find, side by side with thc more receut discoverie~ of ><cicnce, a numlwr of items persistently listcd for tradition'~ sake, ""·hich are strungly link,•d

with custom an d thcrapeutical practicc. To compensate. for the lack of suitahlr means for cnntrolling substan·

ces cancelled from the list, there is an interesting rcgulation in France which treats the variou~ editions of tlw " Cod<'x " as parl of a sìngle corpus under the titlt' "Pharmacopée francaise ". This is an altt',rnate for the Anglo­Sa:xon double-code system of the Pharmaeopocia-}'ormulary.

'lfARlNI•BETrOLO ::!61

If this difficulty can be partly overcome by the means just mentioned which nevertheless bave their disadvantages since they do not uptlate

the specifications with regard to the cancelled suhstances - there stiU re· mains the problem of the inclusion of the substances which are used in thc­rapeutic practice yet do not appear in the pharmacopoeia.

These already numerous substances are suspended in a sort of waiting­list or limbo, until they acquire the right to be included in the pharma­''opueia. At the same time they are used, sold and consumed, 8ubject to a ,•untrol which can be merely relative, both because i t is not related to generai methodologies and because the specifications and methods are known only to some uffices of the health authorities who bave authorized the sale of 1 h e product in question.

Before considering the means for correcting this situation, it will be w..Il to examine the numher of new products which can be authorized, re· gi~tered and then placed on the market every year in the various countries of the world (Fig. 2). In using the term " ncw products" I should like to

,;;i 600~ 601

' 500~

,00

300

200

,00

o 1940 1945 1950 19~ 1960 1965 1970

yeo.rs

Fig. 2. - ~ew dmgs authorized in the world.

point uut that I am refer.ring to new and origina! prnducts, and not merely to ,]jffrrent salts of the same base or of th"' ~amP- acirl, or to those meJici-

.. nes resulting t'rom ~light struetural Yariations of aJr.,ady-known prodncts (*).

("l A ne w drug has Le~n defined a~ a ne w "ingle chemiral entity. l"xr.luding van·ines ,, n d ne w wlts.

PHAR!IfACOI'OEIAS ANJJ QVAUTY CO!>iTJHJI. Ol' llRl t.~

H we consid~r the period following tlw therap ... utical revolution. wc oLserve that tbe numher of thesc suhstance~ i." comparatin·h- smaH cllf•J, vear (TaLk l) (1~. 13, H).

1'-HLI

]ntroduction in the markel of new suL.~taun·~

' ; s,.,,.,.,_ YEAR l ["SA l"!

' (O J<

' l'.,.,' loe<m""~- lhl~ .1"""" l !an d

' ----~------ --,- ----,------- ,----'

1967

l 25 "'

1968 Il 4R

1969 l 9 21 .11! Il> 3:l 8 22

1970 l 16 26 26 21 30 " 33

1971 H 16 3~ 32 2.) 22 2~

1972 Il 20 ,, .3~ 2.) 16 23

1973 19 16 " J:, 21! 2l l~

(') lnciud•d nh ••h•.

Today, then, a pharmacopoeia satisfactory from the controller's point of view ought tu ìncludf' also the specificatiom regarding these new suh· stances. This could be achieved by adopting tbc criteria of thf• "new and non-official drug8 " or of the " extra pharmacopoeias ". In my opinion th" specificatiom regarding a new substance, once it has heen accepted &8 a medicine by a national commission, ought to be inserted, even temporarily, in a pharmacopoeia, iu order to providf" hoth health authoritie.s and contro1lcr with a hasis for control.

These specifications, according to the g1~neral analytical methodologi<'-" of thc existing pharmacopoeia, should be furnished by thc manufacturer to tbc competent authority. Ou the basis of their knowledgt" of productiou cycles, thesc health authoritics may acc!•pt these specifications or modify th('m,

The monograph of the new drug, that could even be printed on loosr s]H·ets of a different co)our, added to thf' pharmacopoeia, should appear simultaneously with the appearance of the product on thf" market. In this manner the problem of new drugs ·would be solved. lt would h(' useless to hury our heads in the sand to a\·oid facing reality. Once such products bave heen authorized, registered and admitted to the market, they should certainly be included in the pharmacopoeia, even if thìs would invoh-e thf' necessity of changing our views about the significance and the philosophy of a pharmacopoeia.

The pharmacopoeia cannot guarantec a product in any way which difi'er, from the guarantee given by the health authoritie~ through regìstration.

_\1_.\RINI•BETTOLO ~63

Loss of time in tlrawing up a complete monograp_h can be avoided by leaving the draft of the proposed monograph to the manufacturer and its rPY·ision to the national health authorities. This monograph can be kr-pt in the pharmacopoeia as long as the product is authorized or up to the time when it is withdrawn for commerciai rcasons from the market. Whcn a product is successful, this simplified syst('m ofupdating the list would facilitate a rapill improvement of methods and specifications for •~ach substancc.

_-\side from " new " substances not inclnded in the pharmacopot•ia, wc must also bear in mind the prohlems connecteù with anotber da~s of products. This class consists of a certain numbf't of substances which, although widdy used in medicine, are not mentioned in the pharmacopoeia for a number of reasons which vary from one country to another depemling on the criteria which dictate the inclusion of snbstances in these lists.

In Italy, for example, the F. U. VIII includcs about 650 active ,..ub­~tances, while surveys by both tbe authorities and private organizations ~how that there are no less than 1500 active substances among the medicincs nn sale in the country witbout counting cxcipients.

There are tbus about 850---900 substances which are not includcd in t be F. U. In my opinion, they should be included: this would not entail any ,pe<'ial recognition of these substances, but it would simply enable hralth authorities to exercise a more effective quality contro!. This case is analoli!,:ous to the preceeding one, as it is a qucstiou of substances which are accepktl and authorized but not deemed worthy of inclusion in the pharmacoporia. These substances include the new drugs, the products canr-ell-ed t'rom the pharrnacopoeia, and those tbat were never considered worthy of inclmion.

Another aspect of ùrug contro! discussed during this meeting conct·ms !be contro! of manufacturing operations (15). Today, pharmacopot'ias n•truire this type nf contro! only in a few cases; for example, the Italian Pharmacopoeia demands contro! during the production of the polio ...-accine. It is .-asily understandable that, especiaHy in the fidd of biologieal products, contro! during manufacture should be extended to a larger number ,,f products; the same should apply to the preparation of some ph.armareutical forms such as vi ales, tablets, etc. l do not consider this to be impossible in a pharmacopoeia of the future, that could include an item specifying, whenever Ht'cessary, how the contro! should be carried out: i. e., whetber on the ra.w ma­lo>rial or before hottling, how many days must dapse after sterilization, f't('.

This, however. would refer only to the products inclutled in the pharrna· ,,,poeia auri tn their pharmact•utical forms as adopted hy the pharmat~opm·ia i tsf'lf; therefore ali proprietary drugs antl ntherA not mrntionf'tl in the pharma­,·nprwia wollld f'hule ~uch .-ontrol.

A:>ìtk from the- practical difhculti<·,o thal t!H· health authoriti'\' would eu<'.ounter ÌJJ controllinp: each Latch of tlw e1wruwu.;: numhcr of indu~trialh product'Ù mediciJJe~. I bcli1•vc tbat iu th(: futur~: a pharmacopot•ia ought tro :r.nakc it comymh;ory - a~; it i~< i11 sonH' ca!><:S al.n,ad~ - tu p1~rform et·rtaiJo absolutely essential assays duriuJ! the manufacturiiiJ:; proce.,;~ "'·hik lca\·m~ it up to the controJier"s discretion tu carr~ out contro},;. whcnen~r be decwcd i t uecessary l accordinç; to tlw. pharmacopot~ia ·., speciiicatiuu,;. h is IJCCt~ssaq . thcrcfol.,, tu concentrate onc.'8 attentiou on thc ~>ystem of quality contruL i. e., ou CQ.ntrul hy the producers them.s!'lvt'é, a,.; pro}JOSI'd by t!w W' HO f,,, tl1e jmprovement of drug qualit~-.

'l'h(• WHO regulatìon!ò may becomf' an integrai part of lu'altll lcgislatioiJ iu Yariou~; countrie:s. The example gi\'en by ltaly in insertiug: the.se regu!a­tìun:s into its pharmacopoeia, sho-w~ how this prohll~m can lw sokt'-d. Ou the othcr hand, the quality contro! system cali aud must be coustanth che-cked hy the health authgritief' regarding: it.s grganization, structurc anrl fuuction~.

Thc duty of reporting on every phasc of prodUI\tiun and on tJw contro!~ p,•rfonned facilitlltes inspection and force.- the prodUt"l~r tu ohserve a strid di~<ciplìnc; abovc ali it dccentralizes contro} and delel(ates it to thc m~­nufactui·er, wbo ma)", however, be suhjected at aH tinw;o; to contro! by th,. authorìties (16).

From this point of vìew it could be usefu), -when dealing with simpk or compound drug~ listed in the pbarmacopoeìa, to a·vail onesdf not merl'ly of tbe genera! regulations for contro!, but also, -where necessary, of thul'>•' SJlt'citic regulati.ons \\·bich should be appropriately ìnclud(',d in pharmacopo(',ia><.

Sonw countries d,_, - and sQmt do not - ìnclud''- in th1~ir pharma<'n· }lOeias a formulary which lists the regulation.s for the pr~·.pa~ation, composition and mctbods of analy!òiS of a certain number of pharmaceutical 1m•paration><.

Som1• countrie:;; (England. USA} followiug the douhk-code system, prt$ent a formul.ary scparately which dot'.s not, however, chang<' the wb~tanC<' nf tlu• questìon, for this, too, is usually a norm as weiL

Whrn tbc control!cr has a furmulary at bis disposal, his work is grcatly facilitatl:'d, because, on the hasis of thc regulations, the proùuct must conform to the prescrihcd composition, and hcnce the analpi~ can be made according W tbe metbods presentcd. Otherwisc a COlllJ'letely new sel'aration nwst h<" envisagt>d with the complications arising from the presenc~~ of surfact•­aetivc substances, exeipicnts, ett~.

This formu1ary is particularly useful when the contro! ha!5 to be carried out in small centers v:h.Ne Jahoratorìeli l:tr~·- poorly equìpp~d, so that tbesc may fo-reset· what equi1)ment and means are neci"ssary hcfor(' tl-1e tests are carried out. Th1• formu!ary should even mention the in~>tances in which the control must be cacried out during tbe manufacturing- proce<.&.

liARlNI•BETTOLO ~65

Obviousiy, the contro) of" formulated medicines" carried out following the formulary, possess also the great advantage of ensuring an easier, more effective and more accurate control.

A detail which often escapes notice but which is quite important, is the adoption of common names or non-proprietary names: this can be effected not only through national commissions and through the WHO, but mainly through the pharmacopoeia.

A unified and compulsory common name inscribed on the !abel of a medicine can be of great help in carrying out contrnls. In the first piace, it prevents misunderstandings. lt also prevents abuses in advertising and npens the way for the distribution of dru.gs for social purposes and on a na­tional scale.

In this connection I must point out once more that ~~ontroJ must ensure that the products distributed through these channels possess the same eharacteristics and properties as the others on the market. This contro! may be confined to essential products distributt>.d for social purposes: bere again, on the hasis of the specifications given in the pharmacopoeias, the cnntrollers must ensure quality and avoid ahove all the introduction of second­class medicines .

..Another important aspect for tbe State cnntroller lies in the generai methodology which is stressed nowadays more and more in tbe pharmar.o· poeias (we bave progressed from the inadequate coverage in the appendices to a cbapter or volume dealing with methods). This is a great advantage hccaase it indicates the type of analytical or biologica) methodology proJJOsed in order to guarantee contro!, and this makes for thorough quality control.

Let ns remember that tbese methods are compulsory for the controllar and also in ali commerciai dealings between manufacturers in ease of dispute. The methods are closely connected with «reference suhstances» and «biolo­gica! standards». The great sensitivity of the latter -- which must he handled in accordance with strict instru.ctions laid down in the pharmacopoe-ia, sometimes as a result of cooperative tcsts - requires that they be entru!lted to special intemational lahoratories (WHO, European Pharmacop•'eia,) nr to laboratories of some countries (L'SP, BP).

The presence in the pharmacopoeia nf rt"gulations w·hich make the •tse of these reference suhstancf'S l'ompulsory leads to a lwtter judgment on the controller's part. The introdm:tinn of these reference .~uhstancP.s ".ndouhtcdly n~presents a r .. markahle step t'orward for the accurate .-:ontrol nf tlrugs. In tbe seetion nn gt"neral methodolngy some pharmacopoeiall lllcntion the r.haracteristics but not the specifications uf the rnost important pharmaceutical forms. Even if the lirnits for the application of t!wse rf'gula-. tions are not vet fJ.Uite dcar -- that is to ,.ay, it is uot dear wh•~ther they

PII\R!I!ACHPOEUS A~Io Ql'AI.II\ (:0:\"THUI. Ol 111!\ lo•

appl.\ onlv tu th\' proJuc~~ mentiuned in the pharmaeupoeia orto allpru­ducts- tlw~- t'Ntainly oflcr hoth tu tlu• controUer and to the- manufactunr 'N~ prer.iw gui<lc)Jm_·~ for determiniug and improviup drug quality.

TLt: cuntroller i~ not merely an analysl. He i~ al~o tht'" one who ntuH enfnrce a scrics of rcgulation~ ~et forth in thf" pharruacOJIOCÌ;t. Thu~ ali pharmacopueia'> JescriLc thc conditium fo1· storaw· the pharmaci~! mu.~t

follow, and souH' eVNl ><pPrify tht· conditiuu~ fu1 distntmtwu: this ty_pt· of information is vita! for the in~p•·ctor~.

I should lile tu mentiou in a generai way thf' reAu..lations conccming poisons aud narcotic~. In many Jcgislatiom the~e are tu be found in laws not included in the pharmacopoeia itself. Perhaps dtu- to the fact tbat they are more directh- Jerived from Renaissanet~ and Medieval tradition, other pharmaCOJJoe,ias - f. i. thc ltalian onc - include in Tahles (IV, V, IX) a genuine legislative text regulating th~· distrihution of drugs, their daily dosage, etc.

Similar statements also appear in tlw " Anlagt' " of tht~ D. A. B. and in the Austrian Pharmacopoein ( Venena, Separamla). The controUer should certainly not ncglect this aspei"t; he ha« hefore him not merely a series of tt•ehnical regulations, hut a Sf'"t of juridical norm" re,garding drugs.

In a world in -which scicilCf'" and technology are evolving rapidly, tlu· pharmacopoeias present UJI tono-w a static clJaracter, not only hecause tlu-ir content is ~;<till tÌI•<l tu a millenary traùitiou, hut also Lecause of tht• dif­ficulties im·oh·ed in a rapid renewal.

Nowadays a pharmacOJJOeia must hf'" con~tantly and <JUickly revised if it is to h1~ useful to thr controlkr. OthcrwÌ~;<e hl' will h<' forced to turn to

other text~ to find out ho-w to test new drugs: tvday severa! years usually elapse hetwceu the appearancf' of a ncw drug on the market and thc inclusio11 of it.s monograph in a pharmacopocia, if it BJlpear~ thert• at ali.

I do not intend to suggest mcans to achieve these aims, hut it shouhl Le possihle to print monograpbs on loose and rencwaLle sheet.s, eacb one ratified by a normativc measure wbich would ensure its validity. Rcvisions should not only apply to tlw speeifications of suhstances, but also to the metbod~< which wc kno\\· are suhject to continuous and rapid changes. :Moreover, tbc collectinn of data on tapes and thf' use of computers would speed up the proces~ of revision ami updating even v.itb rcgard to printing.

The pbarmacopoeia commissions should actually be permancnt aml Le entru.sted '\\-;th tbe task of evaluating thc authorization of «new» drugs, which an• not very numerow_. eacl1 year througbout the world.

These eommissions should not interfere with tbose for thc registratiou of specialtie~<. Such commissious should examine the specialties consisting not only of associations of chemical product.s hut also of pharmaceutical

~1.\IIINI•BETTOLO 267

forms of simple compounds whose specifications for 1fUality must bave ber n already examined by the pharmacopoeia which will bave assessed, acceptell and authorized the basic product.

At the present time the pharmacopoeia commissious are more con­cerned with establishing method.s for testing the purity of a product and its ~pecifications than with choosing new products to be inchuled in the text. In my opinion, for a national pharmacopoeia thl're ~honld be uo problems: once a new product has been authorized, it should be included with its specifications i,n the pharmacopoeia. As for regional pharmacopoeias used in severa! countries of a group, it would suffice to include in them those products approved in eacb country, whicb are subject to intl'ruational trade within the group. The modem pharmacopoeia shonld not be a list of choice drugs, but of the authorized "·idely-used medicines on the market: the contro! would thns gradually improve, hecoming en·r more -~pet'dy and dficient for the protection of public hralth.

Summary. - In every country drug control 1lepends on the rxistf'ncf' of technical norms which are generally represented by the Pharmacupof'Ìa.

In effects, since the beginning of XIII century, when the profession of pharmacist was for the first tirne established hy law, pharmacopoeias have had not only the purpose of supplying the composition and the prt"para­tion of drugs, but also to establish and enforce the quality of the dn1gs.

In the present times the pharmacopol"ias adopted throughout the worlrl by the different countries are intended mainly as a codex of specifications fnr the contro} of drug quality.

These pharmacopoeias are national, regiunal and international. Nevertheless severa! difficulties can be found in the use of the pharmaco­

pof'ias for contro! of drugs, owing to the fact that not all the drugs, allowed and in therapeutical use are included in pharmacopoeias, and also because. in some cases, the final contro! is not ,:;ufficient to r-stablish drug qualìty especially in the case of biological prepar;~.tions.

The existence of a Formulary or "Codex ", heyond pharmacopoeia, may be of help for the contro! authorities but generally is not ~ufficient.

Some suggestions are made in urder to envisage a modern pharmacopot>ia, considered as a dynamic collection of specifications of tlrug quality, always np to date, ami thus in cnndition to fulfil its taiSk for the need of the drug cnntrol by the health authorities in the aim of a better protrction of public hralth.

Résumé (La pharmacopée comme cmiex pharmacrutique desliné 1mx

•mtoriris .~1mitaires).- Dans chaque pays le contrOie Jes médicamcnts dépcnd de l'existence de ri>g:lf'ments techni1IUPS qui ><ont habituellf'meut represrntr.s par la pharmacopée,

l'llARMA(UPOF.IA~ Al'o"I> QUAL/Il f:U_~THUL IJI IJlll<•'

:Eu e/l't't Ì! traver~ 1(·;. l'<ièd,·.~ - di:·~ le di'Lut du l.T'"". lor~qw· la pr". fe~~ion d t Jlharmacicn fUt snumist" pour la Jlrl~mi(~rt· foi~ au rÌ~f!lt·uu·nl tlt· l11 [oi --!t·~ JlLarnHil'OJit'C~ n'eurellt pa~ seuiemeut lt• but de d~critl' et df' rqwrtn la eornpositiou f't la préparatiou u,-~ m~dicaruent,.;, UlUI~ aUSSI celui di' IÌ:'I.I'/

l'l dt• fain· respcetl'r leur qualitl-. A pre~euL h·s pharruaCOJiét~~> aduptl·e~ par les di\·er~ pay.~ dau~ toutn

!es partie~ du rnondr, ont pour lmt prir1r:iJ1al cdui d'u~it coum~t· coch-:'1. d•·­SJ•i-ciiicatwns pour Il: contrOlt· de la qualit1~ d1·~ médiearnents. Ct•!-; plutflrtit· CUJlècs ont uut· Yalidité nationaft", réf!ÌOIJak et aussi intenJationaJ, ..

1\éaurnoin~. pfusieures diH,cult,~b st· pri'scntent dau~ l'emplui dt~-~ pl1ar· ma~opé•·~ pour !t- contròlr des médicanH~nts, puisque pa~ tous cc~ dnuier~. don t I'usagr t'SI 11armi à hut thérapeutiqu;·, sout inclus d an~ Ics pharrnacoJu-;t".~:

et aus~i parce que eu certain~ ca.s, le contrOif' fina! n· est pM sullisant pour déterminer la qualitt~ du médit:ament, surtout lorsqu'i.J s'agit de preJiaf•~~-­

hiologiqu'~~-

L'existeuct> d'un formulairl' ou « Codt~x » outre it la pbarmacOJlée, peut étrt• utile aux autorités de contròlc, mai-" il n'est généralenJent pas suffisant.

Quelques const~ils ont été foumis pour crét>r une pharmacop;~e moderflf', conçut" commr une collection dynamiqut' de spécificatious rep;ardant la qualitt: des médicaments, qui soit toujours ajournée, et qui puisse remplir sa tadlt•. c'est-a-din~ qu'elle puisse satisfaire Ics nécéssités des autorités sanitain·~ à fin de réalisf'r uu contrOie des médicaments capablr d'assurer une protectinu efficact' à la sant~ publique.

REFERENCES

(l) Comtitutione~ regni utriu~que Sicilia{', Cod. Pal. (J\"QJ'O!i, l7l:l6). (2) DIIV.ol.:>i"G, G. Bull. JT'. H. 0., 4, 577 (1951). (3) M,UI''i'I-Bl:TTOLO, G. B. Farm(«:o, Ed. Sri., 21. 3 (1966). (4-) M.oi.HINI-BETTOLO, G. B. Rass. Amm. Sanilii. 10. 3 (I'i65).

(5) MAIIINI--BETTOLO, G. B. Pharm . .T., 53~ (1966).

(6) VoLCJ~;Jil"i'GER, J. E,.)/ution el unificatian desform•dMir.• ~ drs ph<~rmaropù. l'ari~ (l9;i3). (i) M-l.RI:>i"I-BETTOLO, G. B. Pr'-'fac~, f:.Urop~an Ph<lrmacopoPiu. Yol. I. Mai,onn<>un.

S11ìntr ltuffinf' (l\169). (Il) MAIUNI-Bl:TTOLO, G. B. Le btl8i !lorirhe della Farm!lrop~a Europ~<~. Cult•llo. Ul. 3 (1970). (9) W. H. 0.: Quality contro! of dru~s, Officia! rt•cord" n. 176 (1969).

(JO) MARINI-BETTULO. G. B. C .. /wru r Scuoi<~. 38. 239 (1971).

(II) LAUNNE, J. The~e Procr!'dings p. 23.1. (12) \\'AIIDEL!, W. M. Clin. Pharmacol. Ther. 14. 77.l (197:!). (13) DE IIAE!'I, P. Ctìn. Phar>rnt~ol. Ther., 16, 4B (1974).

(14) REI~-AIISDT, E. & n. Er.VERS, New pharmtueutùrhe /rir.•tofl~ 1!161-197(1. Phflrnt(J­diaWg Il, Frankfurt a/Maiu.

(15) MAIIINI-BETTOLO, G. B. La Calidad integrai de lo., Ml'dicamrlllo•. 1° SimJ'· '\a{', de Controlores dt> Droga• y Mrdir.amP.nlos. Bu~no• Aiu~ (19~11).

(H>) MARINI BETTOLO, G. B. Cron. Farm. 13, 226, (l9i0).

Pharmacopoeia as quality codex for the manufacturers

A. SOLDI PrP_sidenl of Pharnux, lta/y

[n 1917 Spahl.ing. chairman of the United States Pharmacopoeia tom•

mìssion, said that " The Pharmacopoeia has the aim to identify among ~"veral compounds developing a therapeutical action the one the usefulness of which has been fully assessed and best interpreted ". Such a definition, which appeared so clear 160 years ago, seems nowadays f"mpirical and open to criticism. In 1952 the World Health Organization identified the pharmaco­poeia as ''a pbarmaceuti~al codex aiming to ensure a uniformity in the origin, •Juality, composition and activity of drugs in a given politica! environment". The latter statement implies the concept of a quality codex which has ac•(Uired a prominent importance in modem pharmaceutical industry.

The lntemational Pharmacopoeia, published in 1955 under the auspices uf the World Health Organization, had its name changed in its 1967 second ('dition - the full title is now "Specifications for the Quality Contro! of the Pbarmaceutical Preparations ". Such a cbange emphasizes the growing importance acquired in modero pharmacopoeias by rules and regulations, t ba t is by the section devoted to methods of chemical, biological and techno­logical contro! previously found in "Appendices ",

In the first pharmacopoeia published after the Second WorJd War -- U. S. P. XIII issued in 1947- the analytical sectiou eovered 355 pages out of a total of 957. This puhlication remained a prototype and laid the ground for the most important pharmacopoeias compiled later in the Wf's­

tern world. _\nothcr basic difference between the ohi pharmacopot>ias puhlished

from the 15th century up to the end of the 19th- that is hefore the heginning ,.f the industriai era for olrugs - and the 20th century pharmacopoeias is represented hy a decreasing numher of' preparations and hy an increasing numher nf monographs on ..;hemically iilentified compounds and immuno­~enic drugs. However difficult it may he to break a tradition, we must adrnowlcdge that the pharmaceutical industry has an eY~r greater impact un the text of pharmacopoeias, while the rht>mists' proft-ssinnal wnrk is not ''"Y more the main critcrion in drawing up monographs.

PIU.H,UUIPOl.l\' A 'Il> fJl AJJn Clt:\THOI IH !Jitl ,,-

llr. JacJ... Lotl}ll'l. a wdi·-J...uowr1 H'tt'ntist frolli tl11· ~ehool of Plturwan (>f tlw l'niyer~ÌtY of Califuruia, ha~ ren•ntl~ ~uruwaràt·d tlw fiiUer•·JH'•· hl'l wt·eu muderH du~a!!<" an d desigu an d traditional furnwlativn by statÌu\' t ha t i t Ìò' neer>ssar~- « t o LrcaJ... awa" deci~i' ('!~- from tlw re.-;idu•· uf an o\·c;­

ca~ual attitud<· toward~ pharmact•utÌe<ll furmulatiull antl prm·t·so.ing J).

HoweYcr. som'-· preparation~ or «galenica!;.» an• includcd iu uwdt·n, pharmaeopo••ia~ 1\en•rthclt·-'-" th, trcuù j,. w kt>f'J> such monol!raph~ in a sin~k yo]umt• called Ftnmulary. This i~ trut· for the 1-'reneh. ~w i~~- ltaliaJo antl Hungarian Pharruacopoeia~. whilt' otlH:r publication1>, such as tht· C.:-. l\atumal Formulary. ha,·e not lH't'll compi led following thc galenica! approad1 Asi(J.. frorn tht· critrria leadiu~ to tht• selection of drugs tu be ìncluded i1, mtii!Op:raphs. toda~· we bave tu outlint· two faccts of modcru pharmacopoeia­that are c\osdy relatrd tu the pharmaePutical irtdustry (we shall di~reg-ard tlH' legai functiuu of sueh a codex):

l) coding nf ofiìcial method"' of drup:s' contro\ (whether it is includ('(\ IJl tiH" monograph or not):

2) quality specification;. t ha t mu"'t lw considcreù a~ minimum standard• for pharmaceutical ust> of somt• simp!t· or compound drugs t"itiH'r dt'M'riLl•d or identified in each monograph.

1f \\"C consider the fact that the most important drug~. that i;; tht· dru)!~ widr>ly used in therapy, are ht'Ìilf! circulated throughout tlw world ami an· ofteu manufactured hy companies o_perating in variou~ countrit'.~ at tiH' same time, ìt would be be~t if ali pharmacopoeias adopted a i"tandard trxt a~ developt'd according a supranational cooperation. In this respect, tht· Europran Pharmacopoeia rcpresents the most authoritatÌ\1' t'xample: Wt· must also acknuwledgl:' that tbe lnternational Pharmacopoeia was nnt only tht' first hut also a sort of a guiddinc for nt'wly indept'ndeut countrie~.

Regarding the selection of 700---800 acti,-e and auxiliary compounds out of a total of ajtproximately 2.000 ust·d a t present in therapy and induded iu tlw most authoritative pharmacopoeias, thf' pharmaceutical industry must remember that such comJIOunds are wcntioned in consideration of th•· fact that tht'" efficacy" to "safetr" relationship may be acct'ptable a t the indicated average doses and that the indicated "quality " i~ also satisfactory.

Such a distinction bt"tWt•en registered drugs and thc one:. not meutioned in pharmacopoeias has a valuc only as an implicit official acknowledgrut'nt of thf' validity of thc registt'red drug~< for therapf'utical purposcs, but it caunot be acct:'pted as a discriminahng criteriou for the two categorie:,. Actually, deletions and additions decided by revising comnùttees bave no impact what so ever on the markt'ting of drugs, because production and

distribution ma~· not take into account tbe fin--year period elapsing between

SOLDl 211

two editions of the same pharmacopoeia, Heaith authorities will provide for a control ·without making any distinction between '' official" and "non official » drugs in order to protect public health. In all countries the closest control on new drugs takes piace in connection with registration, quite independently from what the pharmacopoeia prescribes. Drug enforcement procedures are a must for ali drugs, in consideration of possihle side effects and of proper therapeutical indications; this implies that measures are taken to prevent any abuse, bearing in mind « safety » independently from « effi· cacy ». As regards « quality », the pbarmacopoeia plays a role in setting rules for drug and dosage fonns production in order to ensure an acceptable (1uality level.

In drawing a few conclusions from our preliminary remarks, we should say that at present the pharmacopoeia is important for the pharmaceutical industry for the following reasons:

l) a standard is set for offi.cial methods of control concernìng the products used in the preparation of drugs;

2) technological specifications are set for different pharmaceutical dosage forms, medication materials, sutures, containers and other industriai products;

3) generai rules, tables, reagents, reference standards and biological units' lista are given;

4) prescriptions are given as to specific immunogenic products and animai or vegetai extracts having a different composition according to the

preparation method;

5) models are given for the statistica! analysis of tests and biologìcal assays and suhsequent evaluation of the standard error;

6) quality speci6cations are set in each monograph for each product, so that the phannacopoeia and relevant edition may be mentioned in the label;

7) national or international non proprietary names are gìven.

The reasons mentioned above comply with the need for obtaining a satisfactory quality leve! and a uniform pharmaceutical production~ hut there is no ~onnection with the criteria leading to the :.election of rlru~ for n·gistration. The importance of all rules and regulations set by a pharma­copoeia derives from the fact that they may be enforced by la w, are officially adopted as technical ruii'IS by national health authorities and may even Le included in conventions signed by a number of countries.

Changes in control methods, updating of quality ~pecitications and the introduction of new products (lcmand a constant revi!lion of modero pharmacopoeias. Thcrl."forc it is advisable to provide thc ,-nlumes with

2., ,.

removahle sht:et~ tu avoid correction>' foUowing the publication of sup­

plemeot1'.. Each and aH chan~es should ht• decidt~d upon by revi~<iun com­mìttee~ on the advice of a group of experts from the rdevant industry. so

that the specificatium; adopted wìU be compatible with current manufacturing

procedures, Production on a large scali· is hased upon spccific pharmaceutit~<ll en~ineerin~ practit~es, developed following a lung experiencc with pil()t phmt',

that i~ wh~- thcre j, 1111 room for many chan~s. F.ach and ali national and multinational comJ•anie~ n•ay positively make eonstructive contributions

to tht' wor.k of governmentctl experts as regard~ pharwacopoeia.':!, as too many currectious publìshed withiu a very short timt• will han a negative efi"ect upon the presti~t> of tbe wholf' official code"-.

Asidt> from tht> Jcgitimate satisfaction of a company when an originai

drug de\'eloped by its own investigators is mentioned in tbe most important pharmacopoeias, tlwrc is no otlu•,r sounrl reason for any company to ask

for such a mentiou.

A drug is included iu a munograpb onl:--· aftcr regislration; any dcletion may imply a negative jud11:meut: tht• selectiun of a similar compound may

be tht> cause of considerations that tbe committee is not hound to explain. Should the. traditiou for selection bt> hrokeu, the ncw trcnds couldu't ht•

hut two: ali or none. Given such an alternative, tbc industry might choose the second patl1 as regards organic synthetic products.

In this case a t least 6 out of th(' i good reasons mentioned beforc would remain valid: ouly the sixth would hf'come superfl.uous; pharmacopot~ao

would not be an:r longer the sourct~ of discussion and would stili play tht>ir main roh· as teclmical codiccs. On tbt~ other band, should ali drugs heing

tradcd be mentioned, pbarmacopoeias woulrl partially hecomc therapcutical repertories as tbc ancient Antidotarium. Tbc text should he divided into

two parts or scctions: one of them, that is the o:ffieial list of drug~;;, should he distributed to ali physicians and bf' frequently updated. That would

imply an enormous editoria! work that could not be possihly performed without the cooperation of tbc pbarmaceutical industry, \\·hicl1 plays already

an active role in the prcparation of non official rcpertorie;;. widely distrihutetl

to doctors and pharmacists.

Following the recommendatious of tlw XXII Geueral Assembly of th1•

World Health Organization. the text "Good Practices in tbc Manufacturing and Quality Contro! of DrugE » was included in tbc 1971 Supplement to the

2nd edition ofthf" International Pharmacopoeia (Specifications for the Quality

Control of Pharmaceutical Preparations), ln 1972, in the first volume of tbc

SOLDI 273

eighth edition of the Italian Official Pharmacopoeia, such rnles appeared before the chapter « Prescrizioni e metodi generali » (Prescriptiona and Generai Methods).

Other countrìes, such as the United Kingdom, published official guides of" Good Practiees in the ManufacturiDg of Droga" as an aid for i.napectors and a stimulus for manufaeturers to adopt the same rnles. In September 1971 in Geneva the "International Federation of Pharmaceutical Manu• facturers' As~:~ociatìon" (I. F. P. M. A.) organized the first symposium on good Juanufacturing practices in the pharmaceutical industry, and received a number of authoritative contrihutions from many countries.

The Acta of the symposium represent a basic document in this field. ProbleJllfl invohed in good manufacturing practices bave been discussed for more than ten years by experts of the phlll'maceutical industry hefore the practices were accepted as standards by Health Authorities. In this respect we bave to ack.nowJedge the objective high-leve) contributions brought by technical experts of the most important pharmaceutical com pani es in the Western world as a clear evidence of their constant commitment to the improvement of quality,

Zero defects in modern manufacturing procedures is a target that shaH not be reaehed only by complying with a pharmacopoeia.s' oflicial specifica­tions. The technical character.istics of pharmaceutical preparations ready for use may comply with prescribed tests, hut an optimum quality level in mass production may be obtained ouly by meana of an organization able to check all operationa step by step throughout the manufacturing process: the quality thUB hecomea; an in-feature of eaeh and aU dosage form units as weU aa an out-property as specified by the pharmacopoeia. V ariations in "essential quality •• are much larger than those in "formai quality ".

The latter depends upon formulation, while the former is a coneequence of a comprehensive built-in contro! of the manufacturing process; such a concept has already been accepted by all drug manufacturera. Therefore it is clear that a modero pharmacopoeia should include rules as to " Good ruanufacturing practices » together with specific quality tests on bulk drugs, ancillary substances, intermediates, containers, etc.

The manufacturer must set up controls so as to ensure the highest possible quality of each unìt of the final prodoct in compliance with the .~tandards set to match official specifications. Heahh Authorities carry out a contro! as indicated by the official pharmacopoeia and by national J .. gislation in order to ascertain compliance witb the law.

Such a suhdivision of internai <'ontrols to be performcd by the manu­facturer to obtain the approvai of Health Authorities performing an inspection has heen customary t'or a long time in other ìndustries such as food, and ··osmetics. However drug mauufacturing is most strictly hound by precise

2~-1 PliARliACUI'OUA~ ANI> QliAI.ITY CO!'"l'ROL OF DRU;~

rule!< dur- to the simultaneous enforttmcnt of sanitary law~, pltarmacopm:ia rules and good manufacturing prac~ice~; such a discipline i~ justified ~~~

tlu· necd to proter.t puLlic health. Hol'.·ever. the cost iuvolwd iu fulfillw:.:: wch quality spccifications shall nnt bt· àisrel!.'ardeà. as full--scale produeti .. n of evt•ry pharmaceutical dosagt• form requires the cooperatiou of ~killt<<l

pr•opl(' and sophisticated equipmcut in a suitablt· environmnll. The cinse :relatiorlship brtwcell qualit,_, potency, stahility aud hit>­

a,·aiiahility of a drug is a wcll-kuown concepl. The co~t and àifhculti•· .• inherent in the adoption of such principle~ in industriai productiou are uot a~ ohYious lo tbc mind of many legislators. Today, appli('d research is h1•iu~ carried out to ohtain pl•armaccutical qualit~- as wdl as therapeutic im· provement; tl1e differenct> lies in the fact that the result of tlu· re.'òearch fur a ncw products is an investment for which any risk i~; directly ahsorh('d b~ sales, whiJc thc r('search in view of imJ•roviug quality ìs uot visihJ,.. A classic example is given by rcscarcL on microhial contaunination of ora! mflàicines not required to Le sterile, based upon requirement.-;, of severa/ pharmacopoeia~ for sterility tesH.

Acceptablt• guality lr•t·el and conteni uniformity

In Aprii 1971 the European Free Trade Association organizcd in Gene\·a a seminar on "Safety aspects im·olved in the packaging and Jahelling of pharmaceutical products •·. ~'hilf' discussing thf' various aspccts of thi~ suhject, an Italian investigator, Ivo Sctnikar, outlined tbe problem of "n,,_ liahility in samplìng and contro! procedures " from the point of view of th<-' pharmaceutical industry. lu Decembf't, 1973 in this lnstitute Prof. Cingu· lani took up tbc suhjf'ct again during a meeting focused on th.., influenct< of pharmacopoeias on pharmaceutical research and drug manufacturinp:. Many other authoritath-e statements in this fìeld could he mention('d to emphasize the important role of pharmaco}•oeia~ in setting a quality len~I that may be acce}Jted by health authorities anà ensured by the pharma· ceutical industry, b('aring in mind tl1a1 content uniformity of cach dosag-1• form uni t is a basic requirement for ~~ach drug. If we start with tbc assumptiou that therc are no two quality leve!" in pharmaceutical production. and that a good manufacturing proce~s should theoretically lt>ad to zero defect.;;, thl' tcchnological specifications set by pharmacopoeia.s should hf' interpreted as the minimum acccptable lnel for therapeutical use assuming a content uniformity for the wholc production. In order to achie,-e this aim, rnl('~ for good manufacturing practicl'S ar<" oln-iously useful: it is also clear, howevf'r. that such rules must be eorrectly applied in large COIUJ>anie;;. Actually. preliminary studit~s Ilerformcd tu tlraw up tlw text adupted by thc WHO

SOLDI 275

were based on the results obtained by supranational companies experimenting several models of sequential controls in dilf'erent procedures of pilot and fu]J scale production.

Health Authorities perform controls on small samplea of products already on the market and cannot make any discrimination based on company size; they must decide whether the sample complies with the standarde: or may be accepted, and in their own ju.dgment will set acceptahle deviation limita in relation to the size of the sample availahle.

It is clear that a 5 % difFerencfl on l 00 units bas no t the same meaning as on 20 unita. It is also obvious that sampling takes piace by picking up packages on sale to the public, that may differ 38 to properties and unita content even if they contain the same active principle.

Such properties bave heen stated in the application for registration, and may not be changed without previous authorization by tbe bealtb autbo­rities. Therefore, quality contro! is closely dependent upon the prototYPe, tbe properties of which bave beeo set by means of cxperiments on smaU pilot lots and not on full-scale production. Should the prototype bave a defect being shown when processing large lots, quality contro! should be bound to look for the properties of the registered product or for Pharmaco· poeia standards although an error is manifest.

This is not the proper piace for di.scussing details concerning sampling; the subject has already been dealt with in symposia and in literature. Lct us simply point out that from the statistica! point of view sampling is mfficif'ntly random.ized but the size ofthe sample depends upon limite already mf'.ntioned and is not tnùy significant for the whole lot.

G-iven such conditioWI. a sample with zero defects obviously does not ensure the unifonnity of the whole lot.

However, it is also obvious that a statistically valid sampling may be made only by investigating hundreds of thousands of piece8 a8 a function of the f:lize of the production.

This is de6nitely impossible if sampling implies destruction (which is the ruJe for aU drugs to be teste-d); the industry could not aft'ord such costs anyway. A further remark should be made in this connection: good storage is a basic factor for drug quality. Not only must pack.aging fit the purpose, but conditions prescribed must be complied by distributors 38 well.

The pharmaceutical industry may not issue -any guarantee regarding good preservation of the product if it bas no direct contro! over it. The ·.rholesaler and the pharmacist8 are the responsible one-8, hut whenever ~pecialties are involved the manufacturer is alway8 calle-d upon. Experiments will allow to set an expiration date; that adds to the difficulty in malcing a judgment on uniformity as it depends on whether the sample has bee-n taken at the beginning or at the end of the drug's validity time. Should any

..... ~-

271> l'll!oRMACOPOUA~ A!'>(J (,Il: ALl'n t:O'òTROL Of DRI 1.~

claim be madt" on tht· result~ of an anal~·tical contro!, ont> should k~"ep i11

mind that hcalth autboritif'~ test the ~<ampie with official ml.'thod,. If tlH­druJ? bcing tei<ted i~ rnentioned iu tlu· pharmacopoeia. a procedure ami ~ standard art> already sct.

Tht~ pharmaceutical indu!;try considers tbc quality lew~l sd hy tlw

pharmacopoeia a~ the minimum acccptable leve! for mak.ing a iud~mcnt

on unìformity lor the wholt· lot as hast~d upon tbe analysis of tbe samplt>. However, there i8 no rulc regardin~ the size of thc lot. Conscquently. if the manufacturer is perfectly satisfied with tbt· quality be has achievcù. be will manufacturt largc lots; otherwist-. hf' will produce only small lot~

to limit the damages resulting from a recai!. Tbis is a calculated risk in term~ of economie damage. Should costs appear far too high to ensure uniformity within statit<tically acceptablt• limits, a minimum standard on small lot~

shall be the prefcrred risk from the managerial point of vie"'. Ifa company adopts such a policy, it may be placed on tbc blacklist

by bealth authorities; which means tbat samples may br. taken more frequently and that there shall be no more possihilities for calculating tb.­risk t o be run.

Tbe only solution is to raise tbe acceptablt> quality level by means of controls during manufacturing operations in order to eu t error8 to a minimum and to dispose of all foreseable causes of defects. A maximum safety level requires an efficient quality control service in tbe plant so that suitablt• standards may h~ set for each product. Only largc companies can afford to undertake such a policy, which would be difficult and costly for m.-dium­sized industries, and practically impossible fora smalllaboratory.

Pharmacopoeias prescribe procedures for official tests 011 the assumption that therc is a content uniformity for each dosage form. Wc bave already seen that it ìs diflìcult to comply with such a requirement; besides, it is qur­stionablr that such a point may be assessed by collecting small sample~.

The problem becomes even more complicated in the ca~.- of technological tests on pharmaceuticaJ forms. Let us take the eAamplt' of tablets that art~ submitted to a disintegration test: each and ali d.-tails of tht• test ar(· clearly established and a standardized equipment is used. Results are valid and may hP compared for medium-size tablet8 containing cla~~ic vehicle». In literature it has heen widely reported that " anomalous " tablct~ -- that is thosc that are either too »mali or too big, or thtl ones prepared with special procedurcs such as multilayer tablet.- - do not yield acceptahle rcsuhs with such a test. The continuous changes in modero pharmaceutical technology is not any more compatihle with pharmacopoeia prescriptions that are up­dated only every five years, There is a growing number of spt'cial prepara­tions, w bile pharmacopoeias prescriLt' indications for « uormal » pharma­ceutical forms with parameters tested ten yt>ar8 earlier.

SOLDI 27_7

New techniques such as film and compression coating, micro­incapsulation, fluid energy milling and other improvementa are clU'I'ently applied in full-scale proceS&ing of pharmaceutieals. Tbe quaUty level of ~ucb preparatiolllf, tbat a.re often similar to clasllical one11 at least from tbe outside, is more precisely assessed by tbe manufacturer than by tbe inspector.

ConsequentJy, i( tbe pharmacopoeia is a tecbnical codex, it mnst be rapidly adjusted according to any tecbnological progreu; otherwise it rull8

the risk. of setting standarda for a piston--engine and of ignoring a jet! It is clear tbat caution is a virtue; however, technological research eitber suggests new pbannaceutical fol'DUI tbat may be applied even to traditional druge as described in pharmacopoeias, or it cbanges tbe composition while leaving the outer aspect uncbanged.

Conclu!JiOn3

[o order to draw a conclusion from previous remarb while bearing in mind tbat a pbarmacopoeia is a quality codex for ntanufacturers, I would suggest tbe following topics for discussion:

l) A phannacopoeia is useful as a ~et of quality rules provided it is updated at sbort iotervals. A volume witb removable sbeets appears to be tbe best solution to avoid supplements and " Errata corrige";

2) An accurate selection of drugs and compounds to be included may be useful, hut tbe most important point for the manufacturer is to bave a set of standard official methods for quality contro!;

3) The pharmaceutical industry sball cooperate very closely from the technical point of view with revision committees, shall submit reports and organize meetinga of experts;

t) Good ruanufacturing practice rules constitute an essential con• tributino for improving drug quality: they must, bowever, be applied in loto. Tberefore, we wish tbey would become compulsory and be included in official pharmacopoeias;

.3) Basic properties of pharmaceutical forma are bio-availability and stability. A modt:'rn pharmacopoeia should .~uggest experimental models t o assess tbese two quality parameters in a uniform manner;

6) The ussessment of eompliance witb legai requireruents by means .,f samples analysis has limits that affect its ~tatistical validity. In practice this method eannot be easily replaced. However, parallel inspections ~hould be made in plants in order to check the rruality levels ensurerl by the rnanufacturer with bis own means;

I'HARMACOI'OEIAS Al'> D ()l·Ai.IT~ CO'iTfiOL Or Dflt (;,

7) In order to identif~· the minimum qualit~- lt·n·l fur tlrug~ iu ali countries, contro! methods should hecome a~ much as possibk intt~rnationa!

standards. Modf'rn pharmacopoeias should no lonp:l'r bt> only uational codict·-:

8) Quality standard~ prescribeù by pharmacopoeia~ slutlk lt·arl~

set guidelines for mauufacturen;. Preparations madc L~ a pharmacio-t ma~ not be controlled with tbc samt• mcthod a" the industriai one~. Tht• onh possihlt> way tu ohtain at. acceptahlt· quahty lt>vd ìu li!alenicab o1· I!I'IH'rir produr.tion is to set standard;; in special formularicb:

9) Pharmaceutical specialtie.- may not be rt~placed iu nwd_ecn tlwrap: but quality features shall not be acceptcd if thf'y do not comJl]~· with tlw minimum leve! set hy pharmacopoeia~:

lO) Modem pharmacopocia is much more than a quality codex ami less and lessa codex of drugs composition. Thcreforl', thf' rolr of pharmaco­poeias is to set rules for manufactun~rs an d inspcctors for the df'ft·nse of th•· consumer.

·we bave met bere to discuss tht:> possibilities to match th!.' aucient traditions of pharmacOJloeias with the requireruents of modcru m!.'ÙÌcinc. There may hl' sPveral methods to reach sucb a tarp;et. But we CC'rtainly agree on a basic concept: quality must be as hip;h as possihlt> because it i~ closely related to two essential propcrties for a drug. safety anù efficaC'y.

Summary. ~ Three are the hasic ff'aturt~~ of a medicine legally introduet•d on the market: efficacy, safety and quality.

With regarding to drugs listl'd in a national or international pharmaco· poeia, thc ratio hetweeu efficacy and safety. within the range of dosagt· established by th!." codex, must be considered as oflicial by the industry.

As far as quality is conccrned, the pharmacopocia plays a fundamental role in establishing methods of analysis and tecbnical contro! intend!."d a~

official refcrence in case of controversy. Tb!." quality of drugs, pharmaceutical adjuvants or preparations Jistcd

in a modern pharmacnpoeia must be cousidered by the industry as thc mini­mum level of the acceptable standaJ'd for medicai use, to ensure efficacy under proper storage conditions. In fact, the specifications are largely hased upon suggestions made by manufacturers. Pharmaceutical specialties, being registered by Health Autborities following suitable documentation, do not havt'l to be subjected to the standards established by the pharmaco­poçia for new drug.!< or formulation adjuvants. The constant effort of thl:' manufacturers to minimize risks lcads to optimum quality levels, considering that the samples used for contro! by the Health Authorities arr usually picked from commerciai packages containing a small number of units.

SOLDI 279

To ensure statistica! compliance of every sample with official pbar· macopoeial standarda, manufacturen are forced to exercise the highest care in every process of production and packaging.

There cannot possihly be a guarantee that every single unit at the consumer'a disposal will actually comply w:ith the quality Ievel established by a modero pharmacopoeia,

ÙJ•timum quality level in every package of medicai products can be achieved by following the "Good Manufacturing Practice" sponsored hy the WHO; this goal requires skilled people and sophisticated equipment. The practice of quality control aa an easential part of the manufacturing process in a wide range of pharmaceuticals. provides an excellent experience that may be useful to the pharmacopoeial commissiona.

Therefore a closer co-operation between healtb offi.ciala and industry's experts must be considered the beat way to improve the specificationl!. to ~peed-up the revision of monographs and to collect reports on stahility tf'sts.

The part of a modero pharmacopoeia, devoted to tests and standards appean today as the most important for t be pharmaceutical industry because, when a controversy arisea about drugs, tbe offi.cial methods established hy the pharmacopoeia play a fundamental role in the enforcement of law.

Tbe task of compiling each new edition of a modero pharmacopoeia is becoming increaaingly difficult; to speed revision any time a prohlem arisf's, the revision committeea may seek advice from the numerous experts of the pharmaceutical industry thus acbieving a most profitable collaboration.

Reaumé (La pharmacopée comme codex de qualité pour fi11du.~trie phar­maceutiqlte). - Trois sont lea caractéristiquea qui regardent les médicaments legalement introduits dans le marché: l'effi.cacité, la securitP, et la qualité.

Pour ce qui regarde les médicines cataloguéea dans une pharmacopée nationale, la proportion entre l'efficacité et la securité, en dedans dea limitt'>! de dosage étahlis par le codex, doit ètre considerée par l'industrie comme nn aément établi officiellement,

A J'égard de la qualité, la pharmacopée joue un rOie fondamf'ntal t'n t=tahlissant des méthodea d'analyse et de contrale tl':cbnique qui tloi,·f'nt étre considéréa comme référence officielle en cas de rlisputes.

T ..a qualité d es médicaments, dea adjuvants pharmaceutiquef! ou df's pré­parations enrf'gistrées dans une pharmacopée modf'me, doit ètre consitlhP.., par l'industrie pharmaceutique comme le niveau le plua bas des standards acceptahles pour leur emploi medicai et pour t'D assurer l'effi.cacité ~'D (les mnditions appropriées tle magasinage,. En effet ces rf.gles se hastmt large­rnent sur les suggestiona ,les producteltrS. Les spécialités pharmaceutiques ayant été enrcgistrées par ks autorité., sanitaires par ~uite de documt>ntation