Control of the opium alkaloid manufacturers

Sections

I. INTERNATIONAL OBLIGATIONS
II. FRENCH REGULATIONS
III. CONTROL
IV. CRITICAL STUDY OF THE CONTROL
CONCLUSION

Details

Author: Charles Vaille, Gabriel Stern
Pages: 14 to 17
Creation Date: 1956/01/01

Control of the opium alkaloid manufacturers

Charles Vaille Mr. Charles Vaille, Chief of the Service central de la Pharmacie of the Ministry of Public Health and Population of France, is the delegate of France to the Commission on Narcotic Drugs; he was chairman of the Commission at its ninth and tenth sessions.
Gabriel Stern
Mr. G. Stern, the co-author of the article, is Chief of the Bureau of Narcotics if the above-mentioned Ministry.

The control over the manufacture of opium alkaloids, their salts and derivatives constitutes one of the essential tasks of the national services which are charged with the application of the international narcotic treaties. This control is one of the most important elements in the prevention of drug addiction, its aim being to prevent the diversion of narcotics into the illicit traffic.

The object of this study is to make a critical examination of the present control organization in France.

I. INTERNATIONAL OBLIGATIONS

The obligations to which the Parties to the various international treaties have subscribed provide for measures to be taken to control the manufacture of opium alkaloids.

These obligations derive from the provisions of Articles 6 and 22 of the Convention signed at Geneva on 19 February 1925, and Articles 16 and 17 of the Limitation Convention signed at Geneva on 13 July 1931.

Article 6 of the 1925 Convention lays down the principle of control over persons manufacturing narcotic drugs, as well as over the buildings in which the drugs are manufactured. It provides for the licensing of manufacture and for limiting manufacture to specified establishments and premises; persons licensed to manufacture must also keep registers in which must be entered the quantities manufactured, imported, exported or otherwise distributed.

Article 22 lists the statistics which the Parties must furnish to the Permanent Central Opium Board. In this way the manufacturing countries have to account for their manufacture by specifying the quantities of raw materials used and the quantities of products manufactured.

The 1931 Convention elaborated these provisions, which were rather general in character.

Article 16 of that Convention imposed on the Parties the obligation to exercise strict supervision over the raw materials and the manufactured drugs in the possession of and produced by the manufacturers.

Article 17 obligated the Parties to require manufacturers to furnish quarterly reports stating, in particular :

- the quantities of the raw materials or of drugs received into the factories;

- the quantities of drugs produced from these substances;

- the quantity of morphine which could be produced from the opium received; this proportion to be determined by a method prescribed by the government of the country concerned under conditions considered satisfactory by that government;

- the quantities of raw materials used and of the products manufactured therefrom.

The indications furnished by the Model Code drafted for the application of the 1925 and 1931 Conventions,1 as also the historic and technical study published on the 1931 Convention, 2 do not contain any supplementary details in this connexion. It could not be otherwise. The spirit of the international conventions relating to narcotic drugs was to lay down principles, to impose obligations of a general character and, as regards the practical obligations of the Parties, to determine their general framework in order that the national administrations could apply them in the form most appropriate for them. Moreover, international administration cannot be a substitute for the national administrations.

II. FRENCH REGULATIONS

These international obligations are covered in France by the provisions of the Decree of 19 November 1948 relating to poisonous substances, Chapter III of which is devoted to narcotic drugs.

This text, which deals with all users of narcotic drugs, includes all obligations relative to internal accounting, stocking, delivery, etc., regulations which lead to the complete accounting control of narcotic drugs from their first appearance until their use by the patient. The present study deals only with the special provisions for the opium alkaloid manufacturers, the aim of which is to assure a special control. Such control is, in effect, provided for by Article 38 of the Decree of 1948 under which, by order of the Minister of Public Health, the manufacturers are required to furnish complete information on their activities.

This order is published each year 3 and consists of two parts :

  1. The first part, in application of the provisions of the Limitation Convention of 1931, specifies the maximum quantities of each controlled product which can be supplied for consumption on the one hand, and kept in stock by the manufacturers on the other hand.

  2. The second part repeats each year the special obligations of the manufacturers which supplement or, if need be, replace the general obligations provided for by the Decree of 19 November 1948.

The administration is careful to inform the interested Parties of the date of publication of the order in the Journal officiel so that there can be no excuse for any of the provisions not to be respected.

1

League of Nations Document No. C.774-M. 365-1932 XI.

2

League of Nations Document No. C.191-M. 136-1937 XI.

3

This order also deals with the manufacturers of cocaine, pethidine and the galenical preparations.

The manufacturers must, on the one hand, send in monthly statements of production and, on the other, they must ask for and receive a monthly licence to manufacture, which fixes the quality and the quantity of the drugs they may produce during the month.

These statements must contain details of all the operations carried out during the month. They therefore include the movements of opium (and of the poppy capsules used for the extraction of morphine).

In practice, the following must be entered :

- the quantities which have come into the factory;

- the quantities used in manufacture;

- the quantities which have been disposed of;

- the quantities in stock at the end of the month.

As regards morphine, the following data must be reported :

- the quantities extracted during the month, distinguishing between those emanating from opium and those extracted from poppy capsules;

- the quantities treated for the manufacture of morphine salts and derivatives (methylmorphine, ethylmorphine, etc.);

- the quantities sold;

- the quantities in stock at the end of the month.

As regards the other narcotics, the following must be entered for each:

- the quantities manufactured;

- the quantities sold;

- the quantities in stock at the end of the month.

In regard to sales, a statement must be furnished giving the name of the purchasers and the quantities of each product delivered to them.

The morphine content of the raw materials used must also be entered. This point will be dealt with later.

In practice, these statements are more complicated than described above, as other operations may be involved, such as returns of goods from customers, re-purification of adulterated products, etc.

Account must also be taken of the morphine recovered after conversion (into codeine, dionine, etc.), since such conversions are always incomplete.

The monthly statements must give exact details of all these operations.

Double accounting of these products must be made on the basis of their real weight and also on the basis of the anhydrous base which they contain.

Thus the morphine base which is extracted from the opium and which is finally used for the manufacture of the salts, codeine, etc. as well as all the salts of morphine, are entered as such, the corresponding anhydrous morphine base being shown opposite each figure.

This applies also to commercial codeine base, the salts of codeine converted into anhydrous methylmorphine base, and all other products.

At the beginning of each year, the manufacturers send in their general balance-sheet for the preceding year. This balance sheet again indicates in each case the morphine content of the opium used and consequently gives the total quantity of morphine contained in theory in the raw materials processed (the same applies to the poppy capsules).

The quantities used for manufacturing, both for the production of morphine and for its conversion into salts and derivatives, are given at the beginning and at the end of the year.

The quantity of morphine used must be given for each product made from morphine.

The yields from the various operations carried out are calculated on the basis of these data.

The manufacturers are required to furnish all necessary information.

III. CONTROL

Control is twofold. It is carried out on the basis of accounting, and by inspection at the site.

A. Accounting control

The monthly statements are examined upon receipt; they are checked from a purely accounting point of view so as to ensure that no material error has occurred in the internal accounting of the manufacturer.

The rhythm of manufacture and delivery is also followed monthly to make sure that the relevant quantities remain within the estimates.

The yearly balance-sheet of each manufacturer is prepared by the administration, on the basis of the monthly statements, independently of the balance sheet furnished by the manufacturer.

The results obtained by each Party are compared and if there is a difference an explanation is requested.

B. Inspections

The manufacturers are visited by the pharmacy inspector of their district. His role consists of comparing the internal accounting of the factory with the monthly statements and, in a more general manner, of assuring himself that the manufacturer is complying with his obligations.

Apart from this, inspections of a more technical nature are carried out, though less frequently, in the course of which the variations of yield are analysed with the factory technicians.

The security measures taken to prevent theft are checked during these visits.4

Inventories are taken from time to time, without warning, to check the actual products which have been registered as taken into stock.

Administrative contacts between those responsible for the factory and the officials in charge of the control are very frequent.

Any difficult or anomaly of any importance is brought to the attention of the administration, and no consequent decision is taken without its approval.

4

Here is an example of the precautions taken in France in this respect:

The extraction of morphine and the manufacture of narcotic products are carried out in premises isolated from the other factory buildings; and entry to this building is forbidden except to the personnel working there. An employee is located permanently at the entrance to the building, which is closed during the day by a sliding barrier.

When manufacture ceases in the evening, the apparatus containing products in course of conversion or drying is sealed; this applies also to the room in which the finished goods are stored before delivery to the consumers.

The movement of products within the factory is carried out simultaneously by several people and, for example, as regards morphine being converted into codeine, the workman who delivers the morphine to the person controlling the conversion operation waits until the morphine is mixed with the reagents before he leaves the conversion room.

To summarize, everything is done to ensure mutual control by the various people employed in the building.

The manufacturers have understood that nothing must escape the control services, with whom they maintain confidential relations.

IV. CRITICAL STUDY OF THE CONTROL

The difficulties in control are not administrative. The outline of the way in which control is carried out in France has been given only to show that all data needed by the administration to obtain an exact picture may be required of the manufacturer.

But technical factors of the problem arise which show that however severe the control from the administrative angle, there exist elements of uncertainty. The principal of these are as follows:

1. Determination of the morphine content of processed opium

The price of opium depends upon its morphine content. Buyer and seller are therefore obliged to confide to a third person the determination of this content. For many years the English laboratory of Harrison & Self has handled this work.

The results of this laboratory theoretically guarantee the control organs a large measure of certainty.

But a first problem is posed by the taking of the sample for analysis. If what is taken is not representative of the whole of the lot which was purchased, its analysis does not give sufficient indication.

Then comes the analysis itself. Significant variations have at all times been recognized in this respect, according to the nature of the opium and according to the process used. Extreme variations can be important, as they may lead to great differences regarding the determination of the morphine content of the volume of opium processed.

In France, where in principle the Harrison test is taken as the control basis, the manufacturer has himself to carry out tests on each lot of opium processed, by a method of analysis which must follow as closely as possible the actual process of extraction.

For control purposes, therefore, two runs of titrations are made, as well as random analyses carried out by an official laboratory. Experience has shown, however, that this last mentioned practice does not afford certainty.

Discrepancies have been found between the factory titrations and the Harrison titrations, according to the source of the opium.

For the preparation of the annual balance two figures are available; one is the quantity of morphine determined by means of the Harrison test, the other the quantity determined on the basis of the factory test.

The heavier of the two is taken.

But what yield can one expect from the extraction? In France there are only two factories producing opium alkaloids; they use different processes and one has always had higher yields than the other.

The explanation is evident, and is a technical one, the processing of the one being better than that of the other. During a number of years, a yield of about 95% was obtained as the average for the extraction of morphine base (computed as anhydrous base).

This yield is reduced by the manufacture of salts and by the manufacture of the total opium extracts, which are computed in morphine as they contain more than 20% morphine, and the manufacture of which is rather delicate.

Since a number of years the manufacturers have progressively increased their yield, an average degree of 97% having been reached.

But if there is a variation of from 1 to 2%, what can be done? Such differences are commonplace in industry. On the other hand, on what basis is an industrial yield to be determined? It is obvious that it is not possible to draw an absolute parallel between the laboratory analysis and the analysis of an industrial factory.

The fact that the variations observed in France show an improvement in the yield is extremely reassuring. But even if this were not the case, unfavourable conclusions could still not be drawn.

This, however, makes for an element of uncertainty for which as yet there is no technical solution, in spite of the goodwill of the manufacturers who, as well as the administration, are interested in determining their yield accurately, even if only from an economic point of view.

It was in this spirit that recently a manufacturer completely renovated his equipment in an attempt to improve his yields. His process had resulted in an accumulation of grounds and tar, which were separately put back into production, but the morphine content of which became lower due to the delay in their processing.

The first results are encouraging because the yields obtained in 1955 by this factory were the highest yet reached.

2. Conversion of the morphine

In this paper, the conversions of morphine base into salts, which represent, in France at least, only very small quantities, will be omitted, as also the manufacture of little-used narcotic drugs.

The main part of the problem is the manufacture of methylmorphine, ethylmorphine and their salts, which absorb 96% of the morphine produced.

The methylation and ethylation of morphine are delicate operations.

Here also one comes across variations of yield between the two manufacturers, and even at one and the same factory from one year to another.

In France the yield is calculated by comparing the anhydrous morphine base corresponding to the methylmorphine (or ethylmorphine) produced, with the anhydrous morphine base utilized for this manufacture; naturally account must be taken of the amount of products being manufactured at the beginning and at the end of the year.

For methylmorphine (and its salts) the yield is from 92 to 93% and is fairly constant; this is explained by the process used which is technically excellent, and which is pretty well identical for the two manufacturers.

As regards ethylmorphine, so far it has not been possible to use a process for the ethylation of morphine comparable to that used for methylation. The yield is very inferior, the best being 85%, the least manufacturing hitch lowering it to 80%. Thus, in the Algerian factory it was established that water, which contained iron salts, had adverse effects.

Again, no comparison can be made between a methylation or ethylation carried out in a laboratory and the corresponding industrial operation.

3. Natural codeine

It is in connexion with natural codeine that frauds might be practised. The proportion of this codeine in opium is very problematical. In any case, natural codeine is a by-product of the extraction of morphine.

This means that these processes are based on the manufacture of morphine, the manufacturers of which are attempting to increase their yield. This extraction of natural codeine was relatively low in France, and it was not until the last few years that one of the manufacturers was able to devise a process which has practically doubled his yield. It is easy to imagine that such an improvement could have been used for illicit purposes. It would have sufficed to report that the excess of production arose from the conversion of morphine, and the corresponding quantity of morphine could have been made available for all sorts of illicit practices.

Such fraud, possible theoretically, is difficult in practice if the daily account and the monthly statements are strictly checked; it would involve much collusion.

These three points which have been summarily dealt with are the "bĂȘtes noires" of control. They are not a recent discovery, the French administration having always been aware of them.

How was it possible to avoid the dangers implied? The solution was found after the coming into force of the 1925 Convention, by limiting to three the number of manufacturers authorized to extract opium alkaloids for the whole of the French Union.

An economic monopoly was thus given to these three establishments in exchange for an increasing security. The manufacturers, having no interest in losing such a monopoly, could not afford any fraud, however minor.

In 1949, one of the three manufacturers sent the administration statements which did not agree with actual production. Two weeks after this was established his licence was withdrawn. An investigation proved that there was no illicit traffic, and that it was purely through technical incompetence and for fiscal reasons that the fraud was perpetrated.

The decision taken was nevertheless maintained. Conscious of the possibilities of fraud, the French administration could not allow untrue declarations to be made, whatever the reason.

The uncertain elements of control had not been concealed from the manufacturers, who were very well aware of them; they were informed that nothing should be done to affect the legitimate confidence placed in them. This confidence having been put in question, there was only one solution: to withdraw the licence.

The rapidity of the decision (the time needed to convoke the inter-ministerial commission of narcotics charged with giving advice on the delivery or withdrawal of licences) surprised the manufacturers, and they understood perfectly that the establishment of the facts alone was sufficient.

CONCLUSION

The administrative methods of control of the manufacturers who extract opium alkaloids do not give rise to major difficulties.

The manufacturers are obliged to account faithfully for the operations they carry out, to report periodically to the administrative control, and to be ready to demonstrate their yield.

The international conventions impose this control on the Parties; the administration therefore cannot evade its obligations.

This amounts to practising an accounting control, the technical elements, however, being the determining ones.

In this field there are some uncertainties, the three principal being: the determination of the morphine contained in the opium processed, the yields from the conversion of the morphine, and the natural codeine which can be extracted from the opium.

The administration disposes of technical laboratorymethods of control, which constitute, however, an uncertain basis on which to evaluate industrial results.

However complete the control, it must be recognized that confidence has to be placed in the manufacturers and that this confidence must rest on a solid basis. The standing of the licence holders should be unquestioned.

But it is wiser to link this confidence in the manufacturer with the latter's own interests. The French solution, the greatest possible limitation of the number of manufacturers, is a realistic one. This was seen when the occasion offered itself; by the withdrawal of a licence the manufacturers were shown that they need expect no leniency if they did not fully respect their obligations.

The two French manufacturers show full understanding with regard to the moral obligations of the administration, whose role they appreciate. They furnished proof of this by accepting the principle of an international monopoly for opiates, which the French delegation had proposed in order to find a solution to the difficulties encountered in adopting an International Opium Monopoly. They have proved it again by deciding to exchange their manufacturing secrets in order to obtain the best results in all those fields in which one was superior to the other.

This collaboration of the manufacturers with the control organization is the surest guarantee of the confidence which can be placed in them.