QUALITY OF GENERIC ANTITUBERCULOSIS DRUGS IN TCHAD (1995)

The circulation of low quality, badly manufactured and conterfeitied drugs represents a permanant threat to the public health. This phenomena, already denonced, in a first study made by ReMeD (Network for Medecines and Developement)seems to increase during the last years and touch more particulary the developping countries.

Tchad is an enclaved sahelian zone depending on the international market for its provision of pharmaceutical products. In this country, drugs are subject to quite severe conditions in transportation and storing.

Tchad participates in the WHO systhem of certification

This new study, run by ReMeD, has for initial objective to evaluate the impact of transportation conditions and storing on the quality of drugs used in public health formations in the programme of struggle againts tuberculosis in Tchad.

1. Conduct of the study

This study, achieve with the collaboration of local parteners (Ministry of Health of Tchad, local mission of cooperation) and financed by the french Ministery of Cooperation, was realized with the participation of french quality control laboratories, public and private according to the validated methodology of the first study traced in ReMeD’s newpaper n°18.

In Tchad, samples analysis of the same batch of anti-tuberculosis was done using the central stock from one side and other different health peripheries as well, in order to identify the eventuel consequences of the transportation and storing conditions in this country.

In France, the study involved :
* editting of the research protocoles
* contacts with the quality control labs
* reception of the samples and their distribution around different labs
* compilation and analysis of collected data

1.1 Sampling

Studied products are the products the most frequently used in the rational programme against tuberculosis that were stated in the protocole : ethambutol, isoniazide, isoniazide/thiacetazone, pyrazinamide, rifampicine/isoniazide, streptomycine.

Samples were collected so that for each assessement place, a sufficient quantity of around 20-30 tabs, caps, ampls. At the central pharmacy or the public health peripheries, assessement was made on the stock samples.

Assessement sheets contained the following elements :

* n° of assessesment (n° : day/month/place)
nomination and description of the product :
generic name (DCI),
commercial name,
dose and dosage form,
name and adress of the manufacturer,
batch number,
expiry date,
origine of the wrapping (bulk, box, blister...),
quantity in stock

* identification of the organization and the place of assessement :
place and organisation,
transportation conditions (number of transportating, hours, transporting temperature, conservation conditions (air conditionning, ventilation, Temp),
delay periode of the stock in the final storing phase
external aspects (if abnormal),

1.2 Analytical control

* Distribution of the samples in the quality control labs

In this study, samples were volontarily analysed and according to the availability of the personnel in the controling labs. Before being sent to this lab, and as a intention for abjectivity, each sample was transfered from its original packing box to a plastic pack identifed by a code reassuring the anonymity of the manufacturer and the origine of the assessment. In sample analysis, the lab used it’s usual methods.

1.3 Interprétation of results

 * Data treatement
Information held on assessment sheets and analysis results were analyzed using a data base (access) and the programme excel.

 * Results interprétation

 A sample’s dose was considered consistent if :
- Dose was out of + 10% of the content indicated by the manufacturer
- and/or, the identification and the assay didn’t respond to the specifications stated in the pharmacoepia of reference.

 These margines were judged acceptable, due to the particular conditions of the analysis :
- the nature of the excipients is often unknown
- the analysis procedures weren’t done immediatly by the manufacturer to control its products.
- the nature of the active ingreient is not very accurate (salt ident.,etc.) as it concerns generics repacking.

This non-consistent results were regrouped into three classes according tothe types of inconsistences and/or the risk[1]

- class A = under-dose, with or without the presence of degradation products impurities  
- class B = substitution of the active ingredient by another active ingredient or by an inert product.
- class C = manufacturing défaut, absence of mass uniformity, degradation time higher than normal, overdose.

This study, realized with limited financial means reflects the situation in termes of quality of drugs in a geographical area and a given time. Meanwhile, the number of analyzed samples is insufficient to be able to withdraw conclusion of a statistical value.

2. Résults

2.1 Caracteritics of samples - collection      

In Tchad, antituberculosis drugs, analysed, are all generics.
All analysis of the same batch of antituberculosis agents were realized in the same lab, so as to identify the eventual consequences of the transporting conditions and storing in the country.

Assessments were made in april 1995 at differnet levels for each batch :
- central level:  store of N’Djamena (air conditionned room, 25°C)
- peripheries level : stock of the hospital pharmacies of Mao, Bol, Bongor, Am Timam, Mongo, Moundou and Laï

Table 1 : Tchad, transporting conditions and storing of antituberculosis drugs

health center	storing T°	delay of storing	transporting conditions
Mao hospital pharmacy	> 30°C	7 month	300 km, 6h30, T°>40°C
Bol hospital pharmacy	> 30°C	7 month	400 km, 6h30, T°>40°C
Bongor hospital pharmacy	> 30°C	9 month	250 km, 3h, T°>40°C
Am Timam hospital pharmacy	> 30°C	9 month	800 km, 15h, T°>40°C
Mongo hospital pharmacy	> 30°C	2 month	500 km, 7h, T°>40°C
Moundou hospital pharmacy	> 30°C	9 month	500 km, 10h, T°>40°C
Laï hospital pharmacy	> 30°C	9 mounth	300 km, 7h, T°>40°C

2.2 Presentation of results

 Consistency of analyzed samples

For each active ingredient, samples from the same batch were assessed, at both levels, central store and pheripheric (hospital pharmacies of Mao, Bol, Bongor, Am Timam, Mongo, Moundou, Laï)

Table 2 : Tchad, consistency of antituberculosis drugs

ACTIVE INGREDIENT	DOSAGE FORM	CONSISTANCY	INCONSISTENCY class A     class C     class A+C[2]			TOTAL
ETHAMBUTOL	CP	2	1	6		7
ISONIAZIDE	CP	4	2	6		12
ISONIAZIDE/ THIACETAZONE	CP	4	4	3	2	13
PYRAZINAMIDE	CP	1	3			4
RIFAMPICINE/ ISONIAZIDE	CP		2	3	1	6
STREPTOMYCINE	INJ	6				6
TOTAL		15	33			48

class A = under-dose, 
class C = manufacturing défaut

Figure 1 : Tchad, consistency of antituberculosis drugs

Table 3 : Distribution of antituberculosis drugs, those of wich the content of at least one active ingredient is not  corresponding to the defined standards

Nature                                                 quantity of active ingredient

isoniazide 100	50-75%	75-90% 2	90-110%	110-125% 2	125-150%	n of samples 4	n batch 1
isoniazide 300				4		4	1
éthambutol 400	1		2	4		5	2
INH/Thiac 100/50			1	3	2	5	1
INH/Thiac 150/75	2	3	3	2		7	1
INH/Thiac 300/150	1		1			1	1
R/INH 150/100	1	3	4	4		8	2
pyrazinamide 500	1	2				3	?
	6	10	11	19	3	33 samples	9 batchs

For 33 inconsistent samples, 31 samples showed at least an under-dose or an over-dose of their active ingredient. For the rest, 2 samples (ethambutol), the lab detected the presence of impurities (class C- inconsistency) however, consistent in quantity of active ingredient.

These results shows that, in many cases, samples belonging to the same batche could be inconsistent with a content, of active ingredient, either superior or inferior to normal.

Consistency of analyzed samples, according to country of origin of the manufacturer

According to the indications mentioned on the boxes of the analyzed samples, countries of origine where the manufacturing process took place for the antituberculosis agents, where : Germany (18), Malta (8), Ireland (7), France  (7), Belgium (5) and Switzerland (3) and inconsistent samples producers from all the same countries as well.

Consistency of analyzed samples, according to assessment place

In Tchad, transporting conditions from the central store to the peripheric level (up to 15 hours at temperatures higher than 40°C) and a conservation (9 months at temps. Higher than 30°C) are extremes

The following table shows the analysis results for each batche that present at least, one inconsistent sample, at the central level, (air-conditionned store) and the peripheric level as well.

Table4 : Tchad, results analysis des résultats for each lot

Lot  inconsistent	central store (air-conditionned 25°C)	périphéric level (>30°)
ISONIAZIDE 100 mg	1 éch. surdosé	2 éch. sous-dosés, 1 éch.surdosé et 3 éch. conformes
ISONIAZIDE 300 mg	1 éch. surdosé	2 éch. surdosés et 1 éch. conforme
ETHAMBUTOL 400 mg	1 éch. surdosé	1 éch. surdosé et 1 éch. sous-dosé
ETHAMBUTOL 400 mg	1 éch. avec impuretés	1 éch. avec impuretés et 2 éch. surdosés avec impuretés
ISONIAZIDE 100mg / THIACETAZONE 50 mg	1 éch. surdosé	2 éch. surdosés
ISONIAZIDE 150mg / THIACETAZONE 75 mg	1 éch. sous-dosé (thia)	1 éch. conforme, 2 éch. sous-dosés (thia.) et 2 éch. (sous-dosés (thia.) + surdosés (iso.))
RIFAMPICINE 150mg /ISONIAZIDE 100mg	1 éch. surdosé	2 éch. surdosés et 1 éch. sous-dosé
RIFAMPICINE 150mg /ISONIAZIDE 100mg	1 éch. surdosé (rif.) + sous-dosé (iso.)	1 éch. sous-dosé (rif.+iso)
PYRAZINAMIDE 500 mg	1 éch. conforme	1 éch. sous-dosé
TOTAL	9 lots	26 + 9 = 35 samples

2.3 Comments

The results of this study do not permit to concluate the effect of hot climat on the stability of drugs. In fact, with the exception of pyrazinamide 500mg, consistent sample in the central store stock of N’Djamena and under-dose in that of the prefectoral hospital of Mongo (but only one result cannot allow to withdraw any conclusion), the other results of analysis do not permit any interpretation.

Results of this study lead to such questions about the qulity at the manufacturing level of antituberculosis generic, since the results have showed that in the same lot, samples were found to be under-dosed, normal and over-dosed. It seems that the manufacturer responsible for these non-constency doesn’t master the homogenecity of tablets in the one lot. It obviously doesn’t suggest of a volontary under-dosing of tablets, but, more of an imperfect nkills manufacturing process

The presence of impurities was detected in the 4 samples of a lot of Ethambutol

Finally, these was no assessement of a sample without or with a different active ingredient than indicated by the labels.

3. Communication with the manufactures

A fraternal letter was addressed to the director of each manufacturing compagny, informing him about the consistent in results obtained by the products analysis through this study. ReMeD wishes to establish a constructive dialogue relevant explanation.

This mail was sent to 8 european manufacturing compagnies (Germany, Belgique, France, Ireland, Malte, Suisse) for 33 non-consistent samples.

Six answers (mail post, fax, telephone) were obtained, two compagnies did not respond.

After, analysing the feed back :
*    re-made analysis by the compagny, over the same lot, indicating consistent results : 4 answers
*    demands for precision of analysis technical :1 answer
*    the company does not identify the batch number and indicates the possibility of counterfeiting : 1 answer

The presence of impurities was detected in 4 samples out of which, 2 where consistent and 2 over-dosed : all came from the same european manufacturer and from the same batch. This manufacturer informed us that he had stopped the manufacturing of this product.

A manufactury compagny accepted to do a « against-expertise ».

A European compagny, was thought to be the manufacturer of all its products, as its only name was labelled on the conditionning, send to us :
- analysis results realized by its own treatment
- 3 analysis results signed by 3 other companies

It probably suggests of an establishement that manufactures and makes also reconditionnement of generics or simple re-labelling.

Another company, that we also thought was a manufacturer, informed us, that its an importing-exporting company of pharmaceutical products and raw material. In addition, he under-makes, under his name the manufacturing of some products for a manufacturer from the same country. According to him and to the manufacturer, the batch numbers of all the inconsistent samples do not correspond to any of their products. Further deeper investigation could have determined whether there was an illegal copying.

Conclusion

This study did not allow to know the impact of conservation conditions on the quality of drugs. It has, moreover, revealed the presence, in a one batch, consistent and inconsistent samples, a phenomena, probably due to manufacturing processes of generics in the concerned establishements.

A debate concerning methods of analysis used by the quality control lab that were used in this study and that used by the quality control labs of the manufacturer is created. But the chosen methodology for this study does not permit any such conclusion.

Information exchange with the European countries was rich in information of the mode of functioning of producers. Could we estimate that a more systematic return of information of the quality of their products, would permit to encourage the manufacturer to improuve the quality of his products ? What is the impression towards the non-feedback of the two manufacturers towards the attitude of their directors ?

What are the consequences of sub-standard drugs concerning public health issues ?

Coordination, data treatement and editting :

Carinne Bruneton, pharmacist

Acknowlegments

Committee of pile-work :
Edith Ashehoug-Bellamich, pharmacist ReMeD, Phillippe Bouscharain, pharmacist Ministery of Coopération, François Fauran, pharmacist président of ReMeD, Mme Graby, Agency of Médicament Jeanne Maritoux, pharmacist, Dominique Pradeau, pharmacist, quality controle lab of  Pharmacie Centrale des Hôpitaux, Arnaud Trébucq, doctor, UICTMR[3].

People incharge of data collection :
Tchad : Laurent Ngarmadjigaye Ngaradje, pharmacist, direction des établissements sanitaires,  les délégations sanitaires du Ouaddaï et de Kanam, Dr Morin, Jean-Yves Peron, pharmacist,  Ministery of Coopération.

Lab incharge of  analysis collected samples.

Bibliography 

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UICTMR - Union Internationale Contre la Tuberculose et les Maladies Respiratoires.
                                                                                                                                      

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