What are the chemical specifications of cocaine
Quality of Traditional Chinese Medicine Drugs
For some years now, doctors and alternative practitioners have been prescribing traditional Chinese medicine (TCM) drugs and tea mixtures with increasing frequency. Chinese drugs are usually pharmacy-only and are subject to the obligation to test in the pharmacy laboratory, which is regulated in the pharmacy operating regulations (ApBetrO) (1).
The dispensing pharmacy is responsible for the correct pharmaceutical quality of the starting materials. If a test certificate according to § 6 ApBetrO is available, the pharmacy must at least carry out the identity check, otherwise checks for identity, purity and content are required.
The quality of TCM drugs in the countries of origin is also derived from their provenance and the time of harvest (2). Problems with the test arise in particular from the fact that different species, different stem plants and plant parts are used under the same name in different regions of Asia. Toxicologically relevant mix-ups of drugs have recently been pointed out (3). Serious side effects and even deaths after the ingestion of preparations made from TCM drugs have been reported in the literature (4). Mutagenic and carcinogenic ingredients of numerous official Chinese medicinal plants are known (5).
Since the lay press repeatedly reports on the poor quality and contamination of Chinese medicinal drugs, the Central Laboratory of German Pharmacists in Eschborn has carried out a comparative study of Chinese medicinal drugs as a pilot study as part of its statutory tasks. For this purpose, a total of 16 randomly selected Chinese drugs from various suppliers with certificates of analysis were obtained in February 2000.
The investigation was carried out with regard to the following questions:
- Are customary test certificates based on the requirements of the ApBetrO?
- Are the test results valid?
- Are the acceptance criteria of the specification met?
- Do the drugs meet the requirements for pesticide residues and toxic heavy metals?
The results of the ZL investigation were published and discussed in extracts on the occasion of the ZL seminar at the Expopharm Congress 2000 in Cologne (6).
Requirements and acceptance criteria
For all drugs tested there are specifications of the Chinese Pharmacopoeia (7) or the collection of monographs according to Stöger (8). Limit values for pesticide residues are included in the European Pharmacopoeia (Ph. Eur. 1997, 2.8.13). In addition, the Maximum Residue Quantity Ordinance (RHmV) must be observed (9).
The evaluation of heavy metal residues is based on the contaminant recommendation of the Federal Ministry of Health (10); the draft from 1991 has since been regarded by the health authorities as the current state of the art (11). According to this, with the exception of individual drugs such as linseed, St. John's wort or willow bark, the following maximum values, based on the dry weight, are given:
- Lead 5.0 mg / kg
- Cadmium 0.2 mg / kg
- Mercury 0.1 mg / kg
The Federal Ministry of Health, after hearing experts and in agreement with the highest health authorities of the federal states, developed the recommendation for maximum levels of heavy metals in medicinal products of plant and animal origin (10). The determination of these maximum quantities was based on extensive data from several working groups, including the second author of this work from the ZL. The maximum amounts of lead, cadmium and mercury in herbal raw materials, preparations such as tea infusions and extraction factors to be taken into account (transition rates) were determined from a toxicological point of view on the basis of the ADI published by the FAO-WHO (Food and Agriculture Organization-World Health Organization) (12). Values (acceptable daily intake) and PTWI values (provisional tolerable weekly intake) discussed and defined.
Medicines are taken by sick adults and children alike. From a toxicological point of view, the minimization requirement for toxic heavy metal traces applies. Contamination must be avoided, especially with pharmaceuticals, as is generally stipulated today within the framework of harmonized, international guidelines (13). A comparison between a permitted amount of heavy metals in a food (guideline values of the Central Registration and Assessment Agency for Environmental Chemicals, ZEBS, since 1994 the Federal Institute for Consumer Health Protection and Veterinary Medicine) (14) and in a drug taking ADI values into account is not permitted . Medicines are taken by sick people in addition to food with the addition of contaminants.
The examination was carried out according to the test instructions of the monograph collection in German version (8) and the pharmacopoeia (7).
In order to test for pesticide residues, the drugs (see Table 1) and two other samples, which were obtained comparatively directly from China, were based on the official pharmacopoeia method (2.8.13, Ph. Eur. 97) and according to the S19 method of DFG (15) prepared and extracted. The investigation using capillary gas chromatography and EC detector extended to numerous persistent halogenated pesticides such as quintozene, technazene, hexachlorobenzene, hexachlorocyclohexane isomers a, b, d, lindane (g-hexachlorocyclohexane), heptachlor, endosulfane, DDT, DDE and DDD isomers, Dicofol and 1-1-bis (4-chlorophenyl) -2,2,2-trichloroethanol.
Table 1: Samples examineddrugBatch numbersupplierAlismatis RhizomaCh.-B. 9933H040Fa. HerbasinAngelicae dahuricae RadixCh.-B. 022 / 97KK-p0226Fa. SinomedBenincasae SemenCh.-B. 9938B01Fa. HerbasinBuddlejae FlosCh.-B. 9810430Fa. Chin. Medicinal herbs Ecliptae HerbaCh.-B. 007 / 98KKZ-p0328Fa. SinomedEpimedii HerbaCh.-B. 9904E02Fa. HerbasinHaliotidis ConchaCh.-B. 9904H01Fa. HerbasinLonicerae FlosCh.-B. 023 / 99kk-p0133Fa. Sinomed Lycii CortexCh.-B. 9904L02Fa. Herbasin Lysimachiae HerbaCh.-B. 064 / 97KK-p0221Fa. SinomedMori FoliumCh.-B. 04M9749Fa. Herbasin Platycladi SemenCh.-B. 9904B01Fa. HerbasinPoriaCh.-B. 990702H032Fa. HerbasinSchisandrae FructusCh.-B. 9905403Fa. Chin. Medicinal herbsSchizonepetae HerbaCh.-B. 0001H01Fa. Chin. Medicinal Herbs Xanthii FructusCh.-B. 9905403Fa. Chin. Medicinal herbs
The determination of traces of lead and cadmium was carried out by atomic absorption spectrophotometry (AAS) with a graphite tube cuvette and Zeeman background compensation. To prepare the test solutions, the samples were digested in Teflon containers with a mixture of concentrated acids and oxidizing agents under high pressure at 175 ° C. for four hours. The mercury was recorded quantitatively using the hydride method and AAS cold vapor technology.
Results and discussion
With regard to the formal requirements that the pharmacy business regulations place on test certificates, in particular the issuance by inspectors of companies with manufacturing permits according to § 13 Medicinal Products Act (AMG) (16) or by cross-checking experts according to § 65 AMG, the drugs examined and their declaration deviated from the ApBetrO . While the certificates of the Herbasin and Sinomed companies do not contain any information on formal compliance with the requirements according to § 6 ApBetrO, the company Chinese Medicinal Herbs, Bochum, provides the text "according to § 6 and 11 of the regulation on the operation of pharmacies ( ApBetrO) "ahead.
It can be seen from individual certificates that drug deliveries date from 1995 and 1996 (Ecliptae Herba, Lysimachiae Herba). The delivery and testing dates of some drugs were far apart.
Test certificates according to ApBetrO must contain a series of information. All the necessary information is included in the sample certificate shown here as an example.
Sample certificateMarketing Authorization Holder and Manufacturer: Address: Tel./Fax:
according to § 6 and § 11 of the pharmacy operating regulations
Designation: Batch designation: Test specification / test procedure: Test date: Use by: Re-test date:
Test criterion / test procedure Acceptance criterion test result ......................................... .... .......................... ................... "It is certified that the starting material has been tested according to the recognized pharmaceutical rules, all test criteria have been included, and the result corresponds to the specification. A permit according to § 13 AMG has been granted for the company. (The undersigned is a sworn cross-check expert according to § 65 Paragraph 4 AMG at the [regional council]).
Control supervisor / cross-check expert
In general, the following problems should be considered when assessing test certificates:
- Is the signatory authorized to issue the certificate, that is, is he an inspector or a cross-check expert?
- Are the details complete?
- Do the test results deviate from the requirements?
- Were the results transferred from the pre-supplier's bulk goods without a laboratory test of your own?
- Is the product incorrectly declared or filled?
The monographs of TCM drugs contain requirements on morphology and information on wet-chemical, thin-layer chromatographic and microscopic identity tests. Acceptance criteria for foreign constituents, ash and ash insoluble in hydrochloric acid as well as loss on drying are listed under purity tests. The extract content had to be determined for numerous drugs in the ZL examination, and for some drugs content determinations had to be carried out.
All drugs met the specification in the examined test criteria (Table 2). The results recorded in the certificates of analysis were essentially confirmed.
Table 2: Results of the tests according to the monographs of the Chinese Pharmacopoeia1Test criterion /
ProcedureAcceptance criterionTest resultAlismatis Rhizoma Morphology corresponds to identity corresponds to purity normal ache max. 5.0% 2.8% HCl ash max. 0.5% 0.1%Angelicae dahuricae Radix Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal ash: max. 6.0% 3.0% HCl ash: max. 2.0% 0.5% loss on drying: -6.2% extract content: min. 25% 25%Benincasae Semen Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal ash: max. 5.0% 3.5% Foreign admixtures max. 2.0% 0.5%Buddlejae Flos Morphology: corresponds to Identity: corresponds to corresponds toEcliptae Herba Morphology: Corresponds Corresponds Identity: Corresponds CorrespondsEpimedii Herba Morphology: Corresponds Corresponds Identity: Corresponds Corresponds Content: max. 1.0% icariin - 2ndHaliotidis Concha Morphology: corresponds toLonicerae Flos Morphology: Corresponds Corresponds Identity: Corresponds Corresponds Purity: Stems and leaves: max. 6.0% 3.0% Foreign admixtures: max. 1.0% 0.1% loss on drying: max. 15.0% 9.9% normal ash: max. 10.0% 5.4% HCl ash: max. 3.0% 0.5% extract content: min. 30.0% 33.0%Lycii Cortex Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal: max. 11.0% 8.7% HCl ash max. 3.0% 2.8%Lysimachiae Herba Morphology: Corresponds Corresponds Identity: Corresponds Corresponds Purity: Foreign admixtures max. 8% 3.0%Mori folium Morphology: corresponds to Identity: corresponds to corresponds toPlatycladi Semen Morphology: corresponds to Identity: corresponds to corresponds toPoria Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal ash: max. 1.0% 0.3%Schisandrae Fructus Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal ash: max. 5.0% 3.8% Foreign components: max. 1% 0.8%Schizonepetae Herba Morphology: corresponds to corresponds to Identity: corresponds to corresponds to purity: normal: max. 9.0% 8.8% HCl ash: max. 2.5% 1.8% loss on drying: -10.0% extract content: min. 8.0% 9.3% content: min. 0.6% (ml / g) 0.64%Xanthii Fructus Morphology: corresponds to Identity: corresponds to corresponds to
1 German comment (8), 2 (not checked due to lack of reference standard)
The test for pesticide residues showed an increased value of 3.6 mg / kg for the drug Lonicerae Flos for the pesticide dicofol (limit value for tea: 2 mg / kg). The other examined TCM drugs did not contain any inadmissible amounts of tested organochlorine pesticides according to the assessment according to the maximum residue level regulation.
With several TCM drugs the maximum levels for lead and mercury were clearly exceeded (Table 3), for example with Buddlejae Flos and Schizonepetae Herba. An increased level of cadmium was analyzed in Mori Folium.
Table 3: Results of the tests for heavy metals (data in mg / kg dry weight)elementleadcadmiummercuryRecommendation for maximum quantities50,20,1Alismatis Rhizoma0,300,080,15Angelicae dahuricae Radix0,350,040,22Benincasae Semen0,490,010,37Buddlejae Flos8,290,100,32Ecliptae Herba7,690,190,16Epimedii Herba7,310,120,30Loniceralose 1240 , 16Lonicerae Flos0,750,040,10Lycii Cortex7,990,040,39Lysimachiae Herba5,970,191,11Mori Folium8,320,530,66Platicladi Semen0,290,060,14Poria0,170,020,29Schisandrae Fructus0,320,010,01,010,07,08,470
A drug brought from China, Lonicerae Flos, was found to have a mercury content of 8.5 mg / kg. In order to obtain correct and loss-free values in the nanogram range when determining mercury, particular attention must be paid to the analytical method; The hydride method with enrichment used for this study and the AAS determination (cold vapor mode) are particularly suitable for sensitive mercury determinations.
The contaminant recommendation is used by the health authorities in the sense of a "prefabricated report" (11) to protect patients. Therefore this recommendation should also be observed by distributors and suppliers of TCM drugs. If an extended maximum value is required for some drugs, this should be justified on the basis of extensive data and an exception rule should be sought. Kabelitz has demonstrated this for numerous domestic drugs (17).
The pharmacopoeia of Chinese medicine (official edition in English, 7 as well as German edition, commentary Stöger, 8) and monograph collections (18) are available for pharmacy practice, which allows proper testing of TCM drugs in the pharmacy laboratory. On the other hand, the availability of reference standards and official reference drugs from the Chinese Pharmacopoeia is problematic.
For pharmacies, an offer of TCM drugs with authorized test certificates in accordance with the pharmacy operating regulations is mandatory in order to be able to carry out a comprehensive assessment of the pharmaceutical quality on the basis of the respective specification (19). As early as 1996, the ZL had pointed out the problem of the lack of proper test certificates and asked the supervisory authorities for information regarding the legal status of known TCM drug suppliers.
In view of the special risks (20), exposure of drugs to heavy metals, pesticide residues and microbial contamination is of great importance. Corresponding examinations cannot be carried out with the usual technical equipment of the pharmacy laboratory. The results of contamination tests of the starting materials and their assessment must therefore be taken from the importers' test certificates.
Recommendations for QMS in pharmacy practice
- The offer of TCM drugs with valid test certificates according to ApBetrO is urgently required.
- Test certificates must be carefully assessed whether they formally comply with the requirements of the pharmacy operating regulations.
- The topicality of the test date must be guaranteed.
- The test certificates must contain the results of the tests for contaminants (heavy metals, pesticides, germ status, aflatoxin contamination).
- Ordinance on the operation of pharmacies (Apothekenbetriebsordnung - ApBetrO) of February 9, 1987 (Federal Law Gazette I 547).
- Blasczcyk, T., Pharm. Ztg. 145 (2000) 942.
- Schmolzki, P., Scherges, M. Dtsch. Apoth. Ztg. 140 (2000) 4094.
- Chen, J.K., Herbalgram 48 (2000) 44.
- Eisenbrand, G., Tang, W., Zeitschrift f. Phytotherapy 19 (1998) 39 - 42.
- Wagner, U., TCM drugs on the test stand, Pharm. Ztg. 145 (2000) 3341.
- Pharmacopoeia of The People's Republic of China (English Edition 1997), Chemical Industry Press, Beijing, China.
- Pharmacopoeia of Chinese Medicine, monographs of the Pharmacopoeia of the People's Republic of China 1990 and 1995, translated from Chinese, expanded and commented on by Erich A. Stöger, 7th edition 3/1999, Deutscher Apotheker Verlag, Stuttgart, 1999.
- Ordinance on maximum amounts of residues of pesticides and pesticides, fertilizers and other agents in or on food and tobacco products (Maximum Residues Ordinance - RHmV) of 01.09.1994. Federal Law Gazette I 2299 of 15.09.1994
- Federal Ministry of Health: Publication of recommendations for maximum levels of heavy metals in medicinal products of plant and animal origin (medicinal product contaminants recommendations - heavy metals). Draft from 10/17/1991
- Heavy metal pollution from drugs, Ger. Apoth. Ztg. 132 (1992) 371
- FAO-WHO (Food and Agriculture Organization of the United Nations, World Health Organization), Rome, Geneva
- International Conference of Harmonization (ICH), Draft Consensus Guidelines, Impurities in New Drug Substances, October 1999.
- Guide values for pollutants in food, Bundesgesundhbl. 5 (1997) 182.
- Collection of methods of the German Research Foundation (DFG) for residue analysis of pesticides, Verlag Chemie Weinheim.
- Law on the sale of medicinal products in the version published on December 11, 1998 (Federal Law Gazette I 3585).
- Kabelitz, L., Pharm. Ind. 60 (1998) 444-451.
- Wagner, H., Bauer, R., Peigen, X., Jianming, C., Chinese Drug Monographs and Analysis, Verlag für Holistic Medicine Dr. Erich Wühr GmbH, Kötzting.
- Guidelines of the Federal Chamber of Pharmacists on QMS, Eschborn
- AMK, Pharm. Ztg. 145 (2000) 85.
Sinomed company, Kötzting (letter dated September 15, 2000): On behalf of Sinomed, Professor Dr. H. Wagner, Munich, the following statement: Due to the negative results of the test for pesticide residues of the earlier batches, the Lonicerae Flos batch now examined by the ZL was no longer tested for pesticide residues. The TCM drugs Ecliptae Herba and Lysimachiae Herba (exceeding the maximum values for lead and mercury) now examined by the ZL were not tested for heavy metals, as previous random tests never found heavy metal contamination. Another laboratory reported a mercury value of 0.02 mg / kg (ZL: 0.22 mg / kg) for Angelicae dahuricae Radix. The correctness of the value of 0.02 mg / kg is checked again.
In a fax of November 28, 2000 (dated November 21), Wagner communicated the following results collected by his contract laboratory (Kneipp company): Angelicae dahuricae Radix: 0 mg / kg mercury (0.02 mg / kg, company Dr. Graner) ; Ecliptae Herba: 0.05 mg / kg mercury, 0.40 mg / kg cadmium; Lonicerae Flos: no Dicofol value was determined; Lysimachiae Herba: no mercury, 4.59 mg / kg lead.
Note from the ZL
The ZL traces the deviating results of the mercury determinations back to different analytical methods and batch inhomogeneities, whereby the AAS method used in the ZL is validated. The detection of dicofol and also of the dicofol metabolite in the drug was confirmed by an accredited residue laboratory as stated.
Company Herbasin, Schwabach (letter dated August 28, 2000): "In the initial phase of our work, we used the actual method of preparation of the Chinese herbal mixtures for the preparation method for exposure measurements. These are used almost exclusively in the form of decoctions. For this reason At that time our samples were also opened as decoctions. Only parts of the heavy metals are transferred into the extract, according to our investigation about 10 to 20 percent. The values found in this way were not conspicuous and therefore gave no reason not to put the herbs on the market To enable comparability with other test results, our herbs have been analyzed as full digestions (aqua regia digestion) in accordance with DIN 38406-E29 using ICP-MS since the end of 1999. As our research showed, you mainly used samples whose test date was in the phase mentioned above of the decoction digestion was atum is an average of 1.5 years ago and the batches have long been sold out, with the exception of Epimedii Herba and Mori Folium. We have taken your results with regard to Epimedii Herba and Mori Folium, where there are still remainders of old batches, as an opportunity to destroy the remaining goods immediately without having our laboratory check them again. I assume that the values you found have been determined correctly. We are grateful that we learned of the increased loads in this way. "
It should be noted that the heavy metal limit values are only a recommendation that has so far in no way been based on the material actually available; Reference is made to the exception of higher limit value recommendations for individual European herbs.
Chinese Medicinal Herbs Company, Bochum (letter dated September 14, 2000): "They give the impression that it is prescribed by some authority to examine for these heavy metal traces, and that these limit values are scientifically proven. In fact, it is the" Draft of a recommendation for maximum levels of heavy metals in medicinal products of plant origin "by the former BGA from 1991! Since then, nothing further has been done by this authority in this regard."
The question arises as to whether the dry substance of the herbs is used for the heavy metal traces or the decoction that the patient consumes. A longer paper discusses the WHO guideline on heavy metal limits in food and the comparison of these values with the heavy metal values in decoctions of medicinal herbs. "In TCM, the intended application is the decoction. This means that the intake of heavy metals by the patient tends towards 0, even if the raw substance contains values that are far below those of the WHO, but which are the values of the draft exceed."
For reasons of space, this statement, which is over six pages long, cannot be reproduced in full.
The letter was accompanied by an analysis report from a laboratory which showed that the recommended maximum levels of lead were exceeded in other batches of Buddlejae Flos and Schizonepetae Herba examined on behalf of the company.
Central laboratory of German pharmacists
65760 Eschborn, Germany
© 2001 GOVI-Verlag
Email: [email protected]
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