An excerpt of Qian Zhongzhi’s long article presented at the Hangzhou meeting in October, 2001

 

Seven editions of Pharmacopoeias have been released so far in the People's Republic of China. The TCM quality standard record in all editions was gradually moving towards standardization and modernization. The development in Chinese Pharmacopoeia can be divided into three general phases :

 

The first phase: the 1953 and 1963 editions.The quality standard in 1953 edition was basically a reference to the foreign pharmacopoeia. Only crude drugs were recorded without specific identification and quantification. In the1963 edition, the Pharmacopoeia had two parts: the first dealt with TCM itself and the second part dealt with the chemical drugs. In addition to listing the increasing number of recorded TCM species, the edition included records of characteristics and taste, function, indication, administration, dosage and identification.The crude drugs were identified according to their morphology, based on experience.

 

The second phase: the pharmacopoeia of 1977, in which – due to the efforts of professor Xu Guojun- microscopic identification was presented in addition to the large numbers of crude drugs. Innovative was the microscopic identification of powders.

 

The third phase was a period of great progress. From 1985 to 2000, four pharmacopoeia editions were published. Thin layer chromatography (TLC) was adopted in 1985 and specific identification was introduced into TCM. In the 1990 edition, the complete chromatographic image of the crude drugs plus the test samples displayed not only the specification but also the completeness of the record. Quantitative data were introduced beside the true or false identification. So, since 1990 determination of the contents using modern instruments such as high performance liquid chromatography (HPLC), gas chromatography (GC), thin-layer chromatography (TLC) was started and, up to the 2000 edition, 105 species were quantified by HPLC, 60 species by TLCS, and 11 species by GC. For example, in the case of Rhizome Coptidis (Huang Lian), in the 1985 edition gravimetric analysis was used to determine the content of berberine by precipitation with acetone; in the1990 edition, the method was changed to spectrophotometry to determine the total alkaloid; but in 1995 edition, TLCS technique was adopted to determine the content of berberine which was more specific than the previous method.

 

With respect to quantification, there was a switch of measuring marker constituents to active constituents and from measuring single constituent to multiple constituents. For example, Polygonum multiflorum (He Shou Wu) contains anthraquinones, and emodin was determined previously as the marker constituent, but modern pharmacological research showed that stilbenes possessed the activities of antisenility, immunopromotion, arteriosclerosis prevention, which was in accordance with processed Polygonum multiflorum, therefore stilbenes were the active constituents. Hence in the 2000 edition, stilbenes were determined by the HPLC technique. In order to ensure purity and safety the Chinese patent medicines must be in accordance with the requirements specified for the preparation in various dosage forms under general provisions.

 

The Chinese crude drugs must be tested for impurity, moisture, ash content and some species must be tested for heavy metals. Assay of organic chlorine pesticide residue was added to the Chinese Pharmacopoeia 2000 edition. It stipulates that the total BHC must be less than 20 ppm, DDT less than 20 ppm and PCNB less than 10 ppm in glycyrrhiza uralensis (Gan Cao) and Astragalus membranaceus (Huang Qi). Heavy metal assay was performed for the Chinese patent medicine 'Huanglianshangqingwan'. In addition, micro-organism limit test was also applied to the various preparations.The Chinese Pharmacopoeia 2000 edition has made great progress if compared with the pre-2000 Pharmacopoeias.

 

The new trend of quality control for traditional Chinese medicines in the Chinese Pharmacopoeia 2005 edition.

 

The limitations of the current quality control pattern for Chinese traditional medicines The current quality control pattern for traditional Chinese medicines was established according to the methods for chemical drugs, a quality control for a single constituent.Although it has played an important role and has been widely adopted in the field of TCM production and research, this pattern of quality control is in conflict with "an organic conception of the human body " theory of traditional Chinese medical sciences. For a chemical drug, the identification, test and quantification in quality control are regarded as the index for evaluating quality and therapeutic efficacy. But for TCM herbs, especially if prepared according to the traditional Chinese theory, the quantification of one of the active constituents cannot objectively reflect its overall efficacy because TCM herbs express their effect by multiconstituents and multi-targets. This is the basic difference in quality control between TCM herbs and chemical drugs. For instance, both Coptis chinensis (Huang Lian) and Phellodendron amurense (Huang Bai) contain berberine, and the current quality control method to quantify berberine in the two herbs is the same. Although this method can control the quality of the two herbs correctly, it could not differentiate between the two drugs as applied in TCM.Chinese doctors will never substitute one for the other since they consider the multiple constituents of the drug as a whole instead of a single berberine.Therefore, this quality control method based on the identification of chemical drugs has apparent limitations for TCM.

 

The "organic conception of the human body" in TCM is the basis for developing a modern quality control method for traditional Chinese medicines. As stated above, the synthetic-analytical method which can reflect the integral situation of the drug will be more suitable for the characteristics of traditional Chinese medicines and will definitely become the new aspect of traditional Chinese medicines quality control.
Therefore, the 2005 edition of Chinese Pharmacopoeia will enter the fourth development phase of quality control in TCM: to establish a new synthetic- analytical system and quality standard pattern that will fully reflect the "organic concept" of traditional Chinese medicine. The 2005 edition of Chinese Pharmacopoeia consists of three main parts:Chinese crude drugs, the prepared slices of Chinese crude drugs and traditional Chinese medicine preparations. The pharmacopoeia will be compiled under the guiding ideology of high quality, high standard and modernization. High quality refers to the following aspects: strict control on heavy metals and pesticide residue should be added to a great number of drug monographs. In particular methodology studies should be emphasized. Chinese traditional medicaments containing toxic ingredients should be checked thoroughly for safety consideration. In addition, pharmacology, toxicology and clinical effects should be re-evaluated. For standardization, more emphasis should be put on the validity of analytical methods. For instance, system suitability tests should be carried out for TLC. Chromatographic procedures and volume application should be re-examined. General Requirements on Preparations should also be standardized.Modernization calls for:

1. admission of new Chinese traditional medicaments reflecting fully the progress of modern science and technology, provided they are in accordance with the Pharmacopoeia admission principles;
2. introduction of modern analytical techniques in the Pharmacopoeia.

The development of the HPLC/MS (mass spectroscopy) technique makes the qualitative and quantitative analyses of systems with complex chemical molecules possible. Determination of different types of complex compounds in traditional Chinese medicines by LC/MS/MS technique is becoming mature.
The DNA molecular genetic marker technique has been more frequently used in identification of Chinese crude drugs, since PCR (polymerase chain reaction) made the rapid and sensitive detection of DNA polymorphism possible.These molecular marker techniques for detecting DNA polymorphism are also called DNA fingerprinting. DNA molecules are the direct carrier of genetic messages, unaffected by foreign factors and by the organs and tissues of the different developmental stages. Every somatic cell of the same organism contains identical genetic messages. Therefore, species identification by DNA genetic marker technique is more accurate and reliable.The first step in the standardization procedure of Chinese crude drugs is to clarify their biological origin. There is a plan to establish a set of molecular biological methods, PCR species identification, a DNA fingerprint database including the sequence of specific DNA fragments of Chinese crude drugs.

 

Chemical fingerprinting: a key technique

 

Besides the analytical techniques mentioned above, chemical fingerprinting is another key technique leading to a quality control mode, based on comprehensive analytical techniques which can reflect the completeness of traditional Chinese medicine. This is an overall quality control pattern characterized by a combination of the microscopic analysis of a single compound plus the macroscopic analysis of a group of compounds. Chemical fingerprint is a chromatogram, a spectrum of fingerprints obtained by a certain analytical technique exhibiting the characteristics of different types of chemical constituents in traditional Chinese medicines. The basic nature of a chemical fingerprint is completeness and fuzziness. For completeness, the sum of fingerprints is considered as a whole and analysed and compared according to its comprehensive characteristics. For fuzziness, the analysis and comparison put more emphasis on the similarity of different fingerprints and not on their exact identity only. This idea is more in line with the natural essence and theory of traditional Chinese medicine. Therefore, chemical fingerprinting of medicines can be considered to be an objective and comprehensive analytical method for quality control of traditional Chinese medicines. It can be used to record the identity and quality of traditional Chinese medicines and to evaluate the evenness and the quality stability of raw materials, semi- and finished products. Further studies under the guidance of TCM theory will lead to a new subject, "Fingerprint-Activity Relationships" of traditional Chinese medicines. Different traditional Chinese medicines (single or complex preparations) exhibit fingerprints with different characteristics. Comparison between characteristics of the fingerprint and the bioactivities will constitute the "Fingerprint-Activity Relationships" based on the characteristics of the fingerprint. As in the structure-activity relationship of chemical drugs, changes in the characteristics of the fingerprints will cause changes in the activity of the herbs. The introduction of modern analytical techniques is a digital revolution in traditional Chinese medicine. This development - ensuring clinical effects by analysing the formulae through fingerprint-activity relationship in traditional Chinese medicines - is equivalent to paving a way for the world to understand and to accept Traditional Chinese Medicine. It is a development which could hopefully lead to the correct integration of TCM within the world medical system. In summary, chemical fingerprinting is a key technique in quality control of traditional Chinese medicines. It is the most feasible method which is in keeping with the principles of Traditional Chinese Medicine and can be used to evaluate the authenticity, stability, consistency, and effectiveness of traditional Chinese drugs. So, in the Chinese Pharmacopoeia 2005 edition, quality control is to include chemical fingerprinting together with the determination of active constituents and the necessary inspections.