Scientifically Concentrated TCM Herbal Extracts Part II (Sun Ten Journal NO. 5, Sep 2005, Page 47-54)

Scientifically Concentrated TCM Herbal Extracts Part II

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III. Production


Besides the quality of raw herb materials, the quality of scientific concentrated TCM herbal extracts is also closely associated with the layout of production equipment, design of production procedures, in process controls, setting of production conditions, employees training & education, and environment control of plant.


1.  Production Process


1.1  Decoction and Extraction


The decoction and extraction time, temperature, amount of water used and the sequence of adding each herb ingredient is designed according to the individual formulation requirements and characteristics of herbal ingredients. Generally, about 15 to 20 times of filtered water is added, the herbs is immersed in the water for a while, the temperature is gradually raised to a preset temperature to bring the water to boil with occational stirring. Tonic & replenishing formulas are usually boiled at a lower temperature for a longer time; whereas shell or mineral ingredients that are stiff and rigid and hard to extract their active constituents are loaded first and boiled for 10 minutes before other herbal ingredients are loaded and boiled together. Surface relieving formulas mostly contain herbs rich in essential oil contents are loaded only after the other herbs are almost done, and then allowed to boil another 4-5 minutes longer. Herbs with  constituents tend to become unstable under long boiling process, such as sennosides in rhubarb are also loaded only just before the other herbs are done and allowed to boil for 4~5 minutes longer. Noble herbs such as ginseng are boiled separately in a double-boiler container and the decoction is then condensed together with the decoction of the other herbs.


1.2  Filtration & Separation


After decoction, the remains of the herbs and impurities must be separated from the extracted liquid. Since many herbal constituents show great differences in their solubility in hot, warm or cold solutions, sometimes undergo combination with each other to form lower solubility complexes as the solution temperature lowers gradually.  Therefore, the control and regulation of separation temperature and separation rate are very important. For most herbal formulas, when the temperature of the extracted liquid is lowered during filtration, the solubility of constituents will be lowered and the constituents will precipitate and get absorbed by the herbs remains, thereby lowering the contents of the active constituents in the separated extracted liquid. Prolonged separation also lowers the extracted liquid temperature to result in the same negative effect. Therefore the control of decoction temperature and time, separation mode and separation rate are important factors to the quality of scientific concentration TCM herbal extracts.


1.3  Concentration


Prior to drying, the filtered extracted liquid has about 10~12 fold water content which has to be removed by concentration process to shorten the subsequent drying process time, increase efficiency and save energy. Low temperature vacuum concentration is used to avoid dissociation, decomposition and loss of the active constituents during the concentration process.  For instance, the sennoside A (a thermolabile compound) in the rhubarb extract solution, which when concentrated at 100¢J will be almost totally lost, but if it is concentrated at below 40¢J, it remains intact.


Generally speaking, the physical characteristics of the concentration solutions are different with different drying process. Hence, the concentration ratio is set depending on the requirement of the drying process; so the concentration ratio varies from formula to formula depending on the formulation.


1.4  Drying


The drying process is a process in which the concentrated solution is dried  into concentrated powder. Currently the commonly use methods include spray-drying method, freeze dry method and fluid-bed drying method.


The freeze dry method is freezing the concentrated solution into a solid mass, by taking advantage of the elevating character of ice under low temperature and reduced pressure, the frozen mass dehydrates at low temperature to become dried powder. Because an object gets dry at high vacuum and low temperature, the method is very suitable for thermolabile substances, but it requires a comparatively longer time and hence used more energy to dry; and some active constituents maybe lost during the longer drying time, and the concentrated powder absorbed moisture easily and tend to get lumpy. Hence, it is not a suitable drying process for large quantity production.


The spray-drying method is by spraying concentrated liquid into high temperature air flow and using the hot air to allow the moisture to evaporate instantly into concentrated powder. Even though Spray Drying Method used high temperature, but its drying process is instant, so the drying time is very short, so it is still suitable for thermolabile substance.  For instance, when using spray-drying method on the concentrated rhubarb liquid in air temperature of 200¢J, the sennoside A was not effected, as long as the exhaust air temperature is controlled at below 105¢J. The fluid-bed drying method is also by turning the concentrated liquid into tiny droplets, then using heat exchange principle to adsorb the carrier particles that are flowing by the hot air before the tiny droplets dried up.  Because the entire drying process of fluid-bed drying method takes place in a sealed equipment, the production process cannot be contaminated, and the product quality is well preserved. Besides, fluid-bed drying method simultaneously accomplishes both drying and granulation processes, thereby reducing production processes. The granules made from fluid-bed granulation are porous, very suitable for subsequent tableting or capsule filling process. It is suitable for mass production and is thus widely adopted by the TCM herbal extracts manufacturing industry. However, because this method uses carriers, it is impossible to obtain high concentrated powder. Moreover, only limited type of carriers is suitable for use in fluid-bed drying method and the adsorptive capability is limited too. Hence, the main disadvantage with fluid-bed drying method is inability to obtain high concentrated dry powders.


2.  Extraction Yield and Concentration Ratio


When the TCM formula extracted liquid is processed through concentration and drying process, the resulted product is concentrated powder. The ratio of the weight of the concentrated powder to the total weight of the raw herb ingredients used in the formula is called the extraction yield of that formula. Since different herbs have different extraction yields, different formulas will naturally present different extraction yields. Generally, “Surface Relieving” formulas, “Dampness Dispelling” formulas have lower extraction yields but higher concentration ratio; whereas “ Tonic and Replenishing” formulas show the contrary.  The total weight of the raw herb ingredients used in a formula will affect the extraction yield, a higher total weight of raw herb ingredients in a formula has a higher daily dose. Generally speaking, most formulas have extraction yields ranging between 15~30%, or concentration ratios  between 3 to 10 times.


3.  Excipients and Daily Dose


Concentrated powders of natural herbal products tend to absorb moisture from the air, and would soon get lumpy after putting out in the open air. Hence, it is necessary to add a suitable amount of excipient to stabilize the concentrated herbal products. At present, Taiwan health dept only permit the use of lactose and starch as excipients; in a ratio of 1:1 as a reference value. The excipient quantity is actually varies depending on the moisture absorption characteristic of the formula. For example, formulas containing herbs such as Sheng Di Huang/Shu Di Huang, Mai Men Dong, Tian Men Dong, Ren Shen, Da Zao, Shan Zhu Yu, Gou Ji, Xuan Shen, Dan Shen, etc. have higher extraction yields and are very hygroscopic. The excipient added may be 1:1 to the concentrated powder or higher. For leaves, seeds, animals, minerals such as Xia Ku Cao, Fan Xie Ye, Di Long, Mu Li, Sha Ren, Fu Ling, etc. the extraction yield is low, therefore less hygroscopic, the excipient used is perhaps as low as 0.5 times of the concentrated powder. Based on a ratio of 0.8:1 between excipient and concentrated powder, the daily dose of scientific concentrated TCM herbal extracts mostly falls in the range of 6g?18g. “Surface Relieving” formulas mostly have a daily dose of 7.5g, and “Tonic & Replenishing” formulas are usually between 12g to 18g. Therefore, a quarter of the scientific concentrated TCM herbal extracts have a daily dose of 7.5g; another quarter have daily dose of 9g; another quarter have daily dose of 12g; and the remaining varying among 6g, 15g and 18g.


In addition to the powder and granular dosage forms, the scientific concentrated TCM  herbal extracts are also available in capsule, tablet, film-coated tablet, etc. which may require different ratio of excipient.


4.  Packaging and Shelf Life


The packaging is part of the restricted production control area, the ventilation system for the manufacturing and packaging is designed to deliver air equivalent to “Class 100,000”.  The system has been designed for the air to enter each room above the door and where a return is situated at low level as far from the entry as possible.  The temperature is kept at 23±4¢J and the humidity is below 60%RH.


The product shelf life is based on the results of stability study. For products packaged in direct containers, the smallest units in the same packaging material are sampled for the stability study. If same product packed in different packaging materials, it will be sampled for another stability study. Stability study is conducted at room temperature   and accelerated stability test to determine the product shelf life.


IV. Quality Assurance


The quality of scientifically concentrated TCM herbal extracts is assured through its production control and the testing data on the Certificate of Analysis of the final products. This chapter will explain in detail the various test items, the specifications and final data.  Jia Wei Xiao Yao San (Bupleurum and Peony Formula), is one of the popular and most commonly used TCM formulas, and will be used as an example in this chapter to explain the contents of a Certificate of Analysis (CoA) along with   consistency and stability testing data.


1. Testing Items


Semi-finished bulk products and final products must be inspected based on GMP and ISO quality Systems of Operations Procedures (SOPÕs) and must be in compliance with the specifications.  The following inspections & testing are conducted:


1.1    Test Items for Semi-finished Bulk Products


a.     General Description


b.     General Tests


        i. Particle Size


c.     Impurity Tests


        i. Heavy Metals


d.     Loss on Drying


        i. Total Ash


        ii. Acid-insoluble Ash


e.     Quantitative Tests


        i. Water-soluble Extractives


        ii. Diluted alcohol-soluble Extractives


        iii. Assay


1.2    Test Items for Final Products


a.     General Description


b.     General Tests


        i. Weight Variation


        ii. Average Weight


        iii. Particle Size


c.     Impurity Tests


        i. Heavy Metals


d.     Loss on Drying


        i. Total Ash


        ii. Acid-insoluble Ash


e.     Quantitative Tests


        i. Water-soluble Extractives


        ii. Diluted alcohol-soluble Extractives


        iii. Assay


f.      Identification


2. Testing Methods and Purpose


-General Description: To determine whether the color, smell, and taste conform to specifications.


-Identification Tests: Using TLC (thin-layer chromatography) to compare test sample solution against reference standard to identify active substance.


-Loss on Drying: To determine the water content of the test sample.  The water content will affect the product stability.  Too muchwater will cause decomposition, worm, or mold growth.  


-Water-soluble and diluted alcohol-soluble Extractives: To determine the amount of extractives.  The specifications is set according to the herbal substance.


-Total Ash: To measure total ash.  Each herb has its distinct amount.


-Ash-insoluble Ash: To measure total ash-insoluble ash can determine each herb's basic characteristic, it can be used as an estimate the cleanliness of each herb.


-Quantitative Assay: Using HPLC(high performance liquid chromatography) to measure the level of active constituent within each herb, and use it as quality control data.


-Heavy Metals Analysis: use ICP-MS to test the content of harmful metals like: Arsenic, Lead, Mercury, Copper, Cadmium. Each country has its own acceptable limit.  


Microbiological Contamination Analysis: to determine the Total Aerobic Bacteria Count, Yeast and Mould limit, each country has its own acceptable limit.  E. Coli, Salmonella should be Nil.  In general, if decoction, concentration, granulation, and packaging process are carried out following GMP & ISO SOP's in a sterile controlled condition, the products should be free of living microbes especially  diseases causing E. coli and Salmonella should not be a factor under these production conditions.


3. Quality Specifications


Each manufacturing plant can set their own quality specifications if the test item is not available in pharmacopoeia, or according each country's regulation/requirements.


4. Certificate of Analysis (CoA)


Each batch of final product must have a Certificate of Analysis (CoA) containing all the necessary test items and corresponding test results. The following is an example of  CoA for Bupleurum and Peony Formula.


5. Consistency and Stability


TCM herbal extracts are combinations of natural herbs, natural plants are different and complex. Herb materials can varies in colour and active constituents from batch to batch, which make it extremely difficult in control product consistency. However,  scientific concentrated TCM herbal extracts is using modern science to transform ancient wisdom for modern use and must be in compliance with the fundamental requirements of product consistency and stability. HPLC fingerprint comparison is commonly used to compare the consistency between different batches of the same product. Radar graphs are created based on six major constituents to serve as a reference and quick analysis of the sample product. The following HPLC graphs of the Jia Wei Xiao Yao San (Bupleurum and Peony remedy) from three different GMP certified manufacturing plants. Based on the three HPLC graphs, it is clear that their active constituents of the same formula differ greatly. The following Radar Garph showed 3 different batches of Jia Wei Xiao Yao San from 4 different GMP manufacturing plants. 


There are ways to determine which manufacturing plant produces better quality product. One is to see the quality of the raw herbal materials used; the other is by audit the manufacturing batch records. 


V. Conclusion


There are mainly two sources which TCM herbs are acquired today.  The majority of the herbs are grown in the wild, and small portion are cultivated.  The herbs from the wild are identified by experience and knowledge passed from generations; the cultivated herbs are planted by farmers as part of the farming crops.  Both sources do not have specifications in identifying the right species and the quality of these herbal materials.  Most of the herbs selling in the herb markets were not scientifically authenticated, tested for pesticide residues and heavy metals.


Traditionally, the TCM doctors prescribe the herbal combinations after evaluating the patient mental and physical conditions, patients have to take the prescription to the herb shop to purchase the herbs, take the herbal remedy after home decoction.  Both the doctor and patient do not have any information/data on the authenticity, safety, stability of the herbs.  Yet modern science is now able to use modern equipment to correctly identify the herbs, the active constituent contents, pesticide residues and heavy metals to ensure the safety of the product.  For instance, Mu Tong now can be identified and classified into “Mu Tong”(Akebia), “Chuan Mu Tong”(Clematis), “Guan Mu Tong”(Aristolochia); and “Guan Mu Tong” contains aristolochia acid which can cause renal failure.  Most of the Ginseng contain DDT pesticide residue, almost 80% of the Senna leaves contain pesticide residues; some herbs have heavy metals due to contaminated soil, prolong consumption of these contaminants can lead to serious illness. Thus, consuming medicinal herbs that have not been tested through strict quality control can pose a great threat to human health. That is why Scientific Concentrated TCM Herbal Extracts start the strict quality control from the selection of raw herb materials to the production process and up to the finished product; all the finished products have been tested and analyzed, quality assurance will inspect and ensure the finished products are within specifications and safe before releasing the final products for distribution to the market.


Even though the Chinese people have been practicing TCM for the past two thousand years, but TCM is still being regarded by modern medicinal field as only historical facts without modern clinical trial data.  Therefore, it is imperative that the TCM field should follow Western medical methods to prove and reassess the therapeutic effects of TCM through clinical trials.


The clinical trials require complete manufacturing batch records along with CMC (Chemistry, Manufacturing, Control) quality control data. Scientific concentrated TCM herbal extracts have very clear and precise documentation of all processes concerning selection of raw materials, production process, and quality control that are the basic requirements needed to apply for clinical trials.


Sun Ten Pharmaceutical Co. has been striving to elevate the quality of scientifically concentrated TCM herbal extracts by constantly modernizing quality control and production processes; it is with these commitments that Sun Ten products are able to meet the strict quality standards & regulations set by the health authorities around the world in recent years due to increasing dema.

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