Volume 1, Special Edition | Current Kampo Medicine 2005

Manufacturing Process for the Prescriptionsof Kampo Medicine
The

large

majorityofKampo

Medicines

manufactured by Japanese pharmaceutical companies
are extract preparations (history of which has beenpreviouslydescribed).

There

pharmaceuticalcompanies

manufacturing

Kampo

areinoverJapan

Medicine

fifteenwho

extracts

arewithgovernment approval. Their manufacturing is governedby the regulations of the Pharmaceutical Affairs Law, andstrictly controlled by other government regulations,including GMP (Good Manufacturing Practice). The GMP
for pharmaceutical products include (1) reduction of human errors
to a minimum, (2) prevention of contamination of the drugs ordeceasing quality, and (3) establishment of a system to guarantee
high quality. As a result, products are assured of quality
and safety at the highest level.

Material
Of all the crude drugs used as raw material for
Kampo Medicine, about 200 major drugs(herbalmedicines) are listed in the Japanese Pharmacopoeia (JP),which imposes quality standards on them. The quality
standards provide detailed requirements for identifying
the names of the original plant species (or original animal
species or mineral for crude drugs derived from animals
or minerals), parts used for medicinal purposes (e.g. roots,stems, leaves, flowers or fruits), preparation methods,
methods of purity test and other physical/chemical tests
for the purpose of quality evaluation, as well as the test
methods for the presence of microbes.
Of all the crude drugs not listed in the JP, the ones infrequent use are published in the Japanese Herbal
Medicine Codex (1989) which provides quality standards
established by a research team organized by thegovernment. Pharmaceutical companies must use crude
drugs which comply with these quality standards as theirraw material. Some crude drugs do not have official
specifications such as those above. When this is the case,companies

quality standards.
II. Quality Control of Extracts
Extracts are manufactured in the following processes:
First, liquid extract is made by processing cut crude
drugs mixed according to a prescribed composition in hot
water (separation of effluent and residual). Residues fromthe crude drugs are removed from the liquid extract.
After the liquid is concentrated under reduced pressure,
it is spray-dried into a powdered form. Next, theappropriate measures of the powdered extract and fillers(preparation materials) are mixed together to form a raw
material for preparation. It is then processed into theform of granules or tablets, and filled and packaged as afinished product. As the Kampo Medicine extracts arehighlyhygroscopic,

developtheirown

specifications so as to ensure quality of their products.
At present, of the crude drugs listed in the Japaneseadvancedtechniques are used to protect finished products fromInitially, the quality of Kampo Medicine extracts
released

tomarket varied

manufacturingmethods

due

usedtobydifferencesinpharmaceuticalcompanies. Consequently, the government issued anadministrative guidance (notice) in 1985 in an attempt toensure better quality and uniformity of these products.
Generally, the administrative guidance (notice) prescribesthat standard decoction must be prepared for eachprescription with the prescribed method; that two or moreindicator constituents (“Indicators”) must be selected andquantified for the purpose of ensuring the equivalence
between the final product and standard decoction; andthat the amount of the “Indicators” contained in a daily
dose must be 70% or more of the amount contained in thestandard decoction.
Kanebo Pharmaceutical, Ltd. which agreed to aninterview, is staunchly committed to quality. A consistentquality control system has been employed from thesupply of crude drugs through to the finished products inorder to ensure that the Kampo Medicine extracts forclinical use produced by Kanebo are equivalent in potency
to the standard decoction. For this purpose, Kanebo uses
several technical means to extract various constituentsefficiently from crude drugs, and provide a stable supplyof quality products.

Herbal Medicine Codex, widely used ones are in the50

pharmaceuticallymoisture. (For outline, see diagrams in pages 54-55.)

I. Quality Standards for Crude Drugs Used as Raw

pharmaceuticalprocess of being incorporated into the JP with upgraded

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Volume 1, Special Edition | Current Kampo Medicine 2005

The following example is provided.
(1) Obtaining crude drugs of predictable quality①

The quality of herbal medicines is influenced by

the growing region and climate, so herbal medicinesof predictable quality can be obtained by designating
the area where each medicine is grown.
②To avoid deterioration in quality and bacterial

the cathartic effect is markedly decreased. To
constantly maintain the sennoside content, extractionof Rhubarb is performed in a short time during thelatter half of the extraction process.
③Measures to prevent enzymatic reaction:

It has been reported that herbal medicines containenzymes that degrade various ingredients. Baicalin isa major ingredient of Scutellaria root that iscontamination during the storage of herbal medicines,degraded

thermostatically controlled storage is used, and cut

amygdalin (a major ingredient of Peach kernel andherbal medicines are stored at a low temperature.

Apricot kernel) is degraded by emulsin. Generally,③

A system has been established so that any

problems with the quality of finished products can betraced back to a specific growing area.
(2) Management of the extraction process
The individual steps of the various processes from theextraction during the manufacture in the factory overseparation of solids from liquids and concentration to thedrying of the extract powder are conducted in extremely
large-scale equipment. Neglecting quality control during
any of these processes could have marked effects on thequality of these traditional formulas. The items listed
below are carefully observed during the manufacturing

bybaicalinase

tobaicalein,while

the optimum temperature range for enzyme activity
is 35-40℃ . Heating time is shortened in order toprevent enzymatic reaction.
④Measures to preserve volatile ingredients:

Volatile ingredients, cinnamaldehyde in Cinnamonbark, paeonol in Tree peony bark, ligustilide in
Szechwan lovage rhizoma etc., can diffuse out moreduring the graduation process. To maintain these
ingredients in the finished product at the specified
level, theeffluent after extraction

process

iscontrolled below 60℃ at temperature and between
quadruple to octuple in a graduation rate.

process. Moreover, all processes are controlled via(3) Control of the manufacturing processes of extracts

computer using an automatic control system.

(final products)①

Measures to increase the dissolution rate ofinsoluble ingredients:
Saponins such as Bupleurum saponins, Ginseng
saponins etc. are important ingredients and areinsoluble. The surface structure of Ephedra herb is sotight that it prevents the penetration of water andthis makes it difficult to dissolve ephedrine, a major
ingredient. To promote the efficient dissolution ofthese ingredients, the particle sizes of these herbal
medicines are adjusted appropriately.
②Measures to reduce the degradation of heat

labile ingredients:
Sennosides of Rhubarb are pharmacologically active
ingredients of a crude drug, and are representative
heat labile substances. The sennoside content of a
extract is dependent on the amount dissolved from
Rhubarb and the extent of degradation. When heatedat 100℃ for 1 hour, most sennoside is degraded andThe obtained extract powders are precisely weighed
and then mixed with filling material before they arefurther

processed

into

granulesortablets.

The

manufactured granules or tablets are then packed inaluminum foils (SP package) or else placed in containers.
After that they are further wrapped and packed in boxes
for shipment. In the factory, completely computerized
production control systems have been introduced. Under
this system, all the information pertaining to themanufacturing process, from the receptance of stocks tothe shipment of the final products is completelycontrolled.
①
After storing the various extract powders
serving as crude materials for the products and fillingmaterials in a warehouse with automatic
temperature control, the production control systemreleases upon instruction from the warehouse only
those materials passing quality tests from thewarehouse into the production process.

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

51

Volume 1, Special Edition | Current Kampo Medicine 2005

② Weighing of prescription crude materials isconducted as an interactive process with thecomputer and all weighing results are stored in thecomputer.

As crude drugs are natural products, the presence ofsome bacteria and fungus is unavoidable. The JPprescribes the baseline limit for presence of microbes incrude drugs and preparations made with crude drugs.

After the extract powders and the filling

Although almost all microbes are eliminated by heatmaterials are mixed during the manufacture of fineduring the extraction process, Kanebo employs a brief

granularsterilization of graduated fluid and carries out an③products,

thesystem

automaticallyinspection for microbes in the final stage of themanufactures the relevant granules.
④

Moreover, during the manufacture of tablets, atablet, press observation device, tablet weighingdevice, a metal detector, and a transport device workin unison allowing unmanned operation.
⑤

All the steps involved in packaging or filling incontainers of the granules or tablets obtained inabove described steps (2), (3) and (4) are performed ina clean area.
⑥

production to ensure the safety of its product. The
company ships only products for which inspection hasconfirmed the microbial count to be below the baseline
limit.
Although monographs of crude drugs may indicate
their use in the form of pill or powder, they convert theamount specified in the monograph to water-extracted
equivalent for its extract products. This in itself isirrelevant to the efficacy of our drugs, but it is significant

Sensors are installed to detect whether theindividual packages are properly packaged during

in terms of the elimination of toxic elements such as
microbial contamination.

the packaging process, controlling the entire systemin such a way to prevent the necessity for
replacements due to defective packages or products.
⑦

Products packaged on the individual lines arethen transported by the automatic transfer system tothe automated warehouse.
⑧

Untested products or non-standard products arelocked out by the manufacturing control system andmanaged in a way that prevents them from being
handled or shipped.

IV. Environmental Protection
The factory of Kanebo, which we visited, met thestandards of the ISO 14001: Environmental Management
System.
The original text records the use of pills andpowdered drugs. For our extracts we convert the amounts
given in the original texts into the amount of aqueous
extracts, a form which also allows to achieve a uniform
distribution. This renders carrying the products easierand serves also the function of excluding contamination

III. Prevention of Pesticide and Microbial Contaminations

with bacteria or other hazardous substances.

Pesticides have low solubility in water, instability inheat, and are evaporative. Some residual pesticides may
be found in a crude drug used as material. Less than
one-tenth of the amount will be transferred to theheat-processed extract. The amount of the residue will be
reduced below the detection limit in the final product,meeting the safety standard. Yet, with its strong
commitment to quality and safety, Kanebo carries out astrict inspection of every batch of crude drugs it receives
by measuring residual amounts of several types oforganochlorine,pesticides.

52

organophosphorus

andpyrethroid

Acknowledgements:

We thank Kanebo Pharmaceutical, Ltd., andQingdao Huazhong Pharmaceutical, Co., Ltd. forproviding information to cover this article.

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)Volume 1, Special Edition | Current Kampo Medicine 2005

Cutting raw herbal
medicines

Store cut herbal
medicines

Extraction tank

Top of separator ofsolid and liquid

To promote the efficient dissolution

To maintain volatile ingredients in the finishedof insoluble ingredients, the particle

product at the specified level, the effluent after

siz es of herbal m ed icines areextraction process is controlled below 60℃ at

adjusted appropriately.

temperature and lowered in a graduation rate.

Mixture ofraw herbal
medicines

Decoction(Extraction)

Separationof effluentand residual

Graduation

SplaydryExtraction
powder1) To maintain the sennoside content, extractionof Rhubarb is performed in a short time during
the latter half of the extraction process.
2) Heating time may be shortened in order toprevent enzymatic reaction.

Residua/disposal after
solid/liquid separation

Instant fungus
reduction machine

Hot-air generator
for drying

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Central control room53

Volume 1, Special Edition | Current Kampo Medicine 2005

Weighing

MixingMixingWeighing

Granulating tablets

Fine granule,tablets etc.

SP packaging

Packaging

Fillers

Automatic Transfer System

54

Automated Warehouse

The Journal of Kampo, Acupuncture and Integrative Medicine (KAIM)

Finishedproducts