Traditional Chinese medicine -- General requirements for the manufacturing process of natural products

ISO 19617:2018 specifies the general requirements for manufacturing processes to ensure the quality of finished products used in traditional Chinese medicine (TCM). This document covers premises, documentation, personnel, training, manufacturing control and quality control. This document applies to the manufacturing of natural products used in and as TCM. ISO 19617:2018 does not conflict with general pharmaceutical good manufacturing practices (GMPs). ISO 19617:2018 applies to all materials of natural origin: medicinal plants, medicinal animals, medicinal minerals, crude drugs or crude drug preparations.

Médecine traditionnelle chinoise -- Exigences générales relatives au procédé de fabrication des produits naturels

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Status
Published
Publication Date
11-Apr-2018
Current Stage
6060 - International Standard published
Start Date
02-Mar-2018
Completion Date
12-Apr-2018
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INTERNATIONAL ISO
STANDARD 19617
First edition
2018-04
Traditional Chinese medicine —
General requirements for the
manufacturing process of natural
products
Médecine traditionnelle chinoise — Exigences générales relatives au
procédé de fabrication des produits naturels
Reference number
ISO 19617:2018(E)
ISO 2018
---------------------- Page: 1 ----------------------
ISO 19617:2018(E)
COPYRIGHT PROTECTED DOCUMENT
© ISO 2018

All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may

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Published in Switzerland
ii © ISO 2018 – All rights reserved
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ISO 19617:2018(E)
Contents Page

Foreword ........................................................................................................................................................................................................................................iv

Introduction ..................................................................................................................................................................................................................................v

1 Scope ................................................................................................................................................................................................................................. 1

2 Normative references ...................................................................................................................................................................................... 1

3 Terms and definitions ..................................................................................................................................................................................... 1

4 Assurance of manufacturing process .............................................................................................................................................. 6

4.1 Premises ....................................................................................................................................................................................................... 6

4.1.1 General...................................................................................................................................................................................... 6

4.1.2 Storage areas ....................................................................................................................................................................... 6

4.1.3 Production areas .............................................................................................................................................................. 6

4.1.4 Sanitation ............................................................................................................................................................................... 7

4.2 Documentation ....................................................................................................................................................................................... 7

4.2.1 General...................................................................................................................................................................................... 7

4.2.2 Crude drugs .......................................................................................................................................................................... 7

4.2.3 Finished traditional Chinese medicinal products ............................................................................... 8

4.2.4 Crude drug preparations .......................................................................................................................................... 9

4.2.5 Processing instructions .............................................................................................................................................. 9

4.3 Personnel ..................................................................................................................................................................................................10

4.3.1 General...................................................................................................................................................................................10

4.3.2 Crude drug control manager ..............................................................................................................................10

4.3.3 Training .................................................................................................................................................................................11

4.3.4 Personnel hygiene........................................................................................................................................................11

4.4 Change control .....................................................................................................................................................................................11

4.5 Deviation control ................................................................................................................................................................................11

4.6 Self-inspections ...................................................................................................................................................................................12

Annex A (normative) Manufacturing control ...........................................................................................................................................13

Annex B (normative) Quality control ................................................................................................................................................................15

Bibliography .............................................................................................................................................................................................................................17

© ISO 2018 – All rights reserved iii
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ISO 19617:2018(E)
Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards

bodies (ISO member bodies). The work of preparing International Standards is normally carried out

through ISO technical committees. Each member body interested in a subject for which a technical

committee has been established has the right to be represented on that committee. International

organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.

ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of

electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are

described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the

different types of ISO documents shall be noted. This document was drafted in accordance with the

editorial rules of the ISO/IEC Directives, Part 2 (see www .iso .org/ directives).

Attention is drawn to the possibility that some of the elements of this document may be the subject of

patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of

any patent rights identified during the development of the document will be in the Introduction and/or

on the ISO list of patent declarations received (see www .iso .org/ patents).

Any trade name used in this document is information given for the convenience of users and does not

constitute an endorsement.

For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and

expressions related to conformity assessment, as well as information about ISO's adherence to the

World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following

URL: www .iso .org/ iso/ foreword .html.

This document was prepared by Technical Committee ISO/TC 249, Traditional Chinese medicine.

iv © ISO 2018 – All rights reserved
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ISO 19617:2018(E)
Introduction

Natural products used in traditional Chinese medicine (TCM) are manufactured from materials of

natural origin, the quality of which is varied according to geographical, climatic and seasonal conditions.

For quality assurance of final products, quality evaluation on starting materials for natural products

used in TCM is essential. On the other hand, it is also important to handle these natural materials

appropriately and to control manufacturing processes for natural products used in TCM.

The management of manufacturing processes under good manufacturing practice (GMP) is

indispensable to ensure quality of medicinal products. International GMP was issued by World Health

Organization (WHO) in 1967, and a number of regional and international GMPs have subsequently

been established. Recently, Pharmaceutical Inspection Convention (PIC)/Pharmaceutical Inspection

Cooperation Scheme (PIC/S) has been widely applied around the world. At present, two-thirds of the

member bodies of ISO/TC 249 are affiliated with PIC/S and some other countries are waiting for review

of their applications.

These general GMPs were extensively applied to different fields and complimented with special

supplements for herbal medicines in some countries and organizations. However, these herbal GMPs

are focusing on European herbal medicines, but not covering those in the East Asian regions such as

China, Japan and Korea where traditional medicines are used.

The current herbal GMPs of WHO, EU or PIC/S are mainly based on single herbal products, and the

products consisting of more than one herbs were stipulated as special cases. However, multi-herbal

products are more common than single-herbal products in the East Asian regions. In addition, raw

materials in herbal GMPs of WHO, EU or PIC/S are only exclusive for plant origin, while traditional

medicines in East Asia also include animal and mineral materials. In order to use correct materials,

it is important to identify the starting materials not only by physical/chemical examinations but also

by perceptive identification by well-trained experts. However, the requirement for experts on natural

materials are not described in these international herbal GMPs. For a better safety and quality control of

TCM products, conventional GMPs for the manufacturing of herbal medicines are in need of improving

by this proposed standard.

Therefore, based on Chinese, Japanese and Korean herbal GMPs, and with reference to international

GMPs, this document specifies general requirements for manufacturing processes that are particularly

applied to natural products used in TCM. Implementation of this document with conventional GMPs

for general pharmaceutical products would make it possible for manufacturers to ensure the safety

and quality of natural products used in TCM, and at the same time prevent people in countries where

such products are used from health hazards caused by poor quality products as well as improving

their health. It will allow people to enjoy the benefits of natural products used in TCM for treatments

of diseases as well as promoting health. This document will also allow non-PIC/S member countries

to request quality assurance of the products to manufacturers and manufacturing countries with

reference to this document. Finally, this document will make it possible to complement and/or amend

WHO, EU and PIC/S herbal GMPs.
© ISO 2018 – All rights reserved v
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INTERNATIONAL STANDARD ISO 19617:2018(E)
Traditional Chinese medicine — General requirements for
the manufacturing process of natural products
1 Scope

This document specifies the general requirements for manufacturing processes to ensure the quality

of finished products used in traditional Chinese medicine (TCM). This document covers premises,

documentation, personnel, training, manufacturing control and quality control. This document applies

to the manufacturing of natural products used in and as TCM.

This document does not conflict with general pharmaceutical good manufacturing practices (GMPs).

This document applies to all materials of natural origin: medicinal plants, medicinal animals, medicinal

minerals, crude drugs or crude drug preparations.
2 Normative references
There are no normative references in this document.
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.

ISO and IEC maintain terminological databases for use in standardization at the following addresses:

— ISO Online browsing platform: available at http:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/

NOTE Traditional Chinese medicines include various types of items. The same material can be classified in

different categories (e.g. a powdered plant material can be both a crude herbal drug and a crude herbal drug

preparation or, in a packed form, a traditional Chinese medicinal product).
3.1
active ingredient

crude drug(s) or the crude drug preparation(s) of a traditional Chinese medicine(s)

[SOURCE: WHO guidelines on good manufacturing practices (GMP) for herbal medicines, modified]

3.2
constituent of known therapeutic activity

substance or group of substances that is chemically defined and known to contribute to the therapeutic

activity of a crude drug or of a preparation

[SOURCE: WHO guidelines on good manufacturing practices (GMP) for herbal medicines, modified]

3.3
marker substance
chemically defined constituent of a crude drug utilized for control purposes

Note 1 to entry: Marker substances contribute or not to the clinical efficacy. When they contribute to the clinical

efficacy, however, evidence that they are solely responsible for the clinical efficacy can be available or not.

Note 2 to entry: Marker substances are generally employed when constituents of known therapeutic activity are

not known or are not clearly identified, and are used to identify the crude drug or preparation or calculate their

quantity in the finished product.
© ISO 2018 – All rights reserved 1
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ISO 19617:2018(E)

[SOURCE: WHO guidelines on good manufacturing practices (GMP) for herbal medicines, modified]

3.4
medicinal animal
animal (wild or bred) used for medicinal purposes
3.5
medicinal mineral
mineral used for medicinal purposes
3.6
medicinal plant
plant (wild or cultivated) used for medicinal purposes

Note 1 to entry: Medicinal plants include crude drugs which could be derived from lichen, algae, fungi or higher

plants, such as leaves, flowers, fruit, fruiting bodies, seeds, stems, wood, bark, roots, rhizomes or other parts,

which are entire, fragmented or powdered.

[SOURCE: WHO guidelines on good manufacturing practices (GMP) for herbal medicines, modified]

3.7
bulk product

product that has completed all processing stages up to, but not including, final packaging

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.8
crude drug

medicinal part obtained from plants or animals, cell inclusions and secretions separated from the

origins, their extracts, and minerals

Note 1 to entry: Herbal materials include, in addition to medicinal parts, fresh juices, gums, fixed oils, essential

oils, resins and dry powders of herbs.

Note 2 to entry: In some countries, these materials are processed by various local procedures, such as steaming,

roasting or stir-baking with honey, alcoholic beverages or other materials.
3.9
crude drug preparation

basis for finished traditional medicinal products that may include comminuted or cut crude drugs, or

extracts, tinctures and fatty oils of crude drugs

Note 1 to entry: Crude drug preparations are produced by extraction, fractionation, purification, concentration,

or other physical or biological processes. They also include preparations made by steeping or heating crude drugs

in alcoholic beverages and/or honey, or in other materials.
3.10
extract

preparation of liquid (liquid extracts and tinctures), semi-solid (soft extracts and oleoresins) or solid

(dry extracts) consistency, obtained from medicinal plants, animals and minerals
3.11
finished product

finished dosage form that has undergone all stages of manufacture, including packaging in its final

container and labelling

Note 1 to entry: Natural products in this document includes finished products made from one or more crude drugs.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

2 © ISO 2018 – All rights reserved
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ISO 19617:2018(E)
3.12
finished traditional Chinese medicinal product
product consisting of crude drug preparations made from one or more crude drugs

Note 1 to entry: If more than one crude drug is used, the term “mixture crude drugs product” can also be used.

Note 2 to entry: Finished traditional Chinese medicinal products and mixture crude drugs products contain

excipients in addition to the active ingredients. However, finished traditional Chinese medicinal products

or mixture crude drugs products to which chemically defined active substances have been added, including

synthetic compounds and/or isolated constituents from crude drugs, are not considered to be crude drug

products.
3.13
material of natural origin
medicinal plant, animal or mineral
3.14
pharmaceutical product

material or product intended for human or veterinary use presented in its finished dosage form or as a

starting material for use in such a dosage form

Note 1 to entry: It is subject to control by pharmaceutical legislation in the exporting state and/or the

importing state.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.15
starting material

substance of a defined quality used in the production of a pharmaceutical product, but excluding

packaging materials

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.16
manufacture

operations of purchase of materials and products, production, quality control, release and storage of

pharmaceutical products, and the related controls

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.17
manufacturer

company that carries out operations such as production, packaging, repackaging, labelling and

relabelling of pharmaceuticals

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.18
blending

process of combining materials or different batches to produce a homogeneous intermediate or

finished product

[SOURCE: WHO guidelines on good manufacturing practices (GMP) for herbal medicines, modified]

3.19
packaging

operations, including filling and labelling, that a bulk product has to undergo in order to become a

finished product

Note 1 to entry: Filling of a sterile product under aseptic conditions or a product intended to be terminally

sterilized would not normally be regarded as part of packaging.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

© ISO 2018 – All rights reserved 3
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ISO 19617:2018(E)
3.20
production

operations involved in the preparation of a pharmaceutical product, from receipt of materials, through

processing, packaging and repackaging, labelling and relabelling, to completion of the finished product

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.21
qualification

action of proving that any premises, systems and items of equipment work correctly and actually lead

to the expected results

Note 1 to entry: The meaning of the word “validation” is sometimes extended to incorporate the concept of

qualification.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.22
quality assurance

concept covering all matters that individually or collectively influence the quality of a product

Note 1 to entry: It is the totality of the arrangements made with the object of ensuring that pharmaceutical

products are of the quality required for their intended use. Quality assurance therefore incorporates GMP and

other factors, including those outside the scope of this guide such as product design and development.

Note 2 to entry: Information on manufacturing control and quality control are provided in Annex A and B,

respectively.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.23
quarantine

physical or other effective means of isolation implemented while a decision is awaited on the release,

rejection or reprocessing of starting or packaging materials, intermediates or bulk or finished products

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.24
specification

list of detailed requirements with which the products or materials used or obtained during manufacture

have to conform
Note 1 to entry: They serve as a basis for quality evaluation.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.25
validation

action of proving, in accordance with the principles of GMP, that any procedure, process, equipment,

material, activity or system actually leads to the expected results
Note 1 to entry: See also qualification (3.21).

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.26
packaging material

material, including printed material, employed in the packaging of a pharmaceutical, but excluding any

outer packaging used for transportation or shipment

Note 1 to entry: Packaging materials are referred to as primary or secondary according to whether or not they

are intended to be in direct contact with the product.
4 © ISO 2018 – All rights reserved
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ISO 19617:2018(E)

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.27
contamination

undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into

or on to a starting material or intermediate during production, sampling, packaging or repackaging,

storage or transport

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.28
cross-contamination

contamination of a starting material, intermediate product or finished product with another starting

material or product during production

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.29
clean area

area with defined environmental control of particulate and microbial contamination, constructed and

used in such a way as to reduce the introduction, generation, and retention of contaminants within

the area

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.30
batch
lot

defined quantity of starting material, packaging material, or product that are processed in a single

process or series of processes so that it is expected to be homogeneous

Note 1 to entry: It is sometimes necessary to divide a batch into a number of sub-batches, which are later brought

together to form a final homogeneous batch.

Note 2 to entry: In the case of terminal sterilization, the batch size is determined by the capacity of the autoclave.

In continuous manufacture, the batch corresponds to a defined fraction of the production, characterized by its

intended homogeneity.

Note 3 to entry: The batch size can be defined either as a fixed quantity or as the amount produced in a fixed time

interval.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

3.31
consignment
delivery

quantity of a pharmaceutical(s), made by one manufacturer and supplied at one time in response to a

particular request or order

Note 1 to entry: A consignment comprises one or more packages or containers and includes material belonging to

more than one batch.

[SOURCE: WHO good manufacturing practices for pharmaceutical products: main principles, modified]

© ISO 2018 – All rights reserved 5
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ISO 19617:2018(E)
4 Assurance of manufacturing process
4.1 Premises
4.1.1 General

As a general principle, premises shall be designed, located, constructed, adapted and maintained to

suit the operations according to GMP, as the premises could be potentially affected by degradation

and infestation of certain pests and are sensitive to microbiological contamination, production, and

particularly storage of crude drugs and crude drug preparations.
4.1.2 Storage areas

a) Storage areas shall be well organized and tidy. Special attention shall be paid to cleanliness and

good maintenance. Any accidental spillage shall be cleaned up immediately using methods that

minimize the risk of cross-contamination of other materials, and shall be reported.

b) The areas shall be well labelled and crude drugs stored in such a way as to avoid any risk of cross-

contamination. An area shall be identified for the quarantine of all incoming crude drugs.

NOTE 1 The set-up of storage areas depends on the type of crude drugs stored.

c) Storage areas shall be laid out to permit effective and orderly segregation of the various categories

of materials stored, and to allow rotation of stock. Different crude drugs shall be stored in

separate areas.

d) Duration of storage of any crude drugs in unpacked form shall be kept to a minimum.

NOTE 2 Minimum duration of storage protect stored material, and reduce the risk of pest attacks.

e) Incoming crude drugs shall be processed, unless specified otherwise, as soon as possible and shall

be stored at appropriate temperature to prevent bacterial and fungal growth.

f) Where materials are stored in bulk, to reduce the risk of mould formation or fermentation it is

advisable to store them in aerated rooms or containers using natural or mechanical aeration and

ventilation. These areas shall also be equipped in such a way as to protect against the entry of

insects or animals, especially rodents. Effective measures shall be taken to limit the spread of

animals and microorganisms brought in with the crude drug and to prevent cross-contamination.

g) Crude drugs, even when stored in fibre drums, bags or boxes, shall be stored off the floor and

suitably spaced to permit cleaning and inspection.

h) Appropriate steps shall be taken to ensure that conditions of humidity and temperature or

protection from light are provided, maintained, monitored and recorded.

NOTE 3 The storage of crude drugs, extracts, tinctures and other preparations require special conditions

of humidity and temperature or protection from light.

i) Crude drugs shall be kept in a dry area protected from moisture and processed following the

principle of “first in, first out” (FIFO).
4.1.3 Production areas
a) Production areas shall comply with the general requirements of GMP.
b) As a rule, campaign work in their processing is necessary.
c) If feasible, the use of dedicated premises is encouraged.

d) The special nature of the production of traditional Chinese medicines requires that particular

attention be given to processing products that generate dust.
6 © ISO 2018 – All rights reserved
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ISO 19617:2018(E)

e) When heating or boiling of the materials is necessary, a suitable air exhaust mechanism shall be

employed to prevent accumulation of fumes and vapours.

f) Adequate precautions shall be taken during the sampling, weighing, mixing and processing of crude

drugs, e.g. by use of dust extraction and air-handling systems to achieve the desired differential

pressure and net airflow.
NOTE Adequate precautions facilitate cleaning and avoid cross-contamination.
4.1.4 Sanitation

a) A high-standard sanitation and hygiene requirement during manufacture is necessary.

NOTE 1 Crude drugs contain microbiological contaminants due to their natural origin. During harvesting

and processing, traditional Chinese medicinal products could be contaminated by microorganisms.

NOTE 2 High-standard sanitation and hygiene avoid alterations and reduce contamination.

b) The water supply to the manufacturing unit shall be monitored and, if necessary, treated

appropriately to ensure consistency of quality.

c) The quality of water for manufacturing shall be drinking water grade or higher.

d) Waste from the manufacturing unit shall be disposed of regularly so as to maintain a high standard

of hygiene in the manufacturing area.
e) Clearly marked waste-bins shall be available, emptied and cleaned as needed.
4.2 Documentation
4.2.1 General
The general principles for documentation shall comply w
...

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