GMP in Natural Medicine

 

WHO GMP Guideline

What is GMP?

In July 1969, WHO (World Health Organization) at its 22nd Health Assembly laid the importance of GMP (Good Manufacturing Practices) which has been well accepted worldwide and became a common practice in the pharmaceutical industry. GMP offers guidelines & standards for manufacturing process & premises. It details standards on location, surrounding, building, plant & equipment, quality control, raw material, procedures, etc. to ensure that the consumer gets high quality products as per the prescribed standards laid by the Govt.

Why GMP?

Every consumer is entitled to receive medicines of the Best Quality, thus value for his/her money. The liability of quality lies with the manufacturer, who is bound to keep documented proof for the same.


GMP in Natural Medicine


Government of Bangladesh notified G.M.P. rules for all Natural Medicine manufacturers. Subsequently it came to effect. Any contamination not only reduces the efficacy of the product but can even be detrimental to its action since in Natural Medicine the therapeutic doses are very minute. Extreme cleanliness is an absolute necessity during Natural Medicine manufacturing.


 10 Golden Rule for GMP

 

Golden Rule #1

 

Get the facility design right from the start 

 

all manufacturing processes are clearly  defined,  systematically reviewed in the light  of experience,  and shown  to be  capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;

 

Golden Rule #2

 

Validate processes

 

Qualification and validation are performed;

 

Golden Rule #3

 

Write good procedures and follow them

 

Instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;

 

Golden Rule #4

 

Identify who does what

 

Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

 

 Golden Rule #5

 

Keep good records

 

Records are made (manually and/or  by recording  instruments) during manufacture to show that all the steps required by the defined procedures and  instructions have  in  fact been  taken and that  the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated;

 

Golden Rule #6

 

Train and develop staff

 

Operators are trained to carry out procedures correctly.

 

Golden Rule #7

 

Practice good hygiene

 

The proper storage and distribution of the products minimizes any risk to their quality;

Golden Rule #8

 

Maintain facilities and equipment

 

All necessary resources are provided, including:

(i) Appropriately qualified and trained personnel;

 (ii) adequate premises and space;

(iii) Suitable equipment and services;

(iv) Appropriate materials, containers and labels;

(v) approved procedures and instructions;

(vi) Suitable storage and transport;

(vii) Adequate personnel, laboratories and equipment for in-process controls;

 

Golden Rule #9

 

Build quality into the whole product lifecycle

 

a system is available  to  recall any  batch of  product from sale  or supply;

 

 Golden Rule #10

 

Perform regular audits

 

complaints about marketed  products are  examined, the  causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.

 

GMP for Natural Medicine

 

  1. 1.    Quality assurance in the manufacture of Natural medicines

 

 In addition to the  use of modern analytical techniques (especially high performance  thin-layer chromatography (HPTLC), gas  chromatography  (GC), high performance liquid chromatography (HPLC), capillary electrophoresis (CE), mass spectrometry (MS) and atomic  absorption  (AA) to  characterize  Natural medicines, quality  assurance  also requires  the control of  starting  materials, storage and processing. For this reason, an appropriate quality assurance system should be applied in the manufacture of Natural medicines. 

 

  1. 2.    Good manufacturing practice for Natural medicines

 

2.1   The general principles of GMP are set out in the parent guidelines.  Cultivation and collection of medicinal plants, as the starting materials for natural medicines, are covered by other guidelines (7). The first critical step of their production where the application of GMP starts should be clearly designated (see subsection 16.1). This is of particular importance for those products which consist solely of comminuted or powdered herbal materials.

 

  1. 3.    Sanitation and hygiene

 

3.1   Because of their origin, herbal materials may contain microbiological contaminants. Furthermore, during the course of harvesting and processing, natural products that may be especially prone to microbiological contamination are produced. To avoid alterations and to reduce contamination in general, a high level of sanitation and hygiene during manufacture is necessary (for guidelines on personal hygiene see section 11, and for those on sanitation see section 12).

 

3.2   Water supply to the manufacturing unit should be monitored, and, if necessary treated appropriately to ensure consistency of quality.

 

3.3   Waste from the manufacturing unit should be disposed of regularly so as to maintain a high standard of  hygiene in the manufacturing area. Clearly marked waste-bins should be available, emptied and cleaned as needed, but at least daily.

 

  1. 4.    Qualification and validation

 

4.1   Qualification of critical equipment, process validation and change control are particularly important in the production of natural herbs with unknown therapeutically active constituents. In this case, the reproducibility of the production process is the main means for ensuring consistency of quality, efficacy and safety between batches.

 

4.2   The written procedure should specify critical process steps and factors (such as extraction time, temperature and solvent purity) and acceptance criteria, as well as the type of validation to be conducted (e.g. retrospective, prospective or concurrent) and the number of process runs.

 

4.3   A formal change control system should be established to evaluate the potential effects of any changes on the quality of the natural medicines, particularly content of the active ingredients. Scientific judgment should be used to determine which additional testing and validation studies are appropriate to justify a change in a validated process.

 

  1. 5.    Complaints

 

5.1   The person responsible for handling complaints and deciding on the measures to be taken to deal with them should have appropriate training and/or experience in the specific features of the quality control of natural medicines.

 

5.2   There are basically two types of complaint, product quality complaints and adverse reactions/events.

 

5.3   The first type of complaint may be caused by problems such as faulty manufacture, product defects or deterioration as well as, particular to natural medicines, adulteration of the herbal material. These complaints should be recorded in detail and the causes thoroughly investigated (e.g. by comparison with the reference samples kept from the same batch).  There should also be written procedures to describe the action to be taken.

 

5.4   To address the second type of complaint, reports  of  any adverse reaction/event  should be entered in a separate register in accordance with national and international requirements. An investigation should be conducted to find out whether the adverse reaction/event is due to a quality problem and whether such reactions/events have already been reported in the literature or whether it is a  new observation.  In either case, complaint  records  should be reviewed regularly to detect any specific or recurring problems requiring special

attention and possible recall of marketed products. The          WHO guidelines on safety

monitoring of herbal medicines in pharrmaco vigilance systems         deal with specific issues

relating to adverse reactions and adverse events following treatment with natural medicines (9).

 

5.5   The licensing  authority should be  kept  informed  of any complaints leading to a recall or restriction on supply and the records should be available for inspection.

 

  1. 6.    Product recalls

 

6.1   The  product recall  procedure  depends very much on  the  national regulations. There should be a standard operating procedure (SOP) for storage of recalled  natural medicines in a secure segregated  area,  complying with the requirements specified under subsection 12.1 (Storage areas), while their fate is decided.

 

  1. 7.    Contract production and analysis

 

7.1   The contract partner should have adequate premises and equipment for the production of natural medicines according to GMP. Validated methods should be applied for cleaning the equipment and premises carefully before using them

to produce different natural medicinal, food or cosmetic products. In the case of raw materials used for producing food, it is realistic to require manufacturing departments to be separated from those where the plant raw material will be cut or powdered for use in the preparation of medicines.

 

7.2   Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable on the specific characteristics of herbal medicines, including their production and quality control testing.

 

  1. 8.    Self-inspection

 

8.1   At least one member of the self-inspection team should possess a thorough knowledge of natural medicines.

 

 9.    Personnel

 

9.1          Principle. The establishment and maintenance of a satisfactory system of

quality assurance and the correct manufacture  and control of pharmaceutical products and active ingredients rely upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for which the manufacturer is responsible. Individual responsibilities should be clearly defined and understood by the persons concerned and recorded as written descriptions.

General

9.2  The manufacturer should have an adequate number of personnel with the

necessary qualifications and practical experience. The responsibilities placed on

any one individual should not be so extensive as to present any risk to quality.

9.3.   All responsible staff should have their specific duties recorded in written descriptions and adequate authority to carry out their responsibilities. Their

duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of personnel concerned with the application of GMP. The manufacturer should have an organization chart.

9.4   All personnel should be aware of the principles of GMP that affect them and  receive initial and continuing training, including  hygiene instructions, relevant to their needs.  All personnel should be motivated to support the establishment and maintenance of high quality standards.

9.5   Steps should be taken to prevent unauthorized people from entering production, storage and quality control areas. Personnel who do not work in these areas should not use them as a passageway.

Key personnel

9.6   Key personnel include the head of production, the head of quality control and the authorized person. Normally, key posts should be occupied by full-time personnel. The heads of production and quality control should be independent of each other. In large organizations, it may be necessary to delegate some of the functions; however, the responsibility cannot be delegated.

9.7   Key personnel responsible for supervising the manufacture and quality control of pharmaceutical products should possess the qualifications of a scientific education and practical experience required by national legislation. Their education should include the study of an appropriate combination of:

  1. chemistry (analytical or organic) or biochemistry;
  2. chemical engineering;
  3. microbiology;
  4. pharmaceutical sciences and technology;
  5. pharmacology and toxicology;
  6. physiology;
  7. other related sciences.

They should also have adequate practical experience in the manufacture and quality assurance of pharmaceutical products. In order to gain such experience, a preparatory period may be required, during which they should exercise their duties  under  professional guidance.  The scientific  education and  practical experience of experts should be such as to enable them to exercise independent professional judgement, based on  the  application of  scientific  principles  and understanding to the  practical problems encountered  in  the manufacture  and quality control of pharmaceutical products.

9.8   The heads of the production and quality control generally have some shared, or  jointly  exercised, responsibilities  relating to quality. These may include, depending on national regulations:

  1. authorization of written procedures and other documents, including amendments;
  2. monitoring and control of the manufacturing environment;
  3. plant hygiene;
  4. process validation and calibration of analytical apparatus;
  5. training, including the  application  and  principles of quality assurance;
  6. approval and monitoring of suppliers of materials;
  7. approval and monitoring of contract manufacturers;  

 

  1. designation and monitoring of storage conditions for materials and products;
  2. performance and evaluation of in-process controls;
  3. retention of records;
  4. monitoring of compliance with GMP requirements;
  5. inspection, investigation and taking of samples in order to monitor factors that may affect product quality.

9.9   The head of production generally has the following responsibilities:

  1. to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;
  2. to approve  the instructions relating to  production operations, including  the  in-process controls, and to ensure  their  strict implementation;
  3. to ensure that the production records are evaluated and signed by a designated person;
  4. to check the  maintenance of the department,  premises,  and equipment;
  5. to ensure that the appropriate process validations and calibrations of control equipment are performed and recorded and the reports made available;
  6. to ensure  that the  required initial  and  continuing training of production personnel is carried out and adapted according to need.

9.10   The head  of  the quality  control  generally has the  following responsibilities:

  1. to approve or reject  starting materials, packaging materials,  and intermediate,  bulk and finished  products in relation with  their specifications;
  2. to evaluate batch records;
  3. to ensure that all necessary testing is carried out;
  4. to approve  sampling instructions, specifications,  test  methods  and other quality control procedures;
  5. to approve and monitor analyses carried out under contract;
  6. to  check the maintenance of the  department,  premises  and equipment;
  7. to ensure that the  appropriate  validations,  including those  of analytical  procedures,  and calibrations  of control  equipment are carried out;
  8. to ensure that the required initial and continuing training of quality control personnel is carried out and adapted according to need.

Other duties of the quality control staff are summarized in sections 17.3 and 17.4.

9.11   The authorized person is responsible for compliance with technical or regulatory requirements related to the quality of finished products and the approval of the release of the finished product for sale.

9.12   The authorized person will also be involved in other activities, including the following:

  1. implementation (and,  when  needed, establishment) of  the quality system;

 

  1. participation in the development of the company’s quality manual;
  2. supervision of the regular internal audits or self-inspections;
  3. oversight of the quality control department;
  4. participation in external audit (vendor audit);
  5. Participation in validation programmes.

9.13   The function of the approval of the release of a finished batch or a product can be delegated to a designated person with appropriate qualifications and

Experience who will release the product in accordance with an approved

procedure. This is normally done by quality assurance by means of batch review.

9.14   The person responsible for approving a batch for release should always ensure that the following requirements have been met:

  1. the marketing authorization  and the manufacturing authorization requirements for the product have been met for the batch concerned;
  2. the principles and guidelines of GMP, as laid down in the guidelines published by WHO, have been followed;
  3. the principal manufacturing and  testing processes have  been validated, if different;
  4. all the necessary checks and tests have been performed and account taken of the production conditions and manufacturing records;
  5. any  planned changes  or  deviations in manufacturing  or quality control have been notified  in accordance  with a  well  defined reporting system before any product is released. Such changes may need notification to, and approval by, the drug regulatory authority;
  6. any  additional sampling,  inspection, tests and checks  have been carried out or initiated, as appropriate, to cover planned changes and deviations;
  7. all necessary production and quality control documentation has been completed  and  endorsed by  supervisors trained in appropriate disciplines;
  8. appropriate audits, self-inspections and spot-checks are carried out by experienced and trained staff;
  9. approval has been given by the head of quality control;
  10. all relevant factors have been  considered, including any not specifically associated with the output batch directly under review (e.g. subdivision of output batches  from a common  input, factors associated with continuous production runs).

 

 9.15   The release of natural medicines should be authorized by a person who has been trained in the specific features of the processing and quality control of herbal materials, herbal preparations and finished herbal products.

 

9.16   Personnel dealing with the production and quality control of natural medicines should have adequate training in the specific issues relevant to natural medicines.

 

  1. 10.                        Training

 

10.1   The personnel should have adequate training in appropriate fields such as pharmaceutical technology, taxonomic botany, phytochemistry, pharmacognosy, hygiene, microbiology and related subjects (such as traditional use of natural medicines).

 

10.2   Training records should be maintained and periodic assessments of the effectiveness of training programmes should be made.

 

  1. 11.                        Personal hygiene

 

11.1   Personnel entrusted with the handling of herbal materials, herbal preparations and finished herbal products should be required to have a high degree of personal hygiene and to have received adequate training in maintaining appropriate standards of hygiene. The personnel should not work if they have infectious diseases or skin diseases.  Written procedures listing the basic hygiene requirements should be made available.

 

11.2   Personnel must be protected from contact with toxic irritants and potentially allergenic plant materials by means of adequate protective clothing. They should wear suitable gloves, caps, masks, work suits and shoes throughout the whole procedure from plant processing to product manufacture.

 

 12.                        Premises

 

 12.1   As a general principle, premises should be designed, located, constructed, adapted and maintained to suit the operations to be carried out according to

General

12.2   The layout and design of premises must aim to minimize the risk of errors and  permit effective  cleaning  and maintenance in order to  avoid cross- contamination, build-up of dust or dirt, and, in general, any adverse effect on the quality of products.

12.3   Where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of powder), measures should be taken to avoid cross-contamination and facilitate cleaning.

12.4   Premises should be situated in an environment that, when considered together with measures to protect the manufacturing process, presents minimum risk of causing any contamination of materials or products.

12.5   Premises used for the manufacture of finished products should be suitably designed and constructed to facilitate good sanitation.

12.6   Premises should be carefully maintained, and it should be ensured that repair and maintenance operations do not present any hazard to the quality of products.

12.7   Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Records should be maintained.

12.8   Electrical supply, lighting, temperature, humidity and ventilation should be appropriate and such that they do not adversely affect, directly or indirectly, either the pharmaceutical products during their manufacture and storage, or the accurate functioning of equipment.

12.9   Premises should be designed and equipped so as to afford maximum protection against the entry of insects, birds or other animals. There should be a procedure for rodent and pest control.

12.10   Premises should be designed to ensure the logical flow of materials and personnel.

 

Ancillary areas

12.11   Rest and refreshment rooms should be separate from manufacturing and control areas.

12.12   Facilities for changing and storing clothes and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not communicate directly with production or storage areas.

12.13   Maintenance workshops should if possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.

.

12.14   Because of their potential for degradation and infestation with certain pests as well as their sensitivity to microbiological contamination, production, and particularly storage, of herbal materials and herbal preparations assume special importance.

 

Storage areas

 

12.3   Storage areas should be well organized and tidy. Special attention should be paid to cleanliness and good maintenance. Any accidental spillage should be cleaned up immediately using methods that minimize the risk of cross- contamination of other materials, and should be reported.

 

12.4   The set-up of storage areas depends on the type of materials stored. The areas should be well labelled and materials stored in a such way as to avoid any risk of cross-contamination. An area should be identified for the quarantine of all incoming herbal materials.

 

12.5   Storage areas should be laid out to permit effective and orderly segregation of the various categories of materials stored, and to allow rotation of stock. Different herbal (natural) materials should be stored in separate areas.

 

12.6   To protect the stored material, and reduce the risk of pest attacks, the duration of storage of any herbal (natural) material in unpacked form should be kept to a minimum.

 

12.7   Incoming fresh herbal (natural) materials should be processed, unless specified otherwise, as soon as possible. If appropriate, they should be stored between 2 °C and 8 °C, whereas frozen materials should be stored below –18 °C.

 

12.8   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 should also be equipped in such a way as to protect against the entry of insects or animals, especially rodents.  Effective measures should be taken to limit the spread of animals and microorganisms brought in with the plant material and to prevent cross-contamination.

 

12.9   Herbal (natural) materials, even when stored in fiber drums, bags or boxes, should be stored off the floor and suitably spaced to permit cleaning and inspection.

 

12.10   The storage of plants, extracts, tinctures and other preparations may require special conditions of humidity and temperature or protection from light; appropriate steps should be taken to ensure that these conditions are provided, maintained, monitored and recorded.

 

12.11   Herbal materials, including raw herbal (natural) materials, should be kept in a dry area protected from moisture and processed following the principle of “first in, first out” (FIFO).

 

Production areas

12.12   Production areas should comply with the general requirements of      WHO

good manufacturing practices for pharmaceutical products: main principles.  As a rule, campaign work in their processing is necessary. However, if feasible, the use of dedicated premises is encouraged. Moreover, the special nature of the production of natural medicine requires that particular attention be given to processing products that generate dust. When heating or boiling of the materials is necessary, a suitable air exhaust mechanism should be employed to prevent accumulation of fumes and vapors.

 

12.13   To facilitate cleaning and to avoid cross-contamination, adequate precautions should be taken during the sampling, weighing, mixing and processing of medicinal plants, e.g. by use of dust extraction and air-handling systems to achieve the desired differential pressure and net airflow. 

 
 

  1. 13.                         Equipment

 

13.1   Processing of herbal (natural) materials may generate dust or material which is susceptible to pest-infestation or microbiological contamination and cross- contamination. Effective cleaning of the equipment is therefore particularly important.

 

13.2   Vacuum or wet-cleaning methods are preferred. If wet-cleaning is done, the equipment should be dried immediately after cleaning to prevent the growth of microorganisms. Cleaning with compressed air and brushes should be done with care and avoided if possible, as these methods increase the risk of product contamination.

13.3   Non-wooden equipment should be used unless tradition demands wooden material. Where it is necessary to use traditional equipment (such as wooden implements, clay pots, pallets, hoppers, etc.), this should be dedicated, unless otherwise justified. When such equipment is used, it is advisable that it does not come into direct contact with chemicals or contaminated material. If the use of wooden equipment is unavoidable, special consideration must be given to its cleaning as wooden materials may retain odours, be easily discoloured and are easily contaminated.

 

  1. 14.                         Materials

 

 14.1 All incoming herbal materials should be quarantined and stored under appropriate conditions that take into account the degradability of herbal materials and herbal preparations.

 

14.2   Only permitted substances should be used for fumigation, and allowable limits for their residues together with specifications for the apparatus used should be set according to the national regulations.

 

Reference samples and standards

 

14.3   The reference standard for a natural medicine may be a botanical sample of the herbal material; a sample of the herbal preparation, e.g. extract, or  a chemically defined substance,  e.g. a  known active  constituent,  a marker substance or a known impurity. The reference standard should be of a quality appropriate to its purpose. If the herbal medicine is not described in a recognized pharmacopoeia, a herbarium sample of the flowering or fruiting top of the whole medicinal plant or part of the medicinal plant (e.g. if the whole medicinal plant is a tree) should be available. All reference standards should be stored under appropriate conditions to prevent degradation. Their expiry and/or revalidation date should be determined and indicated.

 

  1. 15.                         Documentation

 

15.1   The general principles for documentation are set out in the       WHO good

manufacturing practices for pharmaceutical products: main principles.

 

15.1        Principle. Good documentation is an essential part of the quality

assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the  specifications and  procedures for  all materials and methods of manufacture and control; to  ensure that all  personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a  drug  for sale, to ensure  the existence of documented  evidence, traceability, and to  provide records and an audit trail that  will  permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of  documents depend  upon the manufacturer. In some cases some or all of the documents described below may be brought together, but they will usually be separate.

General

15.2   Documents should be designed, prepared, reviewed and distributed with care.  They should comply with the relevant parts of the manufacturing and marketing authorizations.

15.3   Documents should be approved, signed and dated by the appropriate responsible persons. No document should be changed without authorization and approval.

15.4   Documents should have unambiguous contents: the title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

15.5   Documents should be regularly reviewed and kept up to date. When a document has been revised, a system should exist to prevent inadvertent use of the superseded version. Superseded documents should be retained for a specific period of time.

15.6   Where documents require the entry of data, these entries should be clear, legible and indelible. Sufficient space should be provided for such entries.

15.7   Any alteration made to a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

15.8   Records should be made or completed when any action is taken and in such a way that all significant activities concerning the manufacture of pharmaceutical products are traceable. Records should be retained for at least one year after the expiry date of the finished product.

15.9   Data (and records for storage) may be recorded by electronic data- processing systems or by photographic or other reliable means. Master formulae

and detailed standard operating procedures relating to the system in use should

be available and the accuracy of the records should be checked. If documentation is handled by electronic data-processing methods, only authorized persons should be able to enter or modify data in the computer, and there should be a record of changes and deletions; access should be restricted by passwords or other means and the entry of critical data should be independently checked. Batch records stored electronically should be protected by back-up transfer on magnetic tape, microfilm, paper print-outs or other means.  It is particularly important that, during the period of retention, the data are readily available.

Documents required

Labels

15.10   Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g. quarantined, accepted, rejected, and clean).

15.11   All finished drug products should be identified by labelling, as required by the national legislation, bearing at least the following information:

  1. a.   the name of the drug product;
  2. b.   a list of the active ingredients (if applicable, with the INNs), showing the amount of each present and a statement of the net contents (e.g. number of dosage units, weight, volume);
  3. c.   the batch number assigned by the manufacturer;
  4. d.  the expiry date in an uncoded form;
  5. e.   any special storage conditions or handling precautions that may be necessary;
  6. f.    directions for use,  and warnings and  precautions  that  may be necessary;
  7. g.  the name and address of the manufacturer or the company or the person responsible for placing the product on the market.

15.12   For reference standards, the  label and/or accompanying document should indicate potency or concentration, date of manufacture, expiry date, date the closure is first opened, storage  conditions and control  number, as appropriate.

Specifications and testing procedures

15.13   Testing procedures described in documents should be validated in the context of available facilities and equipment before they are adopted for routine testing.

15.14   There should be appropriately authorized and  dated  specifications, including tests on identity, content, purity and quality, for starting  and packaging materials and for finished products; where appropriate, they should also be available  for  intermediate or  bulk products. Specifications for water, solvents and reagents (e.g.  acids and bases)  used in  production should  be included.

15.15   Each specification should be approved, signed and dated, and maintained by quality  control, the  quality  assurance unit  or documentation centre. Specifications for starting materials, intermediates, and bulk, finished products and packaging materials are referred to in sections 15.18–15.21.

 

15.16   Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia or other official compendia.

15.17   Pharmacopoeias, reference standards, reference spectra and other reference materials should be available in the quality control laboratory.

Specifications for starting and packaging materials

15.18   Specifications for starting, primary and printed packaging materials should provide, if applicable, a description of the materials, including:

  1. a.   the designated  name  (if  applicable, the INN) and internal code reference;
  2. b.   the reference, if any, to a pharmacopoeial monograph;
  3. c.   qualitative and quantitative requirements with acceptance limits.

Depending on the company’s practice, other data may be added to the specification, such as:

  1. a.   the supplier and the original producer of the materials;
  2. b.   a specimen of printed materials;
  3. c.   directions for sampling and testing, or a reference to procedures;
  4. d.  storage conditions and precautions;
  5. e.   the maximum period of storage before re-examination.

Packaging material should conform to specifications, and should be compatible with the material and/or with the drug product it contains. The material should be examined for compliance with the specification, and for defects as well as for the correctness of identity markings.

15.19   Documents describing testing procedures should state the required frequency for re-assaying each starting material, as determined by its stability.

Specifications for intermediate and bulk products

15.20   Specifications for intermediate and bulk products should be available. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.

Specifications for finished products

15.21   Specifications for finished products should include:

  1. a.   the designated name of the product and the code reference, where applicable;
  2. b.   the designated name(s) of the active ingredient(s) (if applicable, with the INN(s));
  3. c.   the formula or a reference to the formula;
  4. d.  a description of the dosage form and package details;
  5. e.   directions for sampling and testing or a reference to procedures;
  6. f.    the qualitative and quantitative requirements, with acceptance limits;
  7. g.  the storage conditions and precautions, where applicable;
  8. h.  the shelf-life.

Master formulae

15.22   A formally authorized master formula should exist for each product and batch size to be manufactured.  

 

 15.23   The master formula should include:

  1. a.   the name of the product, with a product reference code relating to its specification;
  2. b.   a description of the dosage form, strength of the product and batch size;
  3. c.   a list of all starting materials to be used (if applicable, with the INNs), with the amount of each, described using the designated name and a reference that is unique to that material (mention should be made of any substance that may disappear in the course of processing);
  4. d.  a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable;
  5. e.   a statement of the processing location and the principal equipment to be used;
  6. f.    the methods, or reference to the methods, to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product), assembling, calibrating, sterilizing, use;
  7. g.  detailed step-wise processing instructions (e.g. checks on materials, pretreatments,  sequence for adding materials,  mixing times, temperatures);
  8. h.  the instructions for any in-process controls with their limits;
  9. i.    where necessary, the  requirements for storage of the products, including the container, the  labelling,  and  any  special storage conditions;
  10. j.    any special precautions to be observed.

Packaging instructions

15.24   Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to:

  1. a.   the name of the product;
  2. b.   a description of its pharmaceutical form, strength and, where applicable, method of application;
  3. c.   the pack size expressed in terms of the number, weight or volume of the product in the final container;
  4. d.  a complete list of all the packaging materials required for a standard batch size, including  quantities, sizes and types, with the code or reference number  relating to the  specifications  for each  packaging material;
  5. e.   where appropriate,  an example or reproduction of the relevant printed packaging  materials and specimens,  indicating where  the batch number and expiry date of the product have been marked;
  6. f.    special precautions to be observed, including a careful examination of the  packaging area and equipment in order to ascertain  the line clearance before and after packaging operations;
  7. g.  a description of the packaging operation, including any significant subsidiary operations, and equipment to be used;
  8. h.  details of in-process controls  with instructions  for  sampling  and acceptance limits.

Batch processing records

15.25   A batch processing record should be kept for each batch processed. It

Should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors.  (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.)

15.26   Before any processing begins, a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded.

15.27   During processing, the following information should be recorded at the time each action is taken, and after completion the record should be dated and signed by the person responsible for the processing operations:

  1. a.   the name of the product;
  2. b.   the number of the batch being manufactured;
  3. c.   dates and times of commencement, of significant intermediate stages, and of completion of production;
  4. d.  the name of the person responsible for each stage of production;
  5. e.   the initials of the  operator(s) of  different significant steps  of production and,  where appropriate, of the  person(s) who checked each of these operations (e.g. weighing);
  6. f.    the batch number and/or analytical control number and the quantity of each starting  material actually  weighed (including the batch number  and amount of any  recovered or reprocessed material added);
  7. g.  any relevant processing operation or event and the major equipment used;
  8. h.  the  in-process controls performed, the  initials  of the  person(s) carrying them out, and the results obtained;
  9. i.    the amount of product obtained at different and pertinent stages of manufacture (yield), together  with comments or explanations for significant deviations from the expected yield;
  10. j.    notes on special  problems including  details, with signed authorization for any deviation from the master formula.

Batch packaging records

15.28   A batch packaging record should be kept for each batch or part batch processed. It should be based on the relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors.  (Copying or validated computer programs are recommended. Transcribing from approved documents should be avoided.)

15.29   Before any packaging operation begins, checks should be made that the equipment  and  work station are  clear of previous products, documents  or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. These checks should be recorded.

15.30   The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password:

  1. a.  the name of the product, the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned

 

quantity of  finished  product that will be obtained, the quantity actually obtained and the reconciliation;

  1. b.   the date(s) and time(s) of the packaging operations;
  2. c.   the name  of  the responsible  person carrying out the  packaging operation;
  3. d.  the initials of the operators of the different significant steps;
  4. e.   the checks made for identity and conformity with  the  packaging instructions, including the results of in-process controls;
  5. f.    details of the packaging operations carried out, including references to equipment and the packaging lines used, and, when necessary, the instructions for keeping  the  product unpacked or  a  record of returning product that has not been packaged to the storage area;
  6. g.  whenever possible, samples of the printed packaging materials used, including specimens  bearing the  approval for  the  printing  of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;
  7. h.  notes  on any special  problems,  including details of any deviation from  the packaging  instructions,  with written authorization by  an appropriate person;
  8. i.    the quantities and reference number or identification of all printed packaging  materials and bulk  product issued, used,  destroyed or returned to stock and the quantities of product obtained to permit an adequate reconciliation.

Standard operating procedures (SOPs) and records

15.31   Standard operating procedures and associated records of actions taken or, where appropriate, conclusions reached should be available for:

  1. a.   equipment assembly and validation;
  2. b.   analytical apparatus and calibration;
  3. c.   maintenance, cleaning and sanitization;
  4. d.  personnel matters including  qualification, training, clothing  and hygiene;
  5. e.   environmental monitoring;
  6. f.    pest control;
  7. g.  complaints;
  8. h.  recalls;
  9. i.    returns.

15.32   There should be standard operating procedures and records for the receipt of each delivery of starting material and primary and printed packaging material.

15.33   The records of the receipts should include:

  1. a.   the name of the material on the delivery note and the containers;
  2. b.   the  in-house name and/or code of material if different from (a);
  3. c.   the date of receipt;
  4. d.  the supplier’s name and, if possible, manufacturer’s name;
  5. e.   the manufacture’s batch or reference number;
  6. f.    the total quantity, and number of containers received;
  7. g.  the batch number assigned after receipt;
  8. h.     any relevant comment (e.g. state of the containers).

 

 

15.34   There should be standard operating procedures for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

15.35   Standard operating procedures should be available for each instrument and piece of equipment (e.g. use, calibration, cleaning, maintenance) and placed in close proximity to the equipment.

15.36   There should be standard operating procedures for sampling, which specify the person(s) authorized to take samples.

15.37   The sampling instructions should include:

  1. a.   the method of sampling and the sampling plan;
  2. b.   the equipment to be used;
  3. c.   any  precautions to  be observed  to avoid contamination of the material or any deterioration in its quality;
  4. d.  the amount(s) of sample(s) to be taken;
  5. e.   instructions for any required subdivision of the sample;
  6. f.    the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling, and labelling;
  7. g.  any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material.

15.38   There should be a standard operating procedure describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number.

15.39   The standard operating procedures for batch numbering that are applied to the processing stage and to the respective packaging stage should be related to each other.

15.40   The standard operating procedure for batch numbering should ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing.

15.41   Batch-number allocation should be immediately recorded, e.g. in a logbook.  The record should include at least the date of allocation, product identity and size of batch.

15.42   There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded.

15.43   Analysis records should include at least the following data:

  1. a.   the name of the material or product and, where applicable, dosage form;
  2. b.   the batch number and, where appropriate, the manufacturer and/or supplier;
  3. c.   references to the relevant specifications and testing procedures;
    1. d.                 test results, including observations and calculations, and reference to any specifications (limits); 

 

  1. e.   date(s) and reference number(s) of testing;
  2. f.    the initials of the persons who performed the testing;
  3. g.  the date and initials of the persons who verified the testing and the calculations, where appropriate;
  4. h.  a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.

15.44   Written release and rejection procedures should be available for materials and products, and in particular for the release for sale of the finished product by an authorized person.

15.45   Records should be maintained of the distribution of each batch of a product in order, e.g. to facilitate the recall of the batch if necessary.

15.46   Records should be kept for major and critical equipment, as appropriate,

of any  validations, calibrations,  maintenance,  cleaning, or repair operations,

including dates and the identity of the people who carried these operations out.

15.47   The use of major and critical equipment and the areas where products

have been processed should be appropriately recorded in chronological order.

15.48   There should be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned. Such written procedures should be followed.

 

Specifications

 

15.2   The specifications for herbal starting materials, for herbal preparations and finished herbal products are primarily intended to define the quality rather than to establish full characterization, and should focus on those characteristics found to be useful in ensuring safety and efficacy. Consistent quality for herbal medicines (finished herbal products) can only be assured if the starting herbal materials are defined in a rigorous and detailed manner. In some cases more detailed information may be needed on aspects of collection or agricultural production. For instance, the selection of seeds, conditions of cultivation and harvesting are important aspects in producing a reproducible quality of natural medicines (7). Their characterization (which also includes a detailed evaluation of

the botanical and phytochemical aspects of the medicinal plant, manufacture of the herbal preparation and the finished herbal product) is therefore essential to allow  the establishment  of specifications  which are both comprehensive and relevant.

 

15.3   For this reason, in addition to the data called for in       WHO good

manufacturing practices for pharmaceutical products: main principles          (see above),

the specifications for  herbal materials  should  as far as  possible  include, as a minimum, the following information:

15.4     Herbal materials

            The family and botanical name of the plant used according to the binomial system (genus, species, variety and the authority, i.e. the reference to the originator of the classification, e.g. Linnaeus). It may also be appropriate to add the vernacular name and the therapeutic use in the country or region of origin of the plant.

           

Details of the source of the plant, such as country and/or region (also state and province, if applicable) of origin, whether it was cultivated or collected from the wild and, where applicable, method of cultivation, dates and conditions of harvesting (e.g. whether there was extreme weather), collection procedures, collection area, and brand, quantity and

date of pesticide application, as required by the          WHO Guideline on good

agricultural and collection practices   (7).

           

Whether the whole plant or only a part is used. In the latter case, which part of the plant is used and its state, e.g. whole or reduced. For dried plant material, the drying system should be specified, if applicable.

A description of the plant material based on visual (macroscopic) and/or microscopic examination.

Suitable identity tests including, where appropriate, identification tests (such as TLC or other chromatographic fingerprint) for known active ingredients or markers. A reference sample should be available for identification purposes.

Details of the assay, where appropriate, of active constituents or markers.

Limit tests such as dry residue of liquids, ash value (total ash, and ash insoluble in hydrochloric acid), water-soluble extractives, moisture/water content and loss on drying (taking into account the presence of essential oils if any).

Suitable methods for the determination of possible pesticide contamination and the acceptable limits for such contamination in herbal materials or herbal preparations used in the manufacture of natural medicines.

Tests for toxic metals and for likely contaminants, foreign materials and adulterants.

Tests for fungal and/or microbiological contamination, fumigant residues (if applicable), mycotoxins, pest-infestations, radioactivity and their acceptable limits.

Other  appropriate tests (e.g.  Particle size, swelling index and residual solvents in herbal preparations and biological fingerprints such as induced fluorescent markers).

 

15.5   Specifications for starting materials (and also of primary or printed packaging materials) should include, if applicable, reference to a pharmacopoeial monograph.

 

15.6   If the herbal material for processing does not comply with its quality specifications, the rules that apply for its rejection, and to storage and disposal of the rejected herbal material, should be included.

 

15.7   Starting materials derived from or comprising genetically modified organisms should comply with existing national or international regulations and the label should include this information. Chemical protection of herbal materials

should be in accordance with national and/or international regulations (         7).

 

15.8   Qualitative and quantitative information on the active ingredients or constituents with known therapeutic activity in herbal materials and herbal preparations should be given as described in subsection 17.5 (labelling).

 

15.9     Finished herbal (natural) products

Tests for microbiological contamination and tests for other toxicants. Uniformity of weight (e.g. for tablets, single-dose powders, suppositories, capsules and herbal tea in sachets), disintegration time (for tablets, capsules, suppositories and pills), hardness and friability (for example, uncoated tablets), viscosity (for internal and external fluids), consistency (semisolid preparations), and dissolution (tablets or capsules), if applicable. Physical appearance such as color, odor, form, shape, size and texture.

Loss on drying, or water content.

Identity tests, qualitative determination of relevant substances of the plants (e.g. fingerprint chromatograms).

Quantification of relevant active ingredients, if they have been identified, and the analytical methods that are available.

Limit tests for residual solvents.

 

15.10   The control tests and specifications for the finished herbal (natural) product should be such as to allow the qualitative and quantitative determination of the main active constituents. If the therapeutic activity of constituents is known, these constituents should be indicated in the documentation. If such substances are not known (e.g. because they are part of a complex mixture), the constituents useful for assessing the quality should be identified as markers. In both cases, the assay (i.e. quantitative determination) specifications should be defined. When the therapeutic activity of the constituents cannot be determined quantitatively, specifications should be based on the determination of markers.

 

15.11   If either the final product or the herbal preparation contains several herbal materials and a quantitative determination of each active ingredient is not feasible, the mixture of several active ingredients may be determined. The need for such a procedure should be justified.

 

15.12   The concept of different acceptance criteria for release versus shelf-life specifications applies to finished natural medicine only and not to herbal materials and herbal preparations. Adequate retest periods should be established for the latter. Examples where this may be applicable include assay and impurity (degradation product) levels.

 

15.13   Herbal preparations

The specifications of herbal preparations consist, depending on the preparation in question, of the relevant items of the specifications for herbal materials or for finished herbal products as outlined above.

Processing instructions

 

15.14   The processing instructions should describe the different operations to be performed on the plant material, such as drying, crushing, milling and sifting. They should also include the time and, if applicable, temperatures required in the drying process, and the methods to be used to control fragment or particle size. Instructions on removing foreign matter and other unwanted materials should also be given.

 

15.15   The drying conditions chosen should be appropriate to the type of plant material processed. These depend on both the character of the active ingredients (e.g. essential oils) and the type of plant part collected (e.g. root, leaf or flower).  Drying by direct exposure to sunlight, if not specifically contraindicated, is possible, but drying on the ground should be avoided. If the plant should be processed fresh, without drying, the reasons and criteria determining the use of fresh material should be stated.

 

15.16   For the production of processed extracts, the instructions should specify details of any vehicle or solvent that may be used, the durations and temperatures needed for extraction, and any concentration stages and methods that may be required.

 

15.17 The permissible environmental conditions e.g. temperature, humidity and standard of cleanliness, should be stated.

 

15.18   Any treatment, such as fumigation, used to reduce fungal or microbiological contamination or other infestation, together with methods of determining the extent of such contamination and potential residues should be documented. Instructions on the conduct of such procedures should be available and should include details of the process, tests and allowable limits for residues together with specifications for apparatus used.

 

15.19 Steps in the processes of blending and adjustment to reach defined

contents of pharmacologically active constituents should be clearly documented.

 

15.20   The rules that apply to the disposal of spent herbal material after processing should also be elaborated.

 

 16.                         Good practices in production

 

 16.1   To ensure not only the quality, but also the safety and efficacy of complex products of biological origin such as natural medicines, it is essential that the steps in their production are clearly defined.

Selection of the first production step covered by these guidelines

 

16.2   For medicinal plants—which are either cultivated or collected from the wild, and which may be used in crude form or subjected to simple processing techniques (such as  cutting or comminuting)—the first  critical step of  their production, i.e. where the application of these guidelines starts, should be clearly designated. The rationale for this designation should be stated and documented. Guidance is provided below. However, for processes such as extraction, fermentation and purification, this rationale should be established on a case-by- case basis.

            Collection/cultivation and/or harvesting of medicinal plants should

follow other relevant  guidance  such  as the WHO     Guideline on good

agriculture and collection practices  (GACP) for medicinal  plants     (          7) or  a

national guideline.

            Generally, postharvest processing including primary cutting is (or should be) covered by GACP. If further comminuting is carried out in the manufacturing processing, it should be covered by GMP, or by these

supplementary guidelines. If cutting and comminuting considerably

reduce the probability of detection of adulteration or mix-up of herbal materials,  application of these supplementary guidelines  may be extended to encompass these steps.

                When the active ingredient, as defined in the Glossary, consists exclusively of comminuted or powdered herbs, application of these guidelines starts at the physical processing following primary cutting and comminuting, and includes packaging.

                When herbal extracts are used, the principles of these guidelines should apply to any production step following postharvest processing.

                In the case of finished herbal products manufactured by fermentation, application of GMP should cover any production step following primary cutting and comminuting. Particular attention should be given to the introduction of cells from a cell bank into the fermentation process.

 

General considerations

 

16.3   Materials should be handled in a fashion that is not detrimental to the product.  On arrival at the processing facility, the herbal material should be promptly unloaded and unpacked. During this operation, the herbal material should not come into direct contact with the soil. Moreover, it should not be exposed directly to the sun (except in cases where this is a specific requirement, e.g.  sun-drying) and it should be protected from rain and microbiological contamination.

 

 16.4   Attention should be paid to “classification” of clean area requirements taking into account the possible high degree of initial microbial contamination of herbal materials. Classification of premises as applied to sites for the production of other pharmaceutical substances may not be applicable to processing of herbal materials. Specific and detailed requirements should be developed to cover microbial contamination of equipment, air, surfaces and personnel, and also for rest rooms, utilities, ancillary and supporting systems (e.g. water and compressed air).

 

16.5   Care should be taken to choose cleaning methods appropriate to the characteristics of the herbal materials being processed. Washing dried herbal materials with water is generally inappropriate. When it is necessary to clean them, an air duster or air shower should be employed. In cases when immersion of herbal materials in water or other appropriate agents (such as disinfectants) for cleaning is unavoidable (e.g. to eliminate suspected coliform bacteria), it should be kept to a minimum.

 

16.6   The presence of plant materials from different species and varieties, or different plant parts should be controlled during the entire production process to avoid contamination, unless it is assured that these materials are equivalent.

 

16.7   If time limits are specified in the master production instructions, these limits should not be exceeded, to ensure the quality of intermediates and finished products. The less is known about the constituents responsible for the therapeutic activity, the more strictly this rule should be obeyed. Such time limits, however, may be inappropriate when processing to achieve a target value (e.g. drying to a predetermined specification) because completion of processing steps is determined by in-process sampling and testing.

 

Mixing of batches and blending

 

16.8   Natural medicines with constituents of known therapeutic activity are often standardized (i.e. adjusted to a defined content of such constituents). The methods used to achieve such standardization should be documented. If another substance is added for these purposes, it is necessary to specify, as a range, the quantity that may be added. Blending different batches of a specific herbal material (e.g. before extraction) or by mixing different lots of similar herbal preparations may also be acceptable. Records should be maintained to ensure traceability. The blending process should be adequately controlled and documented and the blended batch should be tested for conformity with established specifications where appropriate.

 

16.9   Batches should be mixed only if it can be guaranteed that the mixture will be homogeneous. Such processes should be well documented.

 

16.10   Out-of-specification batches of herbal medicines should not be blended with other batches for the purpose of meeting specifications, except for standardization of the content of constituents with known pharmaceutical therapeutic effect. Every batch incorporated into the blend should have been manufactured using an established process and should have been individually tested and found to meet appropriate specifications prior to blending.

 

16.11   Where particular physical attributes of the material are critical, blending operations should be validated to show uniformity of the combined batch. Validation should include testing of critical attributes (e.g.  Particle size distribution, bulk density and tap density) that may be affected by the blending process.

 

16.12   The expiry date of the blended batch should be chosen according to the date of manufacture of the oldest batch in the blend.

 

17. Good practices in quality control

 
 

17.1 General

17.1.1   The personnel of quality control units should have the necessary expertise in herbal medicines to enable them to carry out identification tests and recognize adulteration, the presence of fungal growth or infestations and lack of uniformity in a consignment of herbal materials.

 

17.1.2   The quality control of the herbal material, herbal preparations and finished herbal products should establish their quality, but does not imply the control of every single constituent.

 

17.2 Sampling

17.2.1   Because herbal materials are an aggregate of individual plants and/or different parts of the same plant and thus have an element of heterogeneity, sampling should be carried out with special care by personnel with the necessary expertise. 

  

17.2.2   Further advice on sampling and visual inspection is given in the

WHO document Quality control methods for medicinal plant materials (6).

 

17.3 Testing

 

17.3.1   The identity and quality of herbal material, herbal preparations

and of finished herbal products should be tested as described in        the Quality control methods for medicinal plant materials          (6). The minimum requirement for the technical equipment is for instruments to perform the tests described in (6).  Moreover, each country should develop this basic requirement for technical equipment further, according to its own needs.

 

17.3.2   Herbal material, herbal preparations (including extracts) and finished herbal products can be categorized as follows: the active constituents are identified, and may be quantified as such; the main group of components which contribute to the activity (i.e. the constituents with known therapeutic activity) are known and can be quantified as a total (e.g.  Essential oils) or calculated using a representative substance belonging to the group (e.g. flavonoids); the former are not identified and/or not quantifiable, but marker substances are;

others, where quantification (i.e. specification for a certain quantity of a constituent) is not applicable or feasible.

17.3.3   Identification methods may be based on:

 Physical and, if applicable, macroscopic (organoleptic) and microscopic tests;

Chromatographic procedures (TLC, HPLC, HPTLC or gas–liquid chromatography (GLC)), spectrometric techniques (ultraviolet-visible (UV-VIS), IR, nuclear magnetic resonance (NMR), MS); and/or chemical reactions.

 

17.3.4   The identification test methods should be specific for the herbal material, herbal preparation or finished herbal product and ideally should be capable of discriminating between the required herbal material and potential substitutes or adulterants that are likely to occur. The identification methods used for groups a and b should be capable of detecting the said active ingredients and at least the main ingredients should be stated on the label. For group c, the analytical procedure should be based on characteristic constituents, if any.

 

17.3.5   Reference samples of herbal materials should be made available for use in comparative tests, e.g. visual and microscopic examination and chromatography.

 

17.3.6   Quantitative  determination of known  active components for members of groups a  and  b and  of markers  for members  of  group  c  is necessary.

 

17.3.7   The development and execution of quality control methods for herbal materials, herbal preparations

Should be in line with subsection 15.1 (Specifications). Tests and quality requirements that are characteristic of the given analyte should be selected.

 

17.3.8   Particularly for herbal materials in group d and for finished herbal products containing such materials, characteristic chromatograms (and/or fingerprint chromatograms) may be applicable. Using these methods may ensure that the main constituents can be easily followed throughout the production process. Caution is necessary, however, for every delivery of herbal materials and every batch of herbal preparations (including extracts) will have slightly different chromatograms/fingerprints resulting from differences in chemical compositions caused by intrinsic or extrinsic factors.

 

17.4 Stability studies

 

17.4.1   If the expiry date for a herbal material or herbal preparation is given, some stability data to support the proposed shelf-life under the specified storage conditions should be available. Stability data are always required to support the shelf-life proposed for the finished herbal products.

 

17.4.2   Finished herbal products may contain several herbal materials or herbal preparations, and it is often not feasible to determine the stability of each active ingredient. Moreover, because the herbal material, in its entirety, is regarded as the active ingredient, a mere determination of the stability of the constituents with known therapeutic activity will not usually be sufficient. Chromatography allows tracing of changes which may occur during storage of a complex mixture of biologically active substances contained in herbal materials. It should be shown, as far as possible, e.g. by comparisons of appropriate characteristics/fingerprint chromatograms, that the identified active ingredient (if any) and other substances present in the herbal material or finished herbal product are likewise stable and that their content as a proportion of the whole remains within the defined limits.

 

17.4.3   The fingerprint methods used for the stability studies should be as similar as possible to those used for quality control purposes.

 

17.4.4   For identified active ingredients, constituents with known therapeutic activity and markers, widely used general methods of assay, and physical and sensory or other appropriate tests may be applied.

 

17.4.5   To determine the shelf-life of finished herbal products, strong emphasis should also be placed on other tests in subsection 15.1 (Specifications), such as moisture content, microbial contamination and general dosage form control tests.

 

17.4.6   The stability of preservatives and stabilizers should be monitored. When these are not used, alternative tests should be done to ensure that the product is self-preserving over its shelf-life.

 

17.4.7   Samples used for stability studies should be stored in the containers intended for marketing.

 

17.4.8   Normally the first three commercial production batches should be included in the stability-monitoring programme to confirm the expiry date.

 

 

However, where data from previous studies, including pilot batches, show that the product is expected to remain stable for at least two years, fewer than three batches can be used.  The testing frequency depends on the characteristics of the herbal medicinal products and should be determined on a case-by-case basis.

 

17.4.9   The protocol for ongoing stability studies should be documented. This would normally involve one batch per year being included in a stability-monitoring programme.

 

17.5 Packaging materials and labelling

 

17.5.1   All packaging materials, such as bottles and other materials should be stored properly. Controls on the issue and use of these packaging materials should be adequate to ensure that incorrect labels and cartons are not used.

 

17.5.2   All containers and closures should be thoroughly cleaned and dried before being used to pack the products.

 

17.5.3   There should be adequate information on the label (or the package insert) to inform the users of the composition of the product (in addition to the brand name, if any), indications or actions, directions for use, cautions and adverse reactions if any, and the expiry date.

 

17.5.4   Finished herbal products may contain several herbal materials and/or herbal preparations. Unless otherwise fully justified, the full quantitative composition of the herbal ingredients should be stated on the product label. If this is not possible, at least the main ingredients should be stated on the label while the full qualitative composition could appear on the package insert.

 

17.5.5   The qualitative and quantitative particulars of the active ingredients in herbal materials and herbal preparations should be expressed in the following ways:

  For herbal materials and herbal preparations consisting of comminuted or powdered herbal materials:

 the quantity of the herbal material must be stated or, if constituents with known therapeutic  activity  are unidentified,  the quantity of  the  herbal material/herbal preparation should be stated; or

 the quantity of the herbal material/herbal preparation should be given as a range, corresponding to a defined quantity of constituents with known therapeutic activity.

For herbal preparations produced by steps, which exceed contamination, the nature and concentration of the solvent and the physical state of the extract should be given. Furthermore, the following should be indicated:

the equivalent quantity or  the ratio of a  herbal material to  herbal preparation must be stated if therapeutic activity of the constituents is unknown (this does not apply to fatty or essential oils); or

if the therapeutic activity of the constituents is known, the quantity of the herbal preparation may be given as a range, corresponding to a defined quantity of the constituents  with known therapeutic  activity.

 

17.5.6   The composition of any solvent or solvent mixture used and the physical state of the extract should be identified.

 

17.5.7   If any other substance is added during the manufacture of the herbal preparation to adjust the level of constituents of known therapeutic activity,  or for any  other  purpose, the  added substance(s) should be described as such or as “other ingredients” and the genuine extract as the “active ingredient”. However, where different batches of the same extract are used to adjust constituents with known therapeutic activity to a defined content or for any other purpose, the final mixture should be regarded as the genuine extract and listed as the “active ingredient” in the unit formula.