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MCC guidelines on “Complementary medicines”

Posted 12 August 2011

The MCC has released the draft guidelines on "Complementary medicines -Quality, safety, and efficacy" for comments from industry.

As the MCC web site appears to be down frequently, I am posting access to this document h ere.

The deadline for comment is 22 September 2011. I would urge anyone (not just "industry") who is interested in ensuring that all complementary medicines on the market are of adequate quality, are safe, and actually do what they claim to do, to submit comments if you have any, to the Registrar of the MCC, Ms Mandisa Hela. Her email address is [email protected].

MEDICINES CONTROL COUNCIL 

 

COMPLEMENTARY MEDICINES –

 

QUALITY, SAFETY, AND EFFICACY

 

This guideline is intended to provide recommendations to applicants wishing to submit applications for the registration of Complementary Medicines.  It represents the Medicines Control Council’s current thinking on the quality, safety, and efficacy of these medicines.  It is not intended as an exclusive approach.  Council reserves the right to request any additional information to establish the safety, quality and efficacy of a medicine in keeping with the knowledge current at the time of evaluation.  Alternative approaches may be used but these should be scientifically and technically justified.  The MCC is committed to ensure that all registered medicines will be of the required quality, safety and efficacy.  It is important that applicants also adhere to the administrative requirements to avoid delays in the processing and evaluation of applications.

Guidelines and application forms are available from the office of the Registrar of Medicines and the website.

 

First publication released for comment

August 2011

Deadline for comment

22 September 2011

 

 

REGISTRAR OF MEDICINES

MS M HELA

 



 

TABLE OF CONTENTS

 

 

Page

1

INTRODUCTION

5

1.1

Compliance with Good Manufacturing Practices and Good Dispensing Practices

5

1.1.1

Good Manufacturing Practices and Good Laboratory Practices

5

1.1.2

Good Dispensing Practices

5

1.2

Format of submission

5

1.3

Quality

5

1.4

Safety and efficacy

5

1.5

Naming of medicines and substances

6

1.6

Accepted references

7

1.7

Types of substances

7

2

QUALITY

8

2.1

ACTIVE INGREDIENT

8

2.1.1

Manufacture of the Active Ingredient

9

2.1.2

Compositional Information

10

2.1.3

Control of Active Ingredient – Specifications

10

2.1.3.1

Limits and Tests

11

2.1.3.2

Impurities and Incidental Constituents

13

2.1.4

Control of Active Ingredient – Analytical Procedures & Validation

14

2.1.5

Batch Certificates of Analysis

15

2.1.6

Justification of Specification

15

2.1.7

Stability

15

2.2

FINISHED PRODUCT

16

2.2.1

Description and Composition of the Product

16

2.2.1.1

Active ingredients

16

2.2.1.2

Inactive ingredients

16

2.2.1.3

Colouring and flavouring ingredients

16

2.2.1.4

Modified Release Products

16

2.2.1.5

Batch-to-batch variations in the amount of ingredients

16

2.2.1.6

Overages

17

2.2.2

Product Development

18

2.2.3

Manufacture of the Finished Product

18

2.2.3.1

Licensing and Control

18

2.2.3.2

Batch Formulation

18

2.2.3.3

Description of Manufacturing Process and In-process Controls

18

2.2.4

Control of Inactive Ingredients – Specifications

18

2.2.5

Control of the Finished Product – Specifications

18

2.2.5.1

Data Requirements

19

2.2.5.2

Impurity Requirements for Non-pharmacopoeial Products

19

2.2.5.3

Residual Solvents

20

2.2.5.4

Microbiological Requirements

20

2.2.5.5

Tablets and Capsules

20

2.2.5.6

Analytical Procedures & Validation

20

2.2.5.7

Justification of Finished Product Specifications

21

2.2.6

Batch Certificates of Analysis

20

2.2.7

Container

21

2.2.8

Finished Product Stability 

21

2.3

Amendments

22

3

SAFETY AND EFFICACY – GENERAL PRINCIPLES

23

3.1

Well-documented Ingredients

23

3.2

Other points to consider in Preparing an Application for Registration

23

3.2.1

Quality of Data

23

3.2.2

Searching the Literature on Complementary Medicines

24

3.3

Benefits and Risks – Conclusion

24

3.4

Clinical Trials of Complementary Medicines

24

4

SAFETY

25

4.1

Criteria for determining the safety of indications and health claims

25

4.2

Documenting safety

25

4.2.1

Information to include

25

4.2.2

Overview of safety

26

4.3

Post-marketing data

26

5

EFFICACY

27

5.1

Criteria

27

5.1.1

Herbal medicines

27

5.1.2

Traditional Chinese, Ayurvedic, Unani Tibb medicines

27

5.1.3

Homoeopathic medicines

27

5.1.4

Aromatherapy preparations

27

5.2

Documenting efficacy

28

5.2.1

Information to include

28

5.2.2

Overview of efficacy

28

5.2.2.1

Pharmacodynamics

28

5.2.2.2

Pharmacokinetics

28

5.2.2.3

Bioavailability

28

5.2.2.4

Clinical Studies

30

5.2.3

Study Reports and/or Publications

30

6

SCHEDULING

30

7

UNACCEPTABLE PRESENTATION

31

8

REFERENCES

31

9

GLOSSARY OF TERMS

31

10

ABBREVIATIONS AND ACRONYMS

37

11

Update history

37



1        INTRODUCTION

A registerable complementary medicine may fall in Schedule 0, 1, 2 or 3.

Medicines are not scheduled solely on the basis of toxicity.  Although toxicity is one of the factors considered, and is itself a complex of factors; the decision to include a substance in a particular Schedule also takes into account many other criteria such as the purpose of use, potential for misuse, abuse, safety in use and the need for the substance.

Before submitting an application for registration of a complementary medicine, it is first necessary to establish that the product contains substances that are, in fact, complementary medicine substances.

Essentially, if the substance is a designated active ingredient, as defined in the Regulations, that has an established identity and tradition of use, it is a complementary medicine substance.  

1.1       Compliance with Good Manufacturing Practice and Good Dispensing Practice

1.1.1      Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP)

All manufacturers of complementary medicines shall comply with all aspects of Good Manufacturing Practice and Good Laboratory Practice.

1.1.2      Good Dispensing Practice

All dispensing and compounding of medicines by Practitioners shall comply with the provisions of Act 101 of 1965 and all aspects of Good Dispensing Practice in accordance with the provisions of Act 53 of 1974.

1.2       Format of submission

Data provided in applications for registration of complementary medicines should be in the CTD format.

1.3       Quality

Information is required for a product’s active ingredients and its excipients.  The data are evaluated to determine the quality of the product, including the identity, impurities and stability of the ingredients.  The data assessment also takes into account information about the manufacturing processes and levels of good manufacturing practice (GMP), where appropriate.

Details of quality control measures are required to demonstrate that the product will be produced to a consistent quality.  Stability data for the product are required to determine a shelf life over which the product’s quality is maintained.

Should the results of any testing be outside the acceptable limits then appropriate action, which may include rejection or destruction, must be taken immediately.

Safety and Efficacy

Applications for the registration of complementary medicines must include appropriate data that demonstrate the safety and efficacy of the product.

The applicant must provide evidence (data) to support the product’s efficacy for the proposed indication(s) and any claims that the applicant intends to make in the product labelling to determine whether the data supplied adequately support the requested indication(s)/claim(s).

Safety may be established by detailed reference to the published literature and/or the submission of original study data.  Where there is sufficient evidence based on human experience to support safety then conventional studies involving animal and in vitro studies may not always be necessary.

Any complementary medicine that is of animal origin must comply with the importation requirements of the Veterinary Diseases Act.

1.5       The Naming of medicines and substances

1.5.1      General

(i)   Chemical Substance Name

The approved name i.e. International Non-Proprietary Name (INN) or chemical name of substances used as inactive ingredients in topical products must be stated.  In the absence of such name being available, a chemical description or characterisation of the substance should be given.

The approved name (INN) or chemical name of mineral, metal or chemical substances or prepared mineral substances used in Homoeopathic, Traditional Chinese, Ayurvedic or Unani Tibb medicines must be stated.

(ii)  Biological Substance Name

In addition to the name of the organism, the part, preparation and / or biological descriptor may be required to fully name a biological substance.

(iii)  Herbal Name

Herbal names are stated in the Latin binomial format which is the scientific genus and species name.  If necessary the variant should be included.

Herbal Ingredient: The Latin binomial name the part and the preparation (including solvents and ratio if applicable) are used to fully name a herbal ingredient.

(iv) Herbal Substance

Pharmacopoeial names of herbal ingredients (e.g. olive oil) that are fully characterised in a monograph of an accepted pharmacopoeia[1] must be used.

(v)  Herbal Component Name (HCN)

HCNs are names for classes of constituents that are found in herbal ingredients.  The need for a HCN most often arises when a herbal extract is standardised to a particular class of constituents, or where particular classes of constituents are restricted (e.g. hydroxyanthracene derivatives).  Where a herbal extract is standardised to a single constituent, the single constituent should have a chemical name. The HCN is not a stand-alone name and should be used only when expressing a herbal substance.

1.5.2      Nature identical oils are a blend of natural essential oils and aromatic compounds which are made in the laboratory. and have fewer synthetic compounds than 100 % synthetic oils.  Nature identical essential oils are NOT suited for aromatherapy and therapeutic applications.   

Nature identical’ oils cannot be used therapeutically as complete substitutes for the naturally occurring aromatic materials

Wherever ‘nature identical’ oils are used, this must be clearly stated on all documentation including product labels.

1.5.3      Common names, Materia Medica Name, Traditional Chinese Pin Yin, Traditional Sanskrit and other Traditional Unani Tibb Names may be used in addition to the approved names.

The Pin Yin name of the plant may also be used in addition to the English names of the plant parts in the case of Traditional Chinese medicines.



1.6       Accepted References

1.6.1      Herbal medicines

Herbal medicines or substances shall be described as herbal medicines or substances in at least one of the specified references on the herbal medicines reference lists:

·         Australian Therapeutic Goods Authority List of Substances

·         German Commission E Monograph

·         German Commission D Monographs

·         German Homoeopathic Pharmacopoeia

1.6.2      Traditional Chinese Ayurvedic, Unani Tibb

(i)   A Traditional Chinese medicine or substance must be described as a Traditional Chinese medicine or substance in at least one of the following references:

·     the Traditional Chinese pharmacopoeia

·     Advanced Textbook on Traditional Chinese Medicine and Pharmacology.  State Administration of Traditional Chinese Medicine, New World Press, Beijing, China

·     The Yellow Emperor’s Classic of Internal Medicine.  Translated by Ilza Veith

·     A Barefoot Doctor’s Manual.  The American Translation of the Official Chinese Paramedical Manual, Running Press, Philadelphia, Pennsylvania

·     A Clinical Guide to Chinese Herbs and Formulae.  Chen Song Yu and Li Fei.  Translated by Jin Hui De

·     The Practice of Chinese Medicine by Giovanni Maciocia

·     Practical Traditional Chinese Medicine and Pharmacology.  Herbal Formulas by Geng Junying et al

·     Clinical Handbook of Internal Medicines by Will Maclean and Jane Lyttleton

(ii)  An Ayurvedic medicine or substance must be described as an Ayurvedic medicine or substance in at least one of the following references

·     Ayurvedic Materia Medica with Principles of Pharmacology & Therapeutics by H.V.Savnur

·     Indian Materia Medica with Ayurvedic, Unani-tibbi, Siddha, Allopathic, Homeopathic, Naturopathic & Home Remedies, originally edited by the late Dr K.M.Nadkarni

·     Caraka-Samhita by Prof. Priyavrat Sharma

·     The Sushruta Samhita based on original Sanskrit text translated and edited by Kaviraj Kunjalal Bhishagratna M.R.A.S (LOND.)

·     The Ayurvedic Pharmacopoeia of India

·     The Aurvedic Formulary of India

(iii)  A Unani Tibb medicine or substance must be described as a Unani Tibb medicine or substance in at least the Unani Tibb pharmacopoeia.

1.6.3      Homoeopathy

The substance must be described as a homoeopathic substance in at least one of the specified Materia Medica or Homoeopathic Pharmacopoeiae

1.6.4      Aromatherapy

An aromatherapy substance must be described as an aromatherapy substance in at least one of the specified references on the Aromatherapy Substances Reference List – Can be obtained from a standard list – see the following reference www.aromaweb.com/books/default.asp



1.7       Types of Substances

1.7.1      Herbal substance means all or part of a plant or substance (other than a pure chemical or a substance of bacterial origin):

a)    that is obtained only by drying, crushing, distilling, extracting, expressing, comminuting, mixing with an inert diluent substance or another herbal substance or mixing with water, ethanol, glycerol or aqueous ethanol; and

b)    that is not subjected to any other treatment or process other than a treatment or process that is necessary for its presentation in a pharmaceutical form.

1.7.2 Chinese, Ayurvedic and Unani Tibb medicines or substances may be of plant, animal, or mineral origin.  They may include fresh or dried substances, extracts or derivations from these extracts.

1.7.3      Homoeopathic substances may be of plant, animal, metal or mineral origin and may include allersodes, isodes, sarcodes, nosodes and allergens as well as allopathic substances, used in potentised form at acceptable potencies for use as a homoeopathic medicine.

1.7.4      Aromatherapy substances will be of plant origin.  Reference must be made to the part of the plant(s) or the whole plant used to extract the aromatherapy substance.

 

2        Quality  Refer also to Pharmaceutical & Analytical Guideline

Information on the quality of a complementary medicine substance is required to characterise the substance for the purpose of developing a compositional guideline cf 2.1.2 below.

Information that should be provided includes the substance name, composition, structure and general properties; manufacturing details, including process and controls; substance characteristics, including impurities and incidental constituents; specifications and details of analytical test methods, with method validation data; stability data; and a proposed compositional guideline.

Where a substance is the subject of a monograph in an RSA recognised pharmacopoeia, a separate compositional guideline is usually not required.

Types of liquid extracts, and dried plant concentrate preparations include decoctions, macerations, infusions

This section is divided into two subsections:

2.1.    Active Ingredient

2.2     Finished Product

Some complementary medicines are comprised of relatively simple ingredients[2] (e.g. amino acids, mineral salts, vitamins) and, unless the medicine contains multiple active ingredients, the quality parameters applying to such products are essentially the same as for pharmaceutical medicines.

However, complementary medicines that contain complex ingredients that are difficult to characterise and/or certain combinations of multiple active ingredients require special consideration.

The headings used in this section follow the sequence of the International Conference on Harmonisation (ICH) guideline M4: Common Technical Document (CTD).

2.1       ACTIVE INGREDIENT – Complementary Medicine Substance (Module 3.2.S)

The types of information and level of detail depend on the active ingredient and on the risk associated with the finished product.  

In all cases, the application information must be sufficient to:

·         adequately characterise the active ingredient;

·         determine the time during which the product meets appropriate standards when stored under defined conditions;

·         demonstrate that the active ingredient will be of appropriate and consistent quality.

Description (Composition)

Any information not included in the monograph/ standard description should be supplied.

Nomenclature

Provide the name of the substance.  Refer to Section 1.5

Structure

Provide the chemical structure (graphic), molecular formula, molecular weight and Chemical Abstracts Service Registry (CAS) number for the substance, unless this is provided in the relevant monograph or standard.

General properties

Provide any physico-chemical information relevant to the characterisation of the substance or that may be required for the manufacture, performance or stability of its intended final dosage form that is not covered by the relevant monograph or standard (e.g. solubility or particle size).

2.1.1 Manufacture of the Active Ingredient

The manufacture of the active ingredient must be described.

State the part of the plant or animal used and its form, i.e. whether it is a fresh or dried material, together with details of any processing it undergoes before use in the manufacture of the product.

Where appropriate it may be necessary to state the country or region of origin of the ingredient, or give other details such as time of harvesting and stage of growth, which are pertinent to the quality of the ingredient.

If the herb is processed to produce a galenical form, the extraction and any concentration processes should be described or a reference cited, indicating whether the extract or additives, such as calcium phosphate in dry extracts, are present in the final product formulation.

In the case of ‘low dose’ starting substances these must in all cases be manufactured according to suitable pharmacopoeiae to ensure reproducible quality and which form the basis for appropriate documented indications or claims, according to the particular method used. 

Manufacturer(s)

Provide the manufacturer’s name and address, and addresses of all sites involved in the manufacture/ testing of the substance.



2.1.2      Compositional Information

This is, in essence, a physicochemical definition of the substance.

The purpose of the compositional information is to provide detailed characterisation of the substance. For simple complementary medicinal substances, this is usually straightforward and may be a simple extension of the specifications.  For complex complementary medicines, the compositional information is generally more detailed and contains a significant amount of additional qualitative and quantitative data.

The major components of a substance should be determined, as well as any minor but significant ones.

Many complementary medicine substances have yet to be defined or characterised in a monograph that is acceptable to the MCC.  Therefore specifications and control procedures that substantially characterise these substances should be proposed.  In general, these should:

·         substantially define the nature or character of a substance;

·         allow the substance to be distinguished from adulterants, substitutes or counterfeit versions;

·         be specific for components of safety and / or therapeutic significance;

·         take into account the biological, chemical and physical variations that may reasonably occur between batches of the substance; and

·         be capable of objective validation.

Data on the nature or chemistry of the active component should be provided.  This may include citation of pharmacopoeial monographs, photocopies from authoritative references, or in-house data.

Refer to the Australian guideline ARGCM Part III, Evaluation of Complementary Medicine Substances, Appendix 1 for guidance on the type and detail of information to be included.

In addition, information on solubility (in water and other relevant solvents, such as dissolution media), particle size and polymorphic form (which are specific to complementary medicines) should be provided, where relevant.

For additional guidance on herbal ingredients, see the Australian guideline ARGCM Part IV, Herbal Ingredients – Quality.

2.1.3      Control of Active Ingredient / Substance – Specifications

Starting material specifications should be provided or a reference cited for each starting material. Where a pharmacopoeial reference does not apply to an ingredient, the specification should give details of the test methods and test specifications.  Appropriate testing techniques are required in accordance with the SA Guide to GMP Annex 7 – Manufacture of Herbal Medicinal Products.  These would need to cover identity and, where appropriate, adulteration and contamination, both chemical and microbiological.  Where a herbal ingredient is standardised in terms of a component(s) and the statement of activity on the label is based on this standardisation, evidence of how the standardisation is achieved should be provided.

The active ingredient specifications are a set of tests and limits that are applied to the complementary medicine substance in order to ensure that every batch is of satisfactory and consistent quality.  The specifications should monitor all parameters (generally by physico-chemical testing) where variation would be likely to affect the quality or safety of the product.



2.1.3          Control of Active Ingredient – Specifications – continued

The manufacturer of the active ingredient should apply specifications and control procedures for the substance at the time of its manufacture.  The finished product manufacturer is also expected to ensure that the active ingredient complies with specifications before using the substance in the finished product at the time of manufacture.  The two sets of specifications are not necessarily identical.

For most complementary medicines, the manufacturer of the active ingredient will not be controlled to the same extent as the finished product manufacturer, and therefore the focus will be on the specifications applied by the finished product manufacturer before the ingredient is used in the finished product.  For some complex substances, or where the finished product will be a prescription only medicine, the specifications applied to the active ingredient by the ingredient manufacturer may be more closely scrutinised.

The specifications for the active ingredient that are applied by the manufacturer of the finished product to ensure its quality before use should be submitted.  If there are any differences between the active ingredient specifications used by the active ingredient manufacturer and the finished product manufacturer, these should be identified and discussed.

Where non-pharmacopoeial specifications are applied, a tabulated summary of the tests, test methods and limits should be provided.  The specifications applied should be justified for their ability to assure the quality and consistency of the ingredients used.

Similarly, where a pharmacopoeial monograph is used as the specification, any modification to the pharmacopoeial requirements should be justified.

2.1.3.1     Limits and Tests

If there is a recognised pharmacopoeial monograph for the active substance, it must be used unless otherwise justified.  Note that the most recent edition of any pharmacopoeial standard or monograph should be used, or a justification for not doing so provided.  The requirements of the recognised pharmacopoeiae or applicable general monographs in these pharmacopoeiae must also be met except where a justification for not doing so is authorised by the MCC.

In some cases, the pharmacopoeial requirements may not in themselves be sufficient to adequately control the quality and consistency of an ingredient, and applicants may apply additional tests. However, it is generally not acceptable to:

·         adopt only some of the tests from a pharmacopoeial monograph;

·         selectively combine some tests and/or limits from one specific pharmacopoeial monograph with some from another pharmacopoeial monograph (without having ensured full compliance with either);

·         adopt an earlier edition of the pharmacopoeial monograph or standard when there is a more recent edition that has been adopted by the MCC.

Where non-pharmacopoeial specifications are applied, a tabulated summary of the tests, test methods and limits should be provided (e.g. assay (non-aqueous titrimetry): 99,0–101,0 %).  The specifications applied should be justified in respect of their ability to assure the quality and consistency of the ingredients used.

Similarly, where a pharmacopoeial monograph is used as the specification, any modification to the pharmacopoeial requirements should be justified.

The specifications for the active ingredient should be guided by the compositional information.



2.1.3.1         Limits and Tests – continued

A        The minimum tests and limits included in specifications for an active ingredient include:

(i)         appearance/description;

(ii)        identification:

(a)      Plants will generally be identified according to a suitable morphological and histological description system, where acceptable reference specimens are used.  The parts of the plant that are used or the whole plant must be specified. 

(b)      Where the plant material is examined for the first time in a powdered or crude form, it must be subjected to at least macroscopic and microscopic examination.  The organoleptic properties that would confirm the identity must be included.

 (c)     Where it is not possible to confirm the identity by macroscopic and/or microscopic examination, suitable identification tests or assays must be performed by comparing the specimen to reference substances or known active ingredients or markers.

(d)      Where relevant, extracts for identification by suitable and validated methods should be made.

(e)      For homoeopathic medicines where Mother Tinctures or starting substances are prepared, the plant will ideally be identified according to a suitable plant description and identification system where reference authentic specimens are used

The identity of starting substances can, at Mother Tincture level, be established by means of suitable thin layer chromatograms which are congruent with reference chromatograms, or by other suitable methods.  Thereafter product integrity and identity must be ensured by means of a carefully documented paper trail after positive identification by a suitably qualified person.

(f)      ‘Low dose’ herbals are herbal extracts that are not manufactured to create standardized or higher levels of active ingredients in the extract.  They are largely used as ‘drainage’ preparations and are manufactured according to approved pharmacopoeiae.  They can be identified by a suitable description and identification system, where acceptable reference specimens and/or suitable and validated analytical methods are used.

(g)      Therapeutic or pharmaceutical markers/active ingredients, can be used to identify standardized extracts or concentrates.

(h)      Where materials other than plants are used, suitable systems and/or methods that are capable of confirming the identity of the substance must be employed.

(i)       The identification of aromatherapy substances

·         Appropriate methods or systems must used to confirm the identities of the plants and the parts of plants used to manufacture the aromatherapy substance.  For this purpose suitable plant description and/or identification systems may be used.  Where plants are compared, reference to authentic specimens may be made.

·         Large variations, which are caused mainly by geographic and climatic variances may occur from batch to batch with respect to the active principles of aromatherapy substances.  For this reason suitable plant description and/or identification systems should be used together with validated test methods and document trails.



2.1.3.1         Limits and Tests – continued

(iii)       content/assay;

Suitable pharmaceutical or therapeutic markers may be used in conjunction with suitable and validated test procedures to determine the concentration or strength of starting substances and/or final products.

Concentrations or quantities of scheduled substances must be specified and controlled within the Schedule limits

(iv)       impurities (e.g. residual solvents, heavy metals, synthetic impurities and degradants).
See 2.1.3.2

B        Additional tests and limits may be appropriate and will depend on the nature of the active ingredient.  For example, tests for the presence or the proportion of isomers, optical rotation, microbial contamination, particle size distribution, and the clarity, colour and pH of solutions may also be relevant.

C        The specifications might also include controls on the macro components, such as nitrogen content or sodium content.  For complex liquid formulations, solvent content or viscosity might be important.  Additional simple tests that could assist in characterisation could include colour, texture, smell and pH.  More complex or specific tests should be used where there is a need to determine a component in a substance that is significant, such as sodium content in a sodium salt of a substance or gas chromatograph characterisation of key components in an oil.

D        Significant minor components of a substance (e.g. content of a specific alkaloid) are particularly important.  These components are often pivotal to the nature and/or safety of the substance, and their identification and analysis requires the attention of the sponsor.  A good starting point may be to use monographs for similar substances as a model and adapt them to the substance in question.

E        Substances that are intrinsic mixtures (e.g. synthetic polymers or fatty acid esters of glycerol) may require additional tests to control such aspects of the mixture as:

·         acid value;

·         iodine value;

·         saponification value;

·         viscosity;

·         density;

·         refractive index.

For additional guidance on herbal ingredients, see the Australian guideline ARGCM Part IV – Herbal Ingredients – Quality.

2.1.3.2     Impurities and Incidental Constituents

All herbal starting substances and intermediates must be free of contaminants.

The absence of orthodox pharmaceutical substances or chemicals must be confirmed.

The absence of herbal adulterants must be confirmed.

Information concerning impurities that are not dealt with in the monograph or standard should be provided.  Applicants should be aware that the manufacturing process for the substance may differ from the process for the substance upon which the monograph is based and, consequently, different impurities may be present.



2.1.3.2         Impurities and Incidental Constituents – continued

One of the key purposes of raw material specifications for complementary medicines is to determine whether the active raw material is free of contaminants that may have safety implications.  Therefore, incidental constituents and impurities need to be considered and tests and limits included in the active ingredient specifications.

Impurities and incidental constituents are those constituents that may be present in a substance as a by-product of the production, processing or storage of a substance, and are immaterial to the nature of the substance.

The production, processing and storage of substances may result in the presence of impurities and incidental constituents; for example, micro-organisms, microbial toxins, radionuclides, metals and non-metals, pesticide residues, degradation products, general contaminants, solvent residues and manufacturing by-products.  These constituents may be potentially hazardous to human health and their presence therefore needs to be minimised.  Applicants should describe the procedures adopted to achieve this.

Applicants should consider each type of likely impurity and incidental constituent, and determine whether it is relevant to the substance in question.  They should include consideration of the following:

·         microbiological limits (moulds and bacterial endotoxins)

·         microbial toxins / mycotoxins e.g. aflatoxins, and ochratoxins;

·         radionuclides;

·         radiolytic residues;

·         metals and non-metals, e.g. lead, arsenic, selenium;

·         agricultural and veterinary chemicals, e.g. pesticides, fungicides;

·         general contaminants, e.g. dioxins, polychlorinated biphenyls;

·         solvent residues; and

·         manufacturing by-products, e.g. reagents, catalysts, co-extractives, degradation products.

For further guidance on this matter, refer to the Australian guideline ARGCM Part III, Impurities and Incidental Constituents and ARGCM Part III, Guidance on Limits and Tests for Incidental Metals and Non-metals in Therapeutic Goods.

2.1.4      Control of Active Ingredient / Substance – Analytical Procedures and Validation

Details should be provided of all analytical methods used in the specifications, together with validation data that demonstrate the suitability of the method for the material in question.  The information should cover accuracy, precision, specificity (e.g. freedom from interference by degradation products and other likely impurities) and linearity.  Validation data are not required for methods described in an MCC-recognised monograph or standard.

Details of test methods and method validation data should be provided for all non-pharmacopoeial methods.  

For homoeopathic substances the identity of starting substances can, at Mother Tincture level, be established by means of suitable thin layer chromatograms which are congruent with reference chromatograms, or by other suitable methods.  Thereafter product integrity and identity must be ensured by means of a carefully documented paper trail after positive identification by a suitably qualified person.



2.1.5    Batch Certificates of Analysis

Certificates of analysis should be provided for at least two recent commercial-scale production batches to demonstrate routine compliance with the specification or monograph.  If data on commercial-scale batches are not available, certificates of analysis should be provided for pilot-scale batches manufactured using the same process as intended for commercial-scale batches.

Certificates of analysis should also be provided for any batches of material used in toxicity tests and clinical trials reported in support of the application.  This will assist the MCC in determining whether the substance intended for supply is the same as that on which safety data have been provided.  It is important that batch analysis data for the active ingredient are included for batches that were used in clinical trials reported in support of the application.

2.1.6    Justification of specification

If an applicant proposes to use an alternative monograph or standard when a BP, Ph Eur or USP standard exists, justification for doing so is required.  The justification should explain why the standard(s) cannot be met and detail what alternative(s) are proposed and why.

If there is no relevant monograph or standard for the active ingredient, a justification for the proposed specifications should be provided.  The justification should address the central function of the active ingredient specifications, which is to ensure the use of a consistently high-quality substance in the finished product.  Specifically, identification, assay, control of impurities and other critical factors in the quality of the active ingredient should be addressed.

2.1.7      Stability Refer also to the Stability guideline

Stability data should be provided for complementary medicine active ingredients to assist in identifying any particular degradants that may be formed and that should be monitored as part of the overall stability program.

2.1.7.1       Homoeopathic substances

The following criteria shall apply with respect to shelf life and the determination of expiry dates:

(i)       For D4 potencies upwards, with respect to products with single or multiple active ingredients, the shelf-life is consistent with the shelf-life of the vehicle substance containing the active potency.

(ii)      Stability tests must be performed in accordance with the Stability Guidelines.

(iii)     It must be noted that accelerated stability testing in the case of Homoeopathic Substances is not appropriate.

(iv)     For mother tinctures and potencies up to and including the D3 or 3x potency (or equivalent potency), stability testing should be done by means of Thin Layer Chromatography on the Mother Tincture, or on the potencies, where this is applicable and possible.  Standardised reference extracts and thin layer chromatograms can be used for comparison purposes.

2.1.7.2       Aromatherapy

The stability of aromatherapy substances and expiry dates may be related to the stability of the vehicles and/or excipients.



2.2            FINISHED PRODUCT (Module 3.2.P)

2.2.1      Description a