Veterinary Manual of Requirements and Guidelines - Vet MORAG

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Part 2 - Chemistry and Manufacture

1. INTRODUCTION

This chapter sets out the requirements and guidelines for submitting chemistry and manufacturing data as part of applications for:

approval of an active constituent
registration of a veterinary chemical product
approval of a label
variations to an approved active constituent or registered veterinary chemical product or approved label
issue of a permit

With respect to the chemistry aspects of s.14(4) and s.14(5) of the Agricultural and Veterinary Chemicals Code Act 1994 (the Agvet Code).

Chemistry and manufacture includes aspects of:

the active constituent
the formulated veterinary chemical product
manufacturing process
quality control
specifications
batch analysis
storage stability
analytical methods
packaging and labelling.

2. TYPES OF APPLICATIONS

The nature of the application determines which Part 2 (Chemistry and manufacture) data module will be required. Each module requires a number of chemistry and manufacture data elements.

2.1. Modular categories

The data elements for Modules 2.1, 2.2, 2.3 and 2.4 relate to data requirements for a particular type of application and are related to the nature of the application. The modules are more fully explained in Module levels for modular categories’ in Volume 3, and also in the individual category chapters in Volume 2 Category requirements and guidelines.

Comprehensive assessment (Module 2.1) requires submission of a full chemistry and manufacture data package, containing all of the data elements listed in the column titled ‘Data required’ in ‘Module levels for modular categories’ in Volume 3, according to the type of product or application in the column titled ‘Type of application’.

Reduced assessment (Module 2.2) and Limited assessment (Modules 2.3 and 2.4) comprise a sub-set of the data elements contained in Comprehensive assessment (Module 2.1).

2.2. Fixed categories

Applications which are evaluated under a fixed category (eg Category 7) may require submission of chemistry and manufacture data. The level of data corresponds to Module 2.1, 2.2, 2.3 or 2.4, depending on the application category, and is provided in the relevant category chapter in ‘Category requirements and guidelines’ in Volume 2.

Table 1 summarises how the modules relate to broad application types.

Table 1: Module levels and applications types

Module level	Type of application
Module 2.1	New product with new active constituent, or new active constituent only (unless included in Module 2.2)
Module 2.2	New biological product with new active constituent, or new active constituent only (except those described in Module 2.1) New product with new active constituent which is used in household or industrial chemicals, or new active constituent only New product with new source of existing active constituent, or new source of an approved active constituent only Permit, new active constituent New product where the active constituent has been previously assessed under permit
Module 2.3	New product with existing approved active constituent
Module 2.4	Variations to chemistry and manufacture details of registered veterinary chemical products Extension of shelf life Extension of in-use shelf life Change to storage temperature/conditions Change to packaging material (immediate container and/or closure system) Other applications where assessment of stability data may be required Permit application where minor chemistry assessment is required

3. APPROVAL OF AN ACTIVE CONSTITUENT

Section 15 of the Agvet Code requires the APVMA to approve the active constituents which are contained in a veterinary chemical product intended for distribution, sale or use in Australia.

Section 17 of the Agvet Code requires the APVMA to keep a Record of Approved Active Constituents for Chemical Products that includes particulars and any conditions of the approval.

3.1. Approval of a new active constituent

Every active constituent used in the formulation of veterinary chemical products intended for sale, distribution or use in Australia must be approved by the APVMA. This applies regardless of whether the product is formulated in Australia or overseas. Application for approval of a new active constituent may be made under Category 2, 15, 16, or 17.

Data requirements for approval of a new active constituent are described in section 4.

3.2. Source of approved veterinary active constituent

Approved veterinary active constituents (except active constituent in paragraph 3.3 below) can be sourced from any manufacturer who is capable of manufacturing the active constituent to comply with the relevant pharmacopoeial standard or manufacturer’s standard, without prior APVMA approval of the manufacturer. It is the responsibility of the manufacturer of veterinary chemical products to ensure that the veterinary active constituent complies with the standard (pharmacopoeia or manufacturer’s specifications) which applies to the approval of the active constituent.

The product manufacturer must ensure that properly validated analytical methods are used for providing the results of batch analyses of the active constituent.

3.3. New sources of approved agricultural active constituents that are used in ectoparasiticide products

The APVMA must approve new sources of approved agricultural active constituents that are also used as veterinary ectoparasiticides.

A component of the evaluation for approval of agricultural active constituents is the source of the active constituent. A new source of the active constituent results in a new approval for that active constituent. A list of agricultural active constituents which are ectoparasiticide approved active constituents is given in Category 17 in Volume 2.

If a veterinary chemical product contains one or more of the active constituents listed in Category 17 in Volume 2, and the registrant wishes to change the source of the active constituent to a new source which is unapproved, an application must be made under Category 17 for approval of that new source.

The data requirements for a new or additional source of an approved agricultural active constituent, are described in ‘Part 2 Chemistry and Manufacture’ in Ag MORAG Volume 3.

3.4. Variation to the particulars or conditions of approval of an approved active constituent

An application for variation to the particulars or conditions of approval of an approved active constituent, such as changes to quality, specifications, or manufacturing process of an approved veterinary active constituent, must be made under Category 14 or Category 18.

Application to the APVMA is not required for variations to approved veterinary active constituents, including changes to quality or manufacturing process, where the specifications of the varied active constituent are in compliance with the current version of an acceptable pharmacopoeia: eg the European Pharmacopoeia (Ph Eur), British Pharmacopoeia (BP), British Pharmacopoeia (veterinary) BP (Vet), United States Pharmacopoeia (USP), any other pharmacopoeia approved by the APVMA.

The data requirements for variation to approved active constituent are described in section 5.

4. DATA REQUIREMENTS FOR APPROVAL OF AN ACTIVE CONSTITUENT

This section sets out the chemistry and manufacture data that must be submitted to the APVMA in support of an application for approval of a new active constituent. These requirements apply to active constituents of synthetic or semisynthetic origin excluding immunobiological active constituents.

Data requirements for approval of immunobiological active constituents may be found in ‘Guideline 48’ in Volume 4.

Data held by a third party (eg active constituent manufacturer or product formulator) may be required for the purposes of approval or registration purposes, but may not available to the applicant for commercial reasons. In this case arrangements should be made with the third party to provide the data directly to the APVMA, preferably at the same time as the application is lodged, with a covering letter including details of the application to which it relates. This information may be included in a Drug Master File (DMF), which can be filed directly with the APVMA by the holder of the DMF.

4.1. Identification of the active constituent

Details of the identity of each active constituent must be provided. The nomenclature required includes the common name, chemical name, chemical structure and Chemical Abstracts Service (CAS) registry number.

Common name/accepted label name

The preferred name will be the name specified in the Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP). If the substance is not listed in the SUSDP, the following order of priority applies:

the name in the Therapeutic Goods Administration (TGA) Approved Terminology for Medicines – Chapter 1 –Australian Approved Names for Therapeutic Substances

the name, not including synonyms, by which the substance is described in:

the British Pharmacopoeia (BP)

the British Pharmaceutical Codex

the Australian Pharmaceutical Formulary

the British Pharmacopoeia (Veterinary) [BP (Vet)]

the European Pharmacopoeia (Ph.Eur), or

the United States Pharmacopoeia USP)

the name approved by Standards Australia (AS 1719-1994: Recommended Common Names for Pesticides)

the name given by the International Organisation for Standardisation

the name given by the British Standards Institution

the accepted scientific name (Chemical Abstracts or International Union of Pure and Applied Chemistry) or the name descriptive of the true nature and origin of the substance.

A trademark or trade name may not be used as an approved name of an active constituent.

Chemical name

The full chemical name, in accordance with both the International Union of Pure and Applied Chemistry (IUPAC) and the Chemical Abstracts (CA) nomenclature, must be provided.

All accepted and proposed non-proprietary names for the active constituent should be included - International Non-proprietary Name (INN), United States Adopted Name (USAN), British Approved Name (BAN) - with the names of the approving authorities.

Chemical abstracts service (CAS) registry number

The CAS number of the active constituent must be provided, if available. If the CAS number has not been allocated then please state ‘not yet allocated’.

Manufacturer’s code numbers and/synonyms

Manufacturer or laboratory code numbers and synonyms should be provided.

Molecular and structural formula, and molecular mass

The molecular formula, molecular mass and structural formula of the active constituent must be provided. For active constituents existing as salts or hydrates, the molecular mass of the free base or anhydrous form should also be provided. For polymeric compounds this should include weight average (M_w), number average molecular weight (M_n), molecular weight distribution.

The structural formula should include (where relevant), stereochemical properties of the active constituent eg geometric isomerism (cis/trans, E/Z), number of chiral centres and configuration at each centre. Where possible, the structural formula should be given diagrammatically with all known stereochemistry.

Elucidation of structure and other characteristics

Confirmation of the chemical structure of the active constituent must be provided. The elucidation of structure (eg the data and its interpretation) should be based on appropriate physical and chemical test results. This may include the following:

description of the synthetic route as evidence of structure

elemental analysis with theoretical values

discussion on ultraviolet (UV) characteristics including pH dependence shifts

infrared (IR) spectra

¹H and ¹³C nuclear magnetic resonance (NMR) spectra

¹⁹F and ³¹P spectral data, where relevant

mass spectrum (MS)

any other related information used to confirm the structure (eg X-ray diffraction).

Where structure elucidation of the active constituent presents difficulties, the results of studies conducted on the chemical structure of the active constituent would be acceptable.

4.2. Physical and chemical properties

All relevant physical and chemical properties of the active constituent must be provided. The information should include, as appropriate:

a general description (eg appearance, colour, odour, physical state)
when a new active constituent contains one or more chiral centres, it must be specified whether the active is a pure enantiomer, racemate or fixed combination of non-enantiomeric isomers
if the active constituent is optically active, a specific optical rotation value with limits
melting point or range (for solids)
boiling point or range (for liquids)
condensation point (gases)
refractive index (for liquids)
density/specific gravity for liquids
UV absorption maxima and molar absorptivity
pH and pKa values
solubilities in common solvents (eg. water, hydrocarbons, alcohols, chloroform, acetone)
n-octanol/water partition coefficient (Pow or log Pow)
dissociation constant, if appropriate
if the active constituent can exist in more than one physical form (eg polymorph, solvate, or hydrate), information for the form (or forms) of the active constituent that will be used in the manufacture of the veterinary chemical product
particle size distribution for active constituents having poor aqueous solubility.

Note that the above list is by no means exhaustive, but provides an indication as to the type of information that could be included.

The purity of the test substance used to generate the physical and chemical properties must be stated. The applicant must also describe the methods used to generate the data provided.

4.3. Stability data

The results of stability studies (long-term and various conditions of stress such as heat, light, humidity, acid/base hydrolysis and oxidation) on at least two batches of the active constituent must be provided.

Studies must establish the inherent stability of the molecule, in particular the degradation pathway and the identity of the degradation products (especially toxicologically significant impurities) formed on storage. The submission must include information on the containers used, the tests carried out, and analytical methods employed for assay and determination of degradation products. The actual stability results (ie raw data) must be provided.

Recommended storage conditions (temperatures and relative humidities) for long-term and accelerated conditions are given in the table below:

Study	Storage Conditions
Long term	25 ° C ± 2 ° C / 60 % RH ± 5 % RH or 30 ° C ± 2 ° C / 65 % RH ± 5 % RH
Accelerated	40 ° C ± 2 ° C / 75 % RH ± 5 % RH

RH = Relative Humidity

Recommended storage conditions for temperature sensitive active constituents are given in the table below:

Study	Storage Conditions
Long term	5 ° C ± 3 ° C
Accelerated	25 ° C ± 2 ° C / 60 % RH ± 5 % RH

The active constituent content and where appropriate, any toxicologically significant impurities and other critical characteristics of the active constituent, must be monitored initially and at sufficient sampling frequency. The information on the stability data should include:

batch size, number and date of manufacture
storage conditions
test performed with acceptable limits
detailed description of analytical procedures used to generate the data and validation data of these procedures
for quantitative tests (eg active constituent content, individual and total impurities) the actual numerical results rather than vague statements such as ‘within limits’ or ‘conforms’.

Further information on stability of the active constituent is available in the VICH guidance documents:

VICH GL3: Stability Testing of New Drug Substances and Products
and
VICH GL5: Stability Testing: Photostability Testing of New Drug Substances and Products.

4.4. Method of manufacture of the active constituent

(i) Manufacturer and site of manufacture

The name and business address of the manufacturer or manufacturers of the active constituent and the street address of the manufacturing plant(s) in which the active constituent is manufactured must be provided. If a toll or contract manufacturer is involved then their details must also be provided.

(ii) Description of the manufacturing process

(ii a) Active constituents produced by chemical synthesis

Accurate descriptions of the manufacturing process for the active constituent must be provided to adequately describe the manufacturing process and process controls. An acceptable description of the manufacturing process will include the following information:

an introductory paragraph detailing the number of chemical steps, whether the process is a batch or continuous process, and significant purification steps
a flow diagram of the synthetic processes that includes molecular formulae, chemical structural of starting materials, intermediates, reagents and chemical equations of the reactions involved reflecting stereochemistry, where relevant
relative amounts of each starting material and their order of addition
reaction conditions (temperature, pressure, pH and reaction times, etc), where these are critical
the duration and yield of each step of the process
information on intermediates which are isolated and purified
description of any purification procedures for the active constituent, including procedures to recover starting materials, intermediates or the final product
if a manufacturing concentrate is produced, details of the final concentration of the active constituent present, methods used to confirm the concentration, details of the diluents and/or any additives used.

The synthetic process must be described in sufficient detail to enable the APVMA to assess the potential presence of impurities of toxicological significance.

(ii b) Active constituents produced by fermentation

The information about an active constituent produced by fermentation must describe the fermentation process in detail, including full details of:

the strain of micro-organism used in the fermentation process
source
strain improvement procedures
purity and stability checks
cell banking arrangements
storage
propagation
seeding procedures
whether or not it has been deposited in a recognised culture collection organization eg American Type Culture Collection (ATCC), United States Department of Agriculture or the World Federation for Culture Collections (WFCC).

The information must also include:

composition of the media and details on how the reaction conditions are controlled (eg times, temperatures, pH, rates of aeration etc, and name and composition of preservatives)
a description of the isolation and purification procedure of the active constituent including in-process controls used to ensure freedom from potentially pathogenic agents (eg viruses, prions).

(ii c) Semisynthetic antibiotics derived from fermentation

Where the starting material for a semisynthetic antibiotic is obtained by fermentation, the description of the starting material should be provided as detailed under active constituent produced by fermentation (section ii b). The information for the synthesis of the final active constituent from this starting material should be provided as described in section ii a.

(ii d) Feed-grade active constituents

Feed-grade active constituents are permitted as a component of feed-additive drug premixes, which are used in the manufacture of medicated feeds. The feed-grade active constituent is usually derived from fermentation and is marketed as an unpurified or partially purified product. It commonly contains a large percentage of carbohydrates, amino acids, fatty acids, and nucleotides, but it may also contain small amounts of toxic components which are not readily isolated or identified.

For this reason, the microbial fermentation must be described in detail including specifications for all components of the media, and all procedures and precautions employed to prevent contamination or abnormal fermentation. A description of all in-process tests used to determine quality and yield must also be included.

(ii e) Active constituents of plant origin

For an active constituent of plant origin, the submission must include:

a description of the botanical species and the part of the plant used (eg leaf, flower, root)
the geographical origin and, where relevant, the time of the year harvested.

The nature of chemical fertilisers, pesticides, fungicides etc used during cultivation should be recorded. It may be necessary to include limits for pesticide residues resulting from such treatments in the active constituent specifications. Absence of toxic heavy metals may also have to be confirmed.

Full details of the manufacturing procedure of the active constituent from plant material must be described.

(ii f) Sterile active constituents

If the active constituent is microbiologically sterile, a complete description of the method of sterilisation must be provided.

(iii) Quality control

The following information must be provided on the measures taken to assure the quality of the active constituent :

specifications/purity of all starting materials, reagents and key intermediate products
measures used to monitor and assess the performance of an on-going manufacturing operation (eg analysis to determine the concentration of reactant or product to check the completion of a reaction)
tests and acceptance criteria (with justification including experimental data) performed at critical steps of the manufacturing process to ensure that the process is controlled
representative data relating to in-process quality control.

(iv) Biological sourced material

For starting materials of animal origin used in the manufacture of the active constituent, information must be provided about:

biological sources
country of origin
manufacturer
specifications
evidence that the material is free of bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathies (TSEs).

Imported biological agents require a permit from the Australian Quarantine and Inspection Service (AQIS) before they can be brought into Australia.

(v) Genetically Modified Organisms (GMOs)

For starting materials which consist of or contain Genetically Modified Organisms (GMOs), the APVMA seeks advice from the Office of the Gene Technology Regulator (OGTR) on any application for approval of a genetically modified organism (GMO) or the product of a GMO. For approval of a GMO, the applicant must also address OGTR requirements for data for a risk analysis relating to use of the GMO.

(vi) Impurities

Information on impurities that are or may be present in the active constituent at levels of greater than or equal to 0.1% must be provided. Note that levels lower than 0.1% applies to toxicologically significant impurities.

Potential sources of impurities /related substances include:

impurities in the starting materials, intermediates, from incomplete or side reactions, or from isomerisation
residual solvents, reagents and immediate precursors
trace elements arising from the use of catalysts or other sources
degradation of the active constituent that may occur after manufacture.

Each submission with respect to impurities must include a structural chemical formula and possibly a scheme for the formation of the impurity, followed by a text discussion of its formation.

More detailed guidance regarding impurities is available in VICH guidance documents:

VICH GL 10: Impurities in New Veterinary Drug Substances

VICH GL 11: Impurities in New Veterinary Medicinal Products and

VICH GL 18: Residual solvents in New Veterinary Medicinal Products, Active Substances and Excipients

(vii) Impurities of toxicological significance

If there is potential for the formation of toxic impurities and/or by-products, this must be declared and quantified.

Details must be provided of the conditions leading to their formation of toxic impurities and steps taken to control their formation.

4.5. Active constituent standard/specification

Applicants must nominate the appropriate standard with which each active constituent complies. This may be an up-to-date pharmacopoeial standard, or where there is no pharmacopoeial standard, the manufacturer’s specification.

Active constituent listed in a pharmacopoeia

If the active constituent is listed in the European Pharmacopoeia (Ph.Eur.), the British Pharmacopoeia (BP), the British Pharmacopoeia (Veterinary) [BP (Vet)], the US Pharmacopoeia (USP) or any other pharmacopoeia approved by the APVMA, it must be used unless otherwise justified.

Note that the most recent edition of any cited pharmacopoeia should be used, or a justification made for not doing so. Any variation from the established pharmacopoeial standards must be justified.

Active constituent not described in a recognised pharmacopoeia

If the active constituent is not listed in the Ph.Eur, BP, BP (Vet), USP) or any other pharmacopoeia approved by the APVMA, the manufacturer’s specification for the active constituent must be provided.

The specifications must include all tests to which each batch of the active constituent will conform (eg appearance, identity, assay, single individual and total impurities) and the associated acceptance limits. Additional tests and limits may be appropriate and will depend on the nature of the active constituent. For example, tests for isomeric composition ( pure enantiomer, racemate or fixed combination of non-enantiomeric isomers), optical rotation, microbial contamination, particle size distribution and polymorphism may also be relevant. If the active constituent is a pure enantiomer, the specifications should include a test to ensure isomeric identity and purity.

Table 2 provides an example of specification for an active constituent.

Table 2: Example of specification for an active constituent

Tests	Acceptance Criteria	Method
Appearance	White crystalline powder	Visual
Identification tests	Retention time of the major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation obtained as specified in the assay. Spectra are similar to that of corresponding preparation of the reference standard.	HPLC-XYZ IR spectra
Assay	NLT 98.0% and NMT 102% of C wH xN yO z , calculated on a dried basis	HPLC-XYZ
Impurities Impurity A Impurity B Total impurities	NMT 0.5% NMT 0.3% NMT 1.5%	HPLC-XYZ
Residual solvent	NMT 200 ppm	GC- ABC
Residues on ignition	NMT 0.1%	USP <281>
Heavy metals	0.001%	USP <231>
Loss on drying	NMT 1.0%	USP <731>

NLT = not less than

NMT = not more than

Complex active constituents

Where the active constituent is difficult to characterise quantitatively, as is the case with some complex plant/ herbal extracts, it may be difficult to adequately control the constituent through quantitative specifications. In this case, a combination of specifications and the detailed method of manufacture may be required to adequately characterise the active constituent.

4.6. Batch analysis data

Batch analysis results must be provided for at least three recent commercial-scale production batches of the active constituent to demonstrate routine compliance with the pharmacopoeial monograph or manufacturer’s specifications.

If data on commercial-scale batches are not available, batch analyses should be provided for pilot-scale batches manufactured using the same process as intended for commercial-scale batches.

The results should include:

batch size, number, date of manufacture and date of analysis
results of analytical determinations. For quantitative tests (eg active constituent contents, individual and total impurities) the actual numerical results must be provided rather than vague statements such as ‘within limits’ or ‘conforms’
information on the analytical procedures used to generate the data and validation of these procedures
where applicable, chromatograms of the batches showing separation of impurities
chromatograms must be clearly labelled with batch numbers, peak identity and peak integration data
a copy of all raw data used to generate the final results.

For determination of impurities present in the active constituent, reference standards should be prepared for each of the identified impurities, particularly those known to be toxic, and the concentration of impurities quantitated against their own reference standards.

It is acceptable to use the active constituent as an external standard to estimate the levels of impurities, provided the response factors of those impurities are sufficiently close ( ³ 90%) to that of the active constituent. In cases where the response factor is not close, it may still be acceptable to use the active constituent provided a correction factor is applied.

The sum of the quantitative level of active constituent and impurities is often referred to as the mass balance. Mass balance is an important parameter in the batch analysis to ensure that all major impurities have been detected. The mass balance need not add up to exactly 100%, because of the analytical error associated with each analytical procedure, however the mass balance should be in the range 98-102%.

4.7. Analytical methods

Full details of the test procedures used for determining the active constituent, all impurities at or above 0.1% and toxicologically significant impurities (even when present at less than 0.1%) in the active constituent must be provided. The following information must be included in a written analytical method:

principle of the method, method summary, sample preparation techniques, equipment/reagents eg for chromatographic methods details of the column, eluent (including gradients, where applicable), temperature, detector and retention times
purity of reference standards
where chromatographic techniques are used, relevant chromatograms including peak assignment and peak integration data
worked examples of the calculations.

4.8. Validation data

Validation data for the method(s) used to assay the active constituent and impurities must be provided. The following parameters must be addressed, where appropriate.

specificity
linearity
precision
recovery (accuracy)
limit of quantitation.

Further information regarding the validation of analytical methods is available in APVMA Guidelines for the Validation of Analytical Methods and VICH guidance documents ‘VICH GL1: Validation of analytical procedures: definition and terminology’ and ‘VICH GL2: Validation of analytical procedures: methodology’

4.9. Analytical reference standards

Applicants for approval of new active constituents must provide the following samples to the Australian Government National Measurement Institute (NMI):

1 gram analytical reference standard of each pure active constituent, or where the active constituent is a mixture of major isomers which can be separated, 1 gram of each isomer
100 grams of active constituent as manufactured (the percentage purity and the method used to determine purity must be provided)

NOTE: Applicants may provide justification that they should supply less than 1 gram analytical reference standard and/or less than 100 grams of active constituent as manufactured. The APVMA will consider the argument on its merits.

10 mg of analytical reference standards for the toxicologically significant impurities present in the active constituent
100 mg analytical standard for all metabolites identified and for which a maximum residue limit (MRL) applies.

Storage instructions and information on shelf life of the analytical reference standard and active constituent are required, especially if degradation is likely to occur under transport or storage.

The samples should be sent to:

Australian Government National Measurement Institute – Chemical Reference Materials
1 Suakin Street
PO Box 385
PYMBLE NSW 2073
Phone: (02) 9449 0111
Fax: (02) 9449 1653
E-mail: info@measurement.gov.au

Samples must be accompanied by a letter stating:

the reason for submitting the samples
the purity of the materials supplied with the certificate of analysis
storage instructions
acute oral and dermal toxicities of the materials, or the appropriate Material Safety Data Sheet (MSDS).

Care should be taken to ensure that samples are properly packed. Samples that arrive leaking or otherwise damaged will be destroyed and replacement samples will be requested.

Samples must be provided to NMI before approval of a new active constituent. When standards are supplied to NMI, documentation to this effect must be forwarded to the APVMA.

From time to time the APVMA may request replacements for some or all of the above samples, to maintain its inventory.

4.10. Packaging

The packaging or storage/shipping containers must be appropriate for the characteristics of the active constituent.

A description of the packaging materials used for the active constituent and information regarding the corrosive effect, if any, of the active constituent on the packaging materials must be provided. This information is not required if the active constituent is formulated into a product at the site of manufacture.

4.11. Data list

Applicants must provide a Data List, including an entry for all information that meets the definition given in the Data Protection documentation on the APVMA website. This requirement applies irrespective of whether an application is eligible for data protection.

5. DATA REQUIREMENTS FOR VARIATION TO AN APPROVED ACTIVE CONSTITUENT

Reasons to vary the particulars or conditions of approval of an approved veterinary active constituent may include changes to the quality of the active constituent or changes to the manufacturing process.

5.1. Which application category?

Applications should normally be made under Category 14 or Category 18 depending on the active constituent:

if the active constituent is an approved active constituent that has protection under the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement (refer to the APVMA website Active Constituents page), or
if the active constituent is an ectoparasiticide which is an approved active constituent for use in agricultural chemical products (refer to Vet MORAG Category 17)
- the application should be made under Category 18.
if the active constituent does not fit the description above and is contained in a registered veterinary chemical product, the application should be made under category 14.

5.2. Not all variations require an application

Application to the APVMA is not required for variations to veterinary active constituents, including changes to quality or manufacturing process, where the specifications of the varied active constituent are in compliance with the current version of an acceptable pharmacopoeia ie Ph Eur, BP, BP (Vet), USP.

It is the active constituent approval holder’s responsibility to ensure that the APVMA is notified of any proposed changes to the manufacturing process and/or impurity profile.

5.3. Data requirements

The following data must be provided in full, with each application for variation to particulars or conditions of approval of the approved active constituent:

details of manufacturing (eg process, quality control, impurity formation), as specified in paragraph 4.4
a new active constituent standard/specifications as specified in 4.5
a new full three batch analysis results as specified in 4.6
full details of the analytical method(s) used for the determination of the active constituent, any isomers and the impurities present as specified in 4.7
appropriate validation data for the analytical method(s) as specified in 4.8.

5.4. Reference to previously-submitted data

If the manufacturing process or the analytical methods have been assessed and accepted by the APVMA in a previous application, the applicant may reference the data provided in that application.

A suitable reference can be made to the previously accepted data. The reference should include the active constituent approval number or the file reference number. If necessary, the APVMA may request that the referenced data be re-submitted.

5.5. Data list

6. DATA REQUIREMENTS FOR REGISTRATION OF A VETERINARY CHEMICAL PRODUCT

6.1. Distinguishing product name

The distinguishing name is the name by which the product is (or is to be) known, registered, labelled, advertised and sold. It should include such descriptive words or phrases as are needed to distinguish the product from other products and to identify the purpose for which it is to be used. Full information on the requirements relating to the distinguishing name is provided in the ‘Vet Labelling Code’ in volume 5.

6.2. Formulator and formulation plant details

The name and address of all manufacturing facilities involved in any step of the manufacture of the product must be provided. This includes toll or contract manufacturers and sub-contractors involved in packaging and labelling, sterilising and testing, up to and including release for supply.

6.3. Formulation type/pharmaceutical dosage form

The applicant must indicate the type of formulation to be registered eg capsule, emulsifable concentrate, injectable solution, implants, intramammary treatment, oral drench, tablet.

If the product formulation is to be further altered before use (eg reconstituted), the formulation type or pharmaceutical dosage form of the end-use formulation must be provided.

6.4. Formulation composition

The formulation composition describes the qualitative and quantitative formulation of the veterinary chemical product. It must list:

the constituents
their CAS registry number (if available)
their amounts, and
a reference to the quality standards (eg pharmacopoeial standard or manufacturer’s specifications) and each constituent’s purpose in the formulation (eg active constituent, disintegrant, antimicrobial preservative etc).

Constituents used in the manufacture of the veterinary chemical product must be identified by their established common name. If an established common name does not exist for a component, a complete chemical name (IUPAC, CA name) should be used. Trade names alone are not acceptable if common or chemical names exist.

For components that are mixtures (eg colorants, surfactants, coatings, flavours, inks) proprietary names can be used in the chemical product composition statement if the quantitative and qualitative composition of the mixture is provided.

6.5. Reference to quality standards

Standards with which each constituent (active and non-active constituents) comply should be cited as listed below:

Active constituent details

Applicants must nominate the appropriate standard with which active constituent complies. This may be an up-to-date pharmacopoeia [Ph Eur., BP or BP (Vet), USP, any other pharmacopoeia approved by the APVMA] or where a pharmacopoeial standard does not exist, details of the manufacturer’s specifications for the active constituent.

Active constituent listed in a pharmacopoeia

If the active constituent is listed in the Ph. Eur., BP, BP (Vet), USP or any other pharmacopoeia approved by the APVMA, this is the minimum standard that will apply in its entirety, otherwise a justification is required. Note that the most recent edition of any cited pharmacopoeia should be used, or a justification for not doing so included.

A batch analysis/certificate of analysis to show compliance with the nominated pharmacopoeial standard must be provided.

Active constituent not listed in a pharmacopoeia

If the active constituent is not listed in a pharmacopoeia, manufacturer’s specifications must be provided. The minimum tests and limits included in specifications for an active constituent should include:

appearance/description
test for identity
maximum and minimum limits of purity
maximum limits for impurities (eg synthetic impurities and degradation products, residual solvents, heavy metals).

Additional tests and limits may be appropriate and will depend on the nature of the active constituent. For example, test for the presence or proportion of isomers, optical rotation, microbial contamination, particle size distribution and polymorphisms may also be relevant.

Batch analysis/certificate of analysis to show compliance with the nominated manufacturer’s specifications must be provided.

Non-active constituent details

Applicants must nominate the appropriate standard with which each non-active constituent complies. This may be an up-to-date pharmacopoeial standard or where a pharmacopoeial standard does not exist, the manufacturer’s specifications for the non-active constituents.

Non-active constituents complying with a pharmacopoeia

Applicants must nominate the pharmacopoeial standard with which the non-active constituent complies. A reference to an up-to-date standard in the Ph. Eur., BP, BP (Vet), USP, any other pharmacopoeial standard approved by the APVMA, including date of publication, is sufficient. Any variation from the established pharmacopoeial standards should be elaborated in full.

Applicants must provide full details of how they ensure compliance of each non-active constituent with the nominated pharmacopoeial standard.

Non-active constituents not listed in a pharmacopoeia

For non-active constituents not listed in a pharmacopoeia, the manufacturer specifications for the excipient should be provided and should include its physical characteristics (eg identification tests) and chemical characteristics (eg purity tests).

Applicants must provide full details of how they ensure compliance of each non-active constituent with the nominated manufacturer’s specification.

6.6. Colouring additives, flavourings and perfumes

Colouring additives, proprietary flavourings and perfumes should comply with a recognised standard, such as the Food Standards Code, (Food Standards Australia New Zealand) or Excluded Stockfood Non-Active Constituents (Statutory Rules No. 59, 1995). Where these additives comply with a recognised standard, the name and address of the supplier is all that is required.

For colouring additives, flavourings and perfumes that do not comply with a recognised standard, the name and address of the supplier must be given, and arrangements should be made by the applicant to have details of the constituents of that compound supplied to the APVMA. Where necessary, information on constituents can be supplied direct and in confidence to the APVMA by the supplier.

6.7. Materials of animal origin

When materials (active and non-active constituents) of animal origin are used, evidence must be provided that they are free of bovine spongiform encephalopathy (BSE) and transmissible spongiform encephalopathies (TSEs). The biological source, country of origin, manufacturer details and Australian Quarantine and Inspection Service (AQIS) import permit must be provided.

6.8. Function of constituents in the formulation

The function (ie role or purpose) of each constituent in the formulation must be stated.

6.9. Amount of constituents in the formulation

The amounts of the active constituent and all non-active constituents must be listed. All overages must be clearly indicated.

In general, a fixed amount for each constituent should be stated. If a salt or hydrate form of the active constituent is used, the composition for the active constituent should be clearly stated (eg 1 mg of active constituent base = 1.075 mg of active constituent hydrochloride). A quantity sufficient (q.s.) designation can be used when appropriate (eg q.s. to 1 mL, q.s. to pH 5.5).

Based on the actual potency of the active constituent and all non-active constituents, adjustment by calculation of the mass of constituent should be made in formulation composition. For example, if the theoretical batch quantity of an active constituent in a batch of product is 100 grams, and the assay ‘as is’ of the batch of ingredient being used is 92% w/w then the factorised mass of the active constituent to be added would be 100g x 100/92 = 108.7g.

The concentration of all constituents must be expressed in g/L for liquid formulations and g/kg for solid formulations.

For formulations in unit dosage form, concentration may be expressed on a per unit basis (eg mg per tablet, mg per capsule, mg per mL, mg per vial). If these units are not appropriate for a particular formulation, suitable units should be proposed, for example μg/kg or a biological unit (International Unit of biological activity).

A formulation composition statement resembling that shown in Table 3 would be adequate.

Table 3: Example of a formulation composition statement for a tablet

Constituent name	CAS number	Reference to standard		Purpose in formulation
50 mg tablet
Cefalexin monohydrate	23325-78-2	BP	52.59 mg¹	Active
Polyethylene glycol 600		USP/NF	10 mg	Binder/lubricant
Microcrystalline cellulose	9004-34-6	USP/NF	133.4	Diluent/filler
Colloidal-Silicon dioxide	7631-86-9	USP/NF	2	Anti-adherent/glidant
Magnesium stearate	557-04-0	USP/NF	2	Lubricant
Tablet Weight			200 mg

1 Equivalent to 50mg on the anhydrous basis

USP = The United States Pharmacopoeia

NF = The National Formulary

6.10. Overages

Where an overage (small excess) of active constituent is deliberately added to compensate for manufacturing loss or loss during storage, the actual concentration (nominal + overage) must be stated. It should be stated whether this is intended to cover losses during manufacture, loss of potency during storage, or both.

Reference should be made to other sections of the application, which include information relevant to the need for an overage eg product specifications, stability data.

6.11. Scored tablets

Tablet dosage forms may be manufactured with one or more debossed lines (scores) running across the planar surface of the tablet. Scores allow the tablet to be broken into fractions when less than a full tablet is required for a dose.

To ensure accurate dosing, the tablet should be single-scored or cross-scored to deliver the dose to the target animal in accordance with the approved label dose rate, and the applicant should ensure as part of the good manufacturing practice (GMP) that the tablet halves or quarters provide uniformity of content. For further information, refer to the APVMA’s operational notice on this matter.

6.12. Manufacturing process

A description of the method of formulation of the product and the sequence of operations must be provided, plus an indication with the typical size of the production-scale batch. This should include sufficient detail to cover the essential points, for example what happens when the product or its ingredients are subjected to heat, sterilising, or processes affecting particle size or likely to lead to the formation of toxic impurities.

For sterile products, the sterilisation process should be described in detail (eg heat, filtration, gaseous sterilization or radiation).

6.13. Quality control

Full details of the quality control procedures used by the formulator to ensure the batch-to-batch reproducibility of the product should be given. Information should include details of the control checks performed at various stages of the manufacture, processing and packaging of the product. The description of the in-process testing should include the specifications and tests for pivotal and key/critical intermediates.

6.14. Product specifications

Product specifications with suitable upper and lower limits for the active constituent and the relevant physical characteristics of the product must be provided. The specification limits must take into account the use of any overages in the formulation. Specifications are to address the test parameters for the particular dosage form/formulation type applicable [eg capsule, tablet, oral paste, emulsifiable concentrate (EC)] as outlined in the Guidelines for the Generation of Storage Stability Data of Veterinary Chemical Products, available from the APVMA website. An upper and lower limit of preserving agents in the product should be specified.

Where applicable, a clear distinction should be made between the release specification (the requirements for each batch at the time of manufacture) and the expiry specification (the requirements with which any sample must comply during its shelf life).

Different release and expiry specifications are often necessary where a product tends to be unstable, especially where a stability overage has been included. Note that the expiry specification is regulated by the APVMA.

Unless there is appropriate justification, the maximum acceptable deviation in the active constituent content of the product must not exceed ± 5% at product release (time of manufacture). On the basis of stability tests, the applicant must propose and justify maximum acceptable limits in the active constituent content of the product up to the end of the proposed shelf-life.

NOTE: A deviation of ± 10% in the active constituent content of the product is normally acceptable as expiry specification. Larger deviation (greater than ± 10%) in the active constituent content must be justified.

Table 4 gives an example of a suitable format for product specifications listing the tests used, the associated acceptance criteria and the analytical procedures used to perform each test.

Table 4: Example of product specifications for a tablet formulation

Tests	Acceptance Criteria	Method
Appearance	White biconvex film coated tablet	Visual
Identification tests	Retention time of the major peak in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation obtained as specified in the assay.	HPLC XYZ
Assay	95.0 to 105 .0% LC (release) 90.0 to 110 .0% LC (expiry)	HPLC XYZ
Impurities Impurity A Impurity B Total impurities	NMT 0.5% NMT 0.3% NMT 1.5%	HPLC XYZ
Uniformity of content	Comply with Ph Eur requirements	HPLC XYZ
Hardness	5 – 10 kPa
Disintegration	NMT 15 minutes
Dissolution	NLT 80% (Q) in 30 minutes	USP Apparatus 2 etc
Tablet weight	500 mg

LC = label concentration
NMT = not more than
NLT = not less than
Q = The Q value is a percentage of the product's label claim

6.15. Batch analysis

Results on a minimum of three batches of the product are required to demonstrate that the product is formulated within specifications. The data must include results for all parameters listed in the product specifications.

Note: The initial results from stability trials may be sufficient.

6.16. Stability data

Data to demonstrate stability during storage are required for veterinary chemical products. Data from stability studies must be provided on at least three batches of the product. Two of the three batches must be pilot or production scale, the third batch may be laboratory scale. The batches used must be of the same formulation and packaged in the same containers closure system as proposed for registration.

The product should be stored at or above the proposed label storage temperature:

–18°C, –5°C, between 2°C and 8°C, 8°C, 25°C ± 2°C at 60% RH ± 5% RH, and 30°C ± 2°C at 65% RH ± 5% RH for long-term testing, and at 40 °C ± 2°C and 75% RH ± 5% RH for accelerated testing.

The frequency of the testing should be sufficient to establish the stability profile of the product (as soon as practicable following manufacture, and then every 3 months over the first year, every 6 months over the second year and at 12-month intervals thereafter). Bracketing can be applied, where justified. Relevant physical, chemical, and microbiological characteristics of the dosage form product should be monitored. Test results (including initial results) for the test parameters should be included. Characteristics of the packaging material (container/closure interaction with the product) should be examined as part of the stability trial.

The discussion of results should focus on observations noted for the various tests and conclusions concerning the shelf life and storage conditions for the product.

In certain exceptional cases of particularly complex mixtures, where the assay of active constituents which are very numerous, each present in very low amounts, assay of one or more active constituents which are known to be stable (minerals) may be omitted on the condition that the correct amount of active has been added during the manufacture of the product. This may be proven by provision of batch records.

Additionally, stability data is required for following formulations:

• liquid formulations: cold temperature stability (stability data generated at lower temperatures is not required if the product label contains a warning against exposure to low temperatures)
parenteral products in multi-dose containers: stability after first opening of the container
products that are reconstituted before dilution: in-use stability after reconstitution or dilution

Further information regarding the storage stability testing is available in the Guidelines for the Generation of Storage Stability Data of Veterinary Chemical Products available on the APVMA website.

6.17. Extension of shelf life

The stability data from real time and/or accelerated stability studies on at least three batches of the registered product must be provided. The stability study must be conducted in accordance with stability protocol approved in the registration application. The stability testing must be conducted using properly validated analytical methods and the parameters must be tested according to the registered specifications of the product.

Table 5 gives an example of a protocol for shelf life extension of tablet formulation.

Table 5: Example of stability protocol for a tablet formulation

Batch identification	Storage conditions	Storage period	Tests or Specifications	Stations monitored
BN 168, 169, 170	25°C/60% RH	24 months	* see below for example	0, 3, 6, 9, 12, 18, 24 months
BN 168, 169, 170	30°C/65% RH	24 months	* see below for example	0, 3, 6, 9, 12, 18, 24 months
BN 168, 169, 170	40°C/75% RH	12 months	* see below for example	0, 3, 6, 9, 12 months

* Appearance: colourless tablets

Assay: 135-165 mg/tablet

Hardness: < 15

Friability: < 1%

Moisture: < 1%

Disintegration: NMT 15 minutes

Dissolution: > 80% after 30 minutes

Uniformity of content/mass: complies with the requirements of BP

6.18. Checklist for submission of stability data

To reduce delays and requests for further information during the evaluation of stability data by the APVMA, the applicants should use the following checklist:

specify the formulations used in the stability study and state whether it is identical to the product proposed for registration
state whether the batches used in stability study were laboratory, pilot or production scale batches
state whether the product was packaged in the same containers (materials and size) that are proposed for the marketing of the final product
provide stability data from at least 3 batches. Two of the three batches must be pilot or production scale; the third batch may be laboratory scale
specify the storage conditions (temperature, humidity, and light)
provide full details of the analytical method(s) used
provide validation data for the analytical method(s) used (include copies of the relevant chromatograms and raw data)
provide results for relevant test parameters of the dosage form
for quantitative tests provide actual numerical results rather than vague statements such as ‘within limits’ or ‘conforms’
provide results from enough time stations to allow assessment of any trends in the data
where relevant, provide information on shelf life after reconstitution and/or first opening of the product
monitor potential changes to the integrity of the packaging materials during the storage stability studies
specify proposed shelf life and storage conditions.

6.19. Analytical procedures

Full description of the analytical procedures used for testing of the product should be provided. The method(s) of analysis must be appropriate for the type of active constituent and the formulation matrix of the product. The applicant must provide the following information to demonstrate the suitability of the analytical method(s) used to generate data for product registration:

full details of the analytical methods used for determining the active constituent and, where appropriate, relevant toxicologically significant impurities in formulated veterinary chemical products during stability testing
the purity of the reference standards
where chromatographic techniques are used; representative chromatograms of the reference standard, veterinary chemical product and placebo (if available). Chromatograms must be labelled with batch number, peak identity and peak integration data
worked examples of the calculations.

6.20. Validation data

Validation data of the methods used for the determination of active constituent and toxicologically significant impurities must be provided. The following parameters must be addressed:

specificity
linearity
precision
recovery (accuracy)
limit of quantitation

Further information regarding the validation of analytical methods is available in Guidelines for the Validation of Analytical Methods, available from the APVMA website at http://www.apvma.gov.au.

Note: If the analytical methods have been assessed by the APVMA in a previous application, then the applicant may reference the data provided in that application. However, if the formulations are not identical then the applicant will be required to provide specificity and recovery (accuracy) data to demonstrate that the analytical method is appropriate for use on the new formulation.

6.21. Packaging

A description of the container closure system must be provided, including the composition of the construction materials of each primary packaging component and its specification. The suitability of the container should be discussed in terms of its compatibility with the product (including sorption to container and leaching) and its performance in protecting the product physically and also in protecting it from moisture and light.

The integrity of the container must not be impaired by the product it contains nor must the product be adversely affected by the packaging material.

6.22. Data list

7. TEMPLATE FOR SUBMISSION OF PART 2 CHEMISTRY AND MANUFACTURING DATA

7.1. Approval of an active constituent

TABLE OF CONTENTS

OVERALL SUMMARY

IDENTIFICATION OF THE ACTIVE CONSTITUENT

Common name/accepted label name

Chemical name

CAS registry number

Manufacturer’s code numbers and/or synonyms

Molecular and structural formula and molecular mass

Elucidation of structure and other characteristics

PHYSICAL AND CHEMICAL PROPERTIES

STABILITY DATA

METHOD OF MANUFACTURE OF THE ACTIVE CONSTITUENT

ACTIVE CONSTITUENT STANDARD/SPECIFICATION

BATCH ANALYSIS DATA

ANALYTICAL METHODS

VALIDATION DATA

ANALYTICAL REFERENCE STANDARDS

PACKAGING

DATA LIST

7.2. Registration of a product

TABLE OF CONTENTS

OVERALL SUMMARY

DISTINGUISHING PRODUCT NAME

FORMULATOR AND FORMULATION PLANT DETAILS

FORMULATION TYPE/PHARMACEUTICAL DOSAGE FORM

FORMULATION COMPOSITION

REFERENCE TO QUALITY STANDARDS

COLOURING ADDITIVES, FLAVOURING AND PERFUMES

MATERIALS OF ANIMAL ORIGIN

FUNCTION OF CONSTITUENTS IN THE FORMULATION

AMOUNT OF CONSTITUENTS IN THE FORMULATION

OVERAGES

SCORED TABLETS

MANUFACTURING PROCESS

QUALITY CONTROL

PRODUCT SPECIFICATIONS

BATCH ANALYSIS

STABILITY DATA

EXTENSION OF SHELF LIFE

CHECKLIST FOR SUBMISSION OF STABILITY DATA

ANALYTICAL PROCEDURES

VALIDATION DATA

PACKAGING

DATA LIST

8. GLOSSARY

Active constituent

The substance or substances in a product, which is/are primarily responsible for the biological or other effects that make the product an agricultural/ veterinary chemical product

Additive

An ingredient (such as a wetting agent, emulsifying agent, dye etc), which is intentionally added to a product, to improve its physical characteristics, eg sprayability, solubility, spreadability.

Analytical reference standard

A substance of established quality and purity.

Anthelmintics

A veterinary chemical product that is for the treatment of internal parasites.

APVMA approved active constituent

An active constituent that has been approved by the APVMA for use in an agricultural/veterinary chemical products in Australia.

APVMA Standard

The standard determined by the APVMA to which an active constituent contained in chemical products must comply.

Batch

A defined quantity of material produced in a single series of operations.

Batch number

A distinctive combination of numbers and/or letters which specifically identifies a batch and from which the production history can be determined.

3-Batch analysis

A three-batch analysis is analysis for active constituent, isomers and impurities content carried out on five separate batches of production material. The three batch analysis provides evidence that the material conforms to the specifications ie it is within the certified manufacturing limits.

CAS registry number

A database of the Chemical Abstracts Service (CAS) in which numbers are randomly assigned to compounds and are unique for each compound.

Declaration of composition (DoC)

A statement (signed and dated by the Approved person) stating maximum and minimum level of purity of the active and maximum levels of impurities present in the active constituent.

Diastereoisomers

Stereoisomers that are not enantiomers of each other are termed diastereoisomers.

Drug Master File

(Plant Master File) A confidential document filed with the APVMA that provides complete information about a specific manufacturing facility.

Ectoparasiticide

A veterinary chemical product that is administered or applied to an animal by any means for the control, treatment or prevention of infestations with arthropod parasites.

Enantiomers

Stereoisomers, which are non super-imposable mirror images; outside chiral environment they possess identical physico-chemical properties, except that they rotate the plane of polarised light in opposite directions and by equal amounts.

Equivalence

A comparative assessment of the full impurity profile of active constituent produced by different manufacturers against the profile of the active constituent used in the first approval of that active constituent. If the impurity profiles are similar, the active constituent from the new sources can be considered equivalent to the original active constituent.

Formulation

A veterinary chemical product preparation containing active constituent(s) and formulant(s) in a form suitable for use.

Formulation site

Any site/s associated with the formulation/packaging of the agricultural/veterinary chemical product.

Formulation change

A formulation change in relation to a chemical product means:

a variation in the concentration of one or more of the active constituents, or other constituents of the product; or
the addition to the product, or removal from the product, of one or more of the active constituents, or other constituents, of the product.

Formulant

see Additive.

Impurity

Any constituent other than an active constituent or an intentionally added non-active constituent. Impurities include starting materials, intermediates, reaction products, degradation products, contaminant or chemicals added for purposes of extraction or purification.

Laboratory scale batches

Laboratory batch size corresponds to less than 10% of the production scale.

Manufacturer of active constituent

Any person/organisation involved in any stage of the manufacturing process and responsible for the quality of the active constituent.

Manufacturing concentrate

A form of an active constituent, which may contain inert ingredients, such as stabilisers or solvents.

Manufacturing site

The physical location of the site where the active constituent is manufactured.

Manufacturer’s specification

A statement (signed and dated by the manufacturer) of the description of the active constituent including the maximum and minimum limits of purity, the maximum limits of contaminants, test for identity and any other properties as applicable. Note that certificates of analysis or material safety data sheets do not constitute a manufacturer’s specification.

Material safety data sheet (MSDS)

Data sheet produced by manufacturer/importer, which provides the information needed to allow the safe handling of hazardous substances.

New active constituent

An active constituent that has not previously been approved for use in an agricultural/veterinary chemical product in Australia.

Non-active constituent (excipient)

Any ingredient, other than an active constituent, which is part of a product formulation. Non-active constituents are added at the time of manufacture for various reasons including improving formulation characteristics such as stability, solubility and spreadability (see also Additive).

Overage

The excess of active constituent deliberately added to a formulation to compensate for manufacturing loss or loss of potency during storage, or both

Pharmacopoeia

An authoritative work containing descriptions of drugs, which are used in the practice of medicine (or veterinary medicine) listing the specifications, their formulae and dosages, and methods for determining purity and strength. Pharmacopoeias also include specific and general test methodologies.

Pilot scale batches

Pilot batch size corresponds to at least 10% of the production scale batch.

Product

A formulation containing one or more active constituents, and possibly non-active constituent(s), which is intended for application, with or without dilution prior to use, and which is labeled with directions for use.

Production scale batches

Batches which will be produced during routine commercial production of the product.

Racemate

Equimolar mixtures of enantiomers.

Raw data

All original records and documentation, including verified copies thereof, which are the result of original observations and activities in the study.

Record of approved active constituents

The record of the active constituents that the APVMA approves.

Relevant impurity

An impurity that is toxicologically significant to human beings or environment, are phytotoxic to treated plants, affect the stability of the active constituent or cause any other adverse effect (see also Toxicologically significant impurity).

Shelf life

Period of time during which the product remains suitable for use and within the approved shelf-life specifications, provided that it is stored under the conditions specified on the label in the approved container and closure.

Specifications

Specifications describe the requirements to which materials should conform. Specifications for the active constituents and products include a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. Active constituents and products, when tested according to listed analytical procedures, must meet the listed acceptance criteria.

Stereoisomers

Stereoisomers have the same constitution (same molecular formula, same atomic bonding) but differ in the spatial orientation of the atoms or groups of atoms within the molecule.

Toxicologically significant impurity

An impurity that is very highly toxic or sensitising to mammals at very low concentrations.

9. ABBREVIATIONS AND ACRONYMS

AAN	Australian Approved Name
AAT	Administrative Appeals Tribunal
AQIS	Australian Quarantine Inspection Service
BP	British Pharmacopoeia
BP (Vet)	British Pharmacopoeia (Veterinary)
BSI	British Standards Institute
CA	Chemical Abstracts
CAS	Chemical Abstract Services
CVMP	Committee for Medicinal Products for Veterinary Use (of EMEA)
DMF	Drug Master File
DoC	Declaration of Composition
EMEA	European Agency for the Evaluation of Medicinal Products
EU	European Union
FDA	Food and Drug Administration (United States)
FOI	Freedom of Information
FSANZ	Food Standards Australia New Zealand
GC	Gas Chromatography
GLP	Good Laboratory Practice
GMO	Genetically Modified Organism
GMP	Good Manufacturing Practice
HDPE	High Density Polyethylene
HPLC	High Performance Liquid Chromatography
IR	Infra red
IUPAC	International Union of Pure and Applied Chemistry
JECFA	Joint FAO/WHO Expert Committee on Food Additives
LAL	Limulus amoebocyte lysate
NF	National Formulary (United States)
NMI	National Measurement Institute
NDPSC	National Drugs and Poisons Scheduling Committee
NIR	Near Infra Red
OCS	Office of Chemical Safety
OECD	Organisation for Economic Co-operation and Development
OGTR	Office of Gene Technology Regulator
Pdf	Portable document format
Ph Eur	European Pharmacopoeia
PVC	Polyvinyl chloride
PVDC	Polyvinylidene chloride
SUSDP	Standard for the Uniform Scheduling of Drugs and Poisons
TGA	Therapeutic Goods Administration (Australia)
USP	United States Pharmacopoeia
VICH	International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Products
w/w	Weight per weight
w/v	Weight per volume
v/v	volume per volume

10. REFERENCES

Pharmacopoeias

British Pharmacopoeia 2005, ISBN 0 11 322682 9. [plus amendments]

British Pharmacopoeia (Veterinary) 2005, ISBN 0 11 322682 9.

European Pharmacopoeia, 5th Edition 2005. Council of Europe , Strasbourg. ISBN 92-871-5281-0.

United States Pharmacopoeia, USP 29; The National Formulary NF 24 United States , Pharmacopoeial Convention, Rockville , MD , 2005. ISSN 0195-7996, ISBN 1-889788-39-2.

International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH)

VICH GL1: Validation of analytical procedures: definition and terminology

VICH GL2: Validation of analytical procedures: methodology

VICH GL3: Stability testing of new drug substances and products

VICH GL5: Stability testing: Photostability testing of new drug substances and products

VICH GL10: Impurities in new veterinary drug substances

VICH GL 11: Impurities in new veterinary medicinal products

VICH GL 17: Stability testing of new biotechnological/biological products

VICH GL18: Residual solvents in new veterinary medicinal products, active substances and excipients

Other Publications (Including Codes, Regulations and Manuals)

Federal Office of Road Safety, Department of Transport and Regional Services 1992, Australian Code for the Transport of Dangerous Goods by Road and Rail (ADG Code), AGPS, Canberra. ISBN 0 644 25610 9.

Food Standards Australia New Zealand (FSANZ), Food Standards Code plus amendments

Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP), ISBN 1 920746 47 1.

Standards Australia International, Australian Standard, AS1719-1994, Recommended Common Names for Pesticides, (Available from Standards Australia , GPO Box 5420 , Sydney, NSW 2001).

Statutory Rules No. 59 of 1995, Veterinary Chemical Products (Excluded Stockfood Non-Active Constituents) Order under Section 7 of the Agricultural and Veterinary Chemicals Code Act 1994.

Therapeutic Goods Administration (TGA) Approved Terminology for Medicines – Chapter 1 –Australian Approved Names for Therapeutic Substances

REVISION HISTORY

Revision Date	Description of Revision
1 July 2005	First edition unchanged from the original Vet Requirements Series.
1 October 2005	Second edition unchanged from the original Vet Requirements Series.
1 April 2006	Third edition unchanged from the original Vet Requirements Series.
1 July 2007	Fourth edition complete revision of the content.