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Guidance for industry: Preparation of veterinary new drug submissions and abbreviated new drug submissions (new and generic drugs) - Quality requirements: Drug substance

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Background

The term "medicinal ingredient" and "drug substance" are considered interchangeable terms. Medicinal ingredient and drug substance refers to the raw (input) material in the manufacture of a drug product. For further information, refer to HC's "Updated Notice: Interim Policy on Health Canada's Interpretation of Medicinal Ingredient and Assessment of Identical Medicinal Ingredient".

Active Substance Master File (ASMF)

Some information in the drug substance section of the submission may be considered proprietary and may not be available to the sponsor of the NDS or ANDS. In this case, the supplier of the drug substance can file a confidential Type I – MF (ASMF) directly with Health Canada. The supplier would then be considered the ASMF Holder and the letters of access should be provided with the submission. Sponsors should also submit the non-proprietary information provided by the ASMF holder (i.e. the "Applicant Part" of the ASMF), and other information obtained from the public domain (e.g. scientific literature, peer reviewed journals), or developed by the sponsor, with reference sources identified.

For recommendations on the content and process for filing an ASMF, refer to HC's guidance document "Guidance on procedures and administrative requirements for master files".

The proprietary information in the "Restricted Part" of the ASMF is reviewed in connection with the review of the NDS or ANDS. The ASMF holder will be contacted directly only if deficiencies are determined, and comments regarding any deficiencies will be sent directly to the ASMF holder. The sponsor will be notified in writing that a deficiency letter has been sent to the ASMF holder, and comments on deficiencies observed in any other part of the drug substance information in the NDS or ANDS are sent directly to the sponsor of the submission.

Cross reference to an ASMF previously filed with Health Canada in support of a human drug product is considered acceptable; however, it is the responsibility of the sponsor of the NDS or ANDS to ensure that the ASMF holder is aware of the current VDD requirements for the ASMF filing.

Regardless of the information provided by the supplier of the drug substance, the manufacturer of the dosage form is responsible for ensuring that appropriate specifications and properly validated analytical procedures for the drug substance are developed, and for providing the results of batch analyses. These specifications and methods should be provided from the release testing site (i.e. the site where testing is done for the purpose of releasing the drug substance) of the drug substance to be used in the manufacture of the drug product. Determination of the acceptability of the release testing site is determined by the Good Manufacturing Practices (GMP) under Part C, Division 2 of the regulations and is the responsibility of the Regulatory Operations and Enforcement Branch (ROEB) of HC. For more information on GMP, contact HC's Health Product Compliance Directorate at drug.gmp.questions-bpf.medicaments@hc-sc.gc.ca.

Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs)

The VDD encourages the filing of CEPs, when they are available, to support the assessment of the chemistry and manufacturing information of a drug substance.

If a valid CEP is referenced in a drug submission, the quality information should be submitted as described in Section 2.2 of the HC's guidance document on the "Use of Certificates of Suitability as supporting information in Drug Submissions". The CEP can be provided in partial support of the submission in cases mentioned under Section 2.3 of the CEP Guidance Document to expedite the review.

S.1 General information

S.1.1 Nomenclature

The following information on the nomenclature of the drug substance should be included (if relevant or available):

When an in-situ conversion of the drug substance occurs or is likely to occur based on chemical principles during the manufacture of the drug product (e.g. formation of a salt or complex), the compound in the final dosage form of the drug product should also be described. If this is not possible, a justification with detailed information should be provided.

S.1.2 Structure

The structural formula, including relative and absolute stereochemistry, geometric isomerism or a mixture of isomers, the molecular formula, and the relative molecular mass should be provided. For drug substances existing as salts and/or hydrates/solvates, the molecular formula and molecular mass of the free base or free acid or anhydrous form should also be provided.

S.1.3 General properties

A list of physicochemical and other relevant properties of the drug substance should be provided. This information should include the physical description (e.g. polymorphic form, solvate, hydrate) including appearance, colour, and physical state. Solid forms should be identified as being crystalline or amorphous. If the drug substance can exist in more than one physical form, the information should be included for the form(s) of the drug substance that will be used in the manufacture of the drug product or formed through in situ conversion. Detailed information on the characterization of these and other physical forms are provided in section "S.3.1 Structure elucidation and confirmation" below.

Other general properties could also include the following:

Information on polymorphism and particle size distribution data should be provided if these attributes can affect the performance of the drug product. Generally, polymorphism and particle size distribution are not a concern for drug substances that are considered to be highly soluble (as defined in VICH GL39) in aqueous buffers in the physiological pH range (e.g. 1.2-6.8), or as appropriate for the target veterinary species, or that are fully dissolved in the final dosage form. Data on general properties that are not generated in-house should be clearly referenced.

S.2 Manufacture

S.2.1 Manufacturer(s)

The submission should include the name, address, and responsibility of each manufacturer, including contract manufacturers or testing sites involved in the manufacturing, packaging, labelling, and testing of the drug substance. This also includes the facilities involved in the physical manipulation (e.g. micronization/milling), sterilization, sterilization of equipment or primary component of a container closure system (CCS) (e.g. gamma irradiation), and testing of the intermediates. If certain companies are responsible only for specific steps (e.g. milling of the drug substance) this should be indicated. The list of manufacturers should specify the address for the location where the relevant manufacturing or testing operation will be performed, rather than the administrative offices.

Active pharmaceutical ingredients (drug substances) and intermediates for pharmaceutical use are regulated under the Divisions 1A and 2, Part C of the FDR. Good Manufacturing Practices (GMP) compliance is required and must be demonstrated prior to the issuance of an establishment licence (EL).

If an ASMF is filed with HC and is cross-referenced for certain proprietary information (i.e. restricted part), the ASMF number assigned by HC should be provided in the QOS, CPID and Part 1. Reference to a CEP should also be included, if applicable.

S.2.2 Description of manufacturing process and process controls

Information should be provided to adequately describe the manufacturing process and process controls and illustrate the sponsor's commitment for the manufacture of the drug substance.

The information on the preparation and purification of the drug substance and the drug substance starting material should be provided in a manner that allows the assessment of the fate and purging of all potential impurities, including theoretical, specified unidentified and identified impurities (e.g. isomeric impurities, toxic impurities, residual solvents, and elemental impurities) in the drug substance starting materials, intermediates, and the drug substance.

The submission should include a flow diagram or diagrams of the synthetic process(es). The diagrams should also include the chemical structures of the starting materials, intermediates, and drug substance, reflecting stereochemistry and also including reagents, solvents, and operating conditions.

A narrative description of the manufacturing process should be provided, including quantities of raw materials, solvents, catalysts and reagents reflecting the representative batch scale for commercial manufacture, identification of critical steps, and all process controls, equipment, and operating conditions (e.g. temperature, pressure, pH, time). If a cross-referenced ASMF includes a detailed description of the manufacturing process, the sponsor only needs to include a brief summary of the manufacturing process with a flow diagram representing the route of synthesis in the (A)NDS.

Reprocessing and reworking

Alternate processes, reprocessing steps and/or reworking steps, if any, should be justified and described in either the cross-referenced ASMF or the (A)NDS using the same level of detail as is used for the primary process. Any data to support this justification should be included in section S.2.6.

Micronized/Milled or compacted drug substances

Micronization or milling is a critical step for certain drug substances, such as for a low solubility drug substance used in a tablet or to ensure process capability, and should be described in sufficient detail to permit the complete assessment of the safety and quality of the drug substance. In such instances, the type of equipment (e.g. make and milling sieve) and critical process parameters (CPPs) or the procedure used to establish the parameters for a batch (e.g. equipment setting, and operating conditions) necessary to produce lots with consistent particle size distribution should be described. The same information should be provided for compacted materials.

Non-isolated intermediates

If an intermediate is not isolated, an in-process control to test for completeness of reactions should be included before advancing to the next step unless otherwise justified (e.g. in a case when a reaction resulting in a non-isolated intermediate is consistent and well controlled). Tests for completeness of reaction are deemed to be critical and should be included in section S.2.4 unless data is provided to support that the completion of the reaction is noncritical.

Sterile drug substances

For sterile drug substances, the submission should include a complete description of the sterilization method and the controls used to maintain sterility during storage and transportation. Results of the process validation studies of the sterilization process should be provided in section S.2.5.

Drug substances manufactured using a fermentation process

For drug substances produced by fermentation, the detailed description of the manufacturing process and process controls should also include, as appropriate:

Drug substances of plant (botanical) origin

For drug substances of plant origin, the submission should also include:

The submission should record the nature of any chemical fertilizers, pesticides, fungicides, and so on, employed during cultivation (if applicable). The information to be submitted will depend on the controls and characterization of the botanical material, however, it may be necessary to document all processing steps after harvesting (e.g. drying equipment and time, treatment of plant material) to justify controls. Appropriate limits for residues resulting from such treatment should be included in the drug substance specification or as in-process controls. Discussion, including supporting data, may be required to demonstrate the absence of toxic metals and radioactivity.

S.2.3 Control of materials

A list of all materials, and identification of where each material is used in the manufacture of the drug substance and the specifications for each of these materials should be included. The specifications should meet the standards appropriate for their intended use and include tests and acceptance criteria for appearance, identification, impurities (specified, unspecified and total) and assay, where applicable.

The potential of isomeric impurities and mutagenic impurities should be considered, particularly those that could be carried through the synthesis to the drug substance. This information may be cross-referenced to a ASMF; however, the ASMF holder will be required to provide an attestation to inform the drug product manufacturer if there is any change in the supplier to the drug substance starting material or in the route of synthesis of the drug substance starting material. Generally, starting materials specifications would include tests and acceptance criteria for identity, purity, and potency, where applicable.

The specifications for the critical and novel materials used in the synthesis, fermentation, extraction, isolation, and purification steps should be provided in the drug submission. If recovered materials (e.g. solvents, intermediates) are used, a brief description of purification and the specifications for the recovered materials should be provided or confirmation that the specifications are identical to those used for the fresh material along with a justification of their suitability.

For drug substance(s) manufactured from reagents or obtained from sources that have the potential of containing Bovine Spongiform Encephalopathy (BSE) or Transmissible Spongiform Encephalopathy (TSE) agents, the following supporting data should be submitted:

Information assessing the risk with respect to potential contamination with adventitious agents should be provided.

For non-viral adventitious agents

Details should be provided on the avoidance and control of non-viral adventitious agents (e.g. transmissible spongiform encephalopathy agents, bacteria, mycoplasma, fungi). This information can include certification and/or testing of raw materials and excipients and control of the production process as appropriate for the material, process and agent. Potential contamination with mycotoxins should be considered for fermentation products from fungi.

Note: If information on the control of materials is included in a cross-referenced ASMF, it is appropriate for the submission to refer to the ASMF rather than provide the information in the submission.

Starting material

Information on the manufacturing process should start from well-characterized drug substance starting materials. A drug substance starting material is proposed by the sponsor with a justification and assessed by VDD to determine whether the controls on the drug substance (e.g. impurities) and drug substance manufacturing process (e.g. control strategy, critical process controls, intermediate testing) can provide appropriate control of quality. The following general principles for the selection of the starting materials should be considered:

The names and addresses of each manufacturing site of a drug substance starting material should be provided along with the route of manufacture at each site. Suitable specifications for the starting materials using validated analytical procedures should be provided. The specification of a starting material should include tests for identity and purity (e.g. controls on impurities) and, where applicable, could include acceptance criteria for assay, specified, unspecified and total impurities, residual solvents, reagents, elemental impurities and mutagenic impurities. Specific consideration should be given to potential isomeric impurities in the starting material as these contaminants could be carried through the synthesis to the drug substance. Justification of the tests included on the specifications (e.g. purging studies) should be provided.

In most cases, information on the preparation of the drug substance starting material (e.g. flow chart, reagents, potential impurities) should be provided in sufficient detail in order to fully characterize the impurity profile and to justify the specifications for the drug substance starting material and drug substance. In some cases, this information may precede the drug substance starting material by several steps in the synthetic process. The level of detail required in the manufacturing description depends on a number of factors, including the criticality of the process parameters in determining product quality.

There is an increased risk that impurities generated as a result of a change to the manufacturing process upstream of the starting material may not be detected or purged appropriately if the starting material is only a small number of chemical transformation steps from the drug substance (i.e. <3 steps). Justification of the proposed starting material should be provided, including a comprehensive description as to what factors were considered in deciding whether enough of the drug substance manufacturing process is provided in Section S.2.2 of the application to ensure that these risks are appropriately mitigated.

Acids, bases, salts, esters, and similar derivatives of the drug substance and the racemate of a single enantiomer drug substance are considered final intermediates and should not be declared as drug substance starting materials. Each branch of a convergent drug substance synthesis should contain one or more drug substance starting materials unless the point of convergence is upstream (i.e. earlier in the synthesis) of the proposed drug substance starting material.

S.2.4 Controls of critical steps and isolated intermediates

The tests and acceptance criteria performed at each critical step as identified in section S.2.2 of the manufacturing process should be provided with a justification, to ensure the process is adequately controlled. In addition, CPPs of the manufacturing process such as temperature, time, drying conditions, micronization parameters, etc., should also be listed and justified.

The specifications for isolated intermediates, including tests and acceptance criteria for description, identity, purity, and potency should meet standards appropriate for their intended use. Well-defined controls of potential impurities should be included, as well as considerations for potential isomeric impurities and mutagenic impurities that could be carried through the synthesis of the drug substance.

Non-isolated intermediates, where test for completeness of reaction is critical, should be listed in this section.

S.2.5 Process validation and/or evaluation

For sterile drug substances, the submission should include process validation and/or evaluation studies for aseptic processing and sterilization processes (e.g. a validation report for the sterilization steps). Manufacturers who choose to manufacture a sterile drug substance without terminal sterilization (e.g. aseptic processing) should provide scientific justification and supporting data for the proposed sterilization technique. Information on the control of critical steps and intermediates can be cross-referenced to the ASMF if an ASMF is being used to support the (A)NDS. The manufacturing processes for all drug substances should be properly controlled and validated before the commercial distribution of the resulting drug product.

For non-sterile drug substances, process validation and/or evaluation studies need not be provided in a regulatory submission.

S.2.6 Manufacturing process development

A description and discussion should be provided of the significant changes made to the manufacturing process and/or manufacturing site of the drug substance used in producing nonclinical, pilot, clinical, stability, comparative bioavailability, scale-up, and, if available, production scale batches.

Reference should be made to the drug substance data provided in section S.4.4.

Any differences in stereochemistry, polymorphic form or particle size distribution of the drug substance used during development compared to the drug substance used in the commercial product should be discussed in terms of the potential impact to the drug product performance, safety, and efficacy. References to specific sections in the drug product pharmaceutical development should be made as necessary.

S.3 Characterization

S.3.1 Elucidation of structure and other characteristics

Confirmation of the structure based on the synthetic route and spectral analyses should be provided. Information such as the potential for isomerism, the identification of stereochemistry, or the potential for forming polymorphs should also be included.

The spectra, peak assignments, and a detailed interpretation of the data for the primary reference standard should be provided. For drug substances with a compendial reference standard, it is generally sufficient to provide the Infrared (IR) and Ultraviolet (UV) spectra of the drug substance for each source. The sample should be run concomitantly with a suitable primary reference standard which can be obtained from the Schedule B compendia (e.g. USP, Ph. Eur., BP) or a batch of the drug substance that has been fully characterized (e.g. IR, UV, Nuclear Magnetic Resonance (NMR), Mass Spectra (MS)). See section S.5 for further details on references standards and materials, including primary and secondary reference standards.

If comparative studies with the CRP are necessary to establish pharmaceutical equivalence (e.g. for polymeric drug substances in an ANDS), data from the comparative physicochemical studies should be provided.

The studies carried out to elucidate and/or confirm the chemical structure of new chemical entities normally include IR, UV, NMR, and MS studies. Other tests could include elemental analysis, X-ray diffraction (XRD), solid state studies or molecular weight distribution where relevant.

For drug substances (e.g. certain antibiotics, enzymes, and peptides) which may present challenges with respect to structural investigation, more emphasis should be placed on the purification and the specification for the drug substance to ensure a reproducible drug substance.

If a drug substance consists of more than one active component (e.g. conjugated estrogens) the physicochemical characterization of the components and their ratio should be submitted. Where this information is not available, a justification should be provided.

Potential for isomerism and identification of stereochemistry

When a drug substance contains one or more stereocentres, structural elucidation should confirm whether the drug substance is a specific stereoisomer or a mixture of stereoisomers or a meso isomer. A discussion should be included of all possible isomers that can result from the manufacturing process, the steps where they are introduced, and a summary of the results of the studies carried out to investigate the physical, chemical, and biological properties of these isomers. If there is a preferred isomer or isomeric mixture, the drug substance specification should include a test to ensure isomeric identity and purity. If there is no potential for isomerism based on the structure of the drug substance, it is sufficient to include a statement to this effect.

Polymorphs

The potential of polymorphism should be investigated and discussed in terms of potential impact to the drug product performance, safety and efficacy. References to specific sections regarding pharmaceutical development under section P.2 should be made as required. Results from an investigation of several batches of the drug substance, recrystallized from several solvents, should be provided to determine if the drug substance exists in more than one crystalline form. The study should include the characterization of the batch(es) used in the clinical and/or comparative bioavailability studies, using a suitable method (e.g. X-ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR)). The absence of the potential for polymorphism can further be confirmed by providing the results of a literature search. Polymorphism can also include solvation or hydration products (i.e. pseudopolymorphs) which should be appropriately characterized using solid state studies.

Particle size distribution

The particle size distribution of the drug substance can have an effect on the in vitro and/or in vivo behaviour (e.g. absorption of the drug from the gastrointestinal tract) of the drug product, in particular for low solubility drug substances as defined in VICH GL39, with a dose/solubility volume greater than 250 mL over a pH range of 1.2 to 6.8, or as appropriate for specific veterinary species. Particle size can also be important in dosage form performance (e.g. optimum delivery of inhalation products to the lungs), achieving uniformity of content in low-dose tablets, achieving a smooth suspension to prevent irritation in ophthalmic preparations, and stability and redispersibility of suspensions.

S.3.2 Impurities

A risk assessment on the potential and actual impurities arising from the synthesis, manufacture, and/or degradation should be provided. The tables in VDD's QOS (NDS/ANDS) template can be used to summarize the information on impurities (e.g. names, structures, origin, results). The origin refers to how the impurity was introduced (e.g. "Synthetic intermediate from Step 4 of the synthesis", "Potential by-product due to rearrangement from Step 6 of the synthesis"). It should also be indicated if the impurity is a metabolite or degradation product of the drug substance. The discussion on the fate of these impurities should lead to a clear conclusion regarding the need or absence thereof to control them in the drug substance specification. Spiking studies may be necessary to demonstrate purging.

Actual impurities and potential impurities likely to be present in the drug substance should be examined for structural alerts and evaluated for mutagenic potential. This assessment and the control strategies proposed by the sponsor for identified mutagenic or potentially mutagenic impurities should be described.

The discussion should include the possible isomers that can result from the manufacturing process, the steps where they were introduced, and a summary of the results of the studies carried out to investigate the physical, chemical, and biological properties of these isomers. If there is a preferred isomer or isomeric mixture, the drug substance specification should include a test to ensure isomeric identity and purity.

The list of impurities should include both drug-related impurities (e.g. drug substance starting materials, by-products, intermediates, chiral impurities, degradation products) and process-related impurities (e.g. residual solvents, reagents, catalysts). For process-related impurities, the step where the compound is used or formed in a synthesis should be identified.

Purging of impurities originating from the drug substance starting material and intermediates should be discussed in detail. For non-mutagenic related impurities that are present in intermediates at levels above the VICH identification threshold that are not specified in the final drug substance specifications, they should either be shown to be purged to below this threshold in downstream steps, or that the analytical method(s) used to test the drug substance for related substances can detect these impurities to demonstrate that they are controlled as unspecified impurities. A similar concept may apply to reagents and catalysts which are not detected by the related substance method.

The potential for the presence of adventitious agents, including viral and bacterial agents, residual proteins and TSE agents and the probability of removal by manufacturing processes should be discussed.

The ability of the related substances analytical method(s) used to detect and control potential impurities (e.g. intermediates) should also be discussed, including potential impurities that would be controlled as unspecified impurities in the final drug substance specifications.

S.4 Control of drug substance

S.4.1 Specification

The submission should contain the drug substance specification from the company responsible for release of the drug substance for the drug product manufacture as per C.02.009 (5)(c) of the FDR. The person in-charge of quality control at the responsible company should date and sign the specification in accordance with GMP guidelines. The submission should include the specification reference number, version, date, and analytical method type/reference for version control purposes. For drug substances where a compendial monograph exists, the specification can include reference to the compendial analytical procedures in the current version of the monograph with details of any non-compendial analytical procedures to be used.

Although the drug substance specification will normally include tests for appearance, identity, potency, and purity, additional tests (e.g. for particle size distribution, crystal form determination [polymorphism], chirality, bacterial endotoxins, etc.) will be required depending on the characteristics of the drug substance and its end use (e.g. oral, parenteral).

Standard claim

If a Prescribed Standard (e.g. Canadian Standard Drugs as per Part C, Division 6 of the FDR) is applicable then the specifications must meet this standard. If a compendial standard as per Schedule B to the Food and Drugs Act (e.g. USP, Ph. Eur. BP) is declared, then the specifications must meet all compendial requirements, including general chapters, as per the applicable pharmacopoeia.

If a Schedule B compendial monograph is applicable to the drug substance, a sponsor can choose to declare a manufacturer's Standard, which indicates that the material may differ in some respect from the compendial standard. However, the specifications must at minimum meet the pharmacopeial standard.

Assay

The assay should include the chemical formula so that it is clear as to how the dose is declared (i.e. free acid/base vs. salt).

Polymorphic form

If the results of studies conducted on the physical and chemical properties of the various crystalline forms indicate that there is a preferred polymorph, a control strategy that may include a test in the drug substance specification should be described in the submission. This control strategy should ensure polymorphic equivalence of the commercial material to the batch(es) used in the clinical and/or comparative bioavailability studies. If the polymorphic form is unstable, the test criteria should be capable of monitoring for conversion of the polymorphic form.

Generally, controls on polymorphism are less likely to be necessary for drug substances that are highly soluble, although potential impact of polymorphism on manufacturability and stability should be considered. Justification of proposed controls or exclusion of controls for polymorphism should be provided and supported by data, in particular for low solubility drug substances. Where the drug substance is a solvate or a hydrate, specifications for the solvated drug substance should include a range for the percent content by weight of the solvent supported by data.

Bacterial endotoxins

A test for bacterial endotoxins with an appropriate limit should be included in the specifications for drug substances used in injectable products.

Impurities

Chemical names or unambiguous designations of impurities that align with the description of the impurity structures in S.3.2 or in the analytical procedure should be used in the drug substance specification and the summary of the specifications and in the CPID (e.g. USP or Ph. Eur. Naming conventions or unambiguous company codes).

The submission should include quantitative results of actual impurities found in a minimum of three (3) batches of the drug substance with a justification for the proposed acceptance criteria. Impurity limits could be qualified based on conformance with an existing compendial monograph, VICH GL10 guidance document, or in comparison against the CRP. Impurities that are significant metabolites present in animal and/or human studies are generally considered qualified. The level of any impurity present in a new drug substance that has been adequately tested in safety and/or clinical studies would be considered qualified.

Table S.4.1-1: VICH GL10 thresholds for drug substances
  New veterinary drug substances not used in human medicine New veterinary drug substances used in veterinary and human medicine
Identification 0.20% As per ICH
Reporting 0.10% As per ICH
Qualification 0.50% 0.50%

Unidentified impurities that are specified by relative retention time (RRT) at a limit greater than 0.20% require identification. Identified impurities at a limit greater than 0.50% requires qualification. Limits for specified impurities in a Schedule B publication are generally considered acceptable. VICH limits of no more than (NMT) 0.20% for unspecified impurities apply, rather than the general limits for unspecified impurities that appear in the compendial monograph, unless the compendial limits are more stringent. It is possible that there are specified impurities in the compendial monograph that are not likely to be present in a generic drug product due to a different method of synthesis. Appropriate justification should be provided for their exclusion from the submission.

For fermentation products, although relevant guidance VICH GL10 do not address impurities in fermentation products, the principles and levels for reporting, identifying, and qualifying organic impurities as described in the guidance are still applicable to non-complex, well-characterised fermentation products. For complex fermentation products that are not well-characterised in terms of structure, physicochemical properties, biological activity, and purity, it is recommended that the levels for organic impurities be determined on a case-by-case basis. Some flexibility may be appropriate for drug substances of semi-synthetic origin such as those obtained from chemical modification of a precursor molecule of plant or animal origin or derived from a fermentation process. A limit of NMT 0.50% for unspecified impurities would generally be considered appropriate.

Impurities classified as residual solvents need to conform to the levels specified in VICH GL18 "Impurities: Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients".

Particle size distribution

Particle size distribution of poorly soluble drugs may affect in vitro and in vivo performance of the drug product. Although particle size distribution may be important for other reasons related to drug product manufacture and performance such as content uniformity, the most important regulatory concern relates to its possible impact on dissolution and bioavailability.

For low solubility drugs, the submission should appropriately characterize the particle size distribution of batches used in clinical or bioavailability studies, and include a test in the drug substance specification. The acceptance criteria should include controls on the particle size distribution to ensure consistency with drug substance in the batch(es) used in pivotal studies (e.g. limits for d10, d50, and d90). The following is provided for illustrative purposes as possible acceptance criteria for particle size limits:

If the drug substance is dissolved during the drug product manufacturing process, then control of particle size distribution may not be necessary.

S.4.2 Analytical procedures

The analytical procedures used for release and stability testing of the drug substance should be provided. In-house analytical procedures used for routine testing should be provided. Method development history and summaries of changes between current and historical analytical procedures that have been used during drug development, but are not intended for routine testing purposes, can be provided in this section; however, information regarding method development history should be clearly explained under the "Batch analyses" section or the "Stability" section, if applicable. For modified Schedule B compendial analytical procedures, complete details of the revisions/modifications should be described – if no modifications are made, Schedule B compendial analytical procedures are not required. There are restrictions in the compendia for allowable modifications to methods. If compendial procedures are modified more than that allowed by the compendia, the method should be claimed as a manufacturer's method and full details provided.

Although HPLC/UPLC is considered the standard method for determining drug-related impurities, other chromatographic methods such as GC and TLC can also be used if appropriate and justified. Reference standards should be prepared for each of the identified impurities, particularly those suspected or known to be toxic, and the concentration of the impurities quantitated against their own reference standards. It is considered acceptable to use the drug substance as an external standard to estimate the levels of impurities if justified (e.g. the response factors (RF) are greater than 80% when compared to the RF for the drug substance). Where the response factor is not close to that of the drug substance, it is acceptable to use the drug substance as an external standard, provided a correction factor is applied or the impurities are, in fact, being overestimated. Unspecified impurities should be quantitated using a solution of the drug substance as the reference standard at a concentration corresponding to the limit established for unspecified impurities.

System suitability tests (SSTs) are an integral part of chromatographic analytical procedures. At a minimum, HPLC, UPLC and GC methods should include SSTs for repeatability for assay methods and repeatability and resolution for impurities. To determine repeatability for control of drug-related impurities, typically a solution of the drug substance with a concentration corresponding to the limit for unspecified impurities is used. The SSTs serve to demonstrate that the chromatographic system is capable of producing accurate and reproducible results at the concentrations being tested. In accordance with the USP General Chapter on Chromatography, the repeatability test should include 5 or 6 replicate injections. Resolution of the two closest eluting peaks is generally recommended; however, using alternate peaks can be justified (e.g. choice of a toxic impurity).

The number of theoretical plates and tailing factor can be used as additional SSTs for column performance or if there are no suitable impurities for the determination of resolution. For TLC methods, the SSTs should verify the sensitivity and ability of the system to separate impurities by applying a spot corresponding to the drug substance spiked at a concentration corresponding to the limit of unspecified impurities.

The summary of the analytical procedures in the QOS should include details on the various parameters of the method. For example, in the case of an HPLC/UPLC impurity method, a summary of the column, mobile phase, detector, sample/reference solution preparation, and SSTs should be included.

A brief tabulation of the data is recommended but where the level of detail of the summary of the analytical procedures will interrupt the flow of the QOS, the tables can be appended to the QOS. Care should be taken to clarify the data describing solution concentration particularly when it is listed in terms of percentage units. A foot note can be added to clarify whether percentages are against the label claim of the drug substance or as % (w/w) or (w/v).

S.4.3 Validation of analytical procedures

Analytical validation information, including experimental data for the analytical procedures used for release and stability testing the drug substance, should be provided. Validation reports for the analytical procedures employed for routine testing should be provided in Part 2. Validation of current methods to show equivalency with historical methods should be provided if historical methods were used during pivotal clinical trials or during pivotal stability studies, under the batch analyses or stability section, whichever is applicable.

Different sources of the same drug substance may show different impurity profiles which may not have been considered during the development of the monograph and the extent of studies which should be provided is determined by the novelty of the impurities. If compendial methods are modified to include a limit for unspecified impurities at the VICH identification threshold, the method should be validated to ensure that it is sensitive and precise enough at that lower limit. If a Schedule B compendial method is used to control specified impurities that are not listed in the monograph, full validation is expected for those specified impurities.

If a Schedule B compendial standard is claimed and a manufacturer's standard is used in lieu of the compendial method (e.g. for assay or for specified impurities), equivalence of the House and compendial methods should be demonstrated and scientifically justified. This could be accomplished by performing analyses of a batch containing significant levels of impurities by both methods and providing comparative results from the study.

For the control of residual solvents, GC methods for determining residual solvents are considered to be sensitive, linear, and reproducible. Historically, sponsors use essentially the same GC method to determine residual solvents in a number of drug substances. Therefore, although it is expected that a facility will initially perform full validation of the methods used to determine residual solvents, it is acceptable that only limited validation data be submitted (e.g. recovery, repeatability, limit of detection/limit of quantitation, and selectivity of the method). Recovery and repeatability should be determined using a sample of the drug substance spiked with the residual solvents at their acceptance criteria.

The summary of the validation reports for the analytical procedures included in the QOS should be clear, accurate, and concise. This would include details on the various validation parameters (e.g. as in the case of the validation an HPLC/UPLC impurity method, a summary of the results for specificity, linearity, range, accuracy, precision (repeatability, intermediate precision), Limit of Detection (LOD), Limit of Quantitation (LOQ), robustness, stability of solutions). A tabulation of the data is recommended to summarize analytical validation data, but where the level of detail of the summary of the analytical procedures will interrupt the flow of the QOS, the tables can be appended to the QOS.

Care should be taken to clarify the data describing solution concentration particularly when it is listed in terms of percentage units (e.g. a footnote can be added to clarify whether percentages are against the label claim of the drug substance or as % (w/w) or (w/v)). Representative chromatograms should be provided with the validation report.

If validation of analytical methods has not been performed in a GMP compliant facility, the method transfer protocol and report should be provided. This protocol should include impurity studies, where the impurities are present at close to the specified limits or are spiked at the limits.

S.4.4 Batch analyses

A description of the batches and results of batch analyses should be provided. It is expected that drug substance lots used to manufacture drug product lots used in pivotal clinical studies and those submitted in the regulatory application to establish specifications for assay, purity and retest period, are manufactured and tested according to GMP principles to ensure the reliability of the analytical test results. Deviations and Out of Specification (OOS) test results should be investigated in a timely manner and the results of the investigation summarized in the submission. Justifications with supporting data should be provided, where necessary, to support the use of the identified lots for setting regulatory specifications for release and stability.

A tabulated summary in the QOS of batch number, batch size, date and site of production, and specific use, including clinical/pre-clinical study information, the testing site, etc. should be provided for the batches used to support the drug submission. All test sites for pivotal batches should be identified. Of the batches included, analytical results should be provided for those batches used in nonclinical, clinical, comparative bioavailability, comparative in vitro, and stability studies, including batches manufactured to a minimum of pilot scale (e.g. 1/10th commercial scale) by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for, production batches. If the scale of the batch is less than 1/10th commercial scale, a justification for why the smaller scale is representative should be provided. The number of batches should be sufficient to support the specification(s) and assess consistency in manufacturing. Analytical results from a GMP compliant laboratory should be provided for at least three (3) batches from each proposed manufacturing site of the drug substance.

Certificates of Analysis (CoA) should be provided for the pivotal batches. A tabulated summary of batch analysis results should be provided including information on range, mean and relative standard deviation, where applicable, of individual results, results of all tests conducted, quantitative results for all tests, RRT (or other specific designation of impurities), and quantity of all unspecified impurities greater than the VICH reporting limit or the LOQ, as long as the LOQ is less than or equal to VICH reporting limits, and limits of detection where applicable (e.g. when impurities are not detected). Results of additional tests may be provided to justify the omission of certain tests from the specification.

The discussion of results should focus on observations for the various tests, rather than reporting as "All tests meet specifications" and include ranges of analytical results and any observed trends. When results are reported as 'none detected', 'less than LOD' or 'less than LOQ', a footnote should be included that specifies the LOD and LOQ value for each analytical method or impurity as applicable. A discussion and justification should be provided for any incomplete analyses (e.g. batches not tested according to the proposed specification).

S.4.5 Justification of specification

Justification for the drug substance specification should be provided and should include a discussion on the inclusion or exclusion of tests, choice of analytical procedures, acceptance criteria, taking into account any applicable compendial standard, etc. This justification should also include the rationale for the inclusion or the exclusion of tests, discussion of the development of methods and acceptance criteria, and the rationale for differences from compendial tests, methods, or acceptance criteria. Certain specific tests on the drug substance may be justified by the manufacturing process of the drug product that was realized during developmental pharmaceutics, such as particle size determination, or other unique physicochemical property.

If justification for certain tests, analytical procedures, or acceptance criteria have been discussed in other sections of the submission, cross-referencing to those sections are sufficient.

Impurities

If the Schedule B compendial methods have been modified or replaced, a discussion should be included. Limits for specified and identified impurities in a compendial monograph are considered qualified; however, general limits in a compendial monograph for unspecified impurities that exceed the applicable VICH identification threshold are not considered acceptable. Furthermore, a general limit for unspecified impurities would not be considered acceptable as qualification for a newly identified impurity if it exceeds the applicable VICH Qualification Threshold.

If there are identified impurities in a compendial monograph (e.g. as in a Ph. Eur. Transparency section) that are not monitored by the proposed routine analytical method, a justification should be provided for their exclusion from the specifications (e.g. the impurities are not formed by the synthetic route). Alternatively, if acceptable justification cannot be provided, and a house standard is used, it should be demonstrated that the house standard is capable of controlling the impurities identified in the compendial monograph at an acceptable level as unspecified impurities (i.e. with a limit corresponding to the Identification Threshold). Method validation data would be provided in section S.4.3.

Depending on the nature of the drug substance, and the extent of the chemical modification steps, the general principles on the control of impurities (e.g. identification and qualification) can also be extended to drug substances of semi-synthetic origin. For example, a drug substance whose precursor molecule was derived from a fermentation process, or a natural product of plant or animal origin, and has subsequently undergone several chemical modification reactions generally would fall within this scope, whereas a drug whose sole chemical step was the formation of a salt from a fermentation product generally would not fall within this scope. It is understood that there can be some latitude for these types of drug substances provided an acceptable justification supported by a scientific rationale and data is provided (e.g. a limit of NMT 0.20% for unspecified impurities, rather than a limit corresponding to the VICH Identification Threshold).

For a generic drug product, if impurity levels are above the VICH Qualification Threshold, actual test results of impurities/degradation products using an acceptable method determined in at least one recent batch of an appropriately stored sample of the CRP can be provided to qualify the limit. This section should include elements of the overall drug substance control strategy and be provided in tabular form in the VDD QOS (NDS/ANDS) template.

The acceptance criteria for total impurities should be based on the actual levels of impurities found in several batches of the drug substance from each source, including the levels found in the batches used for the nonclinical, clinical, comparative, and stability studies. In the cases where a large number of batches have been tested, it is acceptable to summarize the total number of batches tested with a range of analytical results.

Whenever a proposed acceptance limit for an impurity or degradation product exceeds the applicable VICH GL10 qualification thresholds, the sponsor should ensure that all the required toxicological studies or other scientifically acceptable justification such as metabolite studies and data supporting the proposed limit, is included in the submission. It is essential to establish the link between the proposed qualified limit for a specified impurity and the toxicity study(ies) in which it was qualified. A clear reference to where the qualification studies can be found in Part 4 should also be included in both the QOS and Part 2. The use of a tabulated summary in the QOS, including batch numbers, levels of impurities, and study reference numbers for qualifying studies, is strongly encouraged.

If justification for certain tests, analytical procedures, and acceptance criteria have been discussed in other sections of the drug submission (e.g. impurities, particle size) cross-referencing to the location of those section's discussions are sufficient.

S.5 Reference standards

The submission should include the sources of reference standards or materials used to test the drug substance.

Primary reference standards

Primary reference standards obtained from official pharmacopeial monographs as described in the publications referred to in schedule B to the Food and Drugs Act do not need further characterization. The submission should fully characterize and structurally elucidate any other primary standard (e.g. IR, UV, NMR, MS, etc.). All data supporting structure elucidation, strength, and purity should be submitted. Data regarding assay should also be submitted with the assay assigned based on mass balance or determination of absolute purity.

Primary reference standards other than a compendial standard should be highly purified and fully characterized (e.g. FTIR, UV, NMR, MS). All data supporting structure elucidation, strength, and purity should be submitted. Data regarding assay should also be submitted with the assay assigned based on mass balance or a determination of absolute purity.

Secondary reference standards

A secondary or house reference standard should be validated against a suitable primary reference standard. The secondary standard should be fully characterized, and the IR and UV spectra should be submitted for both the primary and secondary reference standards run concomitantly. Purity and characterization data (e.g. chromatographs) or CoA, should be provided.

If an alternative process for the drug substance is used to increase its purity for the purpose of generating a reference standard, a brief description of the manufacturing process of the secondary reference standard should be provided.

S.6 Container closure system

The submission should include a description of the CCS(s), including the identity of materials used for the primary packaging components with a brief description of the secondary packaging, if warranted. Indicate whether the product is packaged under an inert atmosphere or if desiccants are added, if applicable. Packaging materials should protect the drug substance from light and moisture, as well as be compatible with the drug substance. Specifications for packaging materials should be relevant and include an identification test (e.g. IR) for the packaging materials that are in contact with the drug substance. Validated non-compendial methods should be included, where appropriate.

For functional secondary packaging components, information relevant to the function should be provided (e.g. capacity to protect against light). For non-functional secondary packaging components (i.e. those that do not provide additional protection), a brief description should be provided.

The suitability should be discussed with respect to choice of materials, protection from moisture and light, compatibility of the materials of construction with the drug substance, including sorption to container and leaching of container components, and/or safety of materials of construction. Examples of this would include conformance with USP, Ph. Eur. standards or applicable US Code of Federal Regulations (CFR) or European Commission (EC) Regulations for food safe materials. Certificates of compliance from vendors can be provided to confirm suitability of use of the CCS for the proposed drug substance.

S.7 Stability

S.7.1 Stability summary and conclusions

The purpose of stability testing is to provide evidence of how the quality of a drug substance varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and enables recommended storage conditions, re-test period, or shelf life (where appropriate) to be established. Stability studies, including stress, accelerated, and long-term stability studies should be conducted on the drug substance to establish appropriate packaging and storage conditions, and the re-test period. Information on the type of studies conducted, the protocols used for the studies, and the results obtained should be submitted. The data summarized in the QOS should be tabulated in a manner that clearly supports the proposed shelf life and should be condensed to include an overall summary of relevant data rather than data from individual batches (e.g. ranges, highlighting any trends and/or batch to batch variability, if applicable).

Note: If an ASMF is used to support the (A)NDS, then a majority of the following information can be reproduced or referenced from the applicant part (open part). Inconclusive information within the ASMF may delay (A)NDS approval.

Forced degradation (stress) studies

The results of stress testing provide information on the intrinsic stability of the drug substance, potential degradation pathways, likely degradation products, and the stability indicating power of the analytical procedures. Stress studies should also consider potential changes to physical properties such as polymorphism and particle size distribution. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved. Stress testing is normally carried out on one batch of the drug substance and generally includes the effect of heat, humidity, light, oxidation, and acid/base hydrolysis. The submission should present the quantitative results in tabular form, including treatment conditions. Typical test results would be for assay and degradation products.

The objective of the stress testing study is not to completely degrade the drug substance, but to generate sufficient degradation to achieve its intended purpose. This is typically 10-20% loss of the drug substance by assay when compared with the non-degraded compound. This target is chosen such that some degradation occurs, but it is not so severe that secondary degradation products are generated. Degradation outside of this range should be scientifically justified. Mass balance can be used to demonstrate that methods are stability indicating and all degradation products are detected by the methodology. Mass balance should be demonstrated by comparing the assay and impurities content on the same sample which have been subjected to identical stress conditions.

Tables can be used to summarize the results from the stress testing in the QOS. This summary should include the treatment conditions (e.g. concentrations of solutions prepared, storage temperatures, and durations) and the observations for the various test parameters (e.g. assay, degradation products) as well as a discussion of the results (e.g. mass balance, potential impact on drug product manufacture, likelihood of formation of impurities under long term conditions).

Representative chromatograms of stress studies showing around 10-20% of degradation of the drug substance should be submitted.

Accelerated and long-term studies

The submission should include stability data on a minimum of three (3) batches of the drug substance stored at accelerated and long-term conditions. Two of the three batches should be at least pilot scale. Table S.7.1-1 outlines the recommended storage conditions and minimum data at the time of submission.

Table S.7.1-1: General case for stability studies of the drug substance
Study Storage condition Minimum time period covered by data at submission
Long-term Footnote * 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months
Intermediate Footnote ** 30°C ± 2°C/65% RH ± 5% RH 6 months
Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months
Footnote *

It is up to the sponsor to decide whether long-term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

Return to footnote * referrer

Footnote **

If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Return to footnote ** referrer

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and a "significant change" (see VICH GL3 for definition) occurs at any time during 6 months of testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. Testing at the intermediate storage condition should include all tests, unless otherwise justified. The initial application should include a minimum of 6 months data from a 12-month study at the intermediate storage condition.

Other storage conditions can be proposed based on the proposed labelled storage conditions. For drug substances intended for storage in a refrigerator or freezer conditions, see VICH GL3 for requirements.

To support alternate drug substance manufacturing sites that maintain the same route of manufacture and process conditions, a stability commitment should be included to place the first commercial batch of drug product manufactured with drug substance from the alternate site into the long-term stability program. When drug substance is micronized or compacted, the stability studies should be carried out using micronized/compacted drug substance unless otherwise justified (e.g. when micronization/compaction is done immediately prior to use by the drug product manufacturer). If the route of synthesis is changed, then results for at least 2 pilot scale batches with a minimum of 3 months of long-term and accelerated (or intermediate, as appropriate) testing should be provided at the time of filing. In these cases, it is expected that the original stability data is also available either in the same submission or cross-referenced to a previously authorized one.

Information on the stability lots should include date of manufacture, batch number and size, packaging, storage conditions, test intervals completed and to be completed, tests performed with acceptance criteria, and description and validation of analytical procedures, if different from those described in section S.4.2. The stability results should be presented in a tabular form, including quantitative results for all quantitative tests. The submission should include a discussion of the results and the conclusions reached. Where trends in the data are noted, these should be highlighted and discussed. Statistical analysis of the data should be used as necessary to justify conclusions.

Proposed storage conditions and re-test period

The submission should include proposed storage conditions and re-test period for the drug substance, based on the results of the stability studies. The retest period should begin at the date of manufacture of the drug substance. The proposed storage conditions should normally include a temperature range (e.g. upper and lower temperature limits) representative of temperature conditions for which supporting data were provided.

When the drug substance has been shown to be stable (e.g. under the VICH GL3 conditions with long term studies 25°C ± 2°C/60% RH ± 5% RH and accelerated studies at 40°C ± 2°C/75% RH ± 5% RH) without any adverse trends, recommending to "Store at 15°C to 30°C" would generally be considered acceptable.

Based on the assessment of the stability data, the need for additional storage precautions should be assessed and precautionary statements added to the label if warranted (e.g. "Protect from light", "Protect from moisture"), but are not considered a substitute for selecting the appropriate CCS.

After the end of the established retest period, a batch of drug substance destined for use in the manufacture of a drug product should be retested for compliance with the drug substance specification and then used within 30 days of conducting the test. For drug substances known to be labile (e.g. certain antibiotics), it is more appropriate to establish a shelf life than a retest period.

In certain cases, information available in the public domain may be sufficient to establish an appropriate retest period such as when a substantial body of evidence exists that establishes that the drug substance is inherently stable.

S.7.2 Post-approval stability protocol and stability commitment

The post-approval stability protocol and stability commitment should be provided. When available long term stability data on three (3) production scale batches do not cover the proposed retest period or shelf life (as appropriate) granted at the time of approval, a commitment should be made to continue the stability studies post-approval in order to firmly establish the retest period or shelf life. The long-term stability studies for the commitment batches should be conducted through the proposed retest period/shelf life (and the accelerated studies for six months, if relevant) on at least three (3) production batches.

At least one batch per year of drug substance manufactured at each commercial site (unless none is produced that year) should be added to the continuing stability monitoring program and tested at least annually to confirm the stability.

The stability protocols for commitment and continuing batches should include:

Differences in the stability protocols used for the primary batches and those proposed for the commitment or continuing batches should be scientifically justified.

S.7.3 Stability data

Results of the stability studies (e.g. forced degradation studies and stress conditions) should be presented in a tabular (preferred for presenting raw data from the stability studies used to support the proposed retest period or shelf life), graphical, or narrative format, as appropriate with information on the analytical procedures used to generate the data and validation of these procedures included.

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